Pathology

TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN DIGITAL HANDOUT BY DR.
KEVIN ELOMINA
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This handout is only valid for September 2021 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.
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PATHOLOGY
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By Kevin A. Elomina, MD
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communication. No part of the handout, video or other review material may be reproduced,
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medium or machine-readable form, in whole or in part without the written consent of 1. Cellular Responses to Stress 1
Topnotch Medical Board Preparation Incorporated. Any violation and or infringement, 2. Inflammation and Repair 4
whether intended or otherwise shall be subject to legal action and prosecution to the full
extent guaranteed by law. 3. Hemodynamic Disorders 8
4. Genetic Disorders 11
5. Disease of the Immune System 13
DISCLOSURE 6. Neoplasia 17
The handouts/review materials must be treated with utmost confidentiality. It shall be the
responsibility of the person, whose name appears therein, that the handouts/review 7. Infectious Diseases 20
materials are not photocopied or in any way reproduced, shared or lent to any person or 8. Environmental and Nutritional Pathology 24
disposed in any manner. Any handout/review material found in the possession of another 9. Diseases of Infancy and Childhood 27
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8293. Topnotch review materials are updated every six (6) months based on the current
10. Blood Vessels 30
trends and feedback. Please buy all recommended review books and other materials listed 11. Heart 34
below. 12. WBCs, LNs, Spleen, and Thymus 40
THIS HANDOUT IS NOT FOR SALE!
13. Red Blood Cell and Bleeding Disorders 44
14. Lung and Pleura 49
INSTRUCTIONS 15. Head and Neck 53
To scan QR codes on iPhone and iPad 16. Gastrointestinal Tract 56
1. Launch the Camera app on your IOS device
2. Point it at the QR code you want to scan
17. Liver and Gallbladder 62
3. Look for the notification banner at the top 18. Pancreas 67
of the screen and tap 19. Kidney 68
To scan QR codes on Android 20. Lower Urinary Tract and Male Genital Tract 72
1. Install QR code reader from Play Store 21. Female Genital Tract 77
2. Launch QR code app on your device
3. Point it at the QR code you want to scan
22. Breast 81
4. Tap browse website 23. Endocrine System 84
24. Skin 89
25. Bones, Joints, and Soft Tissue 91
APPROACH TO TOPNOTCH PATHOLOGY 26. Peripheral Nerves and Skeletal Muscles 94
• Please have the following Topnotch materials at hand: 27. Central Nervous System 96
o (1) Topnotch Main Handout will serve as your main 28. Eye 101
reference material (This is based on Robbins and Cotran
Pathologic Basis of Disease 10th ed) This handout is only valid for the September 2021 PLE batch.
o (2) Topnotch Supplement Handout will serve as a quick This will be rendered obsolete for the next batch
refresher prior (few weeks) before the boards since we update our handouts regularly.
• Please buy the following:
• (1) Robbins and Cotran Pathologic Basis of Disease 10th ed. 1. CELLULAR RESPONSES TO STRESS
• (2) Robbins and Cotran Atlas of Pathology 3rd ed. CELLULAR RESPONSES TO STRESS AND
• (3) Robbins and Cotran Review of Pathology, 4th ed.
o (1) will serve as your main reference material (if you have a
INJURIOUS STIMULI
hard time understanding the concise information in your
main handout)
o (2) will serve as your further guide to the images (Lately,
examiners are incorporating actual images to the exam)
o (3) will serve as a supplement item bank (ONLY IF you have
the time)
• The chapters in this handout are matched with those in
Robbins. I have included some photos in this handout,
especially for tumors, but I do not have the luxury of including
everything. So, I recommend that you still open your textbooks
while studying this handout
• I would not recommend resources aside from those previously
mentioned. My motto is stick to few materials and master them.
• Pathology is a broad subject, so DO NOT EXPECT the Topnotch
materials to cover everything. The Topnotch Pathology
Program is meant to equip you with:
o Sufficient knowledge in Pathology as expected from a general
physician (must-know); and
o Some less important concepts that can help you understand
the disease more OR resident-level knowledge that I expect CELL INJURY AND CELL DEATH
Figure 2.1. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 (adapted)
clinicians to know and appreciate (nice-to-know).
• The first nine chapters of general pathology are your friends. Cells can be likened to us doctors. For example, when we (cell) entered
clerkship (stress), we developed the ability to function with less hours of
Master them, and you will have an easier time with systemic
sleep (adaptation). If we (cell) got sick (cell injury), we show signs of
pathology. being sick, but eventually we may recover (reversible injury). If we (cell)
• Annotations are provided for concepts that I believe need to be turned worse (irreversible injury), we may die (cell death).
discussed further. That being said, if a section does not have an Dr. Elomina
annotation, it is understood that the concept is already

presented at its simplest and you just have to digest. J CELL INJURY
CAUSES
“Success is not final; failure is not fatal: It is the courage to
• Oxygen deprivation • Immunologic reactions
continue that counts."
• Physical agents • Genetic derangements
- Winston Churchill
• Chemical agents and Drugs • Nutritional imbalances
• Infectious agents
MAIN REFERENCE:
Kumar V. Abbas AK. Aster JC. Turner JR. Robbins and Cotran Pathologic Basis
of Disease.10th ed. Philadelphia: Elsevier; 2020.
TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN DIGITAL HANDOUT BY KEVIN ELOMINA, MD Page 1 of 103
This handout is only valid for the September 2021 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.
TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN DIGITAL HANDOUT BY DR. KEVIN ELOMINA
PATTERNS OF REVERSIBLE CELL INJURY TYPES OF CELL DEATH

• Refers to a form of cell injury that allows the cell to REVERT to • Cell death occurs due to irreversible cell injury
its normal functional and morphologic features AFTER NECROSIS APOPTOSIS
REMOVAL OF THE DAMAGING STIMULUS • Enlarged
Cell size • Reduced (shrinkage)
• Reversible cell injury has 2 features – cellular swelling, fatty (swelling)
change • Pyknosis → • Fragmentation into
(1) CELLULAR SWELLING Nucleus Karyorrhexis → nucleosome-sized
Karyolysis fragments
• First manifestation of almost all forms of injury to cells
• Intact; altered
• Influx of ions (and water) due to failure of energy-dependent ion Plasma
• Disrupted structure, especially
pumps (Na+-K+-ATPase) membrane
orientation of lipids
• Example: cytotoxic edema in neurons • Enzymatic • Intact; maybe
Cellular
(2) FATTY CHANGE digestion; may released in apoptotic
contents
• Seen in cells dependent on fat metabolism (liver, heart) leak out of cell bodies
• Appearance of cytoplasmic lipid vacuoles Adjacent
• Frequent • None
inflammation
• Plasma membrane alterations Physiologic or • Invariably • Often physiologic;
(blunting, blebbing) pathologic role pathologic may be pathologic
• Mitochondrial changes – Adapted from Table 2.1. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
Ultrastructural changes appearance of amorphous REMEMBER: The apoptotic bodies are intact. There are no leaked
of reversible cell injury densities cellular contents, thus inflammation is NOT INITIATED. Moreover,
(seen in the electron • ER dilatation and appearance of phosphatidylserine is switched from the inner leaflet of the plasma
microscope) myelin figures membrane to the outer leaflet – this process is a marker for apoptosis.
• Nuclear alterations – Dr. Rubio
disaggregation of granular and

fibrillar elements
CELLULAR ADAPTATIONS
ADAPTATION DEFINITION STIMULUS MECHANISM(S) EXAMPLES
• PHYSIOLOGIC
o Myometrial hypertrophy in gravid uterus
• ↑ Workload (hormonal stimulation)
• ↑ in cell size →
Hypertrophy
organ size
• Hormonal • ↑ Protein synthesis o Muscle of bodybuilders (functional demand)
stimulation • PATHOLOGIC
o Left ventricular hypertrophy (LVH) in hypertensive
heart disease
• Growth factor-driven • PHYSIOLOGIC
• Hormonal proliferation of mature o Pubertal breast changes (hormonal)
• ↑ in the number
Hyperplasia
of cells
• Compensatory cells or o Liver regeneration (compensatory)
response • ↑ Output of new cells • PATHOLOGIC
from tissue stem cells o Endometrial hyperplasia (hormonal) and BPH
• ↓ Workload • ↓ Protein synthesis
• Denervation • ↑ Protein degradation • PHYSIOLOGIC
• Ischemia (loss of (via ubiquitin- o Embryonic atrophy (notochord and thyroglossal
• ↓ in cell size AND blood supply) proteasome pathway) duct)
Atrophy
number • Malnutrition • Autophagy (self-eating • PATHOLOGIC
• Loss of endocrine process → formation of o Senile atrophy of brain
stimulation residual bodies – o Cancer cachexia
• Pressure lipofuscin granules)
• Squamous metaplasia (columnar to squamous; most
• Differentiated
common form): cigarette smoking, vitamin A deficiency
cell type replaced • Reprogramming of
Metaplasia
by another cell
• Stress stem cells
• Intestinal metaplasia: Barrett esophagus
• Connective tissue metaplasia: intramuscular
type
hemorrhage (from trauma) → myositis ossificans
Differentiated cells refer to the cells that are terminal, mature, and physiologically functional i.e., muscle cells, neurons, epithelial cells, etc. On the other hand,
undifferentiated cells refer to cells that have the potential to differentiate to a unique cell with certain function in the body e.g.. stem cells.
Dr. Rubio
PATTERNS OF NECROSIS
CELLULAR ADAPTATIONS PATTERN FEATURES
https://qrs.ly/pccmd6c • Preservation of the architecture of dead tissues
• Infarct – refers to a localized area of coagulative
Coagulative
necrosis
necrosis
• Ischemic necrosis occurs in all organs EXCEPT
NECROSIS brain (liquefactive necrosis)
• Unprogrammed & unregulated form of cell death (vs apoptosis) • Digestion of the cellular architecture → liquid
• Common morphologic changes: Liquefactive viscous mass known as pus
Increased • RNA loss, accumulation of necrosis • Ischemic necrosis of the brain
eosinophilia denatured cytoplasmic proteins • Infections of bacterial (of fungal) in origin
Glassy appearance • Due to loss of glycogen • Dry gangrene – ischemic coagulative necrosis
Formation of myelin • Phospholipid masses from damaged Gangrenous of the extremities
figures necrosis • Wet gangrene – occurs in dry gangrene is
cell membranes
superimposed with bacterial infection
Nuclear changes
• Cheese-like, friable, white area of necrosis
Karyolysis • Decreased basophilia of chromatin Caseous
usually seen in a tuberculous infection
• Nuclear shrinkage with increased necrosis
Pyknosis • Granuloma formation
basophilia • Fatty acids from triglyceride breakdown
Karyorrhexis • Fragmentation of pyknotic nucleus combine with calcium ions to form soap
Eosinophilia means it stains pink. Basophilia means it stains blue. (saponification)
Fat necrosis
Nucleic acids are basophilic; hence when they are degraded or destroyed, • Histologic examination: foci of shadowy outline of
eosinophilia occurs. It is just the balance of the colors. :) necrotic fat cells with basophilic calcium deposits
Dr. Rubio • Seen in pancreatitis (leakage if lipase)
• Occurs when complexes of antigens and
antibodies (immune complexes) are deposited
Fibrinoid in the walls of arteries PATTERNS OF NECROSIS
necrosis • Results to bright pink, amorphous densities https://qrs.ly/obcmd6d
(termed fibrinoid, or fibrin-like)
• Seen in immunologically mediated vasculitis
MECHANISMS OF CELL INJURY

• Hypoxia/ischemia
• Radia0on • ROS • Radia0on
• Other injurious agents • Other injurious agents • Muta0ons
MECHANISMS OF CELL
MITOCHONDRIA CELLULAR MEMBRANES NUCLEUS INJURY
https://qrs.ly/hhcmd6k
↓ ATP ↑ ROS Damage to Damage to
lysosomal membranes plasma membranes DNA damage
↓ Energy-dependent Damage to lipids,

func7ons proteins, nucleic acids Leakage of Impaired transport Cell cycle Caspase
enzymes Cellular leakage arrest ac7va7on
Cell injury
NECROSIS NECROSIS APOPTOSIS

Adapted from Figure 2.18. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
ATP DEPLETION • Two phases: • Two pathways of initiation phase:

• Fundamental cause of necrotic cell death, occurring when ATP is o Initiation o Intrinsic (mitochondrial) pathway
depleted to 5-10% of normal levels o Execution o Extrinsic (death receptor) pathway
• Effects of ATP depletion:
Failure of Na+-K+ APOPTOSIS
• Cellular swelling
ATPase AND AUTOPHAGY
Altered cellular • Switch to anaerobic glycolysis → ↑ https://qrs.ly/fxcmd6o
metabolism lactic acid
• ↑ Ca2+ influx → activation of
Please remember that accumulation of damaged DNA (usually due
Failure of Ca2+ pump calcium-dependent enzymes → to viral infections), and misfolded proteins (as seen in enzyme
degradation of molecules deficiencies) are triggers of apoptosis.
Reduction in protein • ↓ turnover of proteins Dr. Rubio
synthesis, ↑ misfolded • ↑ misfolded proteins → unfolded APOPTOSIS: INITIATION PHASE

proteins protein response → apoptosis • Initiation occurs via intrinsic or extrinsic pathway
• Ultimately, destruction of the cell membrane (brought by INTRINSIC EXTRINSIC
activation of calcium-dependent hydrolytic enzymes) → cellular (MITOCHONDRIAL) (DEATH RECEPTOR)
death Inactivation of BCL2 (anti- Activation of death receptors
apoptotic) → Activation of by appropriate ligands →
APOPTOSIS BAX/BAK channel → leakage Activation of initiator
of cytochrome C → Activation caspases → Apoptosis
• Regulated cell death “programmed”
of initiator caspases →
• Can be physiologic (embryogenesis); or pathologic (viral Apoptosis
infections, damaged DNA, misfolded proteins)
APOPTOSIS: EXECUTION PHASE

• Involves the activation of executioner caspases, resulting
to:
o Endonuclease activation → fragmentation of the nucleus
o Breakdown of the cytoskeletal architecture
• Ultimately, these would form apoptotic bodies
CASPASES
• Are cysteine-dependent aspartate-directed proteases
• Serve as mediators of the apoptotic pathway (see figure
above)
Initiation phase – Intrinsic • Caspase 9

• Caspase 8
Initiation phase – Extrinsic
• Caspase 10
MECHANISMS OF APOPTOSIS • Caspase 3
Executioner phase
Figure 2.13. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 • Caspase 6
OTHER MECHANISMS OF CELL INJURY

• Process in which a cell eats its own contents • Has morphological features of necrosis
• Activated by nutrient deprivation Necroptosis • But it is programmed like apoptosis
Autophagy • Seen in aging, exercise and aberrant processes • RIP1, RIP3 – mediators (no caspases)
• Explains the formation of lipofuscin “wear and • Induced by caspases 1 and 11 →
Pyroptosis
tear” pigment in neurons and cardiac muscle inflammasome activation → release of IL0-1
INTRACELLULAR ACCUMULATIONS INTRACELLULAR HYALINE EXTRACELLULAR HYALINE

• Reabsorption droplets seen
MECHANISMS OF INTRACELLULAR ACCUMULATION • Extravasation of plasma
in proximal convoluted tubule
Abnormal metabolism of proteins and deposition at
• Liver steatosis (lipid (PCT)
normal endogenous basement membrane (seen in
accumulation in liver) • Russell bodies
substance diabetes & hypertension)
• Alcoholic hyaline
Accumulation of an abnormal
• Mutated α1-antitrypsin GLYCOGEN
endogenous substance
• (+) PAS positive, diastase sensitive,
• Storage diseases (lipids,
Enzyme deficiencies glycogen granules
glycogen) Diabetes mellitus
• Seen in hepatocytes, renal tubular
Accumulation of exogenous
• Accumulation of carbon epithelium, cardiac myocytes
substance
Glycogen storage • Defects in the synthesis or breakdown of
disease glycogen
ACCUMULATION OF LIPIDS
Glycogen stains rose-to-violet color in Periodic acid – Schiff (PAS)
• Triglycerides stain. Mnemonic: PASS the SUGAR.
Steatosis • Accumulation in liver (major), heart, kidney Dr. Rubio
• Cholesterol esters PIGMENTS

Atherosclerosis • Seen in blood vessels EXOGENOUS PIGMENTS ENDOGENOUS PIGMENTS
Xanthomas • Seen in subepithelium and tendons • Carbon • Lipofuscin
o Anthracosis: asymptomatic o “wear and tear pigment”
Cholesterolosis • Seen in lamina propria of gallbladder o Coal worker’s • Melanin
Niemann-Pick disease pneumoconiosis: with • Ochronosis (deposition of
• Form of lysosomal storage disease
type C associated interstitial lung homogentisic acid)
disease o seen in Alkaptonuria
PROTEINS • Tattooing • Hemosiderin (iron)
MECHANISM CONDITION o Old hemorrhage;
Reabsorption droplets hemochromatosis
in proximal renal • Nephrotic syndrome According to Robbins & Cotran, melanin is the only endogenous brown-
tubules black pigment for practical purposes.
Dr. Rubio
• Multiple myeloma: Plasma cells
Excess of normally CALCIFICATIONS
actively producing
secreted proteins DYSTROPHIC METASTATIC
immunoglobulins (Russell bodies)
Type of
Defective intracellular • Necrotic • Viable
tissue
transport and • α1-antitrypsin deficiency
Serum
secretion • Normal • Increased
calcium
Accumulation of • Alzheimer disease (neurofibrillary • Basophilic, amorphous granular, clumped
cytoskeletal proteins tangles) Histology
appearance; either intra- or extracellular
Aggregation of • Psammoma bodies • Lung involvement
• Amyloidosis
abnormal proteins (sand-like lamellated (respiratory
Clinical
concretions) seen in compromise)
importance
HYALINE CHANGE papillary cancers • Nephrocalcinosis
• Homogeneous, glassy, pink appearance in H&E stain (renal dysfunction)
• A descriptive histologic term, rather than a marker of injury
CELLULAR AGING
• Result of a progressive decline in cellular function Carcinogenic exposure,
sporadic errors
Cellular
senescence
DefecAve protein
homeostasis
Nutrient
sensing
caused by genetic abnormalities and the ROS? Telomere
↓ insulin/IGF signaling
↓ TOR
accumulation of cellular and molecular damage due shortening
Altered sirtuins
to the effects of exogenous influences ↓ cellular
↓ proteins,
damaged
Altered
DNA damage
replica7on transcrip7on
Recent evidence shows that eating less equates to living proteins
longer! If you decrease your caloric intake, there will be Defec7ve

decreased Insulin/IGF signaling intensity, resulting in DNA repair
decreased rates of cell growth, metabolism, and injury. MUTATIONS CELL LOSS DECREASED CELL
Caloric restriction also increases what you call sirtuins. FUNCTIONS
These are enzymes in your body that are adapted to food

deprivation. Their functions basically increase cellular ↑ DNA repair
longevity, including activation of DNA repair mechanisms CELLULAR ↑ protein
AGING COUNTERACTS AGING homeostasis
(Sirtuin-6). It is said that red wine may activate sirtuins. So,
ditch the hard drinks, and be a tita instead. *wink* MECHANISMS THAT PROMOTE AND COUNTERACT CELLULAR AGING
Dr. Elomina Adapted from Figure 2.35. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
2. INFLAMMATION AND REPAIR GENERAL STEPS: 5Rs

INFLAMMATION • Recognition of the injurious agent
• Response of vascularized tissues to infections and damaged • Recruitment of leukocytes
tissues that brings cells and molecules of host defense from the • Removal of the agent
circulation to the sites where they are needed, in order to • Regulation (control) of the response
eliminate the offending agents • Resolution (and repair)
• Generally a beneficial response, but can be harmful (in
autoimmune and allergic states) RECOGNITION OF THE INJURIOUS AGENT
• Has 2 components: vascular and cellular • Activation of Toll-like
• Both activated by mediators (can be cell- or plasma-derived) Cellular receptors for
receptors (TLRs) →
microbes (extracellular)
CAUSES inflammation
• Infections • Presence of foreign bodies Sensors of intracellular
• Uric acid, ATP, K+
• Tissue necrosis • Immune reactions damage
• Recognition of opsonized
FIVE CARDINAL SIGNS OF INFLAMMATION Fc receptor in leukocytes
microbes
• Rubor (redness) • Tumor (swelling)
Circulating proteins • Complement system
• Calor (warmth) • Functio laesa (loss of function)
• Dolor (pain)
Cells have TLRs, which act like a burglar alarm of sort. They sense that • Transmigration of leukocytes across the
there is something foreign in the vicinity. Cells release cytosolic contents endothelium
indicative of cell damage. These substances activate the inflammasome, Diapedesis
• Postcapillary venules – site of diapedesis
which leads to IL-1 release. IL-1 mediates leukocyte recruitment and • Mediated by CD31/PECAM-1
consequently inflammation. The Fc portion of the antibody is the
• Movement towards a chemotactic signal
fragment exposed when an antibody coats a target, and the leukocytes
have receptors for these portions. • Most common exogenous product: N-
Dr. Elomina Chemotaxis formylmethionine
GENERAL TYPES OF INFLAMMATION • Endogenous chemotactic signals: IL-8, C5a,
ACUTE CHRONIC leukotriene B4 (an arachidonic metabolite)
• Fast; minutes or N-formylmethionine is a prominent protein used in protein synthesis
Onset • Slow; days
hours among bacterial microbes. Moreover, please take note that among the
• Monocytes, complement proteins, only C5a can cause chemotaxis.
• Mainly
Cellular infiltrate macrophages, and Dr. Rubio
neutrophils ROLLING VS ADHESION
lymphocytes
Tissue injury, • Usually mild and • Often severe and ROLLING ADHESION
fibrosis self-limited progressive Strength of
• Weak • Strong
Local and interaction
• Prominent • Less Duration of
systemic signs • Transient • Permanent
Adapted from Table 3.2. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 interaction
• Selectins (L, E, P)
Receptor
ACUTE INFLAMMATION (Leukocytes, • Integrins
family
Endothelium, Platelets)
• Components (3):
• Cell adhesion
o Dilation of small vessels Ligand
• Sialyl-Lewis X molecules
o Increased microvascular permeability molecule
(CAM)
o Emigration of leukocytes and their activation
DILATION OF SMALL VESSELS CELLULAR INFILTRATES IN INFLAMMATION
• Increase in caliber of blood vessels TYPE INFILTRATE
o Results in increased blood flow and stasis of blood → • Neutrophils (usually replaced by
Acute
erythema monocytes after 24-48 hours)
o Stasis → accumulation of leukocytes along endothelium Prolonged • Monocytes
• Histamine: most notable mediator that produces vasodilation Pseudomonas • Neutrophils (for several days)
INCREASED MICROVASCULAR PERMEABILITY Viral • Lymphocytes (usually first to arrive)
Allergic • Eosinophils (main infiltrate)
• Mechanisms:
Cell-mediated
o Endothelial cell contraction (Most common mechanism) • Lymphocytes (main infiltrate)
hypersensitivity
o Endothelial injury
o Increased transport of substances across endothelial cells Personally, I do not think you need to cell adhesion molecules. But
(transcytosis) sometimes, an item pops out in samplexes and in the actual exams, so if
you have time, you may want to give this a quick look.
• Results in edema Dr. Elomina
Endothelial cell contraction happens upon exposure to inflammatory

mediators (histamine, bradykinin, leukotrienes, etc.), in which case, the
REMOVAL OF THE AGENT
response is rapid in onset, but transient in duration. There are some cases • Leukocyte activation → phagocytosis → intracellular killing
(UV exposure i.e., sunburn) where the onset is a bit delayed and the (physiologic consequence)
duration is a bit prolonged, and this may be because of endothelial cell o Reactive oxygen species (ROS) and nitric oxide (NO)
contraction or mild endothelial injury. In severe cases of endothelial (intracellular)
injury (burns, severe infection), there is endothelial cell necrosis and o Lysosomal enzymes (through phagolysosome formation)
detachment. In these cases, the response is rapid, and duration may be
prolonged, until the vessels recover.
o Neutrophil extracellular traps (NETs) – extracellular fibrillar
Dr. Elomina networks that trap microbes and concentrate antimicrobial
substances, helping to prevent their spread.
RECRUITMENT OF LEUKOCYTES • Killing mechanisms can also damage normal tissues (pathologic
TO SITES OF INFLAMMATION consequence)
• Mediated by adhesion molecules and chemokines
This is where you can appreciate the double-edged sword nature of the
(chemoattractant cytokines) inflammatory response. It destroys what it intends to destroy
(physiologic consequence) but not without collateral damage, which are
the surrounding normal tissues (pathologic consequence).
Dr. Elomina
REGULATION (CONTROL) OF THE RESPONSE

• Inflammatory mediators have generally short half-lives
• Neutrophils have short half-lives and die by apoptosis
• Anti-inflammatory cytokines: lipoxin, transforming growth
factor-beta (TGF-β), interleukin-10 (IL-10)
MEDIATORS OF INFLAMMATION
• Substances that initiate or regulate inflammatory reactions
• Can be cell-derived or plasma-derived
• Active mediators are produced only in response to various
stimuli
• Most mediators are short-lived
VASOACTIVE AMINES
HISTAMINE SEROTONIN
Figure 3.4. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
Parent
• Histidine • Tryptophan
• Peripheral positioning of the leukocytes along amino acid
the endothelial surface • Platelets,
Margination • Mast cells (richest),
• Results from slower blood flow due to vessel Source neuroendocrine
platelets, basophils
dilation cells
• Transient binding and detachment of • Arteriolar dilation,
Rolling
leukocytes to the endothelium Function increase in venular • Vasoconstrictor
Adhesion • Firm adhesion of leukocytes to endothelium permeability
ARACHIDONIC ACID METABOLITES OR EICOSANOIDS ACTION EICOSANOIDS
• From arachidonic acid (20:4(ω-6)) • PGI2 (Prostacyclin), PGE1, PGE2,
Vasodilation
PGD2
Cyclooxygenase • Produces prostaglandins (PG),
pathway thromboxane (TX) Vasoconstriction • TXA2, LTC4, D4, E4
Lipoxygenase pathway • Produces leukotrienes (LT), lipoxins ↑ Vascular
• LTC4, D4, E4
permeability
Chemotaxis, leukocyte • LTB4, Hydroxyeicosatetraenoic acid
adhesion (HETE)
Adapted from Table 3.6. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
ARACHIDONIC ACID METABOLITES AND THEIR FUNCTION

PROTEIN FEATURE
• Interacts with immune complexes to activate
ARACHIDONIC ACID
classical pathway
METABOLITES REVIEW C1
• Activated by mannose-binding lectin complexed with
https://qrs.ly/fjcmd83
bacterial carbohydrates to activate lectin pathway
• Most abundant complement
C3
CYTOKINES AND CHEMOKINES • Gives rise to C3a (anaphylatoxins), C3b (opsonin)
CYTOKINES CHEMOKINES • Gives rise to C5a (anaphylatoxins), C5b (part of
C5
• Derived from membrane attack complex – MAC)
different types of • Late components of the complement system (part
cells • Chemoattractants for C6-C9
of MAC)
Actions(s) • Mediate and regulate specific types of
ACTION INVOLVED PROTEINS
immune and leukocytes
inflammatory Anaphylatoxins
• C3a, C4a, C5a
reactions (promote histamine release from mast cells)
Chemotaxis • C5a
Opsonin
IMPORTANT CYTOKINES IN INFLAMMATION • C3b
(promotes phagocytosis)
CYTOKINE PRINCIPAL ACTION(S)
Cell lysis via MAC • C5b, C6-C9
ACUTE INFLAMMATION
Tumor • Stimulates expression of endothelial adhesion Opsonization is the process of making a microbe more palatable to the
necrosis molecules, and secretion of other cytokines phagocytes for engulfment. Basically, opsonins make microbes
factor (TNF) “yummy”
• Has systemic effects Dr. Rubio
IL-1 • Similar to TNF; has a greater role in fever COMPLEMENT-RELATED DISEASES
IL-6 • Systemic effects (acute-phase response) C1 inhibitor deficiency • Hereditary angioedema
Chemokines • Recruitment and migration of cells in tissue Decay accelerating factor (DAF) • Paroxysmal nocturnal
IL-17 • Recruitment of neutrophils and monocytes and CD59 deficiency hemoglobinuria (PNH)
CHRONIC INFLAMMATION • Increased risk to Neisseria
IL-12 • Increased production of IFN-γ Deficiency in late complements infections due to inability
Interferon γ • Activation of macrophages (increased ability to to form MAC
(IFN-γ) kill microbes and tumor cells) OTHER MEDIATORS OF INFLAMMATION
IL-17 • Recruitment of neutrophils and monocytes MEDIATOR ACTION
• Platelet aggregation
COMPLEMENT SYSTEM Platelet-
• At high concentrations, vasoconstriction &
• At least 20 soluble proteins that function mainly in host defense activating factor
bronchoconstriction
against microbes and in inflammatory reactions (PAF)
• At low concentrations, vasodilation
• 3 pathways differ in mechanisms leading to C3 cleavage: • Increased vascular permeability
classical, alternative, and lectin Bradykinin • Contraction of smooth muscle
• 3 functional outcomes: inflammation, opsonization and • Vasodilation, pain when injected
phagocytosis, and cell lysis Substance P • Pain modulation
• Regulated by cell-associated and circulating proteins
SYSTEMIC EFFECTS OF INFLAMMATION

SELF-REVIEW OF THE • LPS from bacteria → IL1, TNF → PGE2 →
INFLAMMATORY MEDIATORS Fever
elevation of temperature set point
https://qrs.ly/obcmd8h Acute phase • IL6 → ↑ C-reactive protein (CRP), fibrinogen,
response serum amyloid A
MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION • Cytokines → colony stimulating factors →
Leukocytosis
• Hallmark: dilation of small blood vessels and accumulation of WBC proliferation
leukocytes and fluid in the extravascular tissue • High levels of cytokines → hypotensive shock,
Septic shock
PATTERN FEATURE DIC, insulin resistance, hyperglycemia
• Exudation of cell-poor fluid
Serous
• Seen in viral infections, burns, and transudations RESOLUTION (REPAIR)
• Exudation of fibrinogen and fibrin deposition in
Fibrinous extracellular fluid (ECF) • Restoration of tissue architecture and function after an injury
• Seen in fibrinous pericarditis • General types:
• Exudation consisting of PMNs, and necrotic debris o Regeneration (generally happens in labile and stable tissues;
Purulent
• Seen in abscess formation (collection of pus) influenced by growth factors)
• Excavation of the surface on an organ or tissue due to o Connective tissue deposition (happens in chronic, severe
Ulcers
shedding of inflamed necrotic tissue inflammation, and in permanent tissues)
OUTCOMES OF ACUTE INFLAMMATION
• Resolution CLASSIFICATION OF TISSUES BY REGENERATIVE CAPACITY
• Abscess formation TISSUE DESCRIPTION EXAMPLES
• Progression to chronic inflammation • Continuously lost and
• Healing by fibrosis replaced either by
• Surface epithelium
proliferation of
Labile • Hematopoietic stem
CHRONIC INFLAMMATION residual cells or
cells
maturation of stem
• Response of prolonged duration in which inflammation, tissue
cells
injury, and attempts at repair coexist, in varying degrees
• Cells are quiescent (in • Liver
• Causes: • Kidney
phase G0
o Persistent infection •
• Limited capacity to Pancreas
o Hypersensitivity diseases (autoimmune diseases) Stable
proliferate • Endothelium
o Prolonged exposure to potentially toxic agents • Proliferate in response • Fibroblasts
• Principal cells involved: macrophages, lymphocytes to injury and tissue loss • Smooth muscle cells
• Derived from circulating monocytes •
• Terminally Neurons
• Function in phagocytosis, initiation of tissue
Macrophages Permanent differentiated and • Cardiac and skeletal
repair, secretion of inflammatory mediators,
non-proliferative myocytes
and antigen presentation
CD4 T cells • Secrete cytokines, promotes inflammation It is important to know the type of tissue you’re dealing with to know how
• When activated, convert to plasma cells that it will repair. For example, liver transplant is possible because the liver
B cells has the capacity to regenerate, but once the regenerative capacity of the
secrete immunoglobulins (antibodies)
liver is exceeded, it is also capable of connective tissue deposition, such as
in cirrhosis.
Dr. Elomina
REPAIR BY CONNECTIVE TISSUE DEPOSITION

• Has the following important events
• Formation of new blood vessels from existing
Angiogenesis ones; mediated by Vascular endothelial
growth factor (VEGF)
Formation of • Fibroblasts + loose connective tissue +
granulation angiogenesis + inflammatory cells
tissue • Hallmark of repair
PATHWAYS OF MACROPHAGE ACTIVATION
Adapted from Figure 3.20. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 • Balance between extracellular matrix (ECM)
Remodeling of degradation (metalloproteinases) and
scars synthesis (tissue inhibitor of
REVIEW OF MACROPHAGES metalloproteinases – TIMPs)
https://qrs.ly/k3cmd97 Wound • Mediated by myofibroblasts which contains
contraction actin filaments, thus allowing contraction
• Important cell and mediators in repair:
GRANULOMATOUS INFLAMMATION
• Most important source of growth factors during
• Granuloma: collections of activated macrophages, often with Macrophage repair (TGF- β, Platelet-derived growth factor
peripheral T-lymphocytes, and sometimes associated with (PDGF), Fibroblast growth factor 2 (FGF-2)
central necrosis TGF-β
• Activated macrophages → epithelioid cells (hallmark) or giant • Most important cytokine for the synthesis
(transforming
cells (foreign body or immune if tuberculosis) and deposition of connective tissue proteins
growth factor)
FACTORS THAT IMPEDE REPAIR

TUBERCULOUS GRANULOMA
https://qrs.ly/u2cmd99 • Infections • Pressure
• Diabetes mellitus • Poor perfusion
• Vitamin C deficiency • Foreign bodies
• When you are asked in the exam, “What is the type of inflammation • Glucocorticoids (inhibit TGF-β)
associated with TB”, the best answer is chronic granulomatous Anything that promotes infections impedes repair because for the repair
inflammation. When you are asked in the exam, “What is the pattern process to be complete, the inflammation should subside. Vitamin C deficiency
of necrosis associated with TB”, the answer is Caseation. impedes collagen synthesis, which is essential for repair. DM and pressure may
• Granulomas are not always associated with caseation necrosis. cause inadequate perfusion, which is also important. Foreign bodies are
Caseating granulomas are commonly associated with TB. Non- harder to eliminate, which means longer duration of inflammation.
caseating granulomas can be seen in Sarcoidosis, Crohn disease. Dr. Elomina
• Giant cells also occur in foreign body reactions because these foreign
bodies are harder to eliminate, as evidenced by the body trying to ask
help from cell-mediated immunity to aid the body in eliminating the
foreign body.
Dr. Elomina
ABNORMALITIES IN TISSUE REPAIR • Chronic hepatic
Wound dehiscence • Due to inadequate granulation tissue • Acute hepatic congestion
Proud flesh • Due to excessive granulation tissue congestion o Centrilobular regions
Contracture • Due to excessive wound contraction o Distended central are grossly red-brown
vein and sinusoids and slightly depressed
• Due to excessive collagen formation
o Centrilobular contrasted with tan
• Scar tissue grows beyond the
Keloid scar ischemic necrosis surface (Nutmeg liver)
boundaries of the original wound Liver
(distal end of o Centrilobular
• More common in African Americans blood supply) hemorrhage
• Due to excessive collagen formation o Periportal fatty o Hemosiderin-laden
Hypertrophic scar • Scar tissue does not grow beyond the change (better macrophages
boundaries of the original wound oxygenated, hence o Variable degrees of
not necrotic) hepatocyte dropout
3. HEMODYNAMIC DISORDERS and necrosis
• Edema / Effusion • Embolism Remember: Whenever you hear/see the term “fibrosis”, always think of
• Hyperemia and congestion • Shock a chronic process.
Dr. Rubio
• Hemostasis and thrombosis
EDEMA/EFFUSION
• Accumulation of fluid in tissues (edema) or body cavities (effusion)
• Four main mechanisms:
↑ hydrostatic pressure • Heart failure
• Nephrotic syndrome, liver
↓ oncotic pressure
cirrhosis
↑ vascular permeability • Burns, infections
Lymphatic obstruction • Mass, post-surgery
TRANSUDATE VS. EXUDATE
TRANSUDATE EXUDATE
• Abnormalities in • ↑Vascular
Pathophysiology Liver with chronic passive congestion and hemorrhagic necrosis
Starling forces permeability
Vascular (nutmeg liver)
• Normal • Increased Figure 4.3. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
permeability
Plasma protein
leak
• Absent • Present HEMOSTASIS
Protein content • Formation of blood clots at sites of endothelial injury
• Low • High • Three elements: platelets, coagulation factors, endothelium
of fluid
Specific gravity • < 1.012 • > 1.012
Fibrin • Absent • Present SUMMARY OF HEMOSTASIS
Inflammatory STEP IMPORTANT EVENTS OUTCOME
• Absent • Present
cells Arteriolar • Reflex neurogenic • Transient
Basically, an exudate is a protein-rich fluid. On the other hand, a vaso- mechanisms and endothelin decrease in
transudate is a protein-poor fluid. constriction • Occurs immediately blood flow
Dr. Rubio
• Exposure of subendothelial
MORPHOLOGY • Primary
Primary ECM → platelet adhesion
• Clearing and separation of ECM and subtle cell swelling hemostatic
hemostasis and activation →
• Most common sites: subcutaneous tissue, lungs, and brain plug
aggregation
• In renal dysfunction, edema usually occurs in areas with loose • Factor XII, and exposure of
CT (periorbital area) tissue factor (VII) → • Secondary
Secondary
• Effusions: fluid accumulation in mesothelial spaces: pleural coagulation cascade → fibrin hemostatic
hemostasis
(hydrothorax), peritoneal (ascites), pericardial formation → additional plug
(hydropericardium); transudate or exudate depending on cause platelet aggregation
For example, if a patient has urticaria (superficial dermal edema), you • Permanent plug →
will see considerable separation of the dermal collagen fibers in Clot resorption by
microscopic sections, instead of the tightly compact collagen fibers. That stabilization counterregulatory • Tissue
is interstitial edema. For cellular edema, as in Chapter 1, you will and mechanisms (fibrinolysis: repair
appreciate cellular swelling. resorption tissue plasminogen
Dr. Elomina
activator (tPA)
HYPEREMIA AND CONGESTION
• Refers to the increase in blood volume in tissues
HYPEREMIA CONGESTION HEMOSTASIS
Process • Active • Passive https://qrs.ly/7rcmd9b
• Arteriolar dilation (in • Reduced outflow of
Mechanism inflammation and ↑ blood in a tissue
oxygen demand) (localized/systemic)
Tissue color • Red • Dusky
Hemoglobin • Oxygenated • Deoxygenated
MORPHOLOGY OF CONGESTION
ORGAN ACUTE CHRONIC
• Acute pulmonary
• Chronic pulmonary
congestion
congestion
o Engorged alveolar
o Thickened and fibrotic
capillaries
Lung septa
o Alveolar septal
o Hemosiderin-laden
edema
macrophages (heart
o Focal intra-alveolar
failure cells)
hemorrhage
ARTERIAL THROMBOSIS VS. VENOUS THROMBOSIS
ARTERIAL VENOUS
THROMBOSIS THROMBOSIS
• Turbulence or
Sites • Stasis
endothelial injury
• Extends in a • Extends in the
Propagation retrograde direction of blood
manner flow
Composition • Platelets > RBCs • RBCs > platelets
• Coronary >
Common sites of • Lower extremity
cerebral >
involvement veins (90%)
femoral
The arterial system is a site where there is more “aggressive” blood flow,
while the venous system is associated with a more “chill” blood flow. This
is the reason why turbulence and endothelial injury are associated with
arterial thrombosis and stasis is associated with venous thrombosis.
Dr. Elomina
ANTEMORTEM POSTMORTEM
THROMBOSIS THROMBOSIS
Attached to vessel
Yes No
wall
Lines of Zahn* Yes No
*represent apparent laminations which are platelet and fibrin deposits
alternating with darker red cell-rich layers
Postmortem thromboses are usually bland, and nonlaminated – dark red
dependent portion & yellow chicken fat upper portion (due to gravity).
Dr. Rubio
THROMBOSIS IN THE HEART (MURAL THROMBI)

FEATURE MURAL THROMBI VEGETATIONS
• Heart chambers or
Sites • Heart valves
aortic lumen
• Abnormal • Bacterial adhesion to
myocardial previously damaged
contraction and valves or destruction of
endomyocardial native valves (Infective
injury endocarditis (IE))
Setting
• Aortic: Ulcerated • Hypercoagulable states
atherosclerotic (Nonbacterial thrombotic
plaque and endocarditis (NBTE))
HEMOSTASIS aneurysmal • SLE (Libman-Sacks
Figure 4.4. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 dilation endocarditis)
FATES OF THROMBUS
FATE DEFINITION
• Thrombi accumulate additional platelets
Propagation
and fibrin
• Thrombi dislodge and travel to other sites
Embolization
in the vasculature
• Rapid shrinkage and total disappearance
Dissolution
of recent thrombi
Organization • Thrombi become incorporated in the
& vessel wall with formation of new
recanalization capillary channels that restore blood flow
ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APAS)

• Characterized by the presence of one or more antiphospholipid
(aPL) autoantibodies AND
• Recurrent thrombosis or pregnancy complications (repeated
DISORDERS OF PLATELET FUNCTION miscarriages, unexplained fetal death, premature birth),
thrombocytopenia
THROMBOSIS • Antibody-mediated interference with trophoblast growth and
• Pathologic counterpart of hemostasis differentiation → failure of placentation
• Caused by conditions under Virchow triad: • Antiphospholipid antibodies (anti-cardiolipin, lupus
VIRCHOW TRIAD MECHANISMS OF THROMBOSIS anticoagulant, anti-β2 glycoprotein-I) induce thrombosis
• Normal antithrombotic endothelium Remember the paradox of APAS: thrombosis with thrombocytopenia.
Endothelial injury
becomes prothrombotic on injury Dr. Elomina
• Turbulent injury can injure endothelium

Abnormal
→ prothrombotic EMBOLISM
• Stasis: maximizes platelet contact and • Detached intravascular solid, liquid, or gaseous mass that is
blood flow
retards washout of activated clotting carried by the blood from its point of origin to a distant site,
factors where it often causes tissue dysfunction or infarction
• Genetic or acquired abnormality that • Most common form of thromboembolic disease: Pulmonary
predisposes to thrombosis
embolism
Hypercoagulability • Most common thrombophilia: Factor V
Leiden (renders Factor V resistant to
inactivation by protein C)
MAJOR TYPES OF EMBOLISM MAJOR TYPES OF SHOCK
SYSTEMIC SHOCK SETTING MECHANISM
PULMONARY
FEATURE THROMBO- • Failure of
EMBOLISM • Myocardial
EMBOLISM myocardial pump
Most common • Mural infarction
• Deep venous thrombosis resulting from
source thrombi (80%) • Arrhythmia
intrinsic myocardial
• Pulmonary vasculature Cardiogenic • Cardiac
damage, extrinsic
• Pulmonary artery tamponade
compression, or
bifurcation: saddle • Lower • Pulmonary obstruction to
Sites of embolus (Sudden death) extremities embolism outflow
involvement • Paradoxical embolism: in (75%)
• Fluid loss (e.g.,
systemic circulation • Brain (10%)
through an interatrial/
hemorrhage, • Inadequate blood or
Hypovolemic
ventricular defect vomiting, plasma volume
• Clinically silent (60-80%) diarrhea, burns)
• Clinically
• Pulmonary hemorrhage unapparent • Activation of
• Overwhelming
Clinical (more common due to to symptoms cytokine cascades
Shock microbial
findings dual blood supply) referable to • Peripheral
associated infections
• Acute cor pulmonale end-organ vasodilation and
with systemic • Superantigens
(≥60% obstruction) ischemia pooling of blood
inflammation • Trauma
• Endothelial
Emboli are basically obstructive, so they cause loss of perfusion distal to (Septic shock) • Burns
the obstruction. activation/injury
• Pancreatitis
Dr. Elomina • DIC
OTHER FORMS OF EMBOLISM • Anesthetic
• Loss of vascular
EMBOLISM CLINICAL PICTURE FINDINGS accidents
Neurogenic tone and peripheral
Fat/ Marrow • Long bone • Spinal cord
pooling of blood
(5th MCC of fractures, trauma → • Fat globules in injury
maternal Pulmonary pulmonary • Histamine →
mortality insufficiency, vasculature systemic
worldwide) neurologic symptoms • IgE-mediated
Anaphylactic vasodilation and
• Post-partum → • Fetal skin, lanugo hypersensitivity
increased vascular
Dyspnea, cyanosis, hair, vernix caseosa, permeability
Amniotic
shock, seizures, and mucin in Adapted from Table 4.3. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
fluid
coma, pulmonary pulmonary STAGES
edema, DIC vasculature
STAGE DESCRIPTION
• Gas bubbles in
skeletal muscle and
• Reflex compensatory mechanisms are
Non-
• Divers who did joints (Bends) activated, and perfusion of vital organs is
progressive
rapid ascent → pain • Gas bubbles in maintained
Air on joints, pulmonary • Tissue hypoperfusion and onset of worsening
(100cc: respiratory vasculature Progressive circulatory and metabolic imbalances,
symptomatic) insufficiency (Chokes) • Onset of lactic acidosis
(Decompression • Caisson disease: • Cellular and tissue injury so severe that even
sickness) ischemia of femoral Irreversible if the hemodynamic defects are corrected,
head, tibia, & survival is not possible
humerus
TYPES OF SHOCK: PHYSIOLOGIC PARAMETERS
INFARCTION TYPE OF PCWP
CO SVR
• Area of ischemic necrosis caused by occlusion of either the SHOCK (PRELOAD)
arterial supply or the venous drainage ↑ ↑
↓
• Most common cause: Arterial thrombosis or embolism (impaired (compensato
Cardiogenic (pump
outflow of ry
failure)
MORPHOLOGY blood) mechanism)
RED INFARCT WHITE INFARCT ↓ ↑
↓
1. Venous occlusion 1. Solid organs Hypovolemi (low intra- (compensato
(low stroke
2. Loose, spongy tissues 2. End-arterial c vascular ry
volume)
(lung) circulation (heart, volume) mechanism)
3. Organs with dual spleen, kidney) ↓ ↑ ↓
Setting blood supply (lung &
Distributive
(peripheral (compensato (loss of
bowel) (Septic,
pooling of ry vascular
4. Tissues previously neurogenic)
blood) mechanism) tone)
congested
5. Reperfusion of a site MORPHOLOGY
• Wedge-shaped with occluded vessel at apex and CLINICAL
Gross ORGAN MORPHOLOGIC CHANGE
periphery of organ at base
PRESENTATION
• Ischemic, coagulative necrosis
• Aldosterone and
(EXCEPT in brain: liquefactive necrosis) Adrenals • Cortical lipid depletion
Microscopic cortisol effects
• Most are ultimately replaced by scar tissue
(EXCEPT in septic infarcts: abscess formation) • Acute kidney
Kidneys • Acute tubular necrosis
injury
• Resistant to hypoxic
SHOCK • Acute respiratory
injury in hypovolemic
• State in which diminished cardiac output or reduced effective Lungs distress syndrome
shock; if septic shock:
circulating blood volume impairs tissue perfusion and leads to (ARDS)
diffuse alveolar damage
cellular hypoxia
Adrenal cortical lipid depletion occurs as a result of increased release of
• Changes generally reversible if patient survives EXCEPT in
glucocorticoids (to increase the sensitivity of the vessels to vasopressors)
neurons, myocytes and mineralocorticoids (which increases the effective circulating
volume), in response to shock.
Dr. Rubio
4. GENETIC DISORDERS • Clinical manifestations:

Skin, • Hyperextensible skin, hypermobile joints
• Mendelian disorders
joints • Poor wound healing
• Chromosomal disorders
• Rupture of colon and larger arteries (vascular
• Trinucleotide repeat disorders Visceral
EDS), diaphragmatic hernia (classic EDS)
• Mitochondrial disorders Ocular • Corneal rupture and retinal detachment
• Disorders of genomic imprinting
Not all EDSs are inherited in an autosomal dominant manner. There are
some forms of AR EDS (enzyme deficiency related to collagen synthesis).
MENDELIAN DISORDERS Collagen is found in a lot of tissues, and therefore the manifestations of
• Single gene defects that have large effects collagen deficiency present as a multisystem disorder (see above). Also,
• Basic patterns of transmission: autosomal dominant (AD), since collagen is important in wound healing, the said process is impaired.
Dr. Elomina
autosomal recessive (AR), X-linked
• Co-dominance: both alleles contribute to phenotype AUTOSOMAL RECESSIVE DISORDERS
o Examples: histocompatibility and blood group antigens • Two recessive alleles produce phenotype
• Usually, parents are phenotypically normal, but there are
siblings affected
MENDELIAN DISORDERS o In a cross of two heterozygous parents:
https://qrs.ly/dlcmda3 § 25% chance of having the trait
• More uniform expression: Complete penetrance and early onset
• Usually, enzyme defects (metabolic disorders)
SYSTEM AUTOSOMAL RECESSIVE DISORDER/S
AUTOSOMAL DOMINANT DISORDERS • Cystic fibrosis
• One dominant allele is enough to produce phenotype • Phenylketonuria
(heterozygous) • Galactosemia
• One parent is usually affected • Homocystinuria
o In some cases, no parent is affected; due to newly acquired Metabolic • Lysosomal storage diseases*
mutations • α-1-antitrypsin deficiency
• Variable expression • Wilson disease
• Hemochromatosis
o Penetrance: proportion of those who inherit the gene and
• Glycogen storage diseases
express its phenotype
• Sickle cell anemia
o Expressivity: variability in phenotypic expression among Hematopoietic
• Thalassemias
those who inherit the gene Endocrine • Congenital adrenal hyperplasia
• Usually, key structural proteins/receptor defects • Ehler-Danlos syndrome (some variants)
Skeletal
To understand penetrance and expressivity, I will give an example. There • Alkaptonuria
are ten flowers who inherited gene A for purple petal color. There are 5 • Neurogenic muscular atrophies
purple flowers and 5 white flowers. What is the penetrance? It’s 50% Nervous • Friedreich ataxia
(5/10). For expressivity, suppose that there are 5 purple flowers, 3 • Spinal muscular atrophy
lavender flowers, and 2 light purple flowers, what is the penetrance? It’s Adapted from Table 5.2. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
100% (10/10), but we see variable expressivity. SPHINGOLIPIDOSES
Dr. Elomina
• Tay-Sachs disease
SYSTEM AUTOSOMAL DOMINANT DISORDER/S o Defect: α-subunit of hexosaminidase A → accumulation of
• Huntington disease GM2 ganglioside (most prominent: in neurons and retina)
• Neurofibromatosis o Neurons: ballooned with cytoplasmic vacuoles with
Nervous
• Myotonic dystrophy ganglioside (+) for fat stains (oil red O, Sudan Black B)
• Tuberous sclerosis § EM: cytoplasmic inclusions, whorled (onion-skin)
Urinary • Polycystic kidney disease (ADPKD) o Retina: ganglion cells distended by ganglioside vacuoles: (+)
Gastrointestinal • Familial polyposis coli cherry-red spot in retina
• Hereditary spherocytosis Disorders of lipid metabolism usually affect organs with high lipid content
Hematopoietic (CNS); that’s why these diseases manifest with CNS involvement i.e. MR.
• Von Willebrand disease
The common theme for both Tay-Sachs and Niemann-Pick disease is
• Marfan syndrome*
enzyme deficiency, which leads to accumulation of a substrate (lipid).
• Ehler-Danlos syndrome (some variants)* Clinically, hepatosplenomegaly is seen in Niemann-Pick disease and
Skeletal
• Osteogenesis imperfecta NOT in Tay-Sachs disease.
• Achondroplasia Dr. Elomina
• Familial hypercholesterolemia SULFATIDOSES

Metabolic
• Acute intermittent porphyria • Niemann-Pick disease (Types A and B)
o Defect: sphingomyelinase deficiency → accumulation of
sphingomyelin
MARFAN SYNDROME o Clinically, hepatosplenomegaly, cherry-red spot in macula
• Disorder of connective tissues manifesting principally by § EM: membranous cytoplasmic inclusions of lamellated
changes in the skeleton, eyes, and cardiovascular system myelin figures (zebra bodies)
• Genetic defect of fibrillin-1 gene (chromosome 15) • Gaucher disease
• Most striking feature of Marfan syndrome o Most common lysosomal storage disorder
• Tall stature, long extremities, tapering fingers, lax joint o Defect: glucocerebrosidase deficiency (β-glucosidase)
Skeletal
ligaments, chest deformities, dolichocephalic (long- o Gaucher cells
headed) § Distended phagocytic cells in spleen, liver, Bone marrow,
Ocular • Bilateral subluxation of lens outward and upward Lymph nodes, tonsils, thymus, and Peyer patches
• Most life-threatening feature of this disorder § Fibrillary cytoplasm (“crumpled tissue paper” appearance)
CVS • Mitral valve prolapse (MVP), dilation of the
ascending aorta → aortic dissection X-LINKED RECESSIVE DISORDERS (XR)
• Usually males express phenotype (due to hemizygosity for the
For me, Marfan syndrome are tall and lanky people with weak hearts and
bones. allele)
Dr. Elomina o Females may express the phenotype (because of random
inactivation of one X chromosome)
EHLER-DANLOS SYNDROME • Affected males do not transmit the disease to their sons (because
• Heterogeneous group of disorders; common: defect in fibrillar they get their Y from their dads); but all of their daughters are
collagen carriers (because they get one X from their dads)
• Either defects in structural proteins or enzymes for post- • In a cross of heterozygous female and an affected male:
translation modification of collagen o 50% of sons and 50% of daughters (+)
SYSTEM X-LINKED RECESSIVE DISORDER/S • Cleft lip and palate, and umbilical hernias: distinguish Patau
Musculoskeletal • Duchenne Muscular Dystrophy syndrome
• Hemophilia A and B
Blood • Chronic granulomatous disease
• G6PD deficiency
• Agammaglobulinemia
Immune
• Wiskott-Aldrich syndrome
• Diabetes insipidus
Metabolic
• Lesch-Nyhan syndrome
Nervous • Fragile X syndrome
X-LINKED DOMINANT DISORDERS (XD)

• In a cross of heterozygous female with a normal male:
o 50% of sons and 50% of daughters (+)
• In a cross of affected male with a normal female
o All daughters (+), all sons (-)
• Examples: Alport syndrome and Vitamin D-resistant rickets
CHROMOSOMAL DISORDERS
• Normal karyotype: 22 pairs of autosomes and 1 pair of sex
chromosomes (46XX or 46XY) (Euploid)
• Abnormalities in number (Aneuploidy) or structure
• Can involve autosomes or sex chromosomes
ANEUPLOIDY
ERRORS IN GAMETOGENESIS
• Failure of homologous chromosomes or
sister chromatids to separate during cell
Nondisjunction division
• One gamete has an extra chromosome; the
other gamete lacks a chromosome
• One homologous chromosome (meiosis) or
one chromatid is left out of the cell nucleus
Anaphase lag COMMON AUTOSOMAL DISORDERS
• One gamete is normal; one gamete lacks a Figure 5.20. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
chromosome
ERRORS POST-FERTILIZATION DISORDERS OF SEX CHROMOSOMES
• Two or more populations of cells with • More common and better tolerated than autosomal
different chromosomal complement in one chromosomal disorders
Mosaicism individual o Subtle, chronic problems regarding sexual development and
• Examples: Trisomy 21 (Autosomal), Turner fertility
syndrome (Sex chromosome) o Difficult to diagnose at birth
Errors in chromosome number can happen before or after fertilization. If o Usually detected at puberty
it happens before, then the gametes are affected, and once it participates o The greater the number of X chromosomes, the higher the
in fertilization the zygote will harbor the anomaly, and all the cells in the likelihood of mental retardation
body will also harbor the anomaly. That is the case for nondisjunction
and anaphase lag. If it happens post-fertilization, then it will result to a KLINEFELTER SYNDROME
population of cells that are karyotypically normal, and a population of
cells that are karyotypically abnormal. These are called mosaics. • ≥ 2 X chromosomes and ≥ 1 Y chromosomes
Dr. Elomina o Most common: 47XXY (90%)
• One of the most common genetic diseases involving sex
DISORDERS OF AUTOSOMES
chromosomes and male hypogonadism
TRISOMY 21 o Important cause of reduced spermatogenesis and male
• Most common of the chromosomal disorders; leading cause of infertility
Mental Retardation • Clinical characteristics
• Causes: o Hypogonadism (most consistent finding)
o Nondisjunction (95%) o Eunuchoid body habitus
o Robertsonian translocation (4%) o Mitral valve prolapse (50%)
o Mosaicism (1%) o Gynecomastia
• Advance maternal age: strong influence of occurrence o Low IQ, but mental retardation is uncommon
• Diagnostic clinical features: flat facial profile, oblique
palpebral fissures, and epicanthic folds TURNER SYNDROME
• Notable associations: • Complete or partial monosomy of X chromosome; female
o Cardiac: Endocardial cushion defect hypogonadism in phenotypic females
o GIT: Hirschsprung disease, duodenal atresia • Most common abnormality: lack of entire X chromosome (45XO)
o Acute leukemia: ALL or AML (most common: acute (57%)
megakaryoblastic leukemia) • Single most important cause of primary amenorrhea
o Neuropathologic changes: early-onset Alzheimer disease • Clinical characteristics
The lesson here is that when you have a patient with T21, you have to o Ovarian streaks: Accelerated loss of oocytes due to loss of the
check for the presence of these defects as well. other X chromosome
Dr. Elomina
TRISOMY 18 AND 13 o Absence of secondary sex characteristics & short stature
o Cystic hygromas of neck → regress → webbed neck
• Trisomy 18 (Edward syndrome) and Trisomy 13 (Patau
o Cardiovascular: preductal CoA, bicuspid aortic valve
syndrome) § Most important cause of increased mortality in children with
• More severe than Trisomy 21; most die within first year of life Turner syndrome
• Most common cause: nondisjunction of chromosome during
meiosis
• Common features: mental retardation, cardiac and renal defects,
rocker-bottom feet
HERMAPHRODITISM AND PSEUDOHERMAPHRODITISM 5. DISEASES OF THE IMMUNE SYSTEM
• True hermaphroditism • Components of the immune system
o Presence of both ovarian and testicular tissue • Hypersensitivity reactions (Gell and Coombs classification)
• Pseudo-hermaphroditism • Autoimmune diseases
o Disagreement between phenotypic and gonadal sex
• Transplantation immunology
§ Genotypically male with female phenotype (Androgen
• Immunodeficiency syndromes
insensitivity syndrome)
• Amyloidosis
§ Genotypically female with male phenotype (Adrenogenital
syndromes) COMPONENTS OF THE IMMUNE SYSTEM
In AIS, you are karyotypically male, but with a habitus of that of a female, • Consists of innate and adaptive immunity (cell-mediated,
because your peripheral tissues are insensitive to androgens. So, have your humoral)
girlfriends karyotyped to be sure. :P In the case of adrenogenital syndromes INNATE ADAPTIVE
(congenital adrenal hyperplasia), because of excess adrenal androgens, the
• Epithelia, PMNs,
clitoris enlarges and it appears like a penis, plus you will have virilizing • Lymphocytes and
symptoms. Components Macrophages, Dendritic
antibodies
Dr. Elomina cells, NK cells, Complement
Defense • First • Later
TRINUCLEOTIDE REPEAT DISORDERS
• Develops after
• Important genetic cause of human disease, especially Presence • Always
antigen exposure
neurodegenerative disorders Specificity • Less • More
• Proclivity to expand depends on sex of transmitting parent Potency of
(Female: Fragile X; Male: Huntington disease) • Less • More
response
• Mutations may cause loss-of-function (Fragile X) or gain-of
Dendritic cells – serve as the major antibody-presenting cells (cells who
function (Huntington)
present the antibodies to the helper T cells for recognition) of the body. Other
• Anticipation: disease worsens with each successive generation APCs include macrophages and B cells. NK cells are “large granular
lymphocytes” that kill virally infected cells and neoplastic cells via antibody-
FRAGILE X SYNDROME dependent cellular cytotoxicity (NK cells are the only lymphocytes that
• 2nd most common cause of mental retardation after Trisomy 21 are part of the innate branch of the immune system).
• CGG expansion in FMR1 gene in X chromosome Dr. Rubio
TYPES OF ADAPTIVE IMMUNITY
• Clinically, long face, large mandible, large everted ears, and
macro-orchidism • Cell-mediated immunity (CMI)
o Macro-orchidism: most distinctive feature (90%) o Component: T-cells
o Defense against intracellular pathogens
CGG: Protruding Chin, Giant Gonads.
Dr. Rubio • Humoral immunity (HI)
HUNTINGTON DISEASE o Component(s): B-cells and antibodies
• Autosomal dominant; CAG expansion on HTT gene on Ch4 o Defense against extracellular pathogens
• Clinically, progressive movement disorders and dementia due to
degeneration of striatal neurons TYPES OF IMMUNITY
• Based on the means of acquiring immunity – natural or
Hunter’s CAGe: Caudate has ↓Acetylcholine & GABA.
Dr. Rubio artificial
• Based on the source of the antibodies
MITOCHONDRIAL DISORDERS o Active: host’s immune system makes the antibodies itself
o Passive: antibodies themselves are from exogenous source
• Distinctive feature: maternal inheritance
• Usually, defects in electron transport chain NATURAL IMMUNITY
o Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and
Stroke (MELAS) • Infection and subsequent immunity (active immunity)
o Leber Hereditary Optic Neuropathy (LHON) • Maternal immunoglobulins passed onto fetus (prenatal), or
through breastmilk (postnatal) (passive immunity)
Our extranuclear material usually comes from our mother, including the
mitochondria and their DNA. There are two main pathways that occur in
the mitochondria: the ETC and the TCA cycle; that is why mitochondrial
ARTIFICIAL IMMUNITY: VACCINATION
disorders usually are associated with ETC defects. The diseases are • Administration of immunogen → synthesis of immunoglobulins
discussed further in Biochemistry. against the pathogen of interest (active immunity)
Dr. Elomina
• Administration of immunoglobulin → immediate neutralization
of the antigen/pathogen of interest (passive immunity)
DISORDERS OF GENOMIC IMPRINTING
• Imprinting: silencing of one copy of gene from either parent DISEASES OF THE IMMUNE SYSTEM
during gametogenesis; imprinted gene (silenced) • Excessive, unregulated activity
• Disease occurs once the functional (nonimprinted) gene is deleted o Hypersensitivity: injurious immune reactions; basis for
• Classic examples: Prader-Willi and Angelman syndrome autoimmune diseases
o Clinically, end-organ damage due to immune-mediated injury
PRADER-WILLI ANGELMAN • Decreased or absent activity
FEATURE
SYNDROME SYNDROME
o Immunodeficiency syndromes
• Deletion in • Deletion in
o Clinically, susceptibility to infections, especially opportunistic
Abnormality Paternally derived Maternally derived
Chromosome 15 Chromosome 15
• Mental retardation • Mental retardation,
HYPERSENSITIVITY REACTIONS
• Profound • Ataxic gait IMMEDIATE (TYPE I) HYPERSENSITIVITY
Clinical hyperphagia • Seizure • Commonly known as allergies (exogenous triggers)
features • Obesity • Inappropriate • Key traits: Rapid; occurs in previously sensitized individuals;
• Hypogonadism laughter “happy IgE-mediated
puppet” • Two phases (with different effects and mediators):
Both diseases deal with Chromosome 15, but Prader deals with Paternal Immediate phase • Vascular changes (vasoactive amines)
(both have P) and Angelman deals with Maternal (Both have M). Both
• Leukocytic infiltration and tissue damage
have MR, but Prader is also associated with metabolic and gonadal
problems. Angelman on the other hand, is entirely neurologic.
• Eosinophils: main cells
Late phase
Dr. Elomina • IL-5: most potent eosinophil activating
cytokines from TH2 cells
• First exposure to allergen
o TH2 cell activation and production of IgE that binds to
basophils and mast cells
• Subsequent exposure to allergen AUTOIMMUNE DISEASES
o Antigen binds to IgE on basophils and mast cells → mast cell
• Chronic, sometimes with relapses; damage often progressive
degranulation of vasoactive amines (immediate phase) and
• Clinical and pathologic manifestations determined by nature of
release of cytokines and chemokines (late phase)
the underlying immune response
• Examples
• More common in women
o Anaphylaxis o Allergic rhinitis (hay fever)
o Bronchial asthma o Food allergies • Usually associated with other autoimmune diseases
For autoimmune diseases, I want you to take of note of the following
things:
1. The type of hypersensitivity reaction;
ANTIBODY-MEDIATED (TYPE II) HYPERSENSITIVITY 2. The autoantibodies associated with the disease; and
• The following mechanisms are mediated by antibodies: 3. The major organs involved
EFFECT MECHANISM CONDITIONS Dr. Elomina
• Activation of: C3b SYSTEMIC LUPUS ERYTHEMATOSUS

(opsonin): for • Type III hypersensitivity reaction
phagocytosis • Autoimmune • Autoimmune disease affecting multiple organ systems
• Direct lysis: hemolytic anemia o Failure of the mechanisms that maintain self-tolerance
Opsonization
antibody-dependent (AIHA) • Hallmark: production of autoantibodies
and
cellular cytotoxicity • Immune ANA • Best screening test
phagocytosis
(through NK cells thrombocytopenic • Specific for SLE but has no correlation for
and macrophages) purpura (ITP) Anti-Sm
disease activity
• Fc receptor- • Specific for SLE
mediated Anti-dsDNA • Correlates with disease activity
• Antineutrophil (i.e., nephritis)
• Activation of C3a cytoplasmic Anti-histone • Associated with drug-induced LE
and C5a autoantibodies
Anti-Ro (SS-A) / • Associated with neonatal lupus and in the
(anaphylatoxins): (ANCA) vasculitis
Inflammation Anti-La (SS-B) development of congenital heart block
inflammation • Goodpasture
• Fc receptor- syndrome MORPHOLOGY
mediated • Acute rheumatic ORGAN MORPHOLOGY
fever Blood • Acute necrotizing vasculitis (fibrinoid necrosis) →
• Antibodies bind to vessels fibrosis with luminal narrowing (chronic)
receptors and alter Kidney • Lupus nephritis (6 classes)
Cellular • Myasthenia gravis • Malar skin rash
cellular function; no
dysfunction • Graves disease Skin • Epidermis: Vacuolar degeneration of basal layer
inflammation or cell
injury • Dermis: Variable edema and perivascular inflammation
Joints • Non-erosive synovitis with little deformity
• Acute serositis: fibrinous exudate on mesothelial surface
IMMUNE COMPLEX-MEDIATED (TYPE III) HYPERSENSTIVITY
Body • Chronic: thickening of mesothelial surface → obliteration
• Immune complex deposition in tissues (common: kidneys, joints cavities of serosal cavity
and small blood vessels) • Effusions
• Subsequent inflammatory response (by complement activation) • Libman-Sacks endocarditis: 1-3 mm warty deposits on
CVS
and tissue destruction any heart valve, on either surface of the leaflets
• Diseases tend to be systemic (EXCEPT Arthus reaction: local) • Splenomegaly, capsular thickening, follicular
• Morphology hyperplasia
Spleen
o Inflammation, Necrotizing vasculitis (fibrinoid necrosis) • Concentric intimal and smooth muscle hyperplasia
(onion-skin lesions) in penicilliary arteries
• Examples:
• Interstitial fibrosis and secondary pulmonary
o SLE o Reactive arthritis Lung
hypertension
o PSAGN o Serum sickness • Bone marrow: LE cell/Hematoxylin bodies –
o Polyarteritis nodosa o Arthus reaction Other
represents a phagocyte that engulfed and digested the
organs
Your immune complexes are like garbage—they get deposited nuclei of another cell (that had lysed)
and
everywhere, but blood vessels are their favorite site. The immune • Lymph node: Follicular hyperplasia, necrotizing
tissues
complexes deposited in the blood vessels can activate the complement lymphadenitis
system and cause inflammation, which consequently damages the nearby Please review the SLE criteria (1997 revised criteria & 2012 SLICC
tissues. That is why the classic finding in immune complex-mediated criteria in Internal Medicine)
diseases is a necrotizing vasculitis (with fibrinoid necrosis) (Review your CLASSES OF LUPUS NEPHRITIS
Chapter 1). Since blood vessels are everywhere, the manifestations of this
IMMUNO-
disease tend to be systemic, except for Arthus reaction. CLASS LIGHT MICROSCOPY
Dr. Elomina FLUORESCENCE
Minimal • Immune complex
mesangial • No structural changes (IC) deposition in
T-CELL-MEDIATED (TYPE IV) HYPERSENSITIVITY
(Class I) mesangium
• CD4 -mediated: cytokines induce inflammation
+
• Granular mesangial
o Antigen exposure: CD4+ differentiation to TH1 and TH17 cells Mesangial deposits (Ig,
• Mesangial cell
o On subsequent exposure: proliferative complement)
proliferation
§ TH1: secretes IFN-γ: activates macrophages to secrete (Class II) • (-) glomerular
cytokines: inflammation involvement
§ TH17: produces IL-17 and other cytokines: leukocyte • <50% of glomeruli
recruitment: inflammation • Swelling and
proliferation of
• CD8+ (cytotoxic T-cell)-mediated: direct killing by perforins and
Focal endothelial and
granzymes in lysosome-like granules (Class III) mesangial cells,
o Perforins: help release granzymes neutrophils • Subendothelial IC
o Granzymes: cleave and activate caspases (apoptosis) • Capillary necrosis, deposits
o Cytotoxic T cells: express Fas ligand (apoptosis) hyaline thrombi
• Examples • >50% of glomeruli
o Rheumatoid arthritis o Inflammatory bowel disease Diffuse • Same as Class III
o Multiple sclerosis o Psoriasis (Class IV) • (+) wire loop
o Type I Diabetes o Contact sensitivity structures
Mellitus Membranous • Diffuse capillary • Subepithelial IC
o Tuberculin skin testing (Class V) thickening deposits
Advanced
• Sclerosis of >90%
sclerosing -
glomeruli
(Class VI)
Class I lupus nephritis – least common pattern of LN. • Associated autoantibodies

Class IV lupus nephritis – most common and most severe pattern of LN. • Present in 10-20% of diffuse
Anti-Scl 70
Dr. Rubio scleroderma
(anti-DNA
• Higher risk for pulmonary fibrosis,
topoisomerase I)
peripheral vascular disease
LUPUS NEPHRITIS Anti-centromere • Present in 20-30% of CREST syndrome
https://qrs.ly/i7cmdbc
SYSTEMIC SCLEROSIS: MORPHOLOGY
ORGAN MORPHOLOGY
SJÖGREN SYNDROME • Diffuse, sclerotic atrophy of skin from distal
Skin
• Dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia) regions → proximal regions
secondary to autoimmune-mediated destruction of lacrimal • 90% of the GI tract is affected (most severe in
and salivary glands esophagus)
• Diagnosis: lip biopsy (minor salivary glands) GIT
• (+) rubber-hose-like inflexibility of lower 2/3 of
Most important and most common • Anti-Ro (SS-A) esophagus → ↑ risk for Barrett esophagus
associated autoantibodies • Anti-La (SS-B) • Intimal thickening of interlobular arteries (due to
Renal
Association for early disease onset, longer deposition of mucinous material)
• Anti-Ro (SS-A)
duration, extra-glandular presentation MSK • Synovial hypertrophy, hyperplasia → fibrosis
• Morphology Lung • Interstitial fibrosis and pulmonary hypertension
Earliest • Periductal and perivascular lymphocytic • Pericarditis with effusion, myocardial fibrosis, and
histologic infiltration in salivary glands (lymphoid Heart
thickening of intramyocardial arterioles
finding follicles with germinal centers)
• Acinar atrophy, fibrosis, hyalinization,
Late findings
replacement of parenchyma to fat ANA PATTERNS
Lymphoid infiltration increases the risk of a patient for developing B- https://qrs.ly/cscmdet
cell lymphomas.
Dr. Rubio
SYSTEMIC SCLEROSIS (SCLERODERMA)
• Triad: TRANSPLANTATION IMMUNOLOGY
1. Chronic inflammation (autoimmunity)
• Rejection of transplant tissue can be – cell-mediated or
2. Widespread damage to small blood vessels
antibody-mediated graft destruction
3. Progressive interstitial and perivascular fibrosis in the skin
o Differences in HLA alleles: major antigenic difference leading
and multiple organs
to rejection
• Pathophysiology: T-cell-mediated and activation of humoral
• Allorecognition pathways
immunity (and production of antibodies)
o Direct pathway: donor antigen-presenting cells (APCs) present
Diffuse • Widespread skin involvement, rapid antigens to recipient T-cells
scleroderma progression, early visceral involvement § MHC Class I: CD8 T-cells → active Cytotoxic T-cells
• Limited skin involvement (fingers, forearms, § MHC Class II: CD4 T-cells → TH1 and TH17 effector cells
Limited face), late visceral involvement o Indirect pathway: donor antigens are presented by recipient
scleroderma • CREST syndrome – form of limited APCs to recipient T-cells
scleroderma • Reactions
QUICK SHEET: CREST SYNDROME o T-cell mediated:
§ Calcinosis § Acute cellular rejection, Chronic rejection
§ Raynaud phenomenon o Antibody-mediated:
§ Esophageal dysmotility § Hyperacute rejection, Acute humoral rejection
§ Sclerodactyly
My mnemonic for the allorecognition pathways is:
§ Telangiectasia Direct: D is for Donor (Donor APCs present Ags to recipient T-cells), and
then the opposite is for Indirect.
For the MHC pairing, my mnemonic is that the product of the pair is
8 (4 x 2 = 8, and 8 x 1 = 8).
Dr. Elomina
PATTERNS OF KIDNEY REJECTION

CLINICAL
TYPE ONSET MICROSCOPIC FINDINGS
FINDING(S)
Hyperacute • Immediately • Cyanotic & • Thrombotic occlusion of the capillaries
(pre-formed antibodies from donor) post-transplant mottled kidney • Fibrinoid necrosis in arterial walls
• Tubulointerstitial (Type I): tubulitis (w/ lymphocytic infiltrates)
• Days or weeks
• Vascular (Type II): endotheliitis/intimal arteritis (w/ lymphocytic
Acute cellular post-transplant
infiltrates)
• After tapering
• Type III: Type II + vessel wall necrosis
immuno-
Acute antibody-mediated • Inflammation of glomeruli and peritubular capillaries
suppressants • Clinical and
(Antibodies produced post-transplant) • Focal thrombosis of small vessels
biochemical
signs of renal • Vascular lesions:
failure 1. Intimal thickening with vascular occlusion
• Months to 2. Glomerulopathy with duplication of the basement membrane
Chronic years after 3. Peritubular capillaritis with multilayering of peritubular capillary
transplantation base membrane
• Interstitial fibrosis and tubular atrophy with loss of renal
parenchyma
HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) GRAFT VS. HOST DISEASE (GVHD)
• Indications: hematologic malignancies, bone marrow failure • Setup: immunologically competent cells (from donor) attack
syndromes, inherited HSC defects the immunocompromised body (of the recipient) post-HSCT
• Abolishment of immune system prior to transplantation (by • Morphology: Epithelial injury (acute); fibrosis with end-organ
chemo- or radiotherapy) – important step failure (chronic)
• Complications: Graft vs. host disease (GVHD) and • Usual organs affected: skin, GIT, Hepatobiliary tract, Immune
immunodeficiency system
Acute GVHD • Epithelial injury; causes rashes, GI bleeding
Chronic GVHD • Fibrosis; may resemble systemic sclerosis
IMMUNODEFICIENCY SYNDROMES WISKOTT-ALDRICH SYNDROME

• Primary (congenital) or secondary (acquired) • XR: WAS gene mutation → combined B- and T-cell disorder
• Defects in either innate or adaptive immunity • Triad: (1) Thrombocytopenia, (2) Recurrent infections, (3)
• Clinically: susceptibility to infections; depending on the arm of Eczema
the immune system affected • T-cells in thymus are normal but are depleted in other areas (↓
CMI)
• ↓ IgM, normal IgG, ↑ IgA and IgE (paradoxical) (humoral immune
DEFECTS IN INNATE IMMUNITY: abnormalities)
LEUKOCYTE FUNCTION • Treatment: HSC transplantation
• AR – defect in migration and chemotaxis of WAS shows both defects in humoral and cell-mediated immunity (see
Leukocyte
phagocytes above). Of note, patients are prone to develop B cell lymphomas
adhesion
• Late separation of umbilical cord Dr. Elomina
deficiency ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)
• Recurrent skin and mucosal bacterial
(LAD)
infections (absent pus) • Most common secondary immunodeficiency
• AR – defect in LYST gene (problem in • Hallmark: profound immune deficiency
Chediak- phagolysosome functioning) • At risk groups:
Higashi • Albinism, neurodegeneration, recurrent o Homosexual, bisexual o HIV infection of the newborn
syndrome pyogenic infections men (largest) o Hemophiliacs
• Giant granules in granulocytes/platelets o Heterosexual contacts o Recipients of blood
Chronic o IV drug users components
• XR – defect in NADPH oxidase (↓ ROS burst)
granulomatous
• Susceptibility to catalase-positive organisms
disease (CGD) HIV
• Non-transforming retrovirus (family Retroviridae), Genus:
DEFECTS IN ADAPTIVE IMMUNITY Lentivirus
• B-cell line blocks: depressed humoral immunity • HIV-1 (more common) and HIV-2
• T-cell line blocks: depressed cell-mediated immunity • Two major targets of HIV: Immune system and CNS
• Earlier blocks: depressed activity of both arms of immunity • Sexual (most common), parenteral, and vertical (mother to
• Blocks in immunoglobulin class switching: deficiency of some infant)
immunoglobulins • Mechanism of sexual transmission:
• XR – defect in BTK gene: no B-cell maturation o Direct inoculation into blood vessels breached by trauma
• Absent or scanty lymph nodes and tonsils with o Dendritic cell infection → dendritic cells transported to lymph
X-linked absence of primary follicles and germinal nodes and spleen → both organs act as reservoir of infection
(Bruton) centers Co-existing STDs compromise the integrity of the GUT epithelium, thereby
Agamma- • Absent B cells in blood, decreased Ig of all making it easy for the HIV to enter your body.
globulinemia classes Dr. Elomina
• Recurrent bacterial and enteroviral infections

HIV LIFE CYCLE: IMPORTANT EVENTS
after 6 months • gp120: Attaches to CD4 → conformation change → new
• 22q11 microdeletion: failure to develop 3rd recognition site for CXCR4 and CCR5 → gp120 binds to CXCR4
and 4th pharyngeal pouches and CCR5
Thymic • gp41: Fusion protein → integrates itself into host cell membrane
• Absent thymus (no thymic shadow on CXR),
aplasia → facilitates fusion and delivery of viral genome
parathyroid glands
(CATCH-22) My mnemonic here is: “The cost of attachment (120) is higher than that
• Absent T cells, ↓ PTH, ↓ Ca2+
• Recurrent viral, fungal infections of “fusion” IKYWIM (41). :P
Dr. Elomina
• XR: defective IL-2R gamma chain (MCC) HIV-INDUCED CHANGES IN THE IMMUNE SYSTEM AND CNS
Severe
• AR: adenosine deaminase deficiency • CD4 T-cell depletion: mainly due to direct cytopathic effect
Combined
• Absence of thymic shadow (CXR), germinal • Polyclonal B-cell activation → germinal B-cell hyperplasia, bone
Immuno-
centers (biopsy), and T cells (flow
deficiency marrow plasmacytosis, hypergammaglobulinemia, and immune
cytometry)
(SCID) complex deposition (autoimmune phenomenon)
• Failure to thrive, chronic diarrhea, thrush
o Usually due to EBV infection, viral gp41, and IL-6 from HIV-
CATCH-22 is represented by: Cardiac defects (conotruncal abnormalities), infected macrophages
Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia due to • CNS infection of macrophages and microglia
parathyroid aplasia, 22q11 microdeletion. DiGeorge syndrome has thymic,
o Usually from infected monocytes
parathyroid, and cardiac defects. On the other hand, velocardiofacial
syndrome has palate, facial, and cardiac defects. The polyclonal B cell activation makes HIV patients prone to develop
Dr. Rubio lymphomas (EBV-associated). Despite the increase in B cells, HIV patients
have depressed HI because of T cell loss and B cell dysfunction, making them
DEFECTS IN LYMPHOCYTE ACTIVATION susceptible to encapsulated bacteria like H. influenzae and S. pneumoniae.
AND FUNCTION Dr. Elomina
• Blocks in maturation pathways of B cells → AIDS-DEFINING ILLNESSES

hypogammaglobulinemia (either isolated or multiple) • Infections
• Clinically, susceptibility to pyogenic organisms (because they’re Candidiasis • Most common fungal infection in AIDS
killed primarily by opsonization • Responsible for >50% of all mass
Toxoplasma gondii
lesions in CNS of an AIDS patient
FEATURE ISOLATED IGA DEFICIENCY
CMV chorioretinitis • Occurs in CD4+ count <50/µL
• Impaired differentiation of naïve B cells and
Mechanism Mycobacterial • Early: M tuberculosis
IgA-producing plasma cells
infections • Later: M avium-intracellulare (MAC)
• Decreased serum and secretory IgA →
Features Persistent diarrheal • Cryptosporidium, Isospora belli,
impaired mucosal defense
infections Salmonella, Shigella, MAC
Clinical • Recurrent respiratory, GIT, and GUT
findings infections
• Severe anaphylactic reactions when • Neoplasms
Complications • Most common neoplasm in AIDS
transfused with IgA-containing blood Kaposi sarcoma
• Caused by human herpesvirus 8 (HHV-8)
GIT, GUT, and Respiratory tract rely on secretory IgA for defense; that is
• Most common type of lymphoma in AIDS
why these systems suffer in IgA’s absence. B-cell lymphoma
Question: What red cell product would you transfuse in patients with • Secondary to B-cell hyperplasia
confirmed IgA deficiency? HPV-associated • Increased risk of occurrence among AIDS
Answer: Washed Red Cell squamous cell CA patients
Reason: Washed Red Cell lacks antibodies, serum proteins, and
electrolytes.
Dr. Elomina
HIV: LYMPH NODE MORPHOLOGY • Sarcoma: malignant neoplasm of MESENCHYMAL origin
EARLY DISEASE LATE DISEASE • Leukemia/Lymphoma: malignant neoplasm of
• B-cell follicle hyperplasia • Burned-out lymph nodes HEMATOLYMPHOID origin
(Enlarged follicles with • Hyalinized germinal centers • Mixed tumor: Tumor with more than one distinct identifiable
serpiginous shaped) • Disrupted follicular dendritic component e.g., Pleomorphic adenoma
• Attenuation of mantle zones cell network • Teratoma: Mixed tumor containing mature or immature cells or
• Impingement of tissues belonging to more than 1 germ cell layer (mesoderm,
interfollicular T-cell zones endoderm, ectoderm)
The early findings reflect the polyclonal B-cell activation that happens in
early HIV infection, while the late findings reflect the lymphocyte
depletion that happens in the late phase of HIV infection.
CHARACTERISTICS OF
Dr. Elomina BENIGN AND MALIGNANT TUMORS
DIFFERENTIATION AND ANAPLASIA
AMYLOIDOSIS DIFFERENTIATION ANAPLASIA
• “Starch-like” fibrillar proteins accumulating extracellularly • Extent to which neoplastic • Lack of
causing disease by pressure atrophy on adjacent cells parenchymal cells resemble the differentiation
corresponding normal parenchymal • Considered a
Morphology cells, both morphologically and hallmark of
• Grossly, enlarged organ with gray, waxy, firm consistency functionally malignancy
• Amyloid deposition is ALWAYS EXTRACELLULAR and begins
between cells MORPHOLOGIC FEATURES ASSOCIATED WITH ANAPLASIA
• Congo red: pink to red under ordinary light; apple green FEATURE FINDINGS
birefringence under polarized light Pleomorphism • Variation in size of cells and nuclei
o Due to β-sheet confirmation of amyloid
• Nuclear pleomorphism
• Involved organs:
• ↑ Nuclear : Cytoplasmic (N:C) ratio
• Most common and most serious form of organ Abnormal
Kidney • Hyperchromasia (darkly stained
involvement nuclear
nucleus)
• Presence of amyloid in lymphoid follicles → sago morphology
• Coarse chromatin pattern
spleen (tapioca-like granules);
Spleen • Prominent nucleoli
• Fusion of early deposits → lardaceous spleen
• ↑ Mitotic figures
(map-like areas) Mitoses
• Abnormal forms
• Deposition starts at space of Disse → pressure
Liver Loss of polarity • Disoriented arrangement of tumor cells
atrophy of surrounding liver parenchyma
• Necrosis, due to tumor outgrowing its
• Major organ involved in senile systemic amyloidosis Other features
own blood supply
Heart • May cause conduction abnormalities due to
subendocardial deposition of amyloid
DYSPLASIA
• Disordered growth (with pleomorphism and abnormal nuclear
6. NEOPLASIA morphology) encountered principally in epithelia
• Generalities
• Carcinoma-in-situ: Full-thickness dysplasia without invasion of
• Nomenclature the basement membrane
• Characteristics of benign and malignant tumors • Invasive carcinoma: invasion of the basement membrane
• Cancer epidemiology
• Cancer hallmarks • Basically, when you hear the words dysplasia and atypia, they all mean
one thing: UGLY. When something is not pleasing to the eye, in terms of
• Carcinogenic agents architecture and cytologic appearance, it’s almost always malignant.
• Clinical aspects of neoplasia • Metaplasia is different from dysplasia. Metaplasia is by convention, an
adaptive response to stress. However, metaplastic epithelium serves as
GENERALITIES fertile soil for malignancy. Examples:
o Squamous metaplasia → Squamous cell carcinoma (lung)
• Neoplasia means “new growth” o Barrett esophagus (Intestinal metaplasia) → Adenocarcinoma
• Basic components of a tumor: • Dysplasia is a precursor to malignant transformation, but it DOES NOT
o Parenchyma: composed of neoplastic cells ALWAYS progress to invasive cancer.
o Stroma: connective tissue, blood vessels and infiltrating o Example: Cervical LSIL (most of them regress)
inflammatory cells • Dysplastic epithelium, when resected in its entirety, is curative.
Dr. Elomina
§ Desmoplasia: formation of abundant collagenous stroma
LOCAL INVASION
(desmoplastic tumors are stony hard or scirrhous – such as
tumors of the female breast • Progressive infiltration, invasion, and destruction of the
surrounding tissue
TUMOR-LIKE CONDITIONS • Second most reliable feature that differentiates malignant from
CHORISTOMA benign tumors
HAMARTOMA
(ECTOPIA) Benign tumors are usually encapsulated or well-circumscribed, they have
• Cytologically and a good plane of separation from the surrounding normal tissue.
Appearance • Benign but Malignant tumors are usually infiltrative with irregular borders. I say
architecturally
of tissue disorganized usually for both cases, because there are some exceptions.
normal Dr. Elomina
Location of METASTASES
• Indigenous • Ectopic
tissue • Spread of a tumor to sites that are physically discontinuous with
• Ectopic gastric tissue the primary tumor
• Peutz-Jeghers
Examples in Meckel Unequivocal marker of malignancy
polyp
diverticulum
Direct seeding of • Pseudomyxoma peritonei from
HOME-martoma (Hamartoma) – the tissue is disorganized but is found body cavities mucinous appendiceal/ovarian CA
at home (indigenous).
Dr. Rubio
Lymphatic spread • Primary route for CARCINOMAS
• Primary route for SARCOMAS
NOMENCLATURE • Mostly involves the veins due to its
thinner walls
• -oma: usually connotes a benign tumor, EXCEPT: seminoma, Hematogenous
• Four Carcinomas Route
lymphoma, melanoma, hepatoma, mesothelioma, immature spread
Hematogenously: follicular thyroid
teratoma, high-grade meningioma
CA, choriocarcinoma, renal cell CA,
• Carcinoma: malignant neoplasm of EPITHELIAL origin
hepatocellular CA
Sentinel lymph node is the 1st node in a regional lymphatic basin that • Two important tumor suppressor genes
receives lymph flow from the primary tumor. Hence, this technique is • Governor of the Cell Cycle – chromosome 13
performed in management of breast CA, colon CA, and melanoma. RB • Mutations are associated with Retinoblastoma &
Dr. Rubio
Osteosarcoma
CHARACTERISTICS OF • Guardian of the Genome – chromosome 17
BENIGN AND MALIGNANT • Most frequently mutated gene in human cancers
p53
TUMORS • Li-Fraumeni syndrome – inherited mutations of p53
increases risk for developing a broad variety of tumors
https://qrs.ly/becmdf7
COMMONLY MUTATED TSGS AND ASSOCIATED CANCERS
CANCER EPIDEMIOLOGY TSG REPRESENTATIVE EXAMPLES
(Robbins 10th Edition) RB • Retinoblastoma, osteosarcoma
• Incidence: p53 • Many cancers, Li-Fraumeni syndrome
o Males: Prostate (most common) > Lung > Colorectal • Gatekeeper of Colonic Neoplasia
o Females: Breast (most common) > Lung > Colorectal = Uterus APC • Colorectal CA, Familial adenomatous polyposis
• Mortality: (FAP)
o Males: Lung (most common) > Prostate > Colorectal PTEN • Endometrial CA, Prostate CA, Breast CA
o Females: Lung (most common) > Breast > Colorectal = NF1 • Neurofibromatosis 1
Pancreas NF2 • Neurofibromatosis 2
WT1 • Wilms tumor
CANCER HALLMARKS PTCH1 • Gorlin syndrome
• Self-sufficiency in growth signals VHL • Von Hippel-Lindau disease
• Insensitivity to growth-inhibitory signals MEN1 • MEN1
• Altered cell metabolism (Warburg effect or aerobic glycolysis) BRCA1/2 • Breast CA, Ovarian CA, Pancreatic CA
• Evasion of apoptosis CDKN2A • Melanoma, Pancreatic CA
• Limitless replicative potential (immortality) TSC1/2 • Tuberous sclerosis
• Sustained angiogenesis & First Aid for the USMLE Step 1 2020
• Ability to invade and metastasize
• Ability to evade the host immune response CARCINOGENIC AGENTS
• Inflammatory disorders
SELF-SUFFICIENCY IN GROWTH SIGNALS • Occupational cancers
• Proto-oncogenes: normal cellular genes whose products
promote cell proliferation CHRONIC INFLAMMATORY STATES
• Oncogenes: mutated or overexpressed versions of proto- ASSOCIATED ETIOLOGIC
oncogenes that function autonomously, having lost dependence CONDITION
CANCER AGENT
on normal growth promoting signals Asbestosis, • Mesothelioma • Asbestos fibers,
• RAS: most common type of abnormality involving proto- Silicosis • Lung carcinoma silica particles
oncogenes in human tumors Inflammatory • Colorectal
-
bowel disease carcinoma
COMMONLY MUTATED PROTO-ONCOGENES Lichen • Vulvar squamous
AND ASSOCIATED CANCERS -
sclerosus cell carcinoma
PROTO-
REPRESENTATIVE EXAMPLES • Alcoholism,
ONCOGENE • Pancreatic
Pancreatitis trypsinogen
ALK • Lung adenocarcinoma carcinoma
gene mutations
• Melanoma, Non-Hodgkin lymphoma,
BRAF • Bile acids,
Papillary thyroid CA, Hairy cell leukemia
• Chronic myeloid leukemia (CML), Acute
Chronic bacteria,
BCR-ABL1 • Gallbladder cancer
lymphoblastic leukemia (ALL) cholecystitis gallbladder
BCL-2 • Follicular lymphoma stones
c-KIT • Gastrointestinal stromal tumor (GIST) Reflux
C-MYC • Burkitt lymphoma esophagitis, • Esophageal
• Gastric acid
HER2/neu • Breast CA, Gastric CA
Barrett carcinoma
esophagus
JAK2 • Chronic myeloproliferative disorders
Sjögren
KRAS • Pancreatic CA, Colon CA, Lung CA
syndrome,
MYCL1 • Lung CA • MALT lymphoma -
Hashimoto
N-MYC • Neuroblastoma
thyroiditis
• MEN2A, MEN2B, Papillary thyroid CA,
RET • Opisthorchis
Medullary thyroid CA, Pheochromocytoma Cholangitis • Cholangiocarcinoma
Adapted from Table 7.5. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 viverrini
& First Aid for the USMLE Step 1 2020
• Gastric
ONCOGENES CREATED BY TRANSLOCATIONS Gastritis/ • Helicobacter
adenocarcinoma
TRANSLOCATION ASSOCIATED MALIGNANCY ulcers pylori
• MALT lymphoma
t(9;22) • Chronic myeloid leukemia (CML) • Hepatocellular
t(8;21) • Acute myeloid leukemia (AML) Hepatitis • HCV > HBV
carcinoma
t(15;17) • Acute promyelocytic leukemia • Carcinoma in • Bacterial
t(8;14) • Burkitt lymphoma Osteomyelitis
draining sinuses infection
t(11;14) • Mantle cell lymphoma Chronic • Squamous cell • HPV 16, 18, 31,
t(14;18) • Follicular lymphoma cervicitis carcinoma (SCCA) 33
t(11;22) • Ewing sarcoma • Schistosoma
t(7;21); t(17;21) • Prostatic adenocarcinoma Chronic cystitis • Bladder SCCA
haematobium
INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS

• Tumor-suppressor genes (TSGs)
o Apply brakes to cell proliferation, and abnormalities in these
genes lead to failure of growth inhibition, another fundamental
hallmark of carcinogenesis
OCCUPATIONAL CANCERS
AGENTS ASSOCIATED CANCERS CANCER CACHEXIA
Arsenic • Lung, Skin • Hypercatabolic state defined by loss of muscle mass (w/ or
Asbestos • Lung, Esophagus, Stomach, Colon w/o loss of fat) that cannot be explained by decrease in food
• Mesothelioma intake)
Benzene • Acute myeloid leukemia (AML) • Cause: Cytokine effects (mainly TNF) on muscles and fat
Beryllium • Lung o TNF, IL-1, and IL-6: loss of skeletal muscle
Cadmium • Prostate o Lipid mobilizing factor: loss of fat
Chromium • Lung
Nickel • Lung, Oropharynx PARANEOPLASTIC SYNDROMES
Radon • Lung • Signs and symptoms not referable to the anatomic distribution
Vinyl chloride • Hepatic angiosarcoma of the tumor
• May involve ectopic hormone production by tumor cells
• Importance:
CLINICAL ASPECTS OF NEOPLASIA o Initial manifestation of occult neoplasm
• Cancer cachexia • Tumor lysis syndrome o May cause significant clinical problem
• Paraneoplastic syndromes • Immunohistochemistry o May mimic metastatic disease
• Tumor grading and staging
PARANEOPLASTIC SYNDROMES
SYNDROME CANCERS MECHANISM
Endocrinopathies
• Small cell lung cancer
Cushing syndrome • Pancreatic carcinoma • ACTH or ACTH-like substances
• Neural tumors
• Small cell lung cancer • Antidiuretic hormone (ADH) or atrial
SIADH
• Intracranial neoplasms natriuretic peptide (ANP)
• Squamous cell carcinomas
Hypercalcemia • Breast carcinomas • PTH-related protein (PTHRP), TGF-α,
(Most common paraneoplastic syndrome) • Renal cell carcinomas TNF, IL-1
• Adult T-cell leukemia/lymphoma
• Ovarian carcinoma
Hypoglycemia • Fibrosarcoma • Insulin or insulin-like substance
• Other mesenchymal sarcomas
• Renal cell carcinoma
Polycythemia • Cerebellar hemangioma • Erythropoietin
• Hepatocellular carcinoma
Osteomalacia • Phosphaturic mesenchymal tumor • FGF-23
Nerve and Muscle Syndromes
• Bronchogenic carcinoma
Myasthenia • Immunologic
• Thymic carcinoma
Disorders of the CNS/PNS • Breast carcinoma ----
Dermatologic Disorders
• Gastric carcinomas
• Immunologic; secretion of epidermal
Acanthosis nigricans • Lung carcinomas
growth factor (EGF)
• Uterine carcinomas
Dermatomyositis • Immunologic
• Lung carcinoma
Osseous, Articular, and Soft Tissue Changes
Hypertrophic osteoarthropathy and clubbing of • Bronchogenic carcinoma
• Unknown
fingers • Thymic neoplasms
Vascular, and Hematologic Changes
• Pancreatic carcinoma
Venous thrombosis • Tumor products (mucins that activate
(Trousseau syndrome) clotting)
• Other cancers
• Acute promyelocytic leukemia
Disseminated intravascular coagulation (DIC) • Tumor products that activate clotting
• Prostatic carcinoma
Non-bacterial thrombotic endocarditis • Advanced cancers • Hypercoagulability
Red cell aplasia • Thymic neoplasms • Unknown
OTHERS
Nephrotic syndrome • Various cancers • Tumor antigens, immune complexes
Table 7.11. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
TUMOR GRADING AND STAGING

GRADE STAGE TUMOR GRADE AND STAGE
• Degree of • Size of the primary https://qrs.ly/8scmdgl
differentiation lesion, its extent of
(well- spread to regional
Basis differentiated = lymph nodes, &
low-grade; poorly presence/absence of TUMOR LYSIS SYNDROME
differentiated = metastases • Aggressive chemotherapy leads to lysis of tumor cells with
high-grade) release of their contents
• Gleason scoring for • Abnormalities: hyperkalemia, hyperphosphatemia,
• TNM staging for most
Examples Prostatic hyperuricemia, hypocalcemia
tumors
adenocarcinoma • Clinical consequence: Acute kidney injury (urate nephropathy)
Clinical • Of less clinical • More reflective of Tip: In tumor lysis syndrome, all parameters are elevated EXCEPT
value value than stage biologic behavior calcium = hypocalcemia.
Dr. Rubio
IMMUNOHISTOCHEMISTRY o Determination of origin of metastatic tumors

§ In a post-thyroidectomy patient for poorly differentiated
• Technique that detects cellular products or surface markers in a
thyroid carcinoma with a metastatic carcinoma in the
tissue sample.
supraclavicular lymph node
• Principle: Different cells in the body express different set of
o Detection of molecules that have prognostic or
surface markers and cellular products that make them distinct
therapeutic significance
• Applications:
§ ER, PR, HER2 IHC for breast cancers
o Categorization of undifferentiated malignant tumors
§ Undifferentiated: Histomorphology alone cannot provide a
clue regarding the line of differentiation of a tumor
7. INFECTIOUS DISEASES
For infectious diseases, the most important table is the first one. The rest of the
tables are just enumeration of the associated findings. In your exams, they may
• General pattern of responses
either mention buzz words that will help you diagnose a case or give a classic
to infections case where you have to choose the associated histologic findings. So, you have
• Viral diseases to know two things: The clinical presentation and the key histologic
• Bacterial diseases findings associated with the disease. The buzz words are in bold italic for
• Fungal diseases PATTERN OF RESPONSE TO emphasis. You’re welcome. J
• Parasitic diseases INFECTIONS I highly recommend that you try to integrate this with your Microbiology
to cover for the clinical presentation and pertinent pathogen biology.
https://qrs.ly/zicmdh2 Dr. Elomina
SPECTRUM OF INFLAMMATORY RESPONSES TO INFECTION

RESPONSE PATHOGENESIS EXAMPLES
Suppurative (Purulent) • ↑ Vascular permeability • Pneumonia (S. aureus)
infection • PMN infiltrates → pus formation • Abscesses: Staphylococci, anaerobic bacteria
• Mononuclear cell infiltrates (monocytes, macrophages, plasma cells,
Mononuclear and
lymphocytes) • Syphilis
Granulomatous
• Cell-mediated immune response to pathogens (“persistent pathogens”)
inflammation
• Formation of granulomata • Tuberculosis
Cytopathic- • Viral transformation of cells • Cervical cancer (HPV)
cytoproliferative • Necrosis or proliferation (including multinucleation) • Chicken pox, Shingles (VZV)
reactions • Linked to neoplasia • Herpes (HSV)
• Toxin or lysis-mediated destruction
• Gangrene (Clostridium perfringens)
Tissue necrosis • Lack of inflammatory cells
• Hepatitis (HBV)
• Rapidly progressive processes
Chronic inflammation / • Repetitive injury → fibrosis
• Chronic hepatitis with cirrhosis (HBV, HCV)
scarring • Loss of normal parenchyma
• Mycobacterium avium in untreated AIDS
No reaction • Severe immune compromise • Mucormycosis in bone marrow transplant
patients (neutropenia)
VIRAL DISEASES
VIRUS MORPHOLOGY
RNA VIRUSES
• Rash: Dilated skin vessels, edema, mononuclear perivascular infiltrate
• Koplik spots (Pathognomonic): Necrosis, PMNs, and neovascularization (opening of Stensen duct – near 2nd upper molar)
Measles • Lymphoid organs: Marked follicular hyperplasia, large germinal centers, (+) Warthin-Finkeldey cells
• Warthin-Finkeldey cells (Pathognomonic): Multinucleated giant cells with eosinophilic nuclear and cytoplasmic inclusions (also
in lung and sputum)
• Parotitis (bilateral in 70%): Interstitial edema and mononuclear cell infiltration
• Orchitis: Edema, mononuclear cell infiltration, hemorrhage; compression of swollen testis against tunica albuginea →
Mumps
infarction → scarring, atrophy, sterility (if severe)
• Pancreatitis, Encephalitis: perivenous demyelination and perivascular mononuclear cuffing
Dengue • Widespread hemorrhage, hepatic necrosis and mononuclear infiltrates, alveolar septal thickening, ARDS
SARS-Cov-2 • Lung: Diffuse alveolar damage, mononuclear cell infiltration
DNA VIRUSES
Herpes Simplex • Pink to purple intranuclear inclusion bodies (Cowdry Type A)
(HSV) • Multinucleated syncytia with inclusions
• Intraepithelial vesicles (“dewdrops on a rose petal”)
Varicella Zoster
• Intranuclear inclusions in cells at vesicle base
(VZV)
• Shingles: Mononuclear infiltrates and cells with herpetic intranuclear inclusion bodies in neurons and supporting cells of sensory ganglia
Cytomegalovirus • Large, atypical cells with prominent intranuclear basophilic inclusions, surrounded by a clear halo “Owl’s eye inclusion” + small
(CMV) basophilic perinuclear cytoplasmic inclusions
Epstein-Barr Virus • Peripheral blood: Absolute lymphocytosis with atypical lymphocytes (CD8+)
(EBV) • Lymphoid tissues: Paracortical hyperplasia (T cell), expansion of white pulp follicles in spleen
Notice that the common theme for these infections is the viral cytopathic effect i.e., inclusions and cytoproliferative effect i.e. multinucleation and proliferation
of cells. In terms of inflammation, these infections can have little to intense inflammation (either neutrophilic or mononuclear).
Dr. Elomina
BACTERIAL DISEASES
BACTERIA MORPHOLOGY
GRAM-POSITIVE
Staphylococci • Pyogenic inflammation with local destruction of host tissue
Streptococci • Diffuse interstitial neutrophilic infiltrates with minimal destruction of host tissue
• Pseudomembrane: coagulated fibrinosuppurative exudate
Corynebacterium
• Intense PMN infiltrate, marked vascular congestion, interstitial edema, and fibrin exudation in the underlying
diphtheriae
tissue
• Exudative inflammation with numerous neutrophils
Listeria monocytogenes • Meningitis: G(+) bacilli in CSF: in Listeria meningitis
• Neonatal sepsis: Listerial abscesses in placenta and G(+) bacilli in meconium
• Necrosis and exudative inflammation rich in neutrophils and macrophages
Bacillus anthracis
• Hemorrhagic lesions due to vasculitis
GRAM-NEGATIVE
• Laryngotracheobronchitis: bronchial mucosal erosion, hyperemia, and copious mucopurulent exudate
Bordetella (severe)
• Peripheral lymphocytosis with hypercellularity and enlargement of mucosal and peribronchial lymph nodes
• Fleur-de-lis pattern of necrotizing pneumonia (pale necrotic centers with red, hemorrhagic periphery)
Pseudomonas • Coagulative necrosis due to vasculitis (perivascular infiltration of pseudomonads: “perivascular blue haze”)
• Ecthyma gangrenosum: Well-demarcated necrotic and hemorrhagic oval skin lesions
• Bubonic plague: Lymph node enlargement → infarction or rupture through skin
Yersinia pestis • Pneumonic plague: Severe, confluent, hemorrhagic, necrotizing bronchopneumonia with fibrinous pleuritis
• Septicemic plague: Necrosis in nodes and organs rich in mononuclear phagocyte, fulminant bacteremia, DIC
Notice that the common theme for these infections is the suppurative inflammation. Some of these affect vessels and can cause necrosis or hemorrhagic lesions
(B. anthracis, Pseudomonas, Y. pestis) Moreover, please take note that peripheral lymphocytosis is present in Bordetella infections despite it being bacterial.
Dr. Elomina & Dr. Rubio
OTHER GRAM-NEGATIVE SEXUALLY TRANSMITTED INFECTIONS (STIS)

Haemophilus ducreyi Klebsiella granulomatis
STI • Chancroid • Granuloma inguinale, Donovanosis
Genital • Tender, with shaggy, non-indurated borders with yellow-gray • Non-tender, beefy red ulcer with indurated borders,
involvement exudate at base stricture-forming
Lymph node
• Prominent: buboes → erosion → sinuses • Not prominent
involvement
• Layers (superficial → deep) • Marked epithelial hyperplasia at the ulcer borders
Histologic o Neutrophilic debris and fibrin (pseudoepitheliomatous hyperplasia)
features o Granulation tissue with necrosis and thrombosed vessels • G(-) coccobacilli in macrophages (Donovan bodies)
o Mononuclear infiltrate w/ G(-) coccobacilli (Gram or Silver stains) (Giemsa and Warthin-Starry stain)
MYCOBACTERIUM TUBERCULOSIS Answer: It depends on the immune status of the patient because intact
cell-mediated immunity is needed for granulomas to form.
• Tuberculosis • Immunocompetent: (+) Granulomas
• If cell-mediated immunity (CMI) of patient is intact: chronic, • Severe immunocompromised: ↓ to (-) Granulomas
granulomatous inflammation Dr. Elomina
• Produced by APCs, induces TH1 differentiation (occurs NATURAL HISTORY OF TUBERCULOSIS

IL-12
2-4 weeks post-infection)
• Produced by TH1 cells to activate macrophages →
IFN- γ
epithelioid cells and giant cells
• If depressed CMI: paucity of granulomas; macrophages filled
with AFB
o Depressed CMI (i.e. HIV, all stages) increases risk of TB
Recall your cytokines in Chapter 2. IL-12 and IFN-γ are the principal
cytokines involved in granulomatous inflammation. Recall your Chapter
5. TB is a Type IV (Cell-mediated) HSR, CD4+-mediated (TH1 response).
Dr. Elomina
TUBERCULOUS GRANULOMA
https://qrs.ly/u2cmd99
repeated for emphasis
Question: Are granulomas always present in tuberculosis?

Figure 8.24 Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
CLINICOPATHOLOGIC FORMS OF TUBERCULOSIS
FORM LESIONS SEQUELAE
• Ghon focus (consolidation): subpleural, (lower part of upper • Healing by fibrosis (generally happens in immune-
lobe or upper part of lower lobe) competent individuals, and with anti-TB therapy)
Primary • Ghon complex: GF + pulmonary hilar node involvement • Latency → reactivation (with immune
• Ranke complex: Healed, calcified, later manifestation of Ghon compromise) → Secondary TB
complex • Progressive primary TB
Progressive • Resembles acute bacterial pneumonia
• Miliary pulmonary TB
Primary • Lobar consolidation, Hilar adenopathy, Pleural effusion
• Healing by fibrosis
Secondary • Simon focus (consolidation): apical pleura • Localized caseating destructive lesions
• Progressive secondary TB
• Spread into adjacent lung → erosion into bronchi or vessels
Progressive
(hemoptysis) → cavitation (more contagious/infective) • Healing by fibrosis
Secondary
• Pleural involvement: effusions, empyema, obliterative fibrous • Miliary pulmonary TB
(Pulmonary)*
pleuritis
Miliary pulmonary • Scattered small foci of consolidation throughout the lungs • Systemic Miliary TB
• Your secondary TB can either be because of reactivation of latent lesions with immune compromise (more common in low-prevalence areas), or it can be
because of reinfection in the setting of immune compromise (more common in high-prevalence areas). Secondary TB can also follow primary TB shortly.
• Notice that your progressives have two things in common: pleural involvement, miliary pulmonary disease (due to lymphohematogenous dissemination)
* It is called Progressive Pulmonary TB, according to Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 (p. 373), BUT based on my understanding, I
designated this as progressive secondary (pulmonary) TB, because it is clinically different from the clinical picture of progressive primary TB (p. 369-370).
Dr. Elomina
EXTRAPULMONARY TUBERCULOSIS • Gastrointestinal tract

• Kidneys, Adrenals o Most common segment affected: ileum
• Bones: Osteomyelitis (Pott disease: vertebrae) o Rare; due to ↓ consumption of unpasteurized milk
• CNS: Meningitis (M. bovis)
• Lymph nodes: Scrofula Ileum is most commonly affected due to high amounts of Peyer patches in
o Most common form of extrapulmonary TB the lamina propria of the ileum.
Dr. Rubio
MYCOBACTERIUM AVIUM INTRACELLULARE (MAC) COMPLEX TUBERCULOID LEPROMATOUS
• Disseminated disease in patients with profound Immune
• TH1 > TH2 • TH2 > TH1
immunodeficiency (AIDS and transplant patients) response
• Histologically, macrophages filled with acid-fast bacilli; rare • (+) not protective;
granulomas, lymphocytes, and tissue destruction causes erythema
Antibodies • (-)
nodosum, and GN
Remember: Intact cell-mediated immunity (CMI) is necessary for (Type III HSR)
granuloma formation.
Dr. Rubio
Peripheral
MYCOBACTERIUM LEPRAE nerve • Asymmetric • Symmetric
involvement
• Causes Leprosy (Hansen disease)
• Lipid-laden
• Affects skin and peripheral nerves • Granuloma macrophages
• Three forms; manifestations dictated by host cell-mediated Morphology
formation (Lepra cells) with
immunity (CMI): tuberculoid (paucibacillary), lepromatous globi (AFB)
(multibacillary), borderline (indeterminate) • Rare
AFB • Many (multibacillary)
(paucibacillary)
CLINICAL FORMS OF LEPROSY Treponema pallidum
TUBERCULOID LEPROMATOUS
• Syphilis
CMI • Intact • Depressed
o Four stages (Primary, Secondary, Latent, and Tertiary)
Lepromin skin
• Positive • Negative o Congenital form
test
• Characteristic plasma cell-predominant inflammatory infiltrate
STAGES OF SYPHILIS
STAGE LESIONS MORPHOLOGY
• Plasma cell-rich infiltrate, macrophages, lymphocytes
• Chancre: Painless lesion in penis (males), vulva, and
• Proliferative endarteritis → intimal fibrosis
Primary cervix (females) → erosion → ulcer with indurated borders
• Lymph nodes: non-specific acute or chronic lymphadenitis, plasma cell-rich
(hard chancre)
infiltrates, or granulomas
• Mucocutaneous lesions (oral cavity, palms, and soles)
Secondary • Condylomata lata – warty lesions in perianal and vulvar • Same as chancre, but with less inflammation
area and oral cavity
• Aortitis: obliterative endarteritis of vasa vasorum of proximal aorta →
• Aortitis
medial scarring → loss of elasticity
Tertiary • Neurosyphilis (in CNS module)
• Gumma: central coagulation necrosis with palisading macrophages and
• Gumma (Skin, subcutaneous tissue, bone, joints, liver)
fibroblasts, plasma cell-rich infiltrate, scant treponemes
CONGENITAL SYPHILIS • False-negative result: Prozone phenomenon
ORGAN MORPHOLOGY § Too many antibodies prevent antibody-antigen complex
• Osteochondritis and periostitis formation → no visible flocculation → read as negative
Bones • Tibia: Saber shins (excessive new bone growth) § Can also happen in other assays (pregnancy test)
• Nose: Saddle nose (destruction of vomer)
Liver • Fibrosis (hepar lobatum), mononuclear infiltrates,
ANAEROBIC INFECTIONS
• Diffuse interstitial fibrosis • Abscess formation: morphologically similar with that of
Lung • Pale, airless lung (pneumonia alba) in stillborn pyogenic organisms (usually polymicrobial)
infants • Clostridial infections: causes disease via exotoxins
Triad of late manifestations: (1) Interstitial keratitis, ORGANISM AND CLINICAL
MORPHOLOGY
Others (2) Hutchinson teeth (screwdriver or peg-shaped), (3) TOXIN DISEASE
Eight nerve deafness • Clostridial • Tissue necrosis >
C. perfringens cellulitis inflammation
SEROLOGIC DIAGNOSIS OF SYPHILIS α-toxin (lecithinase, • Gas bubbles
NON-TREPONEMAL TREPONEMAL sphingomyelinase) • Gas gangrene Severe
• Screening myonecrosis
Clinical
• Monitoring response • Confirmation C. difficile • Pseudo- • Volcano-like
use Toxin A: chemokine membranous mucopurulent
to therapy
• Fluorescent Treponemal Toxin B: cytotoxin colitis exudate
• Rapid Plasma Reagin
antibody absorption CHLAMYDIA TRACHOMATIS
(RPR)
(FTA-ABS) • Genital infection: Most common bacterial STI in the world
Tests • Venereal Disease
• Microhemagglutination
Research Laboratory o Urethritis:
assay for Abs of T.
(VDRL) § Purulent like gonorrhea, but NO ORGANISMS SEEN IN GRAM
pallidum (MHA-TP)
STAIN
• Anti-cardiolipin • Anti T. pallidum
Detects § Urethritis in males is usually asymptomatic (vs Neisseria)
antibodies antibodies (specific)
o L1-L3 strains: Lymphogranuloma venereum (LGV)
LIMITATIONS OF SEROLOGIC DIAGNOSTICS FOR SYPHILIS § Chlamydial inclusions in infected cells
• False-positive result § Lymph nodes: granulomatous inflammation with irregular
o Pregnancy, autoimmune diseases, infections other than foci of necrosis containing PMNs (stellate abscesses)
syphilis (Non-treponemal tests are NOT specific) § Chronic: nonspecific chronic inflammation and fibrosis →
local lymphatic obstruction, lymphedema, strictures
FUNGAL DISEASES
YEAST Candida albicans Cryptococcus neoformans Pneumocystis jirovecii
• Most prevalent fungal pathogen of • Important cause of CNS infections in • Important cause of pneumonia in AIDS
Significance
humans immunocompromised patients patients
• Yeast with thick, gelatinous capsule
• Yeast, pseudohyphae at 20oC, germ • Cysts: Cup-shaped or oval with central
Forms containing PAS and mucicarmine (+)
tubes at 37oC dot, Gomori Methenamine Silver (+)
polysaccharide
• Superficial infection on mucosal • Lung (primary site of infection)
Involvement surfaces (Oral thrush, esophagitis) • CNS: Meninges, cortical gray matter, • Rapidly progressive bilateral pneumonia
• Invasive: Heart, CNS, Eye, Liver basal nuclei
• Thrush: matted organisms and • Immunocompromised: Soap bubble
inflammatory debris lesions (in meninges or perivascular • Alveolar interstitial thickening
Morphology • Invasive: Little inflammation, Virchow-Robin spaces) • Eosinophilic honeycomb exudate in the
suppurative, or granulomatous • Immunocompetent: Granulomas, lumen of the lung
(depending on immune status) Suppuration
MOLDS Aspergillus Mucor
Significance • Aflatoxin: ↑ Risk of Liver Cancer (Aspergillus flavus) • Does NOT cause disease in immunocompetent patients
• Allergic bronchopulmonary aspergillosis • Nasal sinuses, lungs: if spores are inhaled
• Colonizing aspergillosis: Respiratory tract (in patients with • Gastrointestinal tract: if spores are ingested
Involvement
cavitation) • Rhinocerebral mucormycosis: from nasal sinuses → orbit
• Invasive aspergillosis: Lung, other tissues (heart valves, brain) and brain (most common in DM patients)
• Mold: Fruiting bodies, SEPTATE filaments, branching at ACUTE
angles (45°)
• Mold: NON-SEPTATE (COENOCYTIC) filaments, branching
• Colonizing: Aspergilloma (fungus ball) with sparse inflammation or
at RIGHT angles (90o)
chronic inflammation and fibrosis; MINIMAL or NO INVASION
Morphology • Rhinocerebral: Angioinvasion, necrosis of periorbital tissues
• Invasive:
and cranial vault → Meningoencephalitis with cerebral
o Hemorrhagic infarction: Angioinvasion
infarction
o Lung: Necrotizing pneumonia with sharply delineated, foci and
hemorrhagic borders (Target lesions)
PARASITIC DISEASES TRYPANOSOMIASIS

DISEASE – AGENT MORPHOLOGIC FEATURES
PROTOZOANS • Involvement of the heart, esophagus,
MALARIA colon
American
• Etiologic agent: Plasmodium sp. • Dilated cardiomyopathy (↑ risk for
trypanosomiasis /
AGENT FEATURES arrhythmia) – myocardial necrosis,
Chagas disease–
• Most virulent malarial parasite (and most interstitial inflammation
Trypanosoma cruzi
common malarial parasite in the Philippines) • Megaesophagus, megacolon –
• Can cause high-level parasitemia, Blackwater destruction of Auerbach plexus
fever (acute renal failure) and cerebral • East African form: Trypanosoma brucei
P. falciparum malaria (Dürck granulomas) rhodesiense
• Represents= vascular stasis and small African • West African form: Trypanosoma brucei
focal inflammatory reactions in cerebral trypanosomiasis / gambiense
vessels African sleeping • Has hemolymphatic form: parasites in
• Infects ALL STAGES OF RBCs sickness capillary loops (glomeruli, choroid
• Infects YOUNG RBCs Trypanosoma plexus, splenomegaly, lymphadenopathy)
P. vivax, • Less virulent infection, no cerebral malaria brucei complex • Has neurologic form: demyelinating
P. ovale • (+) hypnozoites: form seen in the liver panencephalitis, (+) Mott cells – plasma
(responsible for RELAPSE when reactivated) cells with Ig cytoplasmic globules
• Infects OLD RBCs • T. brucei: Small kinetoplast
P. malariae
• Less virulent infection, no cerebral malaria • T. cruzi: Large kinetoplast (kasing laki ni CRUZI-ship ang kinetoplast)
Dr. Elomina
Only Vata (P ovale, P vivax) causes infection of young RBCs. TOXOPLASMOSIS
Matanda (P malariae) causes infection of old RBCs.
Dr. Rubio • Ubiquitous but only causes disease in immunocompromised
• Diagnosis: Giemsa-stained thick and thin blood smears (HIV patients) and pregnant women and their offspring (part
• In tissues: Hemozoin-pigmented laden phagocytic cells → gray of TORCH)
or blackish discoloration of involved organs • Morphology:
• Slow-moving trophozoites found inside
Bradyzoites
cysts in visceral organs
ALGORITHM FOR MALARIA
• Fast-moving trophozoites that may be
IDENTIFICATION Tachyzoites
observed in stained fluid specimens
https://qrs.ly/eecmdiu • Intracranial (cerebral) calcifications,
Congenital
neurocognition problems, hydrocephalus,
PLASMODIUM AND BABESIA toxoplasmosis
chorioretinitis
Plasmodium falciparum Babesia spp.
Diagnostic clue! Cerebral calcifications = congenital toxoplasmosis.
• Ring Periventricular calcifications = congenital CMV infection .
Stages in blood • Gametocyte (banana- • Ring Dr. Rubio
shaped)
Trophozoite • Pleomorphic NEMATODES
• Uniform
appearance • Maltese cross STRONGYLOIDES STERCORALIS
Hemozoin
• Yes • No • Larvae penetrate skin → lungs → GIT
pigment
• Autoinfection: filariform (parasitic) larvae hatched in GIT
RBC inclusion • Maurer’s clefts • None
invade colonic mucosa → lungs
One close mimic of P. falciparum is Babesia spp. For a quick mnemonic – • Hyperinfection (increased worm burden): may result in the
Ferdinand Marcos (P falciparum = Maurer’s). immunocompromised host
Dr. Rubio
LEISHMANIASIS
TYPE MORPHOLOGY
TRICHINELLA SPIRALIS
• General: Enlarged macrophages filled with • Invasive phase: larvae has a widespread penetration across
amastigote different tissues
Visceral
• Skin: Hyperpigmentation (South Asian ancestry; • Patchy interstitial myocarditis w/ eosinophils,
kala-azar) Heart
giant cells
• Kidney: Immune complex-mediated mesangio- • Focal edema, hemorrhage, eosinophilic
proliferative glomerulonephritis; amyloidosis Lung
infiltrates
• Papule surrounded by induration
Cutaneous • Granulomatous with many giant cells and few CNS • Diffuse lymphocytic and eosinophilic infiltrates
parasites • Formation of cysts in striated muscles with
• Moist, ulcerating, or non-ulcerating lesions in richest blood supply: diaphragm, EOMs,
Muco- nasopharyngeal areas laryngeal, deltoid, gastrocnemius, intercostal
cutaneous
Skeletal
• Lymphoplasmacytic infiltrate + macrophages filled muscles
with parasites → granulomatous (few parasites) muscles
• Nurse cell – skeletal muscle losing striations,
Diffuse • Single skin nodule → spreads all over the body and forming a capsule to nurture the growing
cutaneous • Foamy macrophages filled with parasites larva
Kinetoplasts – are large mitochondria with large amounts of Whenever you see the term eosinophilia, always think of parasites!
mitochondrial genes (important for the locomotion) Dr. Rubio
Dr. Rubio
LYMPHATIC FILARIASIS ENVIRONMENTAL PATHOLOGY
• Brugia malayi, Wuchereria bancrofti
ORGAN MORPHOLOGY
AIR POLLUTION
• Persistent lymphedema (extremities, scrotum, • Most common organ system affected: lungs (especially those
penis, vulva) with chronic lung diseases); can affect multiple organ systems
• Hydroceles (testis) → thickening and calcification OZONE (O3)
Lymphatic
of tunica vaginalis • Injury to Type I pneumocytes via free-radical formation
• Elephantiasis: dilated dermal lymphatics,
• Causes decreased lung function, inflammation, airway reactivity
subcutaneous fibrosis, epithelial hyperkeratosis
and increased hospitalizations (in obstructive lung diseases)
• Eosinophilia (tropical pulmonary eosinophilia)
• Usually in combination with SO2 and others (Witch’s brew)
Lung • Meyers-Kouwenaar bodies: dead microfilariae
surrounded by eosinophilic precipitates SOOT (PARTICULATE MATTER)
• Engulfment of soot by alveolar macrophages → inflammatory
ONCHOCERCIASIS (Onchocerca volvulus) response
• Leading cause of preventable blindness in sub-Saharan Africa o Common pathogenesis of Pneumoconiosis (see Lungs)
ORGAN MORPHOLOGY • Fine or ultrafine particles (<10 µm): most harmful form
• Onchocercoma: subcutaneous nodule containing CARBON MONOXIDE (CO)
mating, adult worms, surrounded by mixed infiltrates
• Systemic asphyxiant; cause of accidental and suicidal death
Skin • Leopard, lizard, or elephant skin: alternating areas of
• Non-irritating colorless and odorless gas, also present in
hyperkeratosis & hyperpigmentation, with dermal
atrophy secondary to chronic, itchy dermatitis
cigarette smoke
• Punctate → Sclerosing keratitis • Causes injury by two major mechanisms:
• Mazzotti reaction: Accentuation of keratitis with anti- Decreased O2 • CO has 200x more affinity to Hemoglobin
Eye filarial treatment delivery (Hb) than O2 → hypoxemia → hypoxia
• Anterior chamber: Iridocyclitis and Glaucoma • CO inhibits Complex IV of Electron
• Choroid and retina: Atrophy and loss of vision ↓ ATP production transport chain (ETC) → ↓ ATP
Iridocyclitis – inflammation of the iris and ciliary bodies which can cause
production → cell death
blockade of the trabecular meshwork outflow of aqueous humor leading Recall: hypoxemia – low amount of oxygen in blood circulation; hypoxia
to glaucoma. – low amount of oxygen in peripheral tissues.
Dr. Rubio Dr. Rubio
TREMATODES ACUTE CHRONIC

• Cherry-red discoloration of • CNS: widespread hypoxic
SCHISTOSOMIASIS skin and membranes changes particularly in basal
• Schistosoma japonicum, mansoni, and haematobium • No morphologic changes in ganglia and lenticular nuclei
o GIT and liver: S. japonicum and S. mansoni patients who quickly expired!
o Bladder: S. haematobium • CNS: Slightly edematous brain
ORGAN MORPHOLOGY with punctate hemorrhages
• Granulomas (around eggs), Pipestem fibrosis (late) and hypoxic changes
Liver
→ portal hypertension
Lung • Pulmonary artery involvement → cor pulmonale INDOOR POLLUTANTS
• Mesangioproliferative or membranous CLINICAL
Kidney COMMON INDOOR POLLUTANTS
glomerulopathy (immune causes) OUTCOME
• Most common complication: ureteral inflammation Pulmonary • Wood smoke, bioaerosols (containing pathogenic
Bladder and fibrosis → obstructive uropathy infections organisms, e.g., Legionella, viruses)
• ↑ risk for squamous cell carcinoma (SCCA) • Bioaerosols (pet dander, dust mites, fungi, and
Allergies
molds)
CESTODES • Wood smoke (polycyclic hydrocarbons), Radon
Cancer
• Taeniasis: from ingestion of cysticercus → (in uranium miners), Formaldehyde
Taenia solium
intestinal infection
(pork tapeworm)
• Cysticercosis: from ingestion of egg HEAVY METALS
Taenia saginata LEAD
• Causes intestinal disease only
(beef tapeworm) • Mechanisms of lead toxicity in the body:
Diphyllobothrium Interference with Ca2+ • Deposition in bones, teeth
• Causes intestinal disease only
latum metabolism • Impairs fracture healing
• Leads to vitamin B12 deficiency →
(fish/broad Binding to sulfhydryl groups • Causes neurologic, GI, and
megaloblastic anemia
tapeworm) in proteins renal toxicities
• Causes hydatid disease in liver Inhibition of ALA • Leads to microcytic,
Echinococcus • Contains hydatid sand (degenerating dehydratase, ferrochelatase hypochromic anemia
granulosus scolices)
Recall the pathway of heme formation! ALA dehydratase and
• Can cause anaphylaxis, when ruptured
ferrochelatase are important steps in this pathway.
Dr. Rubio
8. ENVIRONMENTAL LEAD POISONING

ORGAN MORPHOLOGY
AND NUTRITIONAL PATHOLOGY • Ring sideroblasts (iron-laden mitochondria)
• Environmental Pathology • Nutritional diseases
(Prussian Blue stain)
o Air pollution o Severe acute malnutrition Hematologic
o Heavy metals (Marasmus and Kwashiorkor) • Microcytic, hypochromic anemia with
o Tobacco o Anorexia and Bulimia nervosa basophilic stippling of red cells
o Alcohol o Vitamin disorders • Children: CNS damage
o Thermal injuries o Obesity
o Electrical injury
CNS • Adults: peripheral demyelinating neuropathy
o Ionizing Radiation (usually presents with wrist drop, foot drop)
GIT • Lead colic (poorly localized abdominal pain)
FOREWORD
Some topics will be covered in other subjects, and therefore will not be • Proximal tubular damage
discussed here: Kidney • Chronic: interstitial fibrosis and CKD
Drug injury: Pharmacology • Impaired uric acid excretion → “Saturnine gout”
Mechanical trauma: Legal Medicine
The presence of ring sideroblasts indicates a problem in the incorporation
Integration with other subjects is highly encouraged (Biochemistry,
of iron into heme (ferrochelatase) (that’s why it’s stuck in the
Pharmacology, Physiology, Surgery, Medicine)
Dr. Elomina
mitochondria). The basophilic stippling is because of aggregates of
pyrimidine nucleotides (since lead inhibits the enzyme to degrade them).
Dr. Elomina
MERCURY Smoking is an established risk factor for lung, esophagus, pancreas,
• Mechanism of mercury toxicity in the body: bladder, kidney, cervix, bone marrow, liver, and colon. Add to that the
fact that accelerates atherosclerosis (It is one of the four coronary risk
Binding to sulfhydryl groups in • CNS damage
factors). So, if you want to enjoy a long life, do not smoke. If you do smoke,
proteins with high affinity • Kidney damage it’s not too late to quit.
• Forms of mercury and its common sources: Dr. Elomina
Metallic mercury • Elemental mercury

ALCOHOL
Inorganic mercury • Mercuric chloride
• Most commonly abused substance
Organic mercury • Methyl mercury (fish)
• Fish (shark, swordfish, bluefish)
Common sources of
• Dental amalgams
mercury
• Contaminated rivers near gold mines
• Clinical Presentation: Minamata disease
o Cerebral palsy, deafness, blindness, mental retardation, major
CNS defects (in utero exposure)
o Developing brain highly sensitive to methyl mercury
ARSENIC
• “Poison of kings”, “King of poisons”
Primary targets
• CNS, cardiovascular, skin, GI tract
in the body
Most toxic form • Trivalent compounds (arsenic trioxide)
• Alternating hyperpigmentation,
Skin
hyperkeratosis (in chronic exposure)
• Sensorimotor neuropathy → paresthesias,
CNS effects Figure 9.11. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
numbness, pain
• Hypertension, prolonged QT → • Most of the alcohol in the blood is metabolized by 3 enzyme
CVS effects
arrhythmias systems: (1) alcohol dehydrogenase, (2) cytochrome P-450
↑ risk for CA • Lung CA, bladder CA, skin CA system (microsomal ethanol-oxidizing system), (3) catalase
Arsenic-induced skin cancer affects the palms and soles (vs UV-induced • Alcohol dehydrogenase system – main enzyme involved in alcohol
skin cancer affects sun-exposed areas) metabolism
Dr. Rubio • Microsomal ethanol-oxidizing system (MEOS) – plays an
CADMIUM important role at high alcohol blood levels, CYP2E1 isoform
Mechanism • ROS production affecting kidneys, lungs • Catalase system – responsible for 5% contribution
Kidney damage • Renal tubular damage → ESRD • Acetaldehyde produced is then converted to acetate by
Lung damage • Increases risk for lung cancer acetaldehyde dehydrogenase (ALDH)
• Osteoporosis and Osteomalacia associated Remember that NADH decreases NAD, which is needed for fatty acid
Itai-itai disease
with renal disease seen in postmenopausal oxidation and conversion of lactate to pyruvate. At a blood level of 400
“ouch-ouch”
Japanese women working in rice fields mg/dL and above, alcohol will cause coma and respiratory arrest.
Dr. Rubio
TOBACCO
ACUTE EFFECTS OF ALCOHOL
• Smoking: most prevalent preventable cause of death in man
• Depression of the CNS due to insult to the reticular
• >7,000 compounds in cigarette smoke (nicotine: addictive) CNS
formation → respiratory arrest (medullary insults)
• Passive smoking: same effects with active smoking Liver • Reversible steatosis
o Cotinine: metabolite of nicotine; measure of passive smoking GIT • Reversible gastritis and ulceration
(blood levels)
TOBACCO SMOKE COMPOUNDS CHRONIC EFFECTS OF ALCOHOL
EFFECT COMPOUNDS • Liver: Alcoholic hepatitis → Cirrhosis → HCC
HBT
• Tar Pancreas • Pancreas: Acute and chronic pancreatitis
• Polycyclic aromatic hydrocarbons
Carcinogenesis • Massive bleeding from gastritis, ulcers, and
• Benzo[a]pyrene GIT
esophageal varices
• Nitrosamine
• Nicotine
• Wernicke and Korsakoff syndrome (Vitamin B1
Tumor promotion deficiency due to chronic alcoholism)
• Phenol
• Formaldehyde Nervous • Peripheral and optic neuropathy
Mucosal irritation • Nitrogen oxides • Cerebral atrophy
• Phenol • Cerebellar degeneration
• Formaldehyde • Alcoholic cardiomyopathy (Dilated
Toxicity to cilia CVS cardiomyopathy)
• Nitrogen oxides
Impaired O2 transport • Dyslipidemia (↓ HDL) with liver disease
• CO
and utilization • Fetal alcohol syndrome: microcephaly, growth &
Obstetric
Ganglionic stimulation mental retardation, facial abnormalities
• Nicotine
and depression • Cancers in oral cavity, esophagus, liver, possibly
breast and larynx
EFFECTS Others
• Malnutrition (empty calories) and vitamin
ORGAN EFFECT deficiencies (B vitamins)
• Bronchitis
Lung • Emphysema (centriacinar) Moderate alcohol consumption (20-30 g/day) appears to be
protective against coronary artery disease.
• Vaping-associated acute lung injury Dr. Elomina
• Atherosclerosis (MI, Stroke)
o ↑ Platelet aggregation
CVS THERMAL INJURIES
o ↓ O2 supply (pulmonary disease and CO)
o ↓ Threshold for ventricular fibrillation THERMAL BURNS
• ↑ Spontaneous abortions, preterm births, and • Burns are the most common thermal injury
Intrauterine growth restriction (IUGR)
Reproductive • Most common cause: fire or scalding (major cause in children)
• Ectopic pregnancy
• Factors that determine outlook of burns
• Erectile dysfunction
Endocrine • Type 2 Diabetes Mellitus
o Depth of the burn
MSS • Rheumatoid arthritis
o BSA (Recall BSA computation in Surgery)
Eye • Age-related macular degeneration o Internal injuries (from hot and toxic fume inhalation)
Others • Cancers in different organs o Promptness of efficacy of therapy
DEPTH OF BURNS Ionizing radiation damages DNA which is why rapidly dividing cells (i.e.
DEEPEST epithelial cells of the GIT, hematopoietic cells are more vulnerable).
DEPTH GROSS MICROSCOPIC Moreover, the p53 (guardian of the genome) is upregulated during
EXTENT
Superficial • Erythema of ionizing radiation exposure, causing cell cycle arrest and apoptosis).
• Epidermis - Dr. Rubio
burns skin MORPHOLOGY
Partial • Coagulative STRUCTURE MORPHOLOGY
• Pink, mottled,
thickness necrosis: • Chromosomal changes
• Dermis with blisters
(2nd devitalized
• Painful Nucleus • Mitotic disorders → polyploidy, aneuploidy
degree) tissue
• Nuclear atypia, Apoptosis
• Inflammatory
Cells • Cellular atypia (can be confused with cancer)
Full • Subcutaneous cells &
• White, • Acute: Vasodilation
thickness tissue and exudation:
charred, dry • Chronic: Degenerative changes → rupture or
(3rd deeper around Vessels
• Painless thrombosis
degree) structures devitalized
tissues • Late: Fibrosis → obliterated vascular lumen
• Interstitial fibrosis → scarring, contractions
Third degree burns are painless because the nerve endings are already Tissues
• Chronic ischemic atrophy
destroyed.
Dr. Elomina When you hear the word radiation changes, you have to remember:
USUAL CAUSES OF MORTALITY IN BURNS 1. Atypia, 2. Fibrosis, and 3. Ischemia (due to vascular lumen
• Shock: From fluid shift to interstitial component, and SIRS obliteration).
• Sepsis: Burn site: fertile ground for infections Dr. Elomina
o Organisms: P. aeruginosa (Most common), MRSA, Candida

• Respiratory insufficiency NUTRITIONAL PATHOLOGY
o Direct effect of heat SEVERE ACUTE MALNUTRITION
o Water-soluble gases may react with water and produce
• Definition: Weight for height ratio that is 3 standard
acids/alkalis that cause inflammation → airway obstruction
deviations below the normal range
o Lipid-soluble gases reach deeper airways → pneumonitis
• Two forms: Marasmus and Kwashiorkor
HYPERTHERMIA SYNDROMES FEATURE MARASMUS KWASHIORKOR
SYNDROME MECHANISM CLINICAL FINDINGS • Weight ≤ 60% of
• Cramping of Definition and normal • Protein > caloric
• Electrolyte loss voluntary muscles cause • Caloric deprivation
Heat cramps deprivation
through sweating associated with
intense exercise PROTEIN COMPONENT
Heat • Failure of CVS to Somatic protein
• Sudden onset of • Affected • Relatively spared
exhaustion compensate for compartment
prostration and • Minimally
(Most hypovolemia from Visceral protein • Affected (↓
collapse depleted (normal
common) dehydration compartment albumin)
• Failing of albumin)
thermoregulatory FINDINGS
mechanisms Growth failure • Present
• Hyperthermia Edema - • Present
• Hyperthermia
Heat stroke • Generalized Loss of fat
(>40°C) with • More marked • Present
vasodilation → muscle atrophy
multiorgan
↓ effective Liver - • Fatty liver
dysfunction (RYR1
circulating volume • Findings common in Kwashiorkor, and
dysfunction)
• Hyperkalemia are RARE in Marasmus
• Mutations in RYR1
• Tachycardia Small bowel • Mucosal atrophy and loss of villi and
→ ↑ Ca levels in
• Arrhythmias microvilli (and intestinal enzymes)
Malignant skeletal muscle →
• Rhabdomyolysis • Most common: disaccharidase deficiency
hyperthermia muscle rigidity, ↑
heat production • Hypoplastic marrow (↓ precursors)
• Trigger: Anesthetics • Anemia (variable morphology)
Hematologic
• Thymic and lymphoid atrophy (more
Ryanodine receptor (RYR1) is located in the sarcoplasmic reticulum (SR)
of your skeletal muscle cells. It functions to control the release of Ca from marked in Kwashiorkor)
the sarcoplasm. Dantrolene is given to block the release of Ca from the SR. • Cerebral atrophy
Brain
Dr. Elomina & Dr. Rubio • Impaired white matter myelinization
HYPOTHERMIA
The basic premise of SAM is that you do not have enough caloric
• <90°F: loss of consciousness, followed by bradycardia and atrial (Marasmus) or protein (Kwashiorkor) intake. In marasmus, because
fibrillation (lower core temperatures) you do not have enough calories, fat and proteins are used as energy
• Mechanisms: sources. The somatic protein component is used leading to emaciation.
o Direct: physical disruption of cells by high salt concentrations You have increased cortisol (since “fasting”) that leads to lipolysis. In
from crystallization of intracellular water Kwashiorkor, the visceral protein component is depleted
o Indirect: Vasoconstriction and increased vascular (hypoalbuminemia), which leads to edema and fatty liver (because there
is decreased synthesis of the protein component of lipoproteins).
permeability → hypoxia and edema e.g., Trench foot Dr. Elomina
• Marasmus
ELECTRICAL INJURY o Head relatively larger than body
• Cardiac/Neurologic: ventricular fibrillation, cardiac or • Kwashiorkor
respiratory center failure o Skin: alternating zones of hyperpigmentation, desquamation
• Burns: sustained current → heat production and hypopigmentation (“flaky paint” appearance)
• Alternating current (AC): most common form of current at o Hair: Overall loss of color or alternating bands of pale and
homes; causes tetanic muscle spasms (chest wall) → asphyxia darker hair (flag sign)
IONIZING RADIATION ANOREXIA AND BULIMIA NERVOSA

• Radiation: energy that travels in the form of waves or high- FEATURE ANOREXIA NERVOSA BULIMIA NERVOSA
speed particles • Self-induced
• Binge eating →
Definition starvation → weight
• Main sources: X-rays, gamma rays, high-energy neutrons, alpha vomiting (purging)
loss
particles (2 protons & 2 neutrons), beta particles (electrons)
• Highest date rate of
• Clinical consequences: cell death, teratogenesis, Epidemiologic
any psychiatric
• More common than
carcinogenesis significance anorexia nervosa
disorder
FINDINGS OBESITY
• Amenorrhea (↓
• Definition: Accumulation of adipose tissue that is of sufficient
Endocrine GnRH, FSH, LH) ---
magnitude to impair health
• Hypothyroidism
• Important in the etiology of Type 2 DM, dyslipidemia,
FEATURE ANOREXIA NERVOSA BULIMIA NERVOSA
cardiovascular disease, hypertension, and cancer
• Gelatinous
transformation of • Central obesity: accumulation of excess fat in the trunk and in
Bone and the abdominal cavity (mesentery and around viscera)
marrow ---
marrow o Associated with higher risk for morbidity
• ↓ Bone density (↓
Estrogen)
Pulmonary • Aspiration GENERAL CONSEQUENCES OF OBESITY
--- • Esophageal and 1. Insulin resistance → type 2 diabetes mellitus
GIT 2. Hypertriglyceridemia and ↓ HDL → coronary artery disease
gastric rupture
CVS • ↓ K+ → Cardiac arrhythmias 3. Non-alcoholic fatty liver disease
4. Formation of gallstones
What sets Anorexia nervosa apart from SAM is the presence of endocrine
5. Hypoventilation (Pickwickian syndrome), Hypersomnolence
abnormalities. The findings in Bulimia nervosa are related to purging.
Dr. Elomina • Obstructive sleep apnea (OSA), Polycythemia, Cor Pulmonale
6. Degenerative joint disease → osteoarthritis
VITAMIN DISORDERS 7. Persistent proinflammatory state (↑CRP, TNF)
• Fat-soluble (ADEK) and water-soluble vitamins (B and C) • Contributory to the pathogenesis of diseases associated with
o Fat-soluble vitamins are readily stored, hence toxicities are obesity, such as cancer
more common; moreover they are poorly absorbed in fat
malabsorption states OBESITY AND CANCER
o Water-soluble vitamins rarely cause toxicities because they 1. Insulin resistance → Hyperinsulinemia → ↑ IGF-1 → stimulates
are readily excreted in the urine and other bodily fluids RAS/PI3KT pathway → growth of normal and neoplastic
cells
VITAMIN FUNCTIONS AND 2. ↑ Estrogen synthesis from adipose aromatases (with
ASSOCIATED DEFICIENCY SYNDROMES ↓ synthesis of SHBG in liver → ↑ availability), and ↑ androgen
DEFICIENCY synthesis in ovaries and adrenals → ↑ effects of steroid
VITAMIN FUNCTIONS
SYNDROMES hormones on breast, and uterine differentiation
FAT-SOLUBLE VITAMINS 3. ↓ Adiponectin (Adiponectin suppresses cell proliferation and
• A component of visual
• Night blindness, promotes apoptosis) → ↑ cellular proliferation
xerophthalmia, 4. Persistent proinflammatory state → risk for carcinogenesis
pigment
blindness
• Maintenance of Adiponectin is also known as the “fat burning molecule” or “guardian
Vitamin A • Squamous
specialized epithelia angel against obesity” since it increases fatty acid oxidation and insulin
metaplasia
• Maintenance of sensitivity. Moreover, it has anti-inflammatory, anti-proliferative, and
• Vulnerability to
resistance of infection cardioprotective effects (protecting the body from the harmful sequelae
infection (measles)
of obesity).
• Facilitates intestinal • Rickets in children Dr. Elomina
Vitamin D absorption of Ca2+ and • Osteomalacia in
phosphorus adults
• Spinocerebellar
9. DISEASES OF INFANCY AND CHILDHOOD
• Major antioxidant; • Congenital anomalies
Vitamin E degeneration,
scavenges free radicals • Prematurity and complications
hemolytic anemia
• Cofactor in hepatic • Fetal hydrops
carboxylation of factors • Cystic fibrosis
Vitamin K II, VII, IX, and X (1972) • Bleeding diathesis • Sudden infant death syndrome (SIDS)
and protein C and • Tumors and tumor-like conditions
protein S
WATER-SOLUBLE
• As pyrophosphate, is
CONGENITAL ANOMALIES
• Dry and wet beriberi, • Definition of congenital: present at birth
Vitamin B1 coenzyme in
Wernicke and
(thiamine) decarboxylation TERM DEFINITION EXAMPLE
Korsakoff syndrome
reactions • Primary errors of
• Ariboflavinosis, morphogenesis
• Converted to • Anencephaly
cheilosis, stomatitis, • Intrinsically
coenzymes FMN and
Vitamin B2 glossitis, dermatitis, Malformation • Congenital heart
FAD, cofactors for many abnormal
enzymes of metabolism
corneal disease
vascularization developmental
• Derivatives serve as • Pellagra—Three Ds: process
Niacin • Secondary
coenzymes in many Dementia, Dermatitis,
(Vitamin B3) • Amniotic bands
intermediary reactions Diarrhea destruction of a
Disruptions compressing
Vitamin B6
• Derivatives serve as • Cheilosis, glossitis, normally developed
coenzymes in many dermatitis, peripheral parts of fetus
(pyridoxine) organ
intermediary reactions neuropathy • Extrinsic
• Required for normal
• Megaloblastic disturbance of
folate metabolism and
DNA synthesis
pernicious anemia Deformations development • Club feet
Vitamin B12 and degeneration of • Most common cause:
• Maintenance of
posterolateral spinal uterine constraint
myelination of spinal
cord tracts
cord tracts • Cascade of
• Oligohydramnios
• Serves in many REDOX anomalies triggered
reactions and Sequence (Potter)
Vitamin C • Scurvy by one initiating
hydroxylation of sequence
aberration
collagen
• Constellation of
• Essential for transfer • Megaloblastic
Folate and use of one-carbon anemia, neural tube
congenital
units in DNA synthesis defects anomalies that are
• Congenital
Pantothenic • Incorporated in • No non-experimental Malformation pathologically
rubella
acid coenzyme A syndrome seen syndrome related, and cannot
syndrome
• Cofactor in carboxylation • No clearly defined be explained by
Biotin
reactions clinical syndrome single, localized,
Table 9.9. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 (adapted)
initiating defect
PATHOPHYSIOLOGY
• Fundamental defect: pulmonary immaturity and surfactant
deficiency (dipalmitoylphosphatidylcholine, DPPC)
• Deposition of hyaline membranes further aggravate insult
(increased diffusion distance)
OLIGOHYDRAMNIOS (POTTER) SEQUENCE

POTTER SEQUENCE
https://qrs.ly/6ucmdiv
CAUSES OF ANOMALIES
• Most common cause: unknown
• Most common known cause: multifactorial
• Genetic and environmental
o Genetic: Chromosomal aberrations and Mendelian disorders
o Environmental: Infections, maternal disease states, drugs and
chemicals, irradiation
CONGENITAL ANOMALIES SECONDARY TO PATHOPHYSIOLOGY OF NEONATAL RDS
ENVIRONMENTAL EXPOSURES
EXPOSURE DISEASE CLINICAL FINDINGS
• Congenital rubella • Cardiac anomalies NEONATAL RDS
syndrome • Sensorineural hearing https://qrs.ly/1ncmdla
Rubella • I (eye) loss
♥ (heart) ruby • Cataracts
earrings (ears) • Mental retardation MORPHOLOGY
Thalidomide • Phocomelia • Short, deformed limbs • Solid, airless, reddish-purple (liver-like) lung
Gross
• Growth restriction sinking in water
• Fetal alcohol • Facial anomalies • Poorly developed alveoli → Atelectasis
Alcohol
syndrome • Psychomotor • Hyaline membranes: fibrin, cell debris (from
disturbance Microscopic necrotic Type II pneumocytes)
Cigarette • Low birth weight • >48 hours of survival: signs of repair
-
smoking • Increased risk for SIDS (proliferation of alveolar epithelium)
• Fetal macrosomia CLINICAL ASPECTS
Gestational
• Diabetic • Cardiac anomalies
diabetes • 60% of cases occur in <28 weeks, 30% in 28-34 weeks
embryopathy • Neural tube defects
mellitus o Rapid increase in surfactant production after 35th week
• CNS abnormalities
• Clinically, neonatal respiratory distress + typical imaging
PATHOGENESIS OF CONGENITAL ANOMALIES findings (ground-glass appearance of lung)
• Timing is everything! ;) • Complications of hyperoxic injury
o Embryo most susceptible during early embryonic period (1st 3 o Retinopathy of prematurity (ROP)
weeks post fertilization) § Hyperoxia causes vasoconstriction and hypoxia that
o 3rd-9th week: extremely susceptible to teratogenesis increases VEGF → neovascularization
o 4th-5th week: peak sensitivity (height of organogenesis) o Bronchopulmonary dysplasia
§ Impairment of lung development at saccular stage (striking
PREMATURITY decrease in alveolar septations)
We give glucocorticoids at 24-34th weeks AOG to facilitate lung maturity.
• < 37 weeks AOG by Maturity Index At the 35th week, because of the rapid increase in surfactant production,
• Second most common cause of neonatal morbidity, second to the baby would have a better chance of survival.
congenital anomalies Dr. Elomina
• Complications: NECROTIZING ENTEROCOLITIS

o Neonatal Respiratory Distress Syndrome (RDS) (Hyaline • Loss of mucosal integrity (ischemia, infection, inflammation)
membrane disease) permits transluminal bacterial transport → sepsis
o Necrotizing enterocolitis (NEC) • Associations: prematurity, VLBW infants, aggressive enteral
o Sepsis nutrition
o Intraventricular and germinal matrix hemorrhage • Clinically, hematochezia, abdominal distention, circulatory
collapse
NEONATAL RDS (HYALINE MEMBRANE DISEASE) • Radiograph: pneumatosis intestinalis (gas within intestinal
• Most common cause of respiratory distress in newborns wall), pneumoperitoneum in severe NEC
Enteral nutrition contributes to the development of NEC, because of
• Deposition of hyaline proteinaceous material in alveolar air
enteral administration of bacteria that may cause the infection. Platelet
spaces activating factor (PAF) is a mediator implicated in NEC, because it
• Associations: prematurity, male gender, maternal diabetes, CS increases mucosal permeability.
delivery Dr. Elomina
MORPHOLOGY
Maternal diabetes is associated with neonatal RDS, because maternal
hyperglycemia causes maternal hyperinsulinemia, and it causes fetal • Common sites: terminal ileum, cecum, right colon
hyperinsulinemia. Insulin is antagonistic to the development of Type II • Mucosal or transmural coagulative necrosis, bacterial
pneumocytes. colonization, submucosal gas bubbles → ulceration
Dr. Elomina
FETAL HYDROPS SUDDEN INFANT DEATH SYNDROME (SIDS)

• Accumulation of edema in the fetus during intrauterine growth • “Sudden death of an infant under 1 year of age which remains
Immune • ABO incompatibility unexplained after a thorough case investigation, including
hydrops • Rh incompatibility performance of a complete autopsy, examination of the death
• Cardiovascular defects scene, and review of the clinical history”
Non- • Chromosomal abnormalities – Turner syndrome, • Leading cause of death between 1 month and 1 year of age in
immune Trisomy 21, Trisomy 18 the US; 4th cause of death overall
hydrops • Fetal anemia – Twin-twin transfusion syndrome,
PATHOPHYSIOLOGY AND RISK FACTORS
Parvovirus B19 infection, homozygous α-thalassemia
• Multifactorial (“Triple-risk” model)
Homozygous α-thalassemia is implicated as the most common cause of • Delay in the development of “arousal” &
nonimmune hydrops. Vulnerable
cardiorespiratory control – abnormal
Dr. Rubio infant
IMMUNE HYDROPS serotonin-dependent signaling in brainstem
• Pathophysiology: Mother exposed to fetal red cell antigens → Critical • Critical period of homeostatic control
mother produces antibodies against fetal red cell antigens → development development occurs in the first 6 months of
Antibodies travel through placenta to attack fetal red cell period life
antigens • Maternal smoking: doubles risk
Exogenous
• Prone and sideway sleeping increases risk
RH ABO stressor
FEATURE o Supine: only safe sleeping position
INCOMPATIBILITY INCOMPATIBILITY
• Mother: Rh (-) Everything is su-FINE in SUPINE sleeping position for your babies! hehe
• Mother: O Dr. Rubio
Setup • Fetus: Rh (+)
• Fetus: A or B
• Subsequent pregnancy
Severity • More severe • Less severe
TUMORS AND TUMOR-LIKE CONDITIONS
• RhIg in 28 weeks and BENIGN TUMORS AND TUMOR-LIKE CONDITIONS
• No effective
Protection within 72 hours prior to • Hemangiomas: most common tumors of
protection Vascular tumors
delivery infancy
• Hemolysis → Anemia → Hypoxia Fibrous tumors • Fibromatoses
o Cardiac failure (↑ Hydrostatic pressure) →
• Sacrococcygeal teratomas: most
Edema
Consequence o Liver failure (↓ protein synthesis → ↓ Colloid
Teratomas common teratomas of childhood
oncotic pressure) → Edema • Mostly benign in behavior
• Hemolysis → Unconjugated MALIGNANT TUMORS
hyperbilirubinemia, Jaundice & Kernicterus
• Childhood cancers have improved survival or cure rates
• The significant amount of Rh(+) fetal red cells for maternal • Some childhood cancers regress or differentiate spontaneously
alloimmunization is >1 mL. o Neuroblastoma → Ganglioneuroblastoma → Ganglioneuroma
• If you have both Rh and ABO incompatibility, ABO incompatibility
(Differentiation)
protects you from Rh immunization because the incompatible fetal
red cells are being coated with maternal ABO antibodies and are • Have more primitive appearance (blastema: “small, round blue
immediately cleared from her circulation. cells”) → -blastoma
Dr. Elomina Hematopoietic, nervous, • Systems involved in malignant
soft tissues, bones, kidney transformation in children
CYSTIC FIBROSIS (MUCOVISCIDOSIS)
• Most common neoplastic
• Inherited disorder of ion transport that affects fluid secretion in Leukemia
disease
exocrine glands and in the epithelial lining of the respiratory, CNS tumors
gastrointestinal, and reproductive tracts • Most common solid tumor
(mostly infratentorial)
• Most common lethal genetic disease affecting Caucasian
populations NEUROBLASTOMA
• Most common extracranial solid tumor of childhood; most
PATHOPHYSIOLOGY frequently diagnosed tumor of infancy
• Defect: CFTR gene in Chromosome 7 Most common site • Adrenal medulla (40%)
Sweat glands • Na and Cl efflux to the lumen → salty sweat • Abdominal mass crossing midline
• Na and Cl influx to the cells → isotonic but • Systemic signs – fever, weight loss
Respiratory,
low-volume of surface fluid → respiratory Clinical • Blueberry muffin – represents cutaneous
GI tract
and intestinal complications presentation metastases (disseminated)
• Cl efflux to the lumen → HCO3- influx to the cells → • Elevated catecholamines
Pancreas acidic secretions → precipitation of mucin → • Opsoclonus-myoclonus syndrome
pancreatic insufficiency • Lymphohematogenous to the liver, lungs,
Metastases
bones and bone marrow
MORPHOLOGY • Blastemal cells with atypia, in eosinophilic
ORGAN MANIFESTATION fibrillary background (neuropil)
Sweat • Homer-Wright pseudorosettes: tumor
• Morphologically unaffected Morphology
glands cells around a central space with neuropil
Pancreas • Mucus plugs, dilated ducts, squamous • Schwannian stroma: associated with
and salivary metaplasia → atrophy and fibrosis of favorable prognosis
glands exocrine pancreas WILMS TUMOR
• Thick mucus plugs in small intestine → • Most common primary renal tumor of childhood
Intestine
meconium ileus
• Associated with the following syndromes
• Bile plugs with portal inflammation and SYNDROME DEFECT CLINICAL FINDINGS
Liver ductular proliferation, steatosis, and focal WAGR WT1 • Wilms tumor, Aniridia, Genital
biliary cirrhosis syndrome deletion anomalies, Mental Retardation
• Most serious manifestation Denys-Drash • Gonadal dysgenesis (male
• Mucus plugging and secondary bacterial syndrome WT1 pseudohermaphroditism); ↑
Lungs infections (highest protein risk for gonadoblastomas
• Top organisms causing lung infections: S association: dysfunction • Early-onset nephropathy
aureus, H influenzae, P aeruginosa 90%) (diffuse mesangial sclerosis)
Vas • Congenital bilateral absence of vas Beckwidth-
• Enlargement of body organs
deferens deferens → Azoospermia and infertility WT2 (organomegaly), macroglossia,
Wiedemann
imprinting hemihypertrophy, omphalocele,
syndrome
and adrenal cortex cytomegaly
Genetic basis • Chromosome 11 (WT1, WT2) • Essential
• Unilateral abdominal mass NOT crossing Associated hypertension
Clinical • Malignant hypertension
midline (unless really large) conditions • Diabetes
presentation mellitus
• Hematuria
(triad)
• Hypertension
• Classic triphasic tumor ATHEROSCLEROSIS
o Blastema: small, round blue cells
Morphology
o Stromal: myxoid, fibroblasts • Central in pathogenesis of coronary (myocardial infarction),
o Epithelial: glandular, glomerular cerebral (stroke) and peripheral vascular disease (gangrenes)
• Serve as putative precursor lesions • Atheroma/atheromatous plaque: diagnostic lesion
Nephrogenic
• Associated with ↑ recurrence in contralateral
rests RISK FACTORS
kidney if present
NON-MODIFIABLE MODIFIABLE
If both masses cross the midline, how would you know which is which? I
• Hyperlipidemia*
would pick Wilms tumor if there were renal manifestations i.e., hematuria. • Genetic abnormalities
(hypercholesterolemia)
If both masses are composed of small, round, blue cells, how would you • Family history • Hypertension*
know which is which? If it’s mentioned that there are glands, glomerular • Increasing age • Cigarette smoking*
structures (epithelial), and a fibroblastic stroma, aside from the sheets of
• Male gender • Diabetes mellitus*
small, round, blue cells, then I would pick Wilms.
Dr. Elomina • Inflammation (↑ CRP)
* - Coronary risk factors: accelerate atherosclerosis
10. BLOOD VESSELS
• Vascular wall response to injury • Diseases of blood vessel ATHEROGENESIS
• Hypertensive vascular disease hyperreactivity • Endothelial injury
• Atherosclerosis • Veins and lymphatics
Two important causes of • Hypercholesterolemia
• Aneurysms and Dissection • Tumors and tumor-like
endothelial injury • Hemodynamic disturbances
• Vasculitides conditions
• Proinflammatory endothelium
Consequences
• Prothrombotic endothelium
VASCULAR WALL RESPONSE TO INJURY • Accumulation of lipoproteins (LDL and oxidized forms) in the
• Normal endothelium has antithrombotic properties vessel wall
• Endothelial activation: Endothelial cells gain new functions in o In chronic hypercholesterolemia, LDL accumulates in intima
response to stress o ROS from inflammatory cells → oxidize lipoproteins →
o Cytokines, bacterial products (Septic shock) accumulate in macrophages, smooth muscle cells (“foam
o Hemodynamic stress and lipid products (Atherosclerosis) cells”)
o Advanced glycation end-products (Diabetes mellitus) § Oxidized lipoproteins are toxic to cells
• Endothelial dysfunction: alteration in endothelial phenotype § Oxidized lipoproteins induce release of growth factors,
that is often proinflammatory and prothrombogenic cytokines, and chemokines
HYPERTENSIVE VASCULAR DISEASE • Migration of smooth muscle cells into intima (neointima)
• No identifiable cause o Driven by growth factors from platelets and macrophages
Primary or Essential o Capable of proliferation, elaboration of ECM matrix, and
• Seen in 90-95% of cases
Secondary • Renal, endocrine, neurologic causes recruitment of T cells
• Occurs when >200/>120 mmHg
Malignant • Can be primary or secondary MORPHOLOGY
• Severe form of hypertension • Early lesions containing lipid-filled
Fatty streak
macrophages
PATHOGENESIS • Has a fibrous cap and lipid core
FORM EXAMPLES OF PATHOGENESIS • Has the following principal components:
• Genetic factors o Cells: smooth muscles, macrophages, T
• Insufficient renal sodium excretion cells
Atheromatous
Essential • Vasoconstrictive influences o ECM: collagen, elastin, proteoglycans
plaque
• Environmental factors (stress, obesity, smoking, o Lipids: extracellular, intracellular
physical inactivity, heavy salt consumption) o Calcifications: in later stages of plaques
• Renal: ↑ activity of RAAS → ↑ intravascular volume • Neovascularization is present at
o Renal artery stenosis periphery
o Renin-producing tumors
• Endocrine • Lower abdominal aorta and iliac
Most common
o ↑ in aldosterone → ↑ intravascular volume arteries > coronary arteries > popliteal
sites of
§ Conn syndrome, single gene defects in arteries > internal carotid arteries > Circle
involvement
aldosterone metabolism of Willis
Secondary
o ↑ Glucocorticoids → ↑ vascular sensitivity to
pressors → ↑ peripheral resistance PATHOLOGIC CHANGES
§ Cushing syndrome
o ↑ Catecholamines → ↑ peripheral resistance CLINICAL
CHANGE CONSEQUENCE
§ Pheochromocytoma DISEASE
o ↑ Thyroid hormones → ↑ cardiac output • Exposure of thrombogenic
Rupture,
§ Thyrotoxicosis substances → thrombosis →
ulceration, or
partial/total occlusion of the
erosion
VASCULAR PATHOLOGY IN HYPERTENSION vessel lumen
• NSTE-ACS
• Vascular resistance is determined at the level of the arterioles • Rupture of thin-walled
and
o Pathology is seen in the arterioles (arteriolosclerosis) vessels in
STEMI
§ Common feature: Luminal narrowing Hemorrhage neovascularization site →
HYALINE HYPERPLASTIC into a plaque intraplaque hemorrhage
• Concentric, laminated thickening with plaque expansion or
(smooth muscle cells with rupture
reduplicated basement • Plaque rupture can
• Eosinophilic Athero-
membrane) “onion-skin” lesions discharge debris as -
Morphology hyaline embolism
• Malignant hypertension: microemboli
material
Fibrinoid deposition and Aneurysm • Aneurysm
vessel wall necrosis
• Weakening of wall
formation formation
(necrotizing arteriolitis)
CONSEQUENCE OF ATHEROSCLEROTIC DISEASE
ATHEROSCLEROTIC ACUTE PLAQUE PLAQUE REMODELING
FEATURE
STENOSIS CHANGE • Continuous change in the composition of the fibrous plaque
• Plaque rupture/ • Two outcomes: stable plaque, vulnerable plaque (more risk of
• Gradual occlusion of fissuring, erosion, rupture)
the vessel lumen ulceration, and
• Critical stenosis: level hemorrhage GENERALITIES
Definition
at which tissue • Most dangerous • Thickness of fibrous cap is DIRECTLY proportional to stability
ischemia starts (70- consequence • Size of lipid core/amount of lipid accumulation is INVERSELY
75%) (abrupt cessation proportional to stability
of blood flow) • Degree of inflammation is INVERSELY proportional to stability
• Chronic stable angina Collagen is a major component of your fibrous cap. Inflammation in the
pectoris plaque causes increased breakdown of collagen, which makes it prone to
• Mesenteric occlusion rupture. The amount of lipid is directly proportional to the degree of
and bowel ischemia inflammation.
• Acute coronary
• Sudden cardiac death Dr. Elomina
Clinical syndromes:
• Chronic ischemic heart
diseases NSTE-ACS and
disease (IHD)
STEMI
• Ischemic
encephalopathy
• Intermittent
claudication
NATURAL HISTORY OF ATHEROSCLEROSIS

ANEURYSMS AND DISSECTION

ANEURYSM DISSECTION
• Blood tunnels in between layers of the wall; most common
Definition • Localized, abnormal dilatation of the blood vessel or the heart
cause: intimal tear
• True: Attenuated, but intact vascular wall • DeBakey I: Ascending and descending
Types • False: Defect in vascular wall → extravascular hematoma • DeBakey II: Ascending only
(pulsating hematoma) • DeBakey III: Descending only
• Saccular: Spherical outpouchings • Stanford A: DeBakey I and II
Forms
• Fusiform: Diffuse, circumferential dilation • Stanford B: DeBakey III
Risk • Atherosclerosis: Abdominal aortic aneurysm
• Hypertension: Aortic dissection
factors • Hypertension: Ascending aortic aneurysm
TYPES OF ANEURYSMS (A-D) AND DISSECTION (E) TYPES OF AORTIC DISSECTION

Figure 11.19. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 Figure 11.23. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
PATHOGENESIS VASCULITIDES
• Poor intrinsic quality of vessel wall • Inflammation of blood vessels
o Vascular Ehler-Danlos syndrome: Defective Type III • Infectious and non-infectious (immune)
Collagen
• Classified based on vessels affected (large, medium, small)
• Abnormalities in TGF-β signaling
• General morphology:
o Marfan syndrome: ↓ fibrillin → ↑ TGF-β (fibrillin sequesters
o Large vessel: granulomatous
TGF-β) → ↓ ECM content and vascular integrity
o Medium and small vessel: predominantly necrotizing
• Abnormalities in collagen remodeling
• Clinical manifestations
o Inflammation (syphilis, atherosclerosis) → ↑ Collagen
o Systemic findings: depend on the vascular bed involved
breakdown
• Loss of smooth muscle cells or inappropriate synthesis of non- MECHANISMS
elastic ECM because of ischemia Immune • SLE-associated, drug-induced, HBV-associated
o Atherosclerosis: thick atherosclerotic plaque (inner media) complex or • Anti-neutrophilic cytoplasmic autoantibodies
o Hypertension: sclerosis of vasa vasorum (outer media) autoantibody- (ANCA) vasculitis
o Syphilitic aortitis: obliterative endarteritis of vasa vasorum mediated • Anti-endothelial cell antibodies (Kawasaki disease)
(outer media) Cell-
• Granulomatous vasculitides of large vessels
mediated
OTHER CAUSES OF ANEURYSMS
• Advanced age • Vasculitis MAJOR NON-INFECTIOUS VASCULITIDES
• Smoking • Congenital defects (aneurysms) LARGE MEDIUM SMALL
• Trauma • Infections (Mycotic aneurysms) • MPO-ANCA (p-ANCA)
o Microscopic polyangiitis
• Mycotic aneurysms are not necessarily fungal. • Giant cell • Polyarteritis o Churg-Strauss syndrome
• Intracranial arteries do not have external elastic lamina, which arteritis nodosa • PR3-ANCA (c-ANCA)
makes them particularly susceptible to develop aneurysms. • Takayasu • Kawasaki o Granulomatosis with
Dr. Elomina
CLINICAL MANIFESTATIONS arteritis disease polyangiitis (formerly
called Wegener
• General (for aneurysms and dissections) granulomatosis)
o PRESENCE OF A MASS AND MASS EFFECT
§ Palpable, pulsating abdominal mass (abdominal aneurysm) LARGE-VESSEL VASCULITIDES
§ Specific clinical manifestations depend on the site of GIANT CELL ARTERITIS TAKAYASU
FEATURE
aneurysm and structures compressed (TEMPORAL ARTERITIS) ARTERITIS
o EROSION OF BONE • Most common form of • Diagnosed in
Epidemiologic
§ Secondary to contact with aneurysm; presents as pain vasculitis among elderly patients <50
significance
adults in the West years old
o RUPTURE
• Temporal • Aortic arch
§ Presents as hemorrhage and cardiovascular collapse
Vessel • Ophthalmic • Great vessels
affected • Vertebral • Pulmonary,
ABDOMINAL AORTIC ANEURYSM • Aorta (giant cell aortitis) coronary, renal
• Patient profile: >50/M, smoker, with atherosclerosis • Headache • Ocular
• Other clinical manifestations • Pain/tenderness along disturbances
o Ischemia of organs supplied by branches of abdominal aorta, Prominent course of superficial • Weakening of
due to compression of said vessels (Mass effect) clinical temporal artery pulses in the
o Impingement of ureter (Mass effect) findings • Diplopia or complete upper limbs
o Embolism from atheroma or mural thrombus vision loss (pulseless
disease)
AAAs usually arise at the infrarenal aorta because there is fewer elastic
fibers and collagen, and more fragile vasa vasorum that lead to less • Intimal thickening, with lymphocytic infiltrates
oxygenation of the media of that particular segment. Morphology • Medial granulomatous inflammation
Dr. Elomina • Multinucleated giant cells (in GCA)
Because the histology of GCA and Takayasu can be similar, the distinction
is made based on age: ≥ 50 years old are diagnosed as GC aortitis, and
THORACIC AORTIC ANEURYSM those under 50 years are diagnosed as Takayasu aortitis.
Dr. Elomina
• Patient profile:
MEDIUM-VESSEL VASCULITIDES
o Hypertensive
POLYARTERITIS
o Connective tissue defects (Marfan, Loeys-Dietz syndrome) FEATURE KAWASAKI DISEASE
NODOSA
o Inflammatory disorders (aortitis) • Important cause of MI
• Clinical manifestations (Mass effect) Epidemiologic • Associated with
in children (coronary
o Respiratory difficulties (lungs and airways) significance Hepatitis B
artery aneurysms)
o Dysphagia (Esophagus) Vessel • Renal and • Coronary arteries
o Persistent cough (Recurrent laryngeal nerve) affected visceral vessels • Small vessels
o Cardiac manifestations • Fever > 5 days
§ Aortic insufficiency: secondary to dilation of the aortic valve • Abdominal pain - • Conjunctival injection
→ heart failure Prominent visceral ischemia • Mucosal erythema
§ Myocardial infarction: due to narrowing of coronary ostia clinical and infarction • Cervical
findings • Hypertension lymphadenopathy
AORTIC DISSECTION (renal vessels) • Polymorphous
• Patient profiles exanthem
o 40-60/M, hypertensive (90%) • Segmental, transmural necrotizing inflammation
o Young, with connective tissue defects (Marfan syndrome) • Fibrinoid necrosis
• Clinical manifestations Morphology o PAN: prominent fibrinoid necrosis
o Kawasaki: less prominent fibrinoid necrosis
o Sudden, excruciating anterior chest pain, radiating to the back
• Temporal heterogeneity of lesions
o Most common cause of death: rupture into body cavities
SMALL-VESSEL VASCULITIDES (ANCA VASCULITIDES)

FEATURE MICROSCOPIC POLYANGIITIS CHURG-STRAUSS SYNDROME GRANULOMATOSIS WITH ANGIITIS
• Seen in vasculitis associated • Also called allergic
• Previously called Wegener’s granulomatosis
Epidemiologic with Henoch-Schönlein granulomatosis and angiitis
• Widespread GPA looks like PAN + Pulmonary
significance purpura (HSP) and connective • Associated with asthma, allergic
involvement
tissue disorders rhinitis, and eosinophilia
ANCA • MPO-ANCA (p-ANCA) • PR3-ANCA (c-ANCA)
• Small and medium-sized vessels (prominent
• More common: Kidney and
Vessel affected • Cutaneous, GIT, renal pulmonary involvement), may involve renal
Lung
vessels
• Persistent pneumonitis with bilateral nodular
• Palpable purpura, GI bleed, FSGS
Prominent and cavitary infiltrates (95%)
• Hemoptysis • Cardiomyopathy (toxicity from
clinical • Chronic sinusitis (90%)
• Hematuria and Proteinuria myocardial eosinophilic
findings • Renal disease (80%)
infiltrates)
• Mucosal ulcerations of the nasopharynx (75%)
• PAN but temporally • Acute necrotizing granulomas of respiratory
homogeneous lesions tract
• PAN + Extravascular necrotizing
Morphology • Fragmented PMNs in post- • Necrotizing or granulomatous vasculitis
granulomas and eosinophils
capillary venules • Focal, segmental necrotizing glomerulonephritis
(leukocytoclastic vasculitis) (GN) often crescentic GN
THROMBOANGIITIS OBLITERANS (BUERGER DISEASE) PHLEBOTHROMBOSIS AND THROMBOPHLEBITIS

BUERGER DISEASE • Venous thrombosis, inflammation
• Strong association with cigarette • Most common: deep leg veins
Significance
smoking o Most common cause of lower extremity DVT: Decreased blood
Vessels involved • Vessels of the extremities (tibial, radial) flow in the setting of prolonged immobilization
• Hypercoagulability: genetic or acquired
• Raynaud phenomenon
• Instep claudication
o Trousseau syndrome: migratory superficial vein
Prominent clinical
findings • Superficial nodular phlebitis
thrombophlebitis in cancer patients
• Ulcerations → Gangrene (chronic) • Pulmonary embolism: serious complication
Some cancers (lung, pancreatic) are associated with production of
• Acute and chronic vasculitis with
prothrombogenic substances that cause the body to be in a
Morphology thrombosis (thrombus contains hypercoagulable state.
microabscesses) Dr. Elomina
VENA CAVA SYNDROMES
SVC SYNDROME IVC SYNDROME
VASCULITIS ALGORITHM • Bronchogenic • Hepatocellular and
https://qrs.ly/tpcmdos carcinoma renal carcinoma
Setting
• Mediastinal
lymphoma
• Dilation of the veins of • Lower extremity
DISEASES OF BLOOD VESSEL HYPERREACTIVITY
the head, neck, and edema
RAYNAUD PHENOMENON arms • Lower abdominal
• Exaggerated vasoconstriction of arteries and arterioles in Clinical • Respiratory distress superficial collateral
response to cold or emotion findings (pulmonary vessel vein distention
• Most common site affected: Extremities (fingers, toes) involvement) • Massive proteinuria
• Red → white → blue appearance: proximal vasodilation, central (renal vein
vasoconstriction, and distal cyanosis involvement)
TYPES OF RAYNAUD PHENOMENON LYMPHANGITIS AND LYMPHEDEMA
Primary Raynaud • Non-progressive clinical course • Most common cause: GABHS
Lymphangitis
phenomenon • Symmetric involvement (acute • Red, painful, subcutaneous streaks with
• Progressive clinical course inflammation) painful enlargement of nodes (lymphadenitis)
Secondary Raynaud • Asymmetric involvement • Due to isolated or
phenomenon • Associations: SLE, Scleroderma, Primary familial disease (Milroy
Buerger disease, Atherosclerosis lymphedema disease) causing
• Brawny
MYOCARDIAL VESSEL VASOSPASM (CARDIAC RAYNAUD) lymphatic hypoplasia
induration, Peau
• Hyperreactivity of coronary vessels → myocardial ischemia • Due to an obstructive
d’ orange,
pathology
• If spasm lasts for 20-30 minutes: MI or sudden cardiac death Secondary ulceration
• Associated with
lymphedema
neoplasms, post-
VEINS AND LYMPHATICS surgery, filariasis
VARICOSE VEINS If there is poor outflow of blood and lymph drainage, it will cause stasis
• Abnormally dilated, tortuous veins produced by prolonged, dermatitis. The brawny induration that you see in stasis dermatitis
increased intraluminal pressure with vessel dilation and is because of extravasated red cell hemolysis. These patients present
incompetence of venous valves with poor wound healing and ulcerations because of the lack of good
perfusion.
• Common site: Superficial veins of upper and lower leg Dr. Elomina
• Complications: Stasis dermatitis (brawny induration),
ulcerations, poor wound healing, infections TUMORS AND TUMOR-LIKE CONDITIONS
• Other types: esophageal varices, hemorrhoids TUMOR-LIKE CONDITIONS
Remember that SUPERFICIAL lower extremity veins are RARELY • Vascular ectasia: permanent dilation of preexisting small
associated with embolism, while DEEP lower extremity veins are vessels that present with a discrete red lesion on the
COMMONLY involved in thromboembolism. skin/mucous membranes
Dr. Elomina
o NOT neoplastic
o Some are associated with syndromes (see below)
VASCULAR ECTASIAS
CONDITION DESCRIPTION CLINICAL SIGNIFICANCE
• Most common
Nevus flammeus (birthmark) • Light pink to deep purple at lesion on the head or neck
• Most regress spontaneously
• Sturge-Weber syndrome (Encephalotrigeminal
• Nevus flammeus that grow during child childhood, angiomatosis)
Port wine stain thickening of associated skin o Facial port wine nevi
• Persistent o Ipsilateral leptomeningeal venous angiomas
o Intellectual disability, seizures, hemiplegia
CONDITION DESCRIPTION CLINICAL SIGNIFICANCE
• Radial, often pulsatile arrays of dilated subcutaneous
• Associated with hyperestrogenic states
Spider telangiectasia arteries about a central core that blanch with pressure
(pregnancy and liver cirrhosis)
• Common sites: Face, Neck, Upper chest
Hereditary hemorrhagic • Congenital dilated capillaries and veins
• Telangiectasias can rupture → bleeding
telangiectasia • Sites: Skin, oral mucous membranes, Respiratory, GIT,
(presentation depends on site)
(Osler-Weber-Rendu disease) Urinary tracts
• Most port wine stains are caused by somatic single-nucleotide missense mutation in GNAQ.
• Osler-Weber-Rendu disease is an autosomal dominant disease characterized by gene mutations concerning the TGF-β signaling pathway in endothelial cells.
Dr. Elomina
TUMORS INTERMEDIATE-GRADE (BORDERLINE TUMORS)

• Cytologic origin: KAPOSI SARCOMA
o Endothelium: Hemangioma, Lymphangioma, Angiosarcoma • Vascular neoplasm caused by human herpesvirus 8 (HHV8)
o Supporting cells: Glomus tumor (Kaposi sarcoma herpesvirus) that is associated with AIDS
• Benign tumors tend to form obvious vascular channels lined by o HHV8 infects endothelial cells → tumorigenesis
normal-looking endothelium • Most common HIV-related malignancy worldwide
• Malignant tumors tend to form less-organized vascular channels • Aggressive clinical course BUT infections are still the leading
lined by cytologically atypical endothelial cells (if they do), or sheets cause of mortality
• Morphology: patch → plaque → nodule
See table on Benign Tumors below
o Development of the nodule stage heralds lymph node and
visceral involvement of Kaposi sarcoma
GLOMUS TUMOR (GLOMANGIOMA)
• Origin: Modified smooth muscle cells of glomus bodies MALIGNANT TUMORS
(arteriovenous structures involved in thermoregulation)
ANGIOSARCOMA
• Clinical: PAINFUL mass beneath the fingernails
• Malignant endothelial neoplasms
• Morphology: Can look like hemangiomas
• Common sites: skin, soft tissue, breast, liver
Breast • Radiation-induced angiosarcoma
Post-radical • Lymphangiosarcoma, ipsilateral upper
mastectomy extremity
• Hepatic angiosarcoma secondary to
Liver
arsenic, polyvinyl chloride
BENIGN TUMORS
CAPILLARY CAVERNOUS
HEMANGIOMA
• Unencapsulated, infiltrative borders
Morphology • Thin-walled capillaries with scant stroma • Large, cavernous blood-filled vascular spaces separated by
connective tissue stroma
•
Skin, subcutaneous tissues, mucous membranes
Involvement • Deep structures
•
Liver, spleen, kidneys
Regression Usual • • No
•
Juvenile type (strawberry): In neonates; grow • Von Hippel-Lindau disease (Autosomal dominant)
rapidly for a few months; completely regress by o Pathogenesis: VHL (chromosome 3) → loss of function → ↑ HIF-1
age 7 in most cases → ↑ VEGF → Excessive vessel growth
• Pyogenic granuloma: Rapidly growing red o Components:
Special
pedunculated lesions on the skin, gingiva, or oral § CNS Hemangioblastomas
types
mucosa § Cavernous hemangiomas
o Granuloma gravidarum: in gingiva of § Pancreas, kidneys, liver cysts
pregnant patients; may regress after § Renal cell carcinomas
pregnancy § Pheochromocytomas
LYMPHANGIOMA
• Massively dilated lymphatic spaces lined by endothelial cells and
• Thin, endothelial-lined spaces without red
Morphology separated by intervening connective tissue stroma containing
blood cells
lymphoid aggregates
Involvement • Head and neck, axillary subcutaneous tissue • Neck or axilla of children, rarely in retroperitoneum
Associations - • Turner syndrome: Cavernous lymphangiomas of neck
11. HEART HEART FAILURE
• Mechanisms of cardiac • Hypertensive heart disease • Inability of the heart to pump blood at a rate sufficient to meet
dysfunction • Valvular heart disease the metabolic demands of the tissues, or can do so only at an
• Heart failure • Cardiomyopathies elevated filling pressure
• Congenital heart disease • Pericardial diseases
• Ischemic heart disease • Cardiac tumors
MYOCARDIAL HYPERTROPHY AND HEART FAILURE
• Stimuli:
MECHANISMS OF CARDIAC DYSFUNCTION o Increased workload, and β-adrenergic stimulation
MECHANISM REPRESENTATIVE DISEASES Pressure • Parallel formation of new sarcomeres →
Pump failure • Heart failure overload hypertrophy → increase in wall thickness
• Stenotic valvular lesions Volume • Series formation of new sarcomeres
Flow obstruction
• Aortic coarctation overload (lengthening) → dilation → increase in weight
Regurgitant flow • Regurgitant valvular lesions • Pathology: Hypertrophied myocardium that is metabolically
Shunted flow • Congenital heart diseases demanding, with no commensurate increase in blood supply
Disorders of cardiac o Net effect: increased risk for ischemic injury and
• Arrhythmias
conduction decompensation
Rupture of the heart or
• Ventricular rupture post-MI
major vessel
TYPES OF HEART FAILURE

LEFT-SIDED HEART FAILURE RIGHT-SIDED HEART FAILURE
• Ischemic heart disease, Hypertension, Aortic and mitral • LSHF (most common cause)
Etiology
valvular diseases, Primary myocardial diseases • Pulmonary disease (cor pulmonale)
• LV usually hypertrophied and dilated
• LA dilation → atrial fibrillation → mural thrombus
Heart changes • Hypertrophy and dilation of right chambers
o In HF because of mitral valve dysfunction
• Primary myocyte hypertrophy and interstitial fibrosis
• Liver and spleen (congestion)
Other organs • Lungs (congestion) • Pleural, pericardial, and peritoneal spaces (effusions)
affected • Kidneys and brain (hypoperfusion) • Subcutaneous tissues (edema)
• Kidneys and brain (congestion)
There are two subtypes of LSHF: Systolic failure: The blood cannot get out of the heart. Diastolic failure: The blood cannot get into the heart.
Dr. Elomina
CONGENITAL HEART DISEASE VENTRICULAR SEPTAL DEFECT

• Diseases of heart and great vessels present at birth • Most common congenital heart disease
• Most arise at 3-8 weeks AOG • Types:
o Membranous (90%): membranous interventricular septum
• Most common genetic cause: Trisomy 21 (Down syndrome)
o Infundibular: Below pulmonary valve
• Clinical categories:
o Muscular: Within muscular septum
o Left-to-right shunts
• Size:
o Right-to-left shunts
o <5mm: pressure-restrictive VSDs: clinically asymptomatic,
o Obstructive lesions
Mnemonic: Right→Left shunts cause earRLy cyanosis
maintain pressure gradients between sides
Dr. Rubio o >10mm: non-restrictive VSDs: clinically, failure to thrive and
LEFT-TO-RIGHT SHUNTS repeated infections; if uncorrected, would lead to
• Clinically, acyanotic (initially) Eisenmengerization
• Characterized by increased pulmonary blood flow • Closure of defect (Dictum: size matters)
o Causes pulmonary vascular remodeling → pulmonary o Small defects usually (30-50% of cases) close spontaneously;
pressure = systemic pressure → right-to-left shunt most common: 1st 2 years of life
(Eisenmenger mechanism) → clinically cyanotic o Small muscular VSDs are more likely to close (80%) than
o Pulmonary hypertension: marks irreversibility of CHD membranous (35%)
lesions o Vast majority of lesions that close do so before age 4
o Moderate to large VSDs are less likely to close
VSD Blood flow:

RA → RV → PA →
Lungs → PV → LV
–VSD→ RV and
Aorta
For
pathophysiology,
please see
annotation of
Patent Ductus
Arteriosus.
ALGORITHM FOR LEFT-TO-RIGHT SHUNTS Dr. Elomina
Increased pulmonary blood flow manifests as increased pulmonary VENTRICULAR SEPTAL DEFECT
Figure 12.3b. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
vascular markings on X-ray. Depending on the chamber enlarged and PATENT DUCTUS ARTERIOSUS
the state of the aortic knob, you can diagnose your left-to-right shunts.
However, do take note that the gold standard for diagnosis of these • Ductus arteriosus: mechanism to bypass unoxygenated lungs
disorders is 2D-echocardiography. and direct blood flow from pulmonary artery to aorta
Dr. Elomina • Functional closure occurs soon after birth
ATRIAL SEPTAL DEFECT o Increased oxygen tension, ↓PVR, ↓PGE2
• Defect in interatrial septum • Anatomic closure occurs few months after birth → ligamentum
• Types: arteriosum
o Secundum (90%) • Diagnostic clue: continuous machinery-like murmur
o Primum (adjacent to AV valves) (5%) • Duct-dependent lesions: CHDs that rely on PDA for blood flow
o Sinus venosus (near entrance of SVC) (5%) (e.g. TGA)
• Secundum ASDs generally well-tolerated (symptoms appear late o Administration of PGE2 in infants for survival (to maintain
in life (~30 years old) patency of DA)
• Diagnostic clues: PDA Blood flow: RA → RV → PA
o Fixed widely split S2: prolonged ejection of RV, increased BF → Lungs → PV → LV → Aorta –
across PV DA→ PA
o Murmur: pulmonary stenosis-like, due to increased blood • LVH happens because the
flow across PV excess blood flow through the
defect eventually goes to the
lung-left heart circuit.
Basically, the excess volume is
ASD Blood flow:
handled by the left side of the
RA → RV → PA →
heart.
Lungs → PV → LA
• Since there is increased
–(ASD)→ RA
pulmonary blood flow,
RVH happens
eventually there will be
because of the
pulmonary vascular
excess blood PATENT DUCTUS remodeling, which will cause
volume dumped
ARTERIOSUS pulmonary hypertension,
into the right side Figure 12.3c. Robbins and Cotran Pathologic Basis of
of the heart. Disease, 10th ed. 2020 eventually causing RVH.
Dr. Elomina
Dr. Elomina
ATRIAL SEPTAL DEFECT

Figure 12.3a. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
RIGHT-TO-LEFT SHUNTS
• Clinically, cyanotic CHDs
• Other clinical findings: paradoxical embolism, clubbing
(hypertrophic osteoarthropathy), polycythemia
TGA + VSD Blood flow: RA →
• Can either have increased or decreased pulmonary blood flow
RV → Aorta
(lesions with PS or atresia in the pulmonary circulation → ↓ RV –VSD→ LV → PA → Lungs
pulmonary blood flow) → PV → LA → LV
LVH also happens because the
↑pBF ↓pBF
excess blood volume goes into
the LV through the VSD.
Dr. Elomina
LVH/BVH RVH BVH LVH RVH
TRANSPOSITION OF THE
PTA without PTA with Tricuspid
GREAT ARTERIES + VSD
TGA TOF Figure 12.5b. Robbins and Cotran Pathologic Basis of
hypoplastic PA hypoplastic PA atresia Disease, 10th ed. 2020
TGA+VSD TAPVR TGA + PS

Pulmonic
atresia
OBSTRUCTIVE LESIONS
• Usually acyanotic (isolated)
ALGORITHM FOR RIGHT-TO-LEFT SHUNTS • Obstruction offers resistance and therefore pressure overload
TGA and TOF can be differentiated by the pulmonary blood flow. Because TOF on the chamber prior to the obstruction
classically has pulmonic stenosis, the pulmonary blood flow is decreased, o Aortic stenosis → LVH
which manifests as decreased pulmonary vascular markings on X-ray. o Pulmonic stenosis → RVH
Dr. Elomina
TETRALOGY OF FALLOT (TOF)
COARCTATION OF AORTA
• Most common cyanotic CHD
FEATURE INFANTILE ADULT
• Defect: anterosuperior displacement of infundibular septum
• Hypoplasia of • Coarctation opposite
• Ventricular septal defect
aortic arch the ligamentum
• Right ventricular outflow tract obstruction Obstruction
Components of proximal to the arteriosum distal to
(RVOT) – subpulmonary stenosis PDA the arch vessels
TOF
• Aorta overriding the VSD Associations • Turner syndrome -
• Right ventricular hypertrophy
• Upper extremity
Chest
• Boot-shaped heart hypertension
Radiograph Clinical • Lower extremity
• Rib notching on CXR:
• Pink TOF: clinically like isolated VSD findings cyanosis
increased blood flow
Clinical • Classical TOF: considerable pulmonic to intercostal vessels
Features stenosis, (+), hypoxic “tet” spells Chamber
(paroxysmal worsening of cyanosis) • RVH (or BVH) • LVH
hypertrophy
TOF Blood flow:
RA → RV –VSD→ LV → Aorta
RV –PS→ (↓ Blood flow) → PA Infantile CoA Blood flow:
→ Lungs → LA → LV → Aorta RA → RV → PA –DA→ Post-
In Tet spells, when the patient coarctation aorta
does something that increases PA → Lungs → PV → LA → LV
venous return (vigorous crying), → Pre-coarctation aorta
instead of oxygenating that extra • RVH happens because it has
blood in the lungs, because of PS, to supply the post-
the blood goes through the VSD coarctation aorta.
instead. That blood remains • BVH can happen probably
unoxygenated because it because the obstruction
bypassed the lungs, hence the provides additional
TETRALOGY OF FALLOT cyanosis. workload on the LV, causing
Figure 12.5a. Robbins and Cotran Pathologic Basis of Dr. Elomina
Disease, 10th ed. 2020 INFANTILE COARCTATION it to hypertrophy.
TRANSPOSITION OF THE GREAT ARTERIES (TGA) OF THE AORTA Dr. Elomina
Figure 12.8a. Robbins and Cotran Pathologic Basis of
• Distinguishing feature: ventriculoarterial discordance Disease, 10th ed. 2020
o The conotruncal septum fails to develop in a spiral fashion Adult CoA Blood flow: Normal
o Most common type: dextro TGA/d-TGA • LVH happens because of the
§ RV → Aorta, LV → Pulmonary trunk additional resistance from
the coarctation.
Association • Infants of diabetic mothers, males
• Hypertension happens because
Chest radiography • Egg-on-the-side appearance of increased blood flow to the
Associated lesions • PDA, VSD branches of the aortic arch,
including the subclavian artery
that supplies the upper limbs.
• The subclavian artery also gives
rise to the internal thoracic
arteries, giving off anterior
TGA +PDA Blood flow: intercostal arteries, before
RA → RV → Aorta –DA→ PA → ending into the superior
Lungs → PV → LA → LV epigastric and musculophrenic
RVH happens because the RV is arteries. Therefore, there will ADULT COARCTATION OF
connected to a higher-pressure also be increased blood flow THE AORTA
systemic circulation. There is through these vessels, hence the Figure 12.8a. Robbins and Cotran Pathologic Basis of
Disease, 10th ed. 2020
increased pulmonary blood flow rib notching.
Dr. Elomina
to the ductus arteriosus.
Dr. Elomina • The collateral circulation between the pre-coarctation and post-
coarctation aorta develops to supply the distal aorta. This is between
TRANSPOSITION OF THE
the superior epigastric artery (from subclavian artery) and
GREAT ARTERIES + PDA inferior epigastric artery (from external iliac artery).
Figure 12.5b. Robbins and Cotran Pathologic Basis of
Disease, 10th ed. 2020 Dr. Elomina
ISCHEMIC HEART DISEASE (IHD) PATTERNS OF MYOCARDIAL INFARCTION

PATTERN SETTING
• Related entities resulting from myocardial ischemia
• Epicardial vessel occlusion (with no
(imbalance between myocardial supply and demand) Transmural
intervention)
• Most common cause: atherosclerosis of epicardial coronary • Regional: Acute plaque change → thrombosis
arteries (coronary artery disease) → lysis of thrombus → blood flow restored
• Syndromes: Subendocardial
• Circumferential pattern: Shock in people
o Angina pectoris (literally “chest pain”) with non-critical CA stenosis
o Myocardial infarction (MI) Multifocal • Microembolization, vasculitis, vascular
o Chronic IHD with heart failure microinfarction spasm
o Sudden cardiac death (SCD) (under Arrhythmias)
In MI, the subendocardial myocardium suffers first because it is the
farthest from the epicardial coronary arteries. In transmural infarction,
ANGINA PECTORIS the entire thickness of the wall is affected because thrombolysis did not
• Paroxysms of precordial chest discomfort due to myocardial occur. In subendocardial infarction, thrombolysis occurred restoring
ischemia that is insufficient to cause myocyte necrosis blood flow before the infarction affected the entire wall thickness.
Dr. Elomina
Stable or Typical • Occurs due to exertion (demand GROSS MORPHOLOGY
(most common form) problem) • Main vessel involved: left anterior descending (LAD) artery >
Prinzmetal • Secondary to coronary artery spasm right coronary artery (RCA), left circumflex artery (LCX)
• Prolonged, severe; may happen even at rest • Myocardial infarction <12 hours usually grossly unapparent
• Usually caused by plaque disruption and o triphenyltetrazolium chloride: pale zone
Unstable
superimposed thrombosis, distal
(crescendo) • 12-24 hours: reddish-blue
embolization of thrombus, and/or
o Congestion, extravasated blood
vasospasm (supply problem)
• 3-7 days: bounded by hyperemic zone of granulation tissue
o Progression to a more sharply defined, yellow-tan, soft infarct
MYOCARDIAL INFARCTION • Several weeks: Fibrous scar
• Death of cardiac muscle due to prolonged ischemia In early MI, it can be difficult to map the infarcted area.
o Loss of contractility: within 1-2 minutes of onset of severe Triphenyltetrazolium chloride stain can help you with that. It is
ischemia applied on fresh cardiac tissue. If the myocardium is viable, the color
o Irreversible injury: 20-30 minutes, in the setting of severe will be brick-red (indicating intact LDH activity). If the myocardium is
ischemia (blood flow ≤10% of normal) necrotic, the color will be pale (unstained).
• Earliest detectable feature of myocyte necrosis: sarcolemmal Dr. Elomina
MICROSCOPIC MORPHOLOGY
membrane disruption → myocardial proteins in blood
• 6-12 hours: Coagulative necrosis
o Basis for chemical tests in MI
• 1-3 days: Acute inflammation (PMNs)
Because irreversible injury happens 20-30 minutes (in-text) or 20-40 minutes • 3-7 days: Macrophages
(Table 12.4 in Robbins 10th (not shown)), that “golden period” becomes the
basis of time-sensitive diagnosis and management of acute MI.
• 7-10 days: Granulation tissue
Dr. Elomina • Healing occurs by fibrosis
EVOLUTION OF MORPHOLOGIC CHANGES IN MYOCARDIAL INFARCTION
TIME GROSS FEATURES LIGHT MICROSCOPE
REVERSIBLE INJURY
0-½ hour • None • None
IRREVERSIBLE INJURY
½-4 hours • None • Usually none; Variable waviness of fibers at border
4-12 hours • Dark mottling (occasional) • Early coagulative necrosis, Edema, hemorrhage
• Ongoing coagulative necrosis
• Pyknosis of nuclei
12-24
• Dark mottling • Myocyte hypereosinophilia
hours
• Marginal contraction band necrosis
• Early neutrophilic infiltrate
• Mottling with yellow-tan infarct • Coagulative necrosis, with loss of nuclei and striations
1-3 days
center • brisk interstitial infiltrate of neutrophils
• Hyperemic border • Beginning disintegration of dead myofibers with dying neutrophils
3-7 days
• Central yellow-tan softening • Early phagocytosis of dead cells by macrophages at infarct border
• Maximally yellow-tan and soft, with • Well-developed phagocytosis of dead cells
7-10 days
depressed red-tan margins • Granulation tissue at margins
10-14 days • Red-gray depressed infarct borders • Well-established granulation tissue with new blood vessels and collagen deposition
• Gray-white scar, progressive from
2-8 weeks • Increased collage deposition, with depressed cellularity
border toward the core of infarct
>2 months • Scarring complete • Dense collagenous scar
• The earliest detectable feature of MI, which is sarcolemmal disruption, happens in ½ to 4 hours post-MI. It can only be documented through electron
microscopy. The cardiac enzymes leak into the bloodstream, and you can detect these in early MI.
• The inflammatory microenvironment in the necrotic myocardium decreases the threshold for arrhythmias, which are common early complications.
• Because the infarct is softest 3-7 days post-MI, this is the time when the myocardium is prone to rupture.
• Remember that cardiac myocytes are permanent tissues, so they heal by fibrosis, which starts with granulation tissue formation, followed by collagen
deposition.
• Contraction band necrosis happens when there are hypercontracted sarcomeres, because of calcium influx (Recall your Chapter 1) in ATP-depleted
cardiac myocytes. The absence of ATP precludes relaxation of these sarcomeres, leaving the myocardium in a tetanic state.
Dr. Elomina
REPERFUSION INJURY DIAGNOSIS OF MI

• Paradoxically increased myocardial damage with • Three parameters:
restoration in blood flow o Clinical symptoms
o The background damage caused by ischemia are compounded o Electrocardiography
by reperfusion (e.g. free radicals produced during reperfusion § STEMI: Transmural infarction
can cause cell injury and death) § NSTEMI: Subendocardial infarction
o Cardiac enzymes
§ Cardiac troponins (Troponins T and I): Greater sensitivity
and specificity than CK-MB.
§ CK-MB: used to assess reinfarction
TIME OF RETURN TO • Minimum pathologic
BIOMARKER PEAK
DETECTION NORMAL criteria
Cardiac o Concentric LVH
3-12 hrs 24 hrs 5-14 days
troponins usually accompanied
CK-MB 4-8 hrs 24 hrs 2-3 days by interstitial fibrosis
• Acute cor pulmonale:
Aherrera JAM et al. IM Platinum, 3rd ed (2018) p. 169. (impaired filling) →
RV dilation
CK-MB detects reinfarction because its levels persist at a shorter duration Findings LA enlargement
• Chronic cor pulmonale:
than cardiac troponins. o History/evidence of
RV hypertrophy
Dr. Elomina
hypertension in
CONSEQUENCES OF MYOCARDIAL INFARCTION other organs
COMPLICATION NOTES • Earliest change: ↑
Contractile • Ventricular dysfunction → pump failure Transverse diameter
dysfunction (cardiogenic shock) of myocytes
Papillary muscle
• Loss of contractility → post-ischemic MR
dysfunction VALVULAR HEART DISEASE
• Free wall (cardiac tamponade) (Most
• Stenosis and insufficiency
Myocardial common)
o Stenosis: incomplete opening → impedes forward flow
rupture • IVS (acute VSD)
o Insufficiency (regurgitation): incomplete closing → permits
• Papillary muscle rupture (acute MR)
reverse flow
• Myocardial irritability → abnormal
Arrhythmias • Can cause pressure and/or volume overload on upstream
conduction → fatal arrhythmias
chambers → CHF
• Dressler syndrome (intense pericarditis
Pericarditis Mnemonic for DIASTOLIC MURMURS: ARMS PaRTS – aortic
weeks post MI)
• From weakening of necrotic regurgitation, mitral stenosis, pulmonic regurgitation, tricuspid stenosis.
Chamber dilation Dr. Rubio
myocardium ETIOLOGY
• ↓ Myocardial contractility → stasis + DISEASE MOST COMMON CAUSE
Mural thrombus Chamber dilation + endocardial injury • Calcification of anatomically normal or
(thrombogenic surface) Aortic stenosis
congenitally bicuspid aortic valves
• Most common cause: large anteroseptal Aortic • Dilation of the ascending aorta, often
Ventricular
infarct → healing with thin wall of scar tissue insufficiency secondary to hypertension and/or aging
aneurysm
• This does not rupture
Mitral stenosis • Rheumatic heart disease
Progressive late
• Chronic IHD (ischemic cardiomyopathy) Mitral
heart failure • Mitral valve prolapse
insufficiency
CHRONIC ISCHEMIC HEART DISEASE MITRAL VALVE PROLAPSE

• Progressive congestive heart failure as a consequence of
• Floppy mitral valve leaflet/s that prolapse/s into the left atrium
accumulated ischemic myocardial damage and/or inadequate during systole
compensatory responses
• Most common cause: unknown
• Usually due to decompensation of hypertrophied non-infarcted
o Fibrillin-1 gene defect is the common known cause
myocardium
• Usually clinically silent, but may develop:
• Morphology:
o Infective endocarditis, Mitral insufficiency, systemic infarcts
o Gross: Cardiomegaly, LVH and dilation, MI changes (embolization of leaflet thrombi), and arrhythmias
o Microscopic: Myocardial hypertrophy, diffuse subendocardial
• Morphology
myocyte vacuolization and interstitial fibrosis
o Gross: Ballooning (hooding) of mitral leaflets
o Microscopic: Myxomatous degeneration of spongiosa layer
ARRHYTHMIAS + Attenuation of the collagenous fibrosa
• Abnormalities in rhythm
o HR is an important determinant of CO; too slow (↓ HR) or too RHEUMATIC FEVER
fast rhythms (↓ SV) can both depress CO AND RHEUMATIC HEART DISEASE
• Duration: Sustained or paroxysmal RHEUMATIC FEVER
• Origin: Supraventricular or ventricular
• Acute, immunologically mediated, multisystem inflammatory
• Heart rate: Bradyarrhythmia or Tachyarrhythmia
disease classically occurring a few weeks after an episode of
• Common cause: ischemic injury
Group A Streptococcal pharyngitis or pyoderma
• Genetic defects (channelopathies) predispose patients to
• Antibodies and CD4+ T-cells directed against Streptococcal M
arrhythmias
proteins also recognize cardiac self-antigens “molecular mimicry”
Recall the physiologic formula for cardiac output (CO): CO = HR (heart
rate) x SV (stroke volume). HR and SV are directly associated with CO. • Sequelae: Rheumatic heart disease
Dr. Rubio • Morphology
o Aschoff bodies are seen in all heart layers → pancarditis
SUDDEN CARDIAC DEATH (SCD)
Aschoff • Composed of foci of T cells, plasma cells
• Unexpected death from cardiac causes either without symptoms, bodies (occasional), and Anitschkow cells
or within 1 to 24 hours of symptom onset • Activated plump macrophages
• Most common cause: coronary artery disease Anitschkow
• Have central, slender, wavy ribbon of
• Most common mechanism: lethal arrhythmia (asystole or cells
chromatin → (aka as caterpillar cells)
ventricular fibrillation) • Review the Jones Criteria for Rheumatic Fever in IM
HYPERTENSIVE HEART DISEASE (HHD) RHEUMATIC HEART DISEASE

LEFT-SIDED RIGHT-SIDED • Most commonly involved valve: Mitral > Aortic > Tricuspid >
(SYSTEMIC) (PULMONARY) Pulmonic
• Pulmonary • Cardinal changes: Leaflet thickening, commissural fusion and
hypertension shortening, and thickening and fusion of the tendinous cords
o Most common cause: o Fish mouth deformity: Calcification and fibrous bridging of
left-sided heart valvular commissures
failure • Small (1-2 mm) vegetations overlying necrotic
Etiology • Systemic hypertension Verrucae
• Cor pulmonale: foci along the lines of closure
Isolated pulmonary MacCallum • Subendocardial irregular thickenings (usually
HHD plaques in left atrium), exacerbated by regurgitant jets
o Pulmonary and chest
wall disorders
In ARF, the characteristic manifestation of carditis is Mitral regurgitation
(MR). In RHD, the characteristic finding is Mitral stenosis (MS). In the
NON-INFECTED VEGETATIONS
exam, pay close attention to the timing of the murmur if it’s systolic (MR)
or diastolic (MS).
Dr. Elomina
INFECTIVE ENDOCARDITIS (IE)

• Microbial infection of heart valves and mural endocardium
• Hallmark of IE: vegetations
• Types: Acute and Subacute
ACUTE IE SUBACUTE IE FOUR MAJOR FORMS OF VEGETATIONS
• S. aureus (also NBTE*/MARANTIC LIBMAN-SACKS
Common • Viridans Streptococci FEATURE
common in IV drug ENDOCARDITIS ENDOCARDITIS
organisms • HACEK organisms
users) • Hypercoagulable
Valves • Previously healthy • Diseased Associations • SLE
states
Tissue • Immune complex
• More pronounced • Less pronounced • Hypercoagulable state
destruction Pathogenesis deposition →
→ thrombosis
HACEK: Haemophilus spp, Aggregatibacter spp., Cardiobacterium spp., inflammation
Eikenella corrodens, Kingella spp. MORPHOLOGY
Dr. Elomina • Small or medium-
MORPHOLOGY • Small sterile thrombi sized sterile
• Vegetations: friable, bulky, potentially destructive lesions Gross on the leaflets of vegetations on either
containing fibrin, inflammatory cells, and bacteria or other cardiac valves or both sides of the
valve leaflets
organisms → may embolize (septic embolus)
• Bland thrombi • Intense vasculitis and
• Most commonly affected: aortic and mitral
loosely attached to fibrinoid necrosis of
o Right valves in IV drug users Histology underlying valve valve substance
• Large, irregular masses on the valve cusps that may extend into • No invasion or
chordae inflammation
• Acute IE involves more tissue destruction than subacute IE In differentiating the 4 major forms of vegetations, please take note of the
• Subacute IE: granulation tissue at base 1) sterility of the vegetation (sterile or non-sterile), 2) location of the
lesions respective of the involved valve, and 3) the presence of
Because degree of tissue destruction is less in subacute IE, the repair process absence of destruction to the tissue. Refer to the figure below.
catches up, which is why we see granulation tissue (hallmark of repair). Dr. Rubio
Dr. Elomina
• Review the Duke Criteria for Infective Endocarditis in IM
CARDIOMYOPATHIES
• “Heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not
invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic.”
• Groups
o Primary: Predominantly cardiac involvement; genetic or acquired (Viral myocarditis, Anthracycline toxicity)
o Secondary: Cardiac involvement as a consequence of systemic disease (Hemochromatosis, Amyloidosis)
PATTERNS OF CARDIOMYOPATHY
FEATURE DILATED (Most common) HYPERTROPHIC RESTRICTIVE
EF • < 40% • 50-80% • 45-90%
Dysfunction • Systolic (impaired contractility) • Diastolic (impaired compliance or distensibility)
• Genetic
• Alcohol
• Amyloidosis
• Peripartum • Genetic mutations encoding for sarcomeric proteins
• Radiation-induced
• Myocarditis (Most common cause)
fibrosis
Causes • Hemochromatosis • Friedreich ataxia
• Endomyocardial
• Chronic anemia • Storage diseases
fibrosis
• Doxorubicin • Infants of diabetic mothers
• Idiopathic
• Sarcoidosis
• Idiopathic
• Ischemic, valvular, hypertensive, • Hypertensive heart disease • Pericardial
Mimic
congenital heart disease • Aortic stenosis constriction
• Enlarged, heavy, flabby heart with • Massive myocardial hypertrophy, usually without
• Fibrosis
dilation of all chambers, usually with ventricular dilation
• Amyloidosis:
Morphology concomitant hypertrophy o Asymmetrical septal hypertrophy: interventricular
Amyloid deposition
• Non-specific histologic findings septum thicker than ventricular free wall → banana-
like configuration of left ventricular cavity
Dilated cardiomyopathy is characterized by inability to pump blood out of the heart because the dilated chamber cannot contract well. Hypertrophic
cardiomyopathy is characterized by increased wall thickness of a heart chamber that it compromises the volume it can accommodate (filling problem). Restrictive
cardiomyopathy is characterized by stiffened, non-compliant walls that limit the volume the heart chamber can accommodate (filling problem).
Dr. Elomina
MYOCARDITIS Answer: The inflammatory process (due to cytokines and immune cells)
• Etiology: Infectious or non-infectious inflammation lowers the threshold for arrhythmias.
Dr. Elomina &Dr. Rubio
• Coxsackie B (most common cause), Coxsackie A,
Viral
other enteroviruses PERICARDIAL DISEASES
• T spiralis (most common helminthic cause), PERICARDIAL EFFUSIONS
Helminthic
T cruzi (etiologic agent of Chagas disease) • Normal: 50 mL serous fluid
Immune • Hypersensitivity, giant-cell myocarditis
• Accumulation of serous fluid, blood, or pus
• Clinical presentations: 1) asymptomatic, 2) heart failure & • Acute: symptomatic even at low-volume accumulations
arrhythmias, OR 3) dilated cardiomyopathy o Cardiac tamponade (Beck triad: 1. Increased JVP; 2. arterial
• Morphology hypotension; 3. muffled heart sounds)
Active • Mononuclear (lymphocytic) infiltrates • Chronic: asymptomatic even at large-volume accumulations
myocarditis associated with apoptotic myocytes (pericardium dilates)
Question: Why does myocarditis cause arrhythmias? o Radiographically: water-bottle appearance
PERICARDITIS Increased • Immuno-mediated injury (SLE, drugs)
ACUTE CHRONIC /HEALED destruction or • Splenomegaly (sequestration of cells)
• Fibrinous / serofibrinous sequestration • ↑ peripheral utilization (due to
• Adhesive mediastino-
(most common) (HYPERcellular OVERWHELMING bacterial, fungal
pericarditis: parietal
o Causes: Dressler marrow) infections)
pericardium adheres
syndrome, uremia,
with mediastinal
Forms
radiation, rheumatic
structures
REACTIVE PROLIFERATION
fever, SLE, trauma
(surgery) • Constrictive LEUKOCYTOSIS
pericarditis: heart
• Purulent: Infections • Increase in the number of leukocytes in peripheral blood
enclosed in a dense
• Hemorrhagic: Neoplasms • Clinically significant situations (because they can mimic
fibrocalcific scar
• Caseous: TB neoplastic proliferation of white cells)
o Acute viral infections: ↑atypical lymphocytes (can mimic
ACUTE CHRONIC /HEALED lymphoid leukemias)
• Adhesive o Leukemoid reaction: presence of immature granulocytes (can
mediastinopericarditis: mimic chronic myelogenous leukemia - CML)
• Chest pain, relieved when
Systolic retraction of
leaning forward
Clinical the rib cage and TYPES OF LEUKOCYTOSIS
• Pericardial friction rub
findings diaphragm, pulsus FORM CAUSES
(most striking clinical
paradoxus Neutrophilic • Acute bacterial infections, tissue necrosis
finding)
• Constrictive pericarditis: Eosinophilic • Allergies, parasitic infestations, drug reactions
diastolic dysfunction
• Rare; indicative of a myeloproliferative disorder
Basophilic
Do you remember restrictive cardiomyopathy? Well, it’s a bit similar to (CML)
constrictive pericarditis, in that both are characterized by impaired • Chronic infections (TB), autoimmune disorders,
filling. But this time, it’s the pericardium that is fibrosed. Monocytic
inflammatory bowel diseases
Dr. Elomina
• Chronic immunologic stimulation (TB), viral,
Lymphocytic
Pertussis
CARDIAC TUMORS Adapted from Table 13.3. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
• Uncommon; primary malignant tumors are rare: LYMPHADENITIS

o Angiosarcoma, poorly differentiated sarcomas • Reactive changes in lymph nodes secondary to antigenic
Most common primary stimulation
• Myxomas
cardiac tumor in adults • Types of lymphadenitis
Most common primary Acute • PAINFUL, has prominent large reactive
• Rhabdomyoma
cardiac tumor in children lymphadenitis germinal centers; neutrophilic infiltrates
Common sources of • Lung, Breast, Melanomas, Chronic • PAINLESS, with specific patterns
metastasis Leukemias, Lymphomas lymphadenitis depending on pathology (see below)
MYXOMA RHABDOMYOMA
Location • Atria; LA > RA • Ventricles NORMAL LYMPH NODE
• McCune-Albright • Tuberous HISTOLOGY
Associations syndrome sclerosis https://qrs.ly/8ycmdot
• Carney complex complex
• Ball-valve obstruction • Obstruction
PATTERN MORPHOLOGY EXAMPLES
• Embolization • May regress over
Clinical Follicular • ↑ in number of
• Constitutional time (like most • Rheumatoid arthritis
presentation hyperplasia secondary lymphoid
symptoms – due to IL-6 pediatric • Toxoplasmosis
(humoral follicles (with
production tumors) response)
• Early HIV infection
germinal centers)
• Stellate/globular • Large cells with ↑ Paracortical
myxoma cells glycogen hyperplasia • Expansion of the
embedded within acid • Spider cells: • Acute viral infections
Histology (cell-mediated T-cell zones
mucopolysaccharide myocyte with response)
matrix with vessel or thin strands of • ↑ in size and number
gland-like structures cytoplasm Sinus or of cells lining • Nonspecific
reticular lymphatic sinusoids • Usually in
12. WHITE BLOOD CELLS, LYMPH NODES, SPLEEN, histiocytosis • ↑ intrasinusoidal malignancies
AND THYMUS macrophages
DISORDERS OF WHITE BLOOD CELLS

• Deficiency states
NEOPLASTIC PROLIFERATION OF WHITE CELLS
• Leukemia • Myelodysplastic syndrome
• Proliferative diseases (Reactive & Neoplastic)
• Lymphoma • Myeloproliferative neoplasms
DEFICIENCY STATES • Plasma cell neoplasms
LEUKOPENIA CLINICAL PRESENTATIONS OF LEUKEMIA AND LYMPHOMA

• Infiltration of bone marrow → bone marrow
• ↓ number of circulating leukocytes; most commonly neutrophils
failure → anemia, leukopenia, thrombocytopenia
(neutropenia)
Leukemia → pallor, bleeding diathesis, infections
o Agranulocytosis: marked neutropenia
• Escape of leukemic cells form bone marrow →
§ Highly susceptible to bacterial and fungal infections
leukocytosis
§ Most common cause: drug toxicity
Lymphoma • Distinct tissue masses → mass effects
o Lymphopenia (less common)
§ Advanced HIV and other diseases LEUKEMIA
ACUTE CHRONIC
NEUTROPENIA
Age • Usually younger • Usually older
• Mechanisms: Morphological
• Suppression of HSC (aplastic anemia) • Usually more • Usually more
appearance of
• Suppression of precursor cells (drugs) primitive mature
Inadequate cells
• Congenital (Kostmann syndrome) Clinical
granulopoiesis • Usually aggressive • Usually indolent
• Ineffective hematopoiesis (Megaloblastic course and
(HYPOcellular • Severe symptoms • Subtle symptoms
marrow) anemia, Myelodysplastic syndrome – presentation
HYPERCELLULAR MARROW as Amenability
compensatory response) • Usually amenable • Usually resistant
to treatment
LEUKEMIAS CHRONIC LEUKEMIAS
• Acute lymphoblastic leukemia/lymphoma (ALL) CHRONIC LYMPHOCYTIC LEUKEMIA, SMALL LYMPHOCYTIC
Acute
• Acute myeloid leukemia (AML) LYMPHOMA (CLL/SLL)
• Chronic lymphocytic leukemia/Small lymphocytic
Chronic lymphoma (CLL/SLL)
• Most common leukemia of adults in Western world
CLL SLL
• Chronic myeloid leukemia (CML)
Age of onset Elderly (~60 years)
• Constitutional symptoms
ACUTE LEUKEMIAS • Hepatosplenomegaly, lymphadenopathy
ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (ALL) Clinical • Immune abnormalities: Infection or
• Most common cancer in children presentation Autoimmune hemolytic anemia (AIHA)
• Two types: Pre B-cell ALL (more common, 85% of cases), Pre T- and/ or Idiopathic thrombocytic purpura
cell ALL (ITP)
Peripheral blood
B-CELL ALL T-CELL ALL • > 5,000/mm3 • < 5,000/mm3
lymphocytosis
• Adolescent • Lymph node: sheets of small lymphocytes
Age of onset • Early childhood Histologic
males with proliferation centers
Clinical • Bone marrow findings
• Thymic masses • PBS: small lymphocytes with Smudge cells
presentation failure Notable sequela • Richter syndrome (progression to DLBCL)
Unique metastatic • CNS (meningeal spread) and testis
sites (sanctuary sites) • SLL is a CLL that falls short of the absolute lymphocyte count
requirement.
• t(12;21), t(9;22),
Genetic • NOTCH-1 (70%) • Proliferation centers are aggregates of large, activated
etc.
lymphocytes and these are where the growth of neoplastic B cells
• Hypercellular marrow with occurs.
lymphoblasts Dr. Elomina
Histologic findings
• Lymphoblasts in peripheral blood
• PAS (+) cytoplasmic material
Immuno- • TdT (+) – lymphoblast marker
phenotype • Other surface markers depend on lineage
• ALLs are very unique in that they can metastasize to areas devoid of
immune surveillance (sanctuary sites). Therefore, ALLs are capable of
producing CNS symptoms.
CLL WITH SMUDGE CELLS (ARROW).
• The presence of t(12;21) (ETV6-RUNX1) is a favorable prognostic Figure 19-1A. Rodak BF and Carr JH. Clinical Hematology Atlas, 5th ed. 2017.
factor in ALLs. ALLs with Philadelphia chromosome are amenable to
treatment with Tyrosine Kinase Inhibitors. CHRONIC MYELOID LEUKEMIA (CML)
Dr. Elomina • BCR-ABL t(9;22) (Philadelphia chromosome) → preferential
proliferation of granulocytic and megakaryocytic lines
ACUTE MYELOID LEUKEMIA (AML)
• Constitutional symptoms
• Neoplastic proliferation of myeloid precursors • Splenomegaly (extramedullary
• Genetically heterogenous Clinical hematopoiesis)
• Bone marrow biopsy: ≥20% myeloblasts presentation • Accelerated phase: worsening anemia or
• Peculiar clinical manifestations thrombocytopenia with basophilia
o Disseminated intravascular coagulation (APML) • Blast crisis: resembles acute leukemia
o Mucocutaneous deposits (AML with monocytic • Hypercellular marrow w/ sea-blue histiocytes
differentiation) • WBC > 100,000/mm3 (all stages of granulocyte
o Myeloid sarcoma (Soft tissue mass) maturation)
Morphology
• Variable immunophenotype • Low leukocyte alkaline phosphatase (LAP)
o Depending on lineage • Blast count <10%
o Myeloperoxidase (MPO): Immunohistochemical (IHC) stain • Thrombocytosis
• The 20% rule need not be followed as long as the defining genetic • CML belongs to a group of diseases called myeloproliferative disorders.
abnormality is demonstrated e.g., APML. The main theme of these diseases is activating mutations in your tyrosine
• Aleukemic leukemia can happen if the leukemic cells remain contained kinases that lead to cellular proliferation. This is why CML responds to
in the bone marrow. your tyrosine kinase inhibitors e.g., Imatinib (Gleevec).
Dr. Elomina
• Another feature of myeloproliferative disorders is their tendency to
transform into AML, exemplified by CML in Blast crisis.
• LAP is produced by normal leukocytes. In leukemoid reactions
ACUTE PROMYELOCYTIC LEUKEMIA (APML) where there is reactive proliferation of normal leukocytes, LAP is
• Genetic mutation: t(15;17) increased. This differentiates leukemoid reactions from CML.
Dr. Elomina
• Auer rods: needle-like azurophilic granules
• Faggot cells: cells with numerous Auer rods
• Curable in 80% of cases with all-trans retinoic acid
This is the gayest leukemia around. It has a lot of rods inside it. Because
of that, it is called a faggot, and it is associated with the D… IC. HAHAHA
Dr. Elomina
CHRONIC MYELOID LEUKEMIA.

Figure 17-1A. Rodak BF and Carr JH. Clinical Hematology Atlas, 5th ed. 2017.
LYMPHOMA
HODGKIN NON-HODGKIN
• Single axial group • Multiple
Lymph node
ACUTE PROMYELOCYTIC LEUKEMIA WITH AUER RODS (B). of nodes (cervical, peripheral
involvement
Figure 15-4A. Rodak BF and Carr JH. Clinical Hematology Atlas, 5th ed. 2017. mediastinal, etc.) nodes
In practice, it is hard to differentiate lymphoblasts from myeloblasts, so Spread • Contiguous • Non-contiguous
we just call them blasts. Definitive diagnosis is established by flow Mesenteric nodes
cytometry. and Waldeyer ring • Rare • Common
Dr. Elomina
involvement
Extranodal
• Rare • Common
presentation
HODGKIN LYMPHOMA • Arises in sites of chronic

• Regression may
inflammation:
• Proliferation of neoplastic Reed-Sternberg (RS) cells Marginal occur with
o H. pylori: Stomach
o Diagnostic RS cell: Large, multiple nuclei or single with zone removal of
o Sjögren syndrome:
multiple lobes; each with nucleolus (“Owl-eye nucleus”) lymphoma inciting agent
Salivary gland
o Secrete cytokines that recruit other cells → Mixed (MZL) • Richter
o Hashimoto thyroiditis:
inflammatory cell infiltrate (lymphocytes, macrophages, phenomenon
Thyroid gland
granulocytes) • Aggressive: rapidly
• 5 subtypes divided into two broad groups: Diffuse
enlarging mass
o Classical (CHL) large B-cell • Most common
• Significant nuclear atypia,
lymphoma NHL
•
Nodular sclerosis (NSHL) – most common numerous mitosis
(DLBCL)
Classical •
Mixed cellularity (MCHL) • Has large cells
Hodgkin •
Lymphocyte rich (LRHL) • Associated with latent
lymphoma •
Lymphocyte depleted (LDHL) – worst prognosis, EBV infection • t(8;14)
associated with PLHIV patients • Has “starry sky” pattern • One of the
Nodular lymphocyte predominant – non-neoplastic tingible- fastest-growing
Burkitt
body macrophages human tumor
Diagnosis of Hodgkin lymphoma relies on the presence of RS cells on an lymphoma
(Stars) dotting sheets of • Has good
inflammatory background (due to secretion of cytokines → (BL)
neoplastic lymphoid cells response to
chemotaxis). (Sky) intensive
Dr. Elomina
• Has intermediate-sized chemotherapy
cells
Progression to DLBCL (Richter phenomenon) is the most dangerous
consequence of non-aggressive B-cell lymphomas. It is seen in SLL, FL, MZL
Dr. Rubio
REED-STERNBERG CELLS
Figure 28-1. Jaffe ES et al. Hematopathology, 2nd ed. 2017. P. 530
CLINICAL MANIFESTATIONS
• Painless lymphadenopathy
o Spread: Lymph nodes → Spleen → Liver → Bone marrow, other BURKITT LYMPHOMA’S “STARRY SKY” PATTERN
Figure 24-2B. Jaffe ES et al. Hematopathology, 2nd ed. 2017. p. 452
tissues
• Fever, Night sweats, Weight Loss PERIPHERAL T- AND NK-CELL LYMPHOMAS
• Stage: Most important prognostic variable MORPHOLOGY/
LYMPHOMA REMARKS
PRESENTATION
TREATMENT • ALK gene
• Large, anaplastic cells
• Radiotherapy (↑ incidence of lung and breast cancers and mutations –
Anaplastic with horseshoe-shaped
melanomas) positivity
large cell nuclei, and voluminous
• Chemotherapy (↑ incidence of AML) denotes good
lymphoma cytoplasm
prognosis (seen
• Anti-CD30 agents (Brentuximab) (ALCL) • CD30-positive T-cell
in younger
• Immune checkpoint inhibitors (PD-L1/2 inhibitors) lymphoma
patients)
(Pembrolizumab): Used in patients who fail to respond to • Mycosis fungoides:
conventional chemotherapy presence of neoplastic • CD4+ T-cell
T-cells in epidermis & tumor of the
NON-HODGKIN LYMPHOMA Mycosis
upper dermis (Pautrier skin
PERIPHERAL B-CELL LYMPHOMAS microabscesses) • Has indolent
fungoides /
• Small lymphocytic lymphoma (SLL) • Sézary syndrome: prognosis
Small cell Sézary
• Mantle cell lymphoma (MCL) generalized exfoliative • May transform
lymphocytic syndrome
• Follicular lymphoma (FL) erythroderma + leukemia into aggressive
proliferation of Sézary cells (T cells T-cell
• Marginal zone lymphoma (MZL)
with cerebriform lymphoma
Aggressive B-cell • Diffuse large B-cell lymphoma (DLBCL)
nuclei)
lymphomas • Burkitt lymphoma (BL)
PERIPHERAL T-CELL AND NK-CELL LYMPHOMAS ALCL merits special mention because not all CD30-positive lymphomas
• Anaplastic large cell lymphoma, ALK-positive (ALCL) are Hodgkin lymphomas.
Dr. Elomina
• Mycosis fungoides/ Sézary syndrome
PERIPHERAL B-CELL LYMPHOMAS PLASMA CELL NEOPLASMS
MORPHOLOGY/
LYMPHOMA REMARKS • Neoplastic plasma cell proliferation
PRESENTATION
o Multiple myeloma: most important plasma cell neoplasm
• Lymph node: sheets of
Small • Produces monoclonal immunoglobulin (M protein)
small lymphocytes with • Can progress to
lymphocytic
proliferation centers DLBCL (Richter MULTIPLE MYELOMA
lymphoma
• PBS: small lymphocytes phenomenon) FEATURE MULTIPLE MYELOMA
(SLL)
with Smudge cells Age of onset • 65-70 years
• t(11;14) • Plasmacytoma
Mantle cell • Seemingly follicular
• Moderately • Multiple lytic “punched-out” bone lesions
lymphoma architecture with Clinical
aggressive and • Hypercalcemia
(MCL) expanded mantle zones presentation
incurable • Renal failure
• Follicular architecture • t(14;18) • Deficient humoral immunity
with uniformly sized • Most common • Plasmacytoma: diffuse sheets of plasma cells
follicles, with thinned form of indolent or plasmablasts
Follicular
mantle zones NHL in the US • Plasma cells may contain Ig
lymphoma
• Presence of Centroblasts • Indolent, and Histologic o Flame cells: cells with fiery red cytoplasm
(FL)
• Has frequent bone incurable findings o Mott cells: cells with multiple grapelike
marrow involvement • Richter cytoplasmic inclusions
(paratrabecular) phenomenon o Russell bodies: globular cytoplasmic inclusions
o Dutcher bodies: globular nuclear inclusions
• PBS: Rouleaux formation LINEAGE CHANGES
• Hypercalcemia • Ring sideroblasts: erythroblasts with iron-
Laboratory
• Serum protein electrophoresis: monoclonal laden mitochondria (perinuclear granules on
findings
gammopathy (IgG) Prussian Blue stain)
• Bence-Jones proteinuria (Ig light chain) • Megaloblastoid changes
Erythroid
1. Infections (Most common) • Nuclear budding abnormalities:
Mortality
2. Renal failure (misshapen (polypoid outline) nuclei)
• Macrocytosis, poikilocytosis (in peripheral
PATHOPHYSIOLOGY
blood)
• Osteoclast-like activity of tumor cells → Hypercalcemia
• Hypogranular neutrophils
o Lytic bone lesions → Pathologic fractures → Pain
• Pseudo-Pelger Huët cells: bilobed
• ↑ Production of abnormal Igs Granulocytic
neutrophil
o RBCs stick to one another → Rouleaux formation • Monolobated neutrophil
o Bence Jones proteinuria (toxic to renal epithelial cells) → renal • Hypolobation (Normal = 4-6) lobes
failure (Myeloma kidney) Megakaryocytic • Pawn Ball megakaryocyte: multinucleation
• ↓ Production of normal Igs → Impairment of humoral immunity • Giant platelets (in peripheral blood)
→ recurrent bacterial infections • < 20%: Bone marrow
For multiple myeloma, remember CRAB: hyperCalcemia, Renal Blasts
• < 10%: Peripheral blood
dysfunction, Anemia, and Bone lesions.
Dr. Elomina MYELOPROLIFERATIVE NEOPLASMS
• Chronic myelogenous leukemia (discussed in Leukemias)
• Polycythemia Vera (PV)
• Essential thrombocytosis (ET)
• Primary myelofibrosis (PMF)
COMMON FEATURES
• Increased proliferative drive in the bone marrow (hypercellular
MYELOMA CELL WITH RUSSELL BODIES
Figure 26-8. Jaffe ES et al. Hematopathology, 2nd ed. 2017. p. 478. marrow)
Mnemonic: Dutcher is where the DNA is (nucleus); and Russell is where • Extramedullary hematopoiesis (hepatosplenomegaly and
the RNA is (cytoplasm) lymphadenopathy)
Dr. Rubio • Spent phase: marrow fibrosis with consequent cytopenias
• Variable transformation to acute leukemia
MYELODYSPLASTIC SYNDROME • The genetic basis for myeloproliferative neoplasms is constitutive
• Disorder of defective hematopoietic maturation → ineffective activation of tyrosine kinases. Simply put, when you have tyrosine
hematopoiesis kinase activation, it leads to cellular proliferation.
• There will come a time that your marrow has no more left to give and
o May occur de novo or after chemotherapy
it will be fibrosed. At this time, other sites take over the role of
o Usual genetic basis: Cytogenetic abnormalities hematopoiesis (extramedullary hematopoiesis)
(chromosomal deletions, monosomies, trisomies) Dr. Elomina
• Increased risk of transformation to AML

o Genetic mechanisms of MDS overlap with those of AML
MYELOPROLIFERATIVE
• Usually a disease of the elderly NEOPLASMS
• Clinical presentation: bone marrow failure (cytopenias)
https://qrs.ly/a5cmdr2
o Usual cause of death: bleeding and infections
• Poor prognosis
MYELOPROLIFERATIVE NEOPLASMS
PARAMETER PV ET PMF
JAK2 mutations • > 95% • 50-60% • 50-60%
• Extensive collagen deposition in the marrow by non-
Main • Increase in
• Increase in all cell lines neoplastic fibroblasts because of profibrogenic
abnormality megakaryocytic lines
factors from neoplastic megakaryocytes
Transformation
• 1-2% • Uncommon • 5-20%
to AML
• Plethora
• Hyperuricemia • Anemia
Clinical • Bleeding and • Splenomegaly
• Bleeding and thrombosis
presentation thrombosis • Hyperuricemia
• Pruritus and peptic • Constitutional symptoms
ulcer
• Leukoerythroblastosis: release of erythroid and
• Basophilia • Mild leukocytosis
PBS findings early granulocytic precursors into peripheral blood
• Large platelets • Large platelets
• Dacrocytes (teardrop cells)
• Pre-fibrotic phase: trilineage hyperplasia + dysplastic
• Hypercellular marrow • Mild hypercellularity
Marrow megakaryocytes
with increase in • Increased megakaryocytes
findings • Fibrotic phase → Osteosclerosis: fibrotic marrow
trilineage hyperplasia (large but not dysplastic)
space converted into bone
DISEASES OF THE SPLEEN SPLENIC INFARCT
SPLENOMEGALY • Due to the occlusion of major splenic artery and branches
• Can be bland or septic
• Splenomegaly, cytopenias (from
Hypersplenism increased sequestration & destruction of
Bland infarct • Coagulative necrosis
blood cells) Septic infarct • Suppurative necrosis
Acute • Non-specific acute splenitis
splenomegaly • Secondary to bloodborne infections SPLENIC RUPTURE
• Due to chronic venous congestion • Can be due to trauma or acutely enlarged spleens
Chronic o Usually happens in neoplastic cases, infectious pathology (EBV-
(right-sided heart failure, cirrhosis,
splenomegaly associated disease), sequestration crisis in sickle cell anemia
portal or splenic vein thrombosis)
DISEASES OF THE THYMUS ANEMIA

• THYMIC HYPOPLASIA/APLASIA • Reduction of the total circulating red cell mass below normal limits;
o In DiGeorge syndrome (CATCH22) decrease in O2 carrying capacity of blood → tissue hypoxia
• THYMIC HYPERPLASIA • Clinically: pallor, weakness, easy fatigability, dyspnea on mild
o Thymic follicular hyperplasia exertion
§ ↑ B-cell germinal centers in thymus • Laboratory findings:
o In Myasthenia gravis and other autoimmune diseases o ↓ Hgb, ↓ Hct
• TYHMOMA o MCV: microcytic (↓), normocytic (N), macrocytic (↑)
o Thymic epithelial cell tumors o MCH: hypochromic (↓), normochromic (N)
o 3 types:
§ Cytologically benign, noninvasive
ANEMIA OF BLOOD LOSS
§ Cytologically benign, invasive (capsular invasion) • Loss of intravascular volume → redistribution of interstitial fluid to
§ Cytologically malignant (Thymic carcinoma) intravascular component → dilutional anemia → hypoxia
• Most common: Squamous cell carcinoma • Hypoxia → EPO secretion → Reticulocytosis
• Lymphoepithelioma-like carcinoma (looks like • Catecholamine secretion → Granulopoiesis → Leukocytosis
nasopharyngeal carcinoma): associated with EBV • ↑ Platelet synthesis → Thrombocytosis
o Paraneoplastic syndromes: HEMOLYTIC ANEMIAS
§ Myasthenia gravis, pure red cell aplasia (PRCA), other
autoimmune diseases • Common features:
1. Shortened red cell life span (< 120 days)
• ↑ Peripheral destruction of red cells
13. RED BLOOD CELL AND BLEEDING DISORDERS 2. ↑ EPO levels → ↑ Erythropoiesis (compensatory)
RED CELL DISORDERS • Reticulocytosis
• Anemia 3. Accumulation of hemoglobin degradation products
• Polycythemia • Jaundice or Gallstones
CBC PARAMETERS THAT REFER TO ERYTHROCYTE • CAUSE of hemolysis:
NUMBER AND FUNCTION o Intrinsic: Inherent defects in RBCs
§ Usually, defects that render red cells less deformable
PARAMETER DEFINITION o Extrinsic: External causes
• Conjugated protein that serves as § Mechanical injury (microangiopathic hemolytic anemia),
Hemoglobin (Hgb) vehicle for the transportation of O2 complement fixation (PNH), intracellular parasites (P.
and CO2 falciparum), exogenous toxic factors (clostridial sepsis)
Hematocrit (Hct) • Ratio of the volume of erythrocytes • TYPE of hemolysis:
(Packed cell volume) to that of the whole blood o Intravascular: Hemoglobinemia/-uria, hemosiderinuria
Erythrocyte indices o Extravascular: generally, with Splenomegaly
Mean corpuscular § Less deformable red cells get trapped in the spleen
• Average volume of a red cell
volume (MCV) § Splenectomy corrects anemia
Mean corpuscular • Average Hgb content (weight) of a CRISES IN HEMOLYTIC ANEMIAS
hemoglobin (MCH) red cell
• Events that lead to worsening of anemias and other associated
Mean corpuscular
clinical manifestations
hemoglobin • Average concentration of
• Parvovirus B19 infection → destruction of
concentration hemoglobin in each RBC Aplastic
erythroid precursors
(MCHC) crisis
• Seen in sickle cell anemia, hereditary spherocytosis
Red cell distribution • Reflects variability in red cell size • Concurrent conditions what ↑ splenic red cell
width (RDW) and shape Hemolytic
destruction (EBV infection) → splenomegaly
crisis
MATHEMATICAL DERIVATION OF ERYTHROCYTE • Seen in hereditary spherocytosis
PARAMETERS • Massive entrapment of red cells → rapid splenic
Sequestration
enlargement, hypovolemia, shock
• Erythrocyte indices crisis
• Seen in sickle cell anemia
o MCV (fL) = Hct / RBC (x 1012/L)
o MCH (pg) = Hgb (g/dL) / RBC x 1012/L QUICK SHEET
o MCHC (g/dL) = (Hgb (g/dL)/Hct) x 100 HEMOLYTIC ANEMIAS: TIPS
• All intrinsic types exhibit extravascular hemolysis, EXCEPT PNH
• Rule of three (intravascular)
o Hgb (g/dL) x 3 = Hct (%) ± 3% • G6PD is under intrinsic type, but exhibits BOTH intra- and
§ This rule only applies to normocytic, normochromic red cells extravascular hemolysis
§ Can serve as a CHECKPOINT • Immuno-hemolytic anemias may exhibit BOTH intra- and
• If there are discrepancies in Hgb and Hct, blood film should extravascular hemolysis, depending on type
be checked • All extrinsic types exhibit intravascular hemolysis
REPRESENTATIVE HEMOLYTIC ANEMIAS
COMPLETE BLOOD COUNT • Hereditary spherocytosis (HS)
https://qrs.ly/epcmdrw • G6PD deficiency
• Sickle cell anemia (SCA)
• Thalassemia
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Immunohemolytic anemias
• Hemolytic anemias secondary to red cell trauma
REPRESENTATIVE HEMOLYTIC ANEMIAS
HS G6PD DEFICIENCY SCA
Inheritance • Autosomal dominant • X-linked recessive • Autosomal recessive
• Defects in membrane skeleton • ↓NADPH needed for glutathione reduction → • Mutation on the 6th codon of the β-globin
(spectrin, ankyrin, Band 3, and red cells vulnerable to lysis with oxidative gene (glutamate → valine) → Red cells
Main pathology
Band 4.2) → Less deformable red stress (most common cause: infections, by become sickled when exposed to
cells drugs and foods) ↓intracellular pH and ↓O2 tension
Cause of hemolysis • Intrinsic • Intrinsic • Intrinsic
• Intravascular: Heinz bodies cause
• Extravascular (↑ splenic membrane damage
Type of hemolysis • Extravascular
sequestration) • Extravascular: Heinz bodies are “bitten
off” by the spleen
HS G6PD DEFICIENCY SCA
• Sickle cells (drepanocytes), target cells
• Heinz bodies: derived from hemoglobin (codocytes) (dehydrated RBCs)
• ↑ MCHC (in asplenic patients) • Howell-Jolly bodies: nuclear remnants
Laboratory findings • Spherocytes: round cells without • Bite cells (Degmacytes): in patients with (in asplenic patients)
central pallor functional spleen • Protective against malaria
• Protective against malaria • Bone marrow expansion (extramedullary
hematopoiesis)
Diagnosis • Osmotic fragility testing • Newborn screening • Hemoglobin electrophoresis
Treatment • Splenectomy • Aversion to triggers • Hydroxyurea (Increases HbF)
UNIQUE CLINICAL MANIFESTATIONS OF SICKLE CELL ANEMIA α-THALASSEMIA
• Infants do not become symptomatic until 5-6 months of age • Asymptomatic
Silent carrier 1
o Fetal hemoglobin (HbF) prevents sickling • No red cell abnormality
• Microvascular occlusion by sickle cells → vaso-occlusive crises α-thalassemia • Asymptomatic
2
(pain crises): Hypoxic injury, infarction, pain trait (minor) • Like β-thalassemia minor
• Severe
Hand-foot
• Dactylitis of hand and foot bones HbH disease 3 • Like β-thalassemia
syndrome
intermedia
Acute chest
• Chest pain, cough, lung infiltrates • Lethal in utero without
syndrome Hydrops fetalis 4
transfusions
• Infarctions → fibrosis of spleen → ↑ Table 14.3. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 (adapted)
Auto- susceptibility to encapsulated microbes – S PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
splenectomy pneumoniae, H influenzae type b, FEATURE PNH
Neisseriae • PIGA mutations → ↓ complement regulatory proteins
Priapism • Prolonged erection of the penis 1. CD55 (Decay accelerating factor)
Main
2. CD59 (Membrane inhibitor of reactive lysis)
pathology
THALASSEMIA (most important) (inhibits C3 convertase)
• ↓ synthesis of globin chains 3. C8 binding protein
• Defect in the synthesis of α-globin Cause of
α-thalassemia • Intrinsic
• α-globin: 2 copies of gene in Ch 16 x 2= 4 genes hemolysis
• Defect in the synthesis of β –globin Type of • Intravascular (↑ complement-mediated lysis)
β-thalassemia hemolysis (C5-C9)
• β -globin: 1 copy of gene in Ch 11 x 2 = 2 genes
• Nocturnal hemoglobinuria: less blood pH
• The more globin chains absent, the more severe the clinical
during sleep increases complement activity
manifestations Clinical
• Thrombosis: most common disease-related
• Intrinsic cause, extravascular hemolysis findings
death
• Microcytic, hypochromic anemia • AML or MDS as sequelae
• Anisocytosis (variation in size), poikilocytosis (variation in Diagnosis • Flow cytometry
shape) • HSC transplantation
• Protective against malaria • Eculizumab: prevents activation of C5 to C5a; ↓
Treatment
transfusion requirements and ↓ thrombosis risk
QUICK SHEET: by 90%
THALASSEMIA: KEY DIFFERENCES
• β-thalassemia In PNH, your red cells have lost their protection against complement-
o Mutations: Abnormalities in RNA splicing (most common) or ↓ mediated lysis.
Dr. Elomina
transcription IMMUNOHEMOLYTIC ANEMIAS
o Symptoms appear at 6-9 months of age
§ Shift from HbF to HbA synthesis • Caused by antibodies that bind to red cells → premature
§ Major hemoglobins destruction
• β-thalassemia major (Cooley anemia): HbF (α2γ2) • Two common types: Warm antibody (Most common), Cold
• β-thalassemia minor: HbA2 (α2δ2) agglutinin
• α-thalassemia Warm antibody • Primary (idiopathic)
o Mutations: Deletions (IgG) • Secondary to autoimmune disorders (SLE),
o Symptoms appear at birth (↓ HbF synthesis) Active at 37°C drugs, lymphoid neoplasms
§ Major hemoglobins
• Acute (post-infectious) from M pneumoniae
• Newborns: Hemoglobin Barts (γ4) Cold agglutinin
infection, EBV, CMV, influenza, HIV
• Older children and adults: HbH (β4) (IgM)
• Chronic from idiopathic cause, or lymphoid
Active below 37°C
neoplasms
PATHOPHYSIOLOGY OF β-THALASSEMIA
• Defective globin synthesis → abnormal erythroblasts → • Hemolysis usually EXTRAVASCULAR:
Ineffective hemopoiesis Warm • IgG-coated red cells undergo partial phagocytosis
• Accumulation of excess globin chains → extravascular antibody type → spherocytes → splenic hemolysis
hemolysis (spleen) → anemia • IgM binding occurs in cold body areas
(fingers, toes, ears) → vascular occlusion →
• Iron overload secondary to increased iron absorption to Cold agglutinin
pallor, cyanosis, Raynaud phenomenon
compensate for anemia, and repeated transfusions (secondary type
• Complement fixation on cold temperature →
hemochromatosis)
hemolysis in spleen, liver, bone marrow
• Extramedullary hematopoiesis to compensate for ineffective
ANTIGLOBULIN TEST (COOMBS TEST)
hemopoiesis → skeletal deformities (“crew-cut appearance,
skull”, chipmunk facies) FEATURE DIRECT (DAT) INDIRECT (IAT)
Antibodies attached to Free antibodies in
Detects
patient’s red cells patient’s serum
THALASSEMIA SYNDROMES
# AFFECTED Uses Patient’s red cells Patient’s serum
SYNDROME GENES CLINICAL FEATURES
β-THALASSEMIA CLINICAL USES OF DIRECT COOMBS TEST
β-thalassemia • Severe CONDITION PATHOPHYSIOLOGY
2 Hemolytic disease of the Maternal antibodies coating fetal
major • Blood transfusion required
newborn (HDN) red cells
• Severe
β-thalassemia Autoimmune hemolytic Antibody coating individual red
Variable • Regular transfusions not
intermedia anemia (AIHA) cells
required
Hemolytic transfusion Recipient antibodies coating
• Asymptomatic with mild or
β-thalassemia reaction (HTR) donor red cells
1 absent anemia Adapted from Table 5-3. Harmening DM. Modern Blood Banking and Transfusion Practices. 2019. 7th ed.
minor
• (+) red cell abnormalities
CLINICAL USES OF INDIRECT COOMBS TEST IRON DEFICIENCY ANEMIA AND ANEMIA OF CHRONIC
1. Detection of non-agglutinating antibodies to potential donor red INFLAMMATION
cells (Compatibility testing and antibody screening) IRON DEFICIENCY ANEMIA OF CHRONIC
2. Red cell phenotyping (Weak D, etc.) ANEMIA INFLAMMATION
3. Titration of incomplete antibodies • Most common • Common cause of
nutritional anemia in
Significance
HEMOLYTIC ANEMIA RESULTING FROM TRAUMA disorder in the hospitalized
• In patients with cardiac valve prosthesis (macroangiopathic) world patients
and DIC, TTP-HUS, SLE, and disseminated cancer • Chronic microbial
(microangiopathic) infections
• Pathogenesis: Shear stress on red cells → intravascular • Chronic immune
• Lack in diet
hemolysis disorders
• ↓ Absorption
Causes • Neoplasms
o Schistocytes (red cell fragments), burr cells, helmet cells, • ↑ Requirement
o IL-6 → ↑ Hepcidin
triangle cells • Chronic blood loss
→ blocks intestinal
HEMOLYTIC ANEMIAS: SUMMARY iron absorption and
DISEASE CAUSE TYPE macrophage recycling
Hereditary spherocytosis • Microcytic,
Intrinsic Extravascular
(HS) hypochromic
G6PD deficiency Intrinsic BOTH
Anemia • Variable
• Pencil cells: small,
Sickle cell anemia (SCA) Intrinsic Extravascular elongated red cells)
Thalassemia Intrinsic Extravascular Serum Fe ↓ ↓
Paroxysmal nocturnal Transferrin
Intrinsic Intravascular ↑ ↓
hemoglobinuria (PNH) (TIBC)
BOTH (Extravascular Ferritin ↓ ↑
Immunohemolytic Serum
Extrinsic for the more common ↓↓ ↓
anemias Fe/TIBC
forms)
Hemolytic anemia • Loss of stainable Fe
secondary to red cell Extrinsic Intravascular from bone marrow
Marrow
trauma macrophages -
findings
(Prussian Blue
stain)
HYPOPROLIFERATIVE ANEMIAS
In IDA, the body makes more transferrin to get all the iron it can get.
• Megaloblastic anemia • Aplastic anemia (AA)
Serum ferritin is low because the iron stores are depleted. In ACI, the main
• Iron deficiency anemia • Pure red cell aplasia problem is mobilizing the iron from the storage; that’s why ferritin
(IDA) (PRCA) (storage form) is high in ACI. If I’m going to pick a single test to
• Anemia of chronic • Myelophthisic anemia differentiate the two, I’ll pick ferritin.
inflammation (ACI) Dr. Elomina
MEGALOBLASTIC ANEMIA APLASTIC ANEMIA (AA) & PURE RED CELL APLASIA (PRCA)
• Central pathology is impaired DNA synthesis → Ineffective AA PRCA
hematopoiesis • Chronic primary
• Ineffective hematopoiesis → precursors undergo apoptosis → • Selective suppression of
hematopoietic
peripheral blood cytopenias Definition marrow erythroid
failure with
elements
CAUSES pancytopenia
• Deficiency states (responsive to supplementation) • Most common • Thymoma, drugs,
o Vitamin B12 deficiency known: drugs autoimmune
§ Chronic autoimmune gastritis (pernicious anemia) • Others: viral disorders, parvovirus
Major causes
infections, whole- B19 infection (aplastic
§ Gastrectomy, ileal resection
body irradiation, crisis in hemolytic
o Vitamin B9 deficiency
genetic defects anemias)
• Presence of antagonists (unresponsive to supplementation)
• Genetic
o Methotrexate (folate antagonist) alteration of stem
In Vitamin B12 deficiency states, Vitamin B12 supplementation is through cells post-insult: • Probably autoimmune,
the parenteral route, because the important GIT structures for Vitamin 1. ↓ Proliferative except for parvovirus
B12 absorption are absent. Pathogenesis capacity • Parvovirus: preferential
Dr. Elomina
2. ↑ Destruction infection of erythroid
FEATURES
due to precursors
• Hypercellular marrow w/ megaloblastic changes
expression of
• Large, bizarre, multinucleated megakaryocytes new antigens
Bone
• Giant metamyeloyctes, band forms
marrow Anemia • Normocytic, normochromic
• Nuclear-cytoplasmic asynchrony in erythroids:
• Virtually absent
nucleus is immature white cytoplasm matures • Hypocellular
erythroblasts in
• Macro-ovalocytic, normochromic anemia (fat cells,
Marrow marrow
• Marked anisocytosis (differences in size), lymphocytes,
PBS findings • Normal granulocytic
poikilocytosis (abnormally shaped red cells) plasma cells) “dry
and megakaryocytic
• Hypersegmented neutrophils: ≥ 5 lobes tap”
lineages
Not all dysplasia is MDS. Megaloblastic anemia for example, is an
important cause of non-MDS dysplasia. MYELOPHTHISIC ANEMIA
Dr. Elomina
DIFFERENCE BETWEEN B12- AND B9-DEFICIENT • Space-occupying lesions replace normal marrow elements
MEGALOBLASTIC ANEMIAS • Most common cause: Metastatic cancer
VITAMIN B12 VITAMIN B9 • Leukoerythroblastosis: release of immature granulocyte and
• Subacute combined erythroid precursors into peripheral blood
Neurologic o Dacrocytes: teardrop-shaped cells
degeneration (Degeneration • None
manifestations In myelophthisic anemia, marrow becomes uninhabitable for the marrow
of posterolateral cord tracts)
• Vitamin B12 elements, so they are released into the blood. The lesions compromise the
• Also responsive to Vitamin exit passages of the red cells to the blood, so the red cells have to squeeze
themselves out to escape and they become deformed as a consequence.
Treatment B9, but it does not address • Vitamin B9
The red cells shed TEARS as they squeeze out of the bone marrow
neurologic manifestations of Dr. Elomina, Dr. Rubio
B12 (sometimes exacerbates)
POLYCYTHEMIA CHRONIC ITP ACUTE ITP

• Indicated only
• Abnormally high red cell count with increase in hemoglobin Glucocorticoids • Indicated
when severe
• Three types: • Splenectomy
Relative • Due to hemoconcentration • Rituximab (anti-
• Production of red cells independent of EPO Other treatment CD20) in B-cell • Usually self-
Primary
stimulation (↓EPO) modalities neoplasms limited
absolute
• Polycythemia vera • TPO-mimetic
• Increase in red cells secondary to ↑ EPO (Romiplostim)
Secondary
• EPO-secreting tumors, High altitude, Cyanotic
absolute • Presence of megakaryocytes in the spleen indicate extramedullary
congenital heart diseases
hematopoiesis.
• Large platelets indicate accelerated thrombopoiesis.
BLEEDING DISORDERS Dr. Elomina
• Disorders of vessel wall • Disorders of platelet DRUG-INDUCED THROMBOCYTOPENIA

fragility function
• Mechanisms involved:
• Disorders of platelet • Disorders of coagulation
o Drug-dependent antibody binding to platelet glycoproteins
number
§ Quinine, Quinidine, Vancomycin
BLEEDING PARAMETERS o Drugs modify platelet glycoproteins → immunologic epitope
BLEEDING BLEEDING CLINICAL o Direct platelet-aggregating effect
TEST
FUNCTION DISORDER FINDINGS § Type 1 Heparin-induced thrombocytopenia
Platelet count Platelet Disorders of • Superficial o Antibody-mediated platelet dysfunction
(PC) number platelet number (skin and § Type 2 Heparin-induced thrombocytopenia
mucosal) • Antibodies against heparin-platelet factor 4 complex →
Bleeding time Platelet Defects of
bleeding, platelet activation → paradoxical thrombosis in the
(BT) function platelet function
petechiae
setting of thrombocytopenia
Coagulation
Prothrombin
time (PT)
Extrinsic THROMBOTIC MICROANGIOPATHIES
pathway • Deep-seated
Disorders of FEATURE TTP HUS
Activated bleeding
Coagulation coagulation 1. Microangiopathic
partial • Hemarthroses
Intrinsic hemolytic anemia
thromboplastin 1.Microangiopathic
pathway 2. Thrombocytopenia
time (aPTT) hemolytic anemia
Syndrome 3. Renal failure
2. Thrombocytopenia
4. Fever
DISORDERS OF VESSEL WALL FRAGILITY 3. Renal failure
5. Neurologic
• Mechanisms involving vessel wall fragility manifestations
Infections • Endothelial injury • Typical HUS: E. coli
Drugs • Drug-induced vasculitides •↓ ADAMTS13: O157:H7 (Shiga-like
Scurvy & Ehler-Danlos accumulation vWF toxin makes
• Defects in collagen synthesis multimers → endothelium
syndrome Pathogenesis
Henoch-Schönlein • Immune complex-mediated promote platelet procoagulant)
purpura (HSP) vascular injury activation and • Atypical HUS: defects
aggregation in excessive
• AKA Osler-Weber-Rendu
complement activation
Hereditary hemorrhagic syndrome
telangiectasia • TGF- β mutation → dilated • In thrombotic microangiopathies, thrombocytopenia results from
tortuous thin-walled vessels consumption of because of thrombosis. The thrombi traumatize red
• Amyloid deposition → cells, which causes hemolysis.
Perivascular amyloidosis • ADAMTS13 is basically an enzyme that breaks down vWF multimers.
weakening of vessel walls
Therefore, lower levels will promote thrombosis. Aside from the clinical
In these disorders, you would expect no laboratory abnormality, because manifestations, ADAMTS13 levels can be used to differentiate TTP from HUS
there’s nothing wrong with the platelets and coagulation systems. Dr. Elomina
Dr. Elomina
DISORDERS OF PLATELET FUNCTION

DISORDERS OF PLATELET NUMBER
INHERITED DISORDERS OF PLATELET FUNCTION
• Mechanisms involved:
• Bernard-Soulier Syndrome (BSS) (Giant platelet syndrome)
↓ platelet synthesis • Aplastic anemia, leukemia, alcohol, HIV
• Glanzmann Thrombasthenia (GTA)
• Immune thrombocytopenia
↓ platelet survival BSS GTA
• DIC, thrombotic Microangiopathies
Sequestration • Occurs in splenomegaly Inheritance • Autosomal recessive
Dilution • Occurs after massive blood transfusions Deficiency • GPIb-IX • GPIIb-IIIa
Platelet process • Platelet • Platelet
• Immune thrombocytopenic purpura (ITP) affected adhesion aggregation
• Drug-induced thrombocytopenia Thrombocytopenia • Present • Normal PC
• Thrombotic microangiopathies
o Thrombotic thrombocytopenic purpura (TTP) The thrombocytopenia in BSS is thought to be secondary to increased
clearance of BSS platelets from the circulation.
o Hemolytic uremic syndrome (HUS) Dr. Elomina
ACQUIRED DEFECTS
IMMUNE THROMBOCYTOPENIC PURPURA
• NSAIDs (Aspirin)
CHRONIC ITP ACUTE ITP
o COX inhibition → ↓ Prostaglandins and Thromboxane A2
Age group • Adults • Children needed for platelet aggregation and release reactions
• SLE, HIV, B-cell • Post-viral • Uremia: affects platelet adhesion, activation & aggregation
Associated illness
neoplasms (CLL) illness
Autoantibodies
• Antibodies against GPIIb-IIIa and GPIb-IX DISORDERS OF COAGULATION
(80%) IgG
• Bone marrow: ↑ Megakaryocytes
INHERITED DISORDERS OF COAGULATION
• Spleen: Congestion, follicular hyperplasia, • Von Willebrand Disease (VWD): Most common inherited
Morphology scattered megakaryocytes within bleeding disorder
sinuses • Hemophilia: Most common hereditary disease associated with
• PBS: large platelets life-threatening bleeding
VWD HEMOPHILIA
• Autosomal (usually DISSEMINATED INTRAVASCULAR COAGULATION
Inheritance • X-linked recessive
dominant)
• Factor VIII • Excessive activation of coagulation and the formation of
• Quantitative or (Hemophilia A) thrombi in the microvasculature → consumption of platelets
Abnormality qualitative • Factor IX and coagulation factors
depending on type (Hemophilia B, • Morphology
Christmas disease) o Thrombi: brain, heart, lungs, kidneys, adrenal, spleen, liver
Platelet count and • PC: Normal • PC: Normal § Waterhouse-Friderichsen syndrome: Bilateral adrenal
function • PF: Impaired • PF: Normal hemorrhage secondary to fibrin thrombi
• Desmopressin (↑ § In giant hemangiomas (Kasabach-Merritt syndrome)
vWF) • Factor
Treatment
• Factor VIII and replacement
vWF replacement
PATHOPHYSIOLOGY OF DIC
Basically, DIC happens because there is something in the body that causes the coagulation system to activate, and that is the first phase of DIC, which is thrombosis. This
consumes your platelets and coagulation factors, which results to the second phase of DIC, which is bleeding.
Dr. Elomina
• Clinical aspects • Definition: Allergic symptoms during or within 2 hours after

o Acute DIC: usually presents with bleeding the end of transfusion
§ Obstetric/trauma patients • Pathophysiology:
o Chronic DIC: usually presents with thrombosis o IgG antibodies against IgA in blood product (in patients with
§ Cancer patients IgA deficiency) → can lead to anaphylaxis
o Deranged bleeding parameters (↓ PC, prolonged BT, PT, aPTT) o IgE-mediated: Presence of allergen in donor blood product
o ↑ fibrin split products • Treatment: Antihistamines
BLEEDING DISORDERS: SUMMARY

HEMOLYTIC TRANSFUSION REACTIONS
DISEASE PC BT PT PTT
Ehler-Danlos syndrome N N N N ACUTE HEMOLYTIC TRANSFUSION REACTION
Immune thrombocytopenic purpura ↓ ↑ N N • Definition: Clinical and biochemical evidence of hemolysis and
Thrombotic thrombocytopenic purpura ↓ ↑ N N serologic evidence of RBC incompatibility during or within 24
Bernard-Soulier disease ↓ ↑ N N hours after transfusion
Glanzmann thrombasthenia N ↑ N N • Most common cause: ABO incompatibility
Von Willebrand disease N ↑ N ↑ • Pathophysiology: Preformed IgM antibodies against donor red
Hemophilia N N N ↑ cells that fix complement → complement-mediated lysis and
Vitamin K deficiency N N ↑ ↑ intravascular hemolysis
DIC ↓ ↑ ↑ ↑ • Clinical manifestations: fever (most common manifestation),
flank or lower back pain , hemoglobinuria, positive DAT
TRANSFUSION REACTIONS
FEBRILE NON-HEMOLYTIC TRANSFUSION
ABO INCOMPATIBILITY
REACTION (FNHTR) https://qrs.ly/v6cmdu1
• Most common adverse transfusion reaction
• Definition: Temperature of 38°C or a 1°C increase from pre-
transfusion temperature during or within 4 hours after the end
of transfusion (Robbins: within 6 hours of a transfusion of red DELAYED HEMOLYTIC OR SEROLOGIC TRANSFUSION
cells or platelets) REACTION (DHTR/DSTR)
• Pathophysiology: Proinflammatory cytokines produced by • Definition: Positive DAT 24 hours to 28 days after transfusion
donor leukocytes and platelets with either
• Treatment: antipyretics o Positive eluate or newly identified alloantibody
• Prevention: avoid using old blood products, use of o Evidence of hemolysis (if absent, then classify as DSTR)
leukoreduced blood products • Common cause: Exposure to non-ABO antigens
• Pathophysiology: Host sensitization to antigens encountered in
ALLERGIC REACTIONS previous transfusion) → development of IgG antibodies →
• Most common reaction encountered in platelet transfusion hemolytic reaction in subsequent exposure
and second most common reaction encountered in RBC
transfusions (second to FNHTR)
TRANSFUSION-RELATED ACUTE LUNG INJURY PATHOGENESIS

(TRALI) • Endothelial activation: expression of chemokines →
inflammation & tissue injury → type I and II pneumocyte
• Definition: Acute lung injury during or within 6 hours after necrosis → ↓ surfactant & formation of hyaline membranes →
transfusion diffusion defect → hypoxemia
• Pathophysiology: Antibodies or non-antibody compounds
activate neutrophils in the lung microvasculature → capillary
leakage and pulmonary edema OBSTRUCTIVE AND RESTRICTIVE LUNG DISEASES
• Clinical manifestations: fever, hypotension, hypoxemia, OBSTRUCTIVE RESTRICTIVE
radiographic evidence of pulmonary edema • ↓ Expansion of the
Fundamental • ↑ Airway resistance
lung parenchyma
Pathology due to obstruction
with ↓ TLC
INFECTIOUS COMPLICATIONS
OBSTRUCTIVE RESTRICTIVE
INFECTIOUS COMPLICATIONS • Bronchial asthma • Pulmonary
• Major transfusion-transmitted pathogens screened in the blood • Emphysema fibrosing diseases
bank: Hepatitis B, Hepatitis C, HIV, Malaria, and Syphilis Examples
• Chronic bronchitis • Chest wall
• Transfusion-transmitted bacterial infection (TTBI) • Bronchiectasis disorders
o More common in platelet transfusions (because platelets are Lung volumes ↑ ↓
stored in room temperature) FEV1 ↓↓ ↓
FVC ↓ ↓↓
14. LUNG AND PLEURA FEV1/FVC ratio ↓ (<0.7) Normal to ↑
• Atelectasis • Pulmonary infections
• Pulmonary edema • Tumors OBSTRUCTIVE AND
• Acute lung injury and ARDS • Diseases of the Pleura
RESTRICTIVE LUNG DISEASES
• Obstructive lung diseases o Pleural effusion
• Restrictive lung diseases o Pneumothorax https://qrs.ly/q9cmdu8
• Pulmonary vascular diseases o Tumors
ATELECTASIS OBSTRUCTIVE LUNG DISEASES

• Definition: Collapsed lung parenchyma
• Chronic obstructive pulmonary disease (COPD)
• Complications: inadequate oxygenation, & ↑ risk of infection § “Emphysema
TRACHEAL
TYPE CAUSE § Chronic bronchitis
DEVIATION
• Bronchial asthma
Resorption • Airway obstruction • Ipsilateral
• Bronchiectasis
• Fluid, air, or mass in • Contralateral (due to
Compression
the pleural cavity mass effect)
CHRONIC OBSTRUCTIVE PULMONARY DISEASES
• None in initial stages
• Pulmonary or pleural EMPHYSEMA CHRONIC BRONCHITIS
Contraction • Ipsilateral if
fibrosis • Irreversible • Persistent cough with
longstanding
enlargement of sputum production for
the airspaces at least 3 months in at
PULMONARY EDEMA Definition
distal to the least 2 consecutive years
CARDIOGENIC NONCARDIOGENIC terminal in the absence of any
• Imbalance of • ↑ Capillary bronchiole other cause
Starling Forces in permeability • Inflammation and subsequent tissue
Pathology Fundamental
the pulmonary (Microvascular damage caused by cigarette smoke or
pathogenesis
circulation injury) particles
• ↑Hydrostatic • Infection, Aspiration • Smoking • Smoking
pressure (LSHF) • Near-drowning Risk factors • α-1-antitrypsin • Particles from dust,
Causes • ↓ Oncotic pressure • Toxic substances deficiency grain, and silica
• Lymphatic (gases, drugs) • Hyperemia, swelling,
obstruction (rare) • Transfusion (TRALI) and edema of the
• Large alveoli →
Edema fluid • Transudate • Exudate mucous membranes
Gross voluminous
• Acute: Intra- • Excessive mucinous or
lungs
alveolar finely mucopurulent
granular pale-pink secretions
transudate • Bronchiolar wall
• Chronic: thickening (fibrosis)
• Inflammatory • Goblet cell hyperplasia
o Hemosiderin-
exudate in the • Enlargement of mucus-
Morphology laden
interstitium, and secreting glands of the
macrophages
alveoli in severe cases trachea and bronchi
o Fibrous
thickening of o ↑ Reid index: Ratio of
alveolar septa • Abnormally the thickness of the
(brown large alveoli mucus gland layer to
Histology
induration) separated by thin the wall thickness
septa (between the
Hemosiderin-laden macrophages are formed when macrophages
epithelium and
phagocytose erythrocytes. The hemosiderin is contained in residual
cartilage) (N = 0.4)
bodies derived from lysosomes, called telolysosomes (telo- means late).
Dr. Elomina • Bronchiolitis
obliterans: obliteration
ACUTE LUNG INJURY/ARDS of lumen
GENERALITIES • Squamous metaplasia
Acute lung • Abrupt onset of hypoxemia & bilateral and dysplasia
injury (ALI) pulmonary edema in absence of cardiac failure
• Acute respiratory distress syndrome CHRONIC OBSTRUCTIVE
ARDS
• Refers to the severe manifestation of ALI PULMONARY DISEASES
• Diffuse alveolar damage: histologic https://qrs.ly/yrcmdua
DAD
manifestation of ALI/ARDS
• Most common causes (4): sepsis, diffuse pulmonary infections,
gastric aspiration, mechanical trauma (head)
CLINICALLY SIGNIFICANT FORMS OF EMPHYSEMA • Associated conditions
FEATURE CENTRIACINAR PANACINAR o Congenital or hereditary conditions that predispose to chronic
Incidence • Most common (95%) • Less common infections (Cystic fibrosis, primary ciliary dyskinesia,
• α-1-antitrypsin Kartagener syndrome)
Risk factors • Smoking
deficiency o Infections
• Inflammation and • Deficiency of o Bronchial obstruction
increase in proteases protective anti- § Obstructed segment can be a nidus of infection
Pathogenesis
(from inflammatory protease → tissue o Autoimmune disorders (SLE, RA, IBD)
cells) → tissue destruction destruction Primary ciliary dyskinesia is different from Kartagener syndrome. Kartagener
One of the pathogenetic mechanisms of tissue damage in emphysema is the syndrome is characterized by situs inversus, bronchiectasis, sinusitis, and male
imbalance between protease and anti-protease activity, with the protease activity infertility. The abnormal position of the organs is secondary to ciliary
being greater. Components of tobacco smoke can induce inflammation and with it dysfunction. The recurrent infections are secondary to impaired mucociliary
is increase in protease levels. In α-1-antitrypsin deficiency, there is deficiency of anti- clearance. The male infertility is secondary to sperm dysmotility.
Dr. Elomina
protease, which leads to unopposed protease activity. MORPHOLOGY & CLINICAL PRESENTATION
Dr. Elomina
• Other types: • Dilated airways, cystic and filled with

Gross
o Distal acinar (Paraseptal) mucopurulent secretions
§ Associated with spontaneous pneumothorax • Acute: intense inflammatory exudation
o Irregular (Clinically insignificant) within walls of the bronchi, bronchioles,
§ Acinus irregularly involved desquamation of the lining, necrosis of
Microscopic bronchial and bronchiolar walls
• Chronic: fibrosis of the bronchial and
PREDOMINANT FEATURES OF COPD
bronchiolar walls → obliteration of lumen
BRONCHITIS EMPHYSEMA
of airways
Age (years) • 40-45 • 50-75
• Haemophilus influenzae (50%)
Dyspnea • Mild; late • Severe; early Microbiology
• Pseudomonal aeruginosa (12-30%)
• Early; copious • Late; scanty
Cough Clinical • Severe, persistent cough
sputum sputum
manifestations • Foul-smelling sputum, hemoptysis
Infections • Common • Occasional
Respiratory Foul-smelling sputum: occurs due to necrosis and bacterial growth
• Early, periodic • End-stage Hemoptysis: due to destruction of vessels in the bronchial walls.
insufficiency Dr. Elomina, Dr. Rubio
BRONCHITIS EMPHYSEMA
• Uncommon, end- RESTRICTIVE LUNG DISEASES
Cor pulmonale • Common
stage • Heterogeneous group of disorders characterized predominantly by
Airway resistance •↑ • N or slightly ↑ inflammation and fibrosis of the lung interstitium
Elastic recoil • Normal •↓ • Complications:
• Prominent o Secondary pulmonary hypertension → cor pulmonale
• Hyperinflation
Chest radiograph vessels o “Honeycomb lung”
• Normal heart size
• Large heart • Common interstitial lung diseases
Appearance • Blue bloaters • Pink puffers • Idiopathic pulmonary fibrosis (IPF)
Adapted from Table 15.4 Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
• Non-specific interstitial pneumonia
BRONCHIAL ASTHMA • Cryptogenic organizing pneumonia
Fibrosing diseases
• Condition characterized by chronic airway inflammation and • Pneumoconiosis
variable expiratory outflow obstruction • Connective tissue disease-associated
o Atopic asthma: IgE-mediated (Type 1 hypersensitivity) (RA, SLE, Systemic sclerosis)
o Non-atopic asthma: Not immunologically mediated Granulomatous
• Sarcoidosis
§ Noxious stimuli (pollutants, infections) can cause airway disease
hyperresponsiveness • Desquamative interstitial pneumonia
Smoking-related (DIP)
PATHOGENESIS diseases • Respiratory bronchiolitis-associated
• First exposure: ↑ TH2 response → IgE production and interstitial lung disease
eosinophil recruitment
FIBROSING DISEASES
• Subsequent exposure: Mast cell degranulation →
Bronchoconstriction, ↑ mucus production, variable degrees of DISEASE MORPHOLOGY REMARKS
vasodilation, and ↑ vascular permeability (Immediate phase) • Histologic pattern of • Clinico-
fibrosis: usual interstitial pathologic
• Recruitment of leukocytes, notably eosinophils, neutrophils, and
Idiopathic pneumonia (UIP) syndrome
more T cells (Late phase)
pulmonary • Early lesion: fibroblastic focus marked by
MORPHOLOGY fibrosis • Late lesion: honeycomb progressive
Occlusion of • Characteristic finding in status (IPF) fibrosis fibrosis and
airways by thick, asthmaticus (acute severe asthma) • DIFFERENT stages of respiratory
mucus plugs • Autopsy findings lesions failure
Curschmann spirals • Extruded mucus plugs seen in atopic asthma • Cellular pattern: chronic • Better
Charcot-Leyden inflammation prognosis
• Derived from eosinophil-derived galectin-10 Nonspecific • Fibrosing pattern: than IPF
crystals
• Bronchial wall muscle interstitial interstitial fibrosis • Clinical picture:
hypertrophy/hyperplasia pneumonia • Lesions can be patchy or female
Airway • Increased vascularity diffuse with SAME STAGE of nonsmokers
remodeling • Goblet cell hyperplasia (& submucosal development in 60s
gland hypertrophy) • Seen as a
• Masson bodies: polypoid
• Sub-basement membrane fibrosis Cryptogenic response to
plugs of loose organizing
organizing infectious or
connective tissue within
pneumonia inflammatory
CLINICAL MANIFESTATIONS airways and alveoli
injury
• Chest tightness, Dyspnea, Wheezing, Coughing (non-
productive or productive) According to Harrison’s Principles of Internal Medicine, the most common
indication for lung transplantation nowadays is IPF, followed by COPD
• Severe attack: marked airway obstruction (cyanosis and death) Dr. Rubio
PNEUMOCONIOSIS
BRONCHIECTASIS • Nonneoplastic lung reaction to inhalation of mineral dusts
• Permanent dilation of bronchi and bronchioles due to encountered in the workplace
destruction of smooth muscle and elastic tissue by inflammation • Common pathogenesis: particles phagocytized by pulmonary
associated with persistent severe infections. (alveolar) macrophages → inflammation → fibrosis
COAL DUST-RELATED DISEASES
ENTITY MORPHOLOGY REMARKS SMOKING-RELATED INTERSTITIAL DISEASES
• Anthracotic pigments in • Common morphologic finding
Anthracosis • Innocuous
alveolar macrophages o Smokers’ macrophages
• Coal macules (1-2 mm); § Dusty brown pigment-laden macrophages
Simple coal
carbon-laden macrophages § May contain surfactant-derived bodies due to phagocytosis
workers’ • Non-
• Coal nodules (larger); of necrotic Type 2 pneumocytes
pneumoconiosis severe
carbon-laden macrophages
(CWP) Desquamative interstitial • Smokers’ macrophages in
+ collagen fiber network
Complicated pneumonia (DIP) alveolar spaces
CWP • Smokers’ macrophages in
• Dense collagen and pigment, Respiratory bronchiolitis-
(Progressive • Severe bronchioles, alveolar ducts
often with central necrosis associated interstitial
massive • Chronic inflammation and
fibrosis) lung disease
peribronchiolar fibrosis
SILICOSIS
Etiology
• Crystalline form of silica (quartz): more PULMONARY VASCULAR DISEASES
fibrogenic
• Most prevalent chronic occupational disease
PULMONARY HYPERTENSION
Significance • Increased susceptibility to tuberculosis • Mean pulmonary artery pressure ≥ 25 mm Hg at rest
• Increased risk of lung cancer • WHO pulmonary hypertension classification:
• Fine nodularities, UPPER LOBES • Autoimmune-induced pulmonary
Radiography
• “Eggshell calcifications”: lymph nodes Group 1 vasculature/interstitium damage;
• Hard collagenous scars: central whorled • Genetic basis: BMPR2 mutations
Morphology
collagen + rim of dust-laden macrophages Group 2 • Secondary to heart failure
ASBESTOS-RELATED DISEASES Group 3 • Secondary to lung disease and/or hypoxia
• Serpentine chrysotile form: 90% of asbestos Group 4 • Chronic thromboembolism
Etiology
• Amphibole form: more pathogenic Group 5 • Unclear and/or multifactorial mechanisms
• Risk of bronchogenic CA > risk of mesothelioma • Morphology: Medial hypertrophy of the pulmonary muscular
Significance
• Increases risk of extrapulmonary neoplasms and elastic arteries → right ventricular hypertrophy
• “Ivory white” calcified supradiaphragmatic
Radiography and pleural plaques
• Recurrent pleural effusions PULMONARY HYPERTENSION
• Asbestos bodies: golden-brown, rods with https://qrs.ly/7ycmdv0
translucent center consisting of asbestos
fibers coated with an iron-containing
Morphology proteinaceous material
• Ferruginous bodies: other inorganic (non- PULMONARY INFECTIONS
asbestos) particulates coated with similar iron-
RESPIRATORY TRACT ORGANIZATION
protein complexes
• Divided in upper and lower respiratory tracts with laryngeal
Mnemonic: Asbestos is from the roof (common in insulation products)
vocal folds as a point of reference
but affects the lower lobes. Silica, coal is from the earth (from mining),
but affect the roof (upper lobes).
Dr. Rubio PNEUMONIA
GRANULOMATOUS DISEASES • Infection of pulmonary parenchyma (basically, lung infection)
SARCOIDOSIS • Clinical manifestations: cough, adventitious breath sounds,
• Systemic granulomatous disease of unknown etiology abnormal vital signs
• Diagnostic histologic feature: Non-caseating granulomas with • Complications of pneumonia: abscess, empyema, bacterial
giant cells that may contain: dissemination
o Schaumann bodies: laminated concretions composed of
calcium and proteins
o Asteroid bodies: stellate inclusions
• Most common organs involved: Lymph nodes and Lung
PATTERNS OF PULMONARY INFECTIONS
BRONCHOPNEUMONIA LOBAR PNEUMONIA
Consolidation • Patchy • Lobar or large portion of lobe
• Congestion: red, heavy, boggy
• Consolidated areas of acute • Red hepatization: red, firm, airless
Gross
suppurative inflammation • Gray hepatization: grayish brown
• Resolution: resorption of exudates, or organization (fibrosis)
• Congestion: vascular engorgement with intra-alveolar fluid, few PMNs, and numerous bacteria
• Neutrophil-rich exudate that • Red hepatization: PMNs, RBCs, and fibrin
Histology
fills the airways • Gray hepatization: RBC disintegration, fibrinosuppurative exudate
• Resolution: exudates resorbed or ingested by macrophages; or fibrosis
BACTERIAL PNEUMONIA VS. VIRAL PNEUMONIA • 2nd most common bacterial cause of acute
Moraxella
• Neutrophilic infiltrates exacerbations of COPD
Bacterial pneumonia catarrhalis
• Intra-alveolar inflammation • Common cause of otitis media in children
Staphylococcus • Important cause of secondary bacterial
• Mononuclear infiltrates
Viral pneumonia aureus pneumonia in post-viral respiratory illnesses
• Interstitial inflammation
• Most common cause of Gram-negative
Klebsiella
CLINICALLY SIGNIFICANT ETIOLOGIC AGENTS OF ACUTE pneumonia
bacterial pneumonia
PNEUMONIAS • Current jelly sputum
ORGANISM SIGNIFICANCE • Common cause of hospital-acquired infections
Pseudomonas
BACTERIA • Common in cystic fibrosis and neutropenic
aeruginosa
• Most common cause of community-acquired patients
Streptococcus Legionella • Common in individuals with co-morbidities and
acute pneumonia
pneumoniae pneumophila in organ transplant patients
• Common cause of in otitis media children
• Most common bacterial cause of acute Mycoplasma • Common among children and young adults
Haemophilus pneumoniae (atypical pneumonia)
exacerbations of COPD
influenzae
• Common cause of otitis media in children
ORGANISM SIGNIFICANCE PNEUMONIA IN THE IMMUNOCOMPROMISED HOST
VIRUSES
COMMON ETIOLOGIC AGENTS
Influenza virus • Responsible for influenza pandemics and
Type A epidemics DIFFUSE INFILTRATES FOCAL INFILTRATES
• Common in extremes of age and • Gram (-) bacteria
Human Meta- immunocompromised patients • CMV • S. aureus
pneumovirus • Clinically similar of respiratory syncytial virus • Pneumocystis jirovecii • Aspergillus
(RSV) infections • Drug reaction • Candida
• SARS-CoV-2 (COVID-19) • Malignancy
o Lung tropism: Virus binds to ACE2 receptors
Human The common theme of these etiologic agents (most, if not all of them), is that they
found in pulmonary alveolar epithelial cells
Coronaviruses are considered opportunistic agents—agents that do not cause significant
o Host immune response and cytokine storm
→ ARDS disease in otherwise immunocompetent hosts. Most of them are fungi and
viruses.
LUNG ABSCESS Dr. Elomina
• Local suppurative process that produces necrosis of lung tissue TUMORS

• Cardinal histologic change • Most common: Carcinomas (90-95%)
o Suppurative destruction of the lung parenchyma within the • Bronchial carcinoids (5%)
central area of cavitation • Mesenchymal and Miscellaneous (2-5%)
• Causes: Aspiration of infective material (Most common),
Neoplasia, Antecedent primary lung infection, Septic embolism,
Miscellaneous (direct trauma, local spread from adjacent organs, LUNG CARCINOMA
hematogenous seeding) • Most frequently diagnosed major cancer in the world
In cases of lung abscess secondary to aspiration, the lesion is most likely • Most common cause of cancer mortality
found in the right lung because of the anatomy of the right mainstem • Risk factors:
bronchus i.e. shorter and more vertical. o Smoking
Dr. Elomina
o Industrial hazards (Asbestos, Arsenic, Chromium, Uranium,
Nickel, Vinyl chloride, Mustard gas, High-dose ionizing radiation)
o Air pollution (Secondhand smoke, Particulates, Radon Gas)
o Acquired mutations
COMMON LUNG CARCINOMAS
FEATURE ADENOCARCINOMA SQUAMOUS CELL SMALL CELL
MUST-KNOW
Prevalence • Most common (50%) • 2nd most common (20%) • 3rd most common (15%)
Site • Peripheral • Central/hilar • Either
Association with • Yes but low (Most common
• Yes • Almost always
tobacco smoke type in never smokers)
• Hypertrophic
Paraneoplastic • Hypercalcemia (PTH, PTHrP, PGE, • SIADH (ADH)
osteoarthropathy
syndromes Cytokines • Cushing syndrome (ACTH)
(clubbing)
• Small cells with salt and pepper
• Glandular differentiation
• Keratinization (squamous pearls or chromatin
(with different patterns)
cells with intensely eosinophilic • Azzopardi effect: Basophilic staining of
Morphology • Mucin production (Invasive
cytoplasm) vascular walls
mucinous
• Intercellular bridges • Chromogranin A(+), neuron-specific
adenocarcinomas)
enolase (+), synaptophysin (+)
NICE-TO-KNOW
• Chromosome deletions or mutations
• MYC amplification (derived from
Mutations • KRAS, EGFR, ALK involving TP53, CDKN2A
Kulchitsky cells)
• FGFR1 amplification
OTHER LUNG NEOPLASMS CLINICAL ASPECTS
• Highly anaplastic undifferentiated tumor • Most common symptoms: cough (50-75%), hemoptysis, chest pain
• Poor prognosis, less responsive to • Secondary pathologies
Large cell chemotherapy, removed surgically o Focal emphysema (partial obstruction)
carcinoma • Strong association with smoking o Atelectasis (total obstruction)
• Peripheral location o Severe suppurative or ulcerative bronchitis or bronchiectasis
• Histology: pleomorphic giant cells (impaired drainage of secretions)
• Symptoms due to mass effect (as intraluminal o Pulmonary abscess
polypoid mass, “collar-button’’ lesion) or o SVC syndrome, pleuritis, and pericarditis (local spread)
carcinoid syndrome (flushing, diarrhea, • Distant spread (via lymphohematogenous route)
Bronchial wheezing) o Less common in squamous cell carcinomas
carcinoid o Secondary to serotonin & bradykinin o Most common site: Adrenal glands (> 50%)
tumor • Excellent prognosis, metastasis is rare o Other sites: Liver (30-50%), Brain and Bone (20%)
• Central or peripheral location PARANEOPLASTIC SYNDROMES
• Histology: nests of neuroendocrine cells, • More commonly encountered in small cell carcinomas
chromogranin A(+) SYNDROME DETAILS
Lung • Most common site of metastasis: lungs Hypocalcemia Calcitonin
metastasis • Presentation: “cannon ball” lesions Gynecomastia Gonadotropins
Lambert Eaton Myasthenic Autoantibodies against
Syndrome (LEMS) neuronal calcium channels
Peripheral neuropathy Usually purely sensory
LUNG CARCINOMAS Hypertrophic pulmonary Associated with clubbing of
https://qrs.ly/k9cmdv9 osteoarthropathy digits
Trousseau syndrome Hypercoagulable state
Horner syndrome Enophthalmos, ptosis, miosis,
(Pancoast tumors) and anhidrosis
Acanthosis nigricans -
Leukemoid reactions -
Note: Other paraneoplastic syndromes are described in the previous sections
under the neoplasms they’re commonly associated with.
PLEURA 15. HEAD AND NECK

PLEURAL EFFUSION • Oral cavity • Neck
• Upper airways • Salivary glands
• Pleural fluid; 15 mL normally, serous, acellular, clear fluid • Ears
• Pleural effusion: excess fluid in pleural cavity
CAUSES OF PLEURAL EFFUSION
ORAL CAVITY
CONDITION MECHANISM • Demineralization of enamel and dentin due to
Congestive Heart Failure • ↑ Capillary hydrostatic pressure Dental caries bacterial fermentation of sugars → acids
• Main cause of tooth loss before 35
Pneumonia • ↑ Capillary permeability
Nephrotic syndrome • ↓ Capillary oncotic pressure
Gingivitis • Inflammation of oral mucosa surrounding teeth
• Inflammation of periodontal ligaments
Atelectasis • ↑ Intrapleural pressure
alveolar bone, & cementum
Mediastinal carcinomatosis • ↓ Lymphatic drainage
• Causes loosening & eventual tooth loss
Periodontitis
TYPES OF PLEURAL EFFUSIONS • Origin of infective endocarditis, pulmonary &
INFLAMMATORY brain abscesses
SEROUS, SEROFIBRINOUS, FIBRINOUS • May be a component of systemic diseases
• Inflammation of pulmonary parenchyma (Most common) • Painful, superficial oral mucosal ulcerations
• Radiation • Can be associated with immunologic diseases:
Aphthous
• Autoimmune (RA, SLE) celiac diseases, IBD, Behçet disease
ulcers
• Metabolic (Uremia) • Typically regresses in 7-10 days, except in
• Neoplastic (Metastatic involvement of pleura) immunocompromised patients
PURULENT
• Infections (Bacterial or Fungal)
HERPES SIMPLEX VIRUS INFECTIONS
o Contiguous spread from intrapulmonary infection • Clinical forms
o Lymphohematogenous dissemination o Gingivostomatitis: children
o Extension from a subdiaphragmatic infection o Pharyngitis: adults
HEMORRHAGIC o Chronic mucocutaneous infection: immunocompromised
• Hemorrhagic diatheses individuals
• Rickettsial diseases • Etiologic agent
• Neoplastic involvement of pleura (Most important) o HSV-1 and HSV-2 (HSV-1 more common)
NON-INFLAMMATORY o HSV exhibits latency in trigeminal ganglia; reactivation →
HYDROTHORAX Recurrent herpetic stomatitis
• Heart failure (Most common) § Triggers: Trauma, allergies, exposure to ultraviolet light,
• Renal failure URTI, pregnancy, menstruation, immunosuppression,
• Liver Cirrhosis exposure to temperature extremes
HEMOTHORAX • Clinical manifestations
• Trauma (Most common) o Vesicobullous lesions with clear, serous fluid → rupture →
• Surgery painful, shallow ulcerations with surrounding erythema
• Ruptured aortic aneurysm • Diagnosis: Tzanck smear
CHYLOTHORAX Ultraviolet light as a trigger of herpes is the reason why patients present
• Thoracic duct trauma (Most common) with recurrence of herpetic lesions with prolonged sun exposure.
• Obstruction of a major lymphatic duct by malignancy Dr. Elomina
PNEUMOTHORAX PRECANCEROUS LESIONS

• Presence of air in pleural cavity LEUKOPLAKIA AND ERYTHROPLAKIA
• Associations: emphysema, asthma, tuberculosis • Leukoplakia: “A white patch or plaque that cannot be scraped
TYPE FEATURES off and cannot be characterized clinically or pathologically as
Spontaneous • Rupture of emphysematous alveoli any other disease” –WHO
• Young patients • Erythroplakia: Red, velvety area within the oral cavity; may be
Spontaneous
• Due to rupture of subpleural blebs eroded and slightly depressed
idiopathic
• Self-limiting, Recurrent attacks common o More ominous than leukoplakia (can be markedly dysplastic,
Traumatic • Caused by perforating injury to the chest wall and may show areas of carcinoma in situ)
• Pneumothorax sufficient to cause circulatory The reason why erythroplakia is red is because of the vascular dilation that
Tension
collapse (hypotension) due to compression to occurs with the subepithelial inflammation that occurs in erythroplakia.
pneumothorax
mediastinal structures Dr. Elomina
TUMORS SQUAMOUS CELL CARCINOMA

• Primary tumors • Most common cancer of the head and neck (95%)
o Solitary fibrous tumor o Most common histology of cancers of the oral cavity,
o Malignant mesothelioma oropharynx, nasopharynx, and larynx
• Secondary involvement of pleura (More common) FEATURE SQUAMOUS CELL CARCINOMA
o Most common primary sites: Lung and Breast • High-risk HPV infection
MALIGNANT MESOTHELIOMA Prominent
o Tonsils, Tongue base, Oropharynx
FEATURE MALIGNANT MESOTHELIOMA • Tobacco and alcohol
risk factors
Clinical • Chest pain, Dyspnea • Betel chewing
presentation • Recurrent pleural effusions • Sunlight and pipe smoking: Lower lip
Association • Associated with asbestos exposure • Non-HPV-associated: Keratinizing squamous
• Thick layer of soft, gelatinous, grayish pink cell carcinoma
Gross o Sites: Ventral surface of tongue, floor of
tumor tissue enclosing the affected lung
• Epithelioid (Most common) Morphology mouth, lower lip, soft palate, gingiva
o Cuboidal, columnar, or flattened cells forming • HPV-associated: Non-keratinizing squamous
tubular or papillary structures (looks like cell carcinoma
adenocarcinoma) o Sites: Tonsils, Tongue base, Oropharynx
Histology • Sarcomatoid • Non-HPV-associated: Worse prognosis than
o Malignant-looking spindle cells (looks like HPV-associated
fibrosarcoma) o Cervical lymph nodes: most common site of
• Biphasic (combination of both epithelioid and Prognosis local metastasis
sarcomatoid) o Distant metastasis is common
§ Sites: Mediastinal lymph nodes, lung, liver,
Mutation • Deletion of 9p (CDKN2A) (Most common)
bones
ODONTOGENIC LESIONS
SQUAMOUS CELL CARCINOMA • Odontogenic cysts: from remnants of odontogenic epithelium
https://qrs.ly/9mcmdvg present within the jaws
o Dentigerous cyst
o Keratocystic odontogenic tumor (KCOT)
o Radicular cyst (Periapical cyst)
• Odontogenic tumors
o Odontoma
o Ameloblastoma
ODONTOGENIC CYSTS
DENTIGIROUS CYST KCOT RADICULAR CYST
• True cysts lined by nonkeratinizing • True cysts lined by keratinized • True cysts lined by nonkeratinizing
Histology stratified squamous epithelium with stratified squamous epithelium stratified squamous epithelium with
stromal chronic inflammation with a corrugated epithelial surface stromal acute and chronic inflammation
• Usually associated with impacted or • Apex of non-viable tooth
Location • Posterior mandible
unerupted tooth • Usually with history of dental caries or trauma
• Locally aggressive and can recur
Behavior • Can recur with incomplete excision • Can recur with incomplete excision
with incomplete excision
• Patients with multiple KCOTs
Clinical • Can become a periapical abscess
• Can progress to ameloblastoma should be evaluated for nevoid
significance • Does not give rise to ameloblastoma
BCCA syndrome (Gorlin syndrome)
Additional reference: Wenig, B. Atlas of Head and Neck Pathology. 2016. 3rd ed. pp. 232-235, 239-241.
ODONTOGENIC TUMORS 1. Keratinizing squamous cell carcinoma
ODONTOMA 2. Non-keratinizing squamous cell carcinoma
• Most common odontogenic tumor o Undifferentiated carcinoma: Syncytial
Morphology nests of markedly atypical cells in a
• Ectomesenchymal differentiation present (i.e. enamel and
lymphocytic background (T cells)
dentin deposition)
3. Basaloid squamous cell carcinoma
• Treatment: Local excision (+) for EBV-encoded RNAs (EBER-1 and LMP-1)
AMELOBLASTOMA Clinical • Nasal obstruction, Epistaxis
• No evidence of ectomesenchymal differentiation picture • Cervical lymphadenopathy (metastasis)
• Locally invasive Treatment • Radiotherapy
• Treatment: Wide excision • Keratinizing: least radiosensitive
Prognosis
• Undifferentiated: most radiosensitive
UPPER AIRWAYS
NOSE
RHINITIS
NASOPHARYNGEAL CARCINOMA
• Causes: infectious (usually viral: rhinovirus, coronavirus,
adenovirus; can have secondary bacterial infection); allergic https://qrs.ly/61cmdw6
(IgE-mediated)
• Sequelae: chronic rhinitis, sinusitis, nasal polyps
• Masses with edematous mucosa with loose
Morphology of
stroma, with hyperplastic/cystic mucous
LARYNX
nasal polyp LARYNGITIS
glands and inflammatory cells
Nasal polyp is an important differential diagnosis for patients presenting • Infectious causes: Viral, Bacterial
with chronic nasal congestion. • H influenzae, RSV, GAHBS →
Dr. Elomina Laryngoepiglottitis laryngeal obstruction
NASOPHARYNX (pediatric emergency)
PHARYNGITIS AND TONSILLITIS Laryngotracheobronchitis
• Paramyxovirus
(croup)
• Causes:
Viral • Rhinitis agents, RSV, and influenza • Non-infectious causes: Allergic, Chemical (tobacco, GERD),
• (may be a superinfection or primary): GABHS (Most smoking-related (can cause squamous metaplasia &
Bacterial carcinoma)
common) and S aureus
• Morphology of tonsillopharyngitis Children are at a particular risk of airway obstruction because of a
• Inflamed mucosa, w/ or w/o exudates smaller larynx.
Dr. Elomina
Morphology • Follicular tonsillitis: Reactive lymphoid
hyperplasia of the tonsils REACTIVE NODULES
BENIGN TUMORS • Heavy smokers and voice strainers
• Common benign tumors of nasopharynx are histologically o Clinically present with voice changes (hoarseness)
benign but biologically aggressive (compounded by close • Nodules (bilateral), polyp (unilateral)
association with the intracranial area) • Morphology
• Incomplete excision leads to recurrence o Lining: Squamous epithelium
• Arises from posterolateral wall of nasal cavity roof o Core: Loose myxoid connective tissue
Nasopharyngeal
• Commonly seen in young, adolescent males • Virtually never give rise to cancers
angiofibroma
• Highly vascular → can lead to hemorrhage
• Arises from the respiratory mucosa lining SQUAMOUS PAPILLOMA AND PAPILLOMATOSIS
Sinonasal
the nasal cavity and paranasal sinuses
(Schneiderian) • Benign, but may present with hemoptysis
• Associated with low-risk HPV (6 and 11)
papilloma o If located in free edge of cord, and is traumatized
• Most common form: exophytic
• Morphology: Papillary fronds with fibrovascular cores (true
MALIGNANT TUMORS papillae) covered by an orderly stratified squamous epithelium
NASOPHARYNGEAL CARCINOMA • Solitary (adults) or multiple (children) (juvenile respiratory
NASOPHARYNGEAL CARCINOMA papillomatosis)
1. Geography: Africa (usually children), China o Associated with low-risk HPVs (HPV 6 and 11)
(usually adults) o No malignant transformation, but may recur
Prominent
2. EBV infection
risk factors
3. Diet: Nitrosamines, salted fish
4. Environmental: Smoking and chemical fumes
LARYNGEAL CARCINOMA SALIVARY GLANDS

• Risk factors: XEROSTOMIA
o Smoking o Radiation • Most common cause: drugs (anticholinergics, antihistamines,
o Alcohol o HPV infection antipsychotics, antidepressants)
o Asbestos • Prominent component of Sjögren syndrome (with lacrimal
• Most common histology: Squamous cell carcinoma (95%) gland involvement)
• Commonly a disease of elderly males (6th decade) • Increased incidence of ulcerations and fissuring
o Clinical symptoms: persistent hoarseness, dysphagia,
dysphonia
SIALADENITIS
EARS • Mucocele: most common type of inflammatory salivary gland
OTITIS MEDIA lesion
o Most common site: Lower lip
• Common in children
o Trauma → Ductal obstruction/destruction → leakage of saliva
• Causes:
into stroma → walled by fibrous tissue (pseudocysts)
Acute otitis • Viral, Bacterial (superinfection): S pneumoniae,
media
• Ranula: true cysts (with epithelial lining) when sublingual
non-typeable H influenzae, M catarrhalis
gland duct is damaged
Chronic otitis • Bacteria: P aeruginosa, S aureus, Fungi, Mixed
media pathogens • Mumps: Most common form of viral sialadenitis
o Most common gland involved: Parotid gland
• Complications:
• Non-neoplastic cystic lesions forming as
SIALOLITHIASIS AND NONSPECIFIC SIALADENITIS
complication of chronic otitis media
• Lining: Keratinizing stratified squamous or • Most common gland involved: major (submandibular)
Cholesteatoma o Unilateral, single gland involvement
metaplastic mucus-secreting
• Contents: Keratinous debris, Cholesterol • Duct obstruction by stones → bacterial infection and
spicules inflammation
• Infection spreading to surround structures o Most common organisms: S. aureus and viridans streptococci
Brain abscess
and to the brain • Inflammation usually interstitial
o Overt necrosis and abscess formation with pyogenic
NECK organisms
BRANCHIAL CLEFT CYST
NEOPLASMS
(CERVICAL LYMPHOEPITHELIAL CYST)
• Most common site of tumors regardless of behavior: parotid
• Remnant of 2nd branchial arch
gland
• Clinically, upper lateral neck mass along SCM
• Likelihood of a tumor being malignant is usually inversely
• Morphology: proportional to size of gland
o Lining: stratified squamous or pseudostratified columnar
• Most common tumor: Pleomorphic adenoma
o Contents: serous or mucinous with desquamated cells
• Second most common tumor: Warthin tumor
o Wall: lymphoid tissue with prominent germinal centers
• Most common primary malignant: Mucoepidermoid carcinoma
• No malignant transformation
The most important differential diagnosis when you have a branchial BENIGN SALIVARY TUMORS
cleft cyst is cystic metastasis of squamous cell carcinoma.
MORPHOLOGY/
Dr. Elomina
TUMOR REMARKS
PRESENTATION
THYROGLOSSAL DUCT CYST • Most common site: • Benign but may
• Remnants of thyroid gland descent Pleomorphic Parotid recur w/
• Morphology: adenoma • Has mixed epithelial/ incomplete
o Lining: depends on location; either stratified squamous (benign mixed myoepithelial and excision due to
(upper) or pseudostratified columnar (lower) tumor) mesenchymal poorly developed
• Rare malignant transformation components capsule
• Most common site:
PARAGANGLIOMA (CAROTID BODY TUMOR) Parotid gland
• Neuroendocrine neoplasm associated with ANS Warthin (almost exclusively)
• Location tumor • Has double-layer of • Smoking is a
o Most common: Adrenal medulla (pheochromocytomas) (papillary oncocytic epithelial notable risk
o Most common location of extra-adrenal paragangliomas: cystadenoma cells: eosinophilic, factor
lymphomatosum) granular cytoplasm
Head and neck
§ Carotid body tumor: near or at carotid artery bifurcation and large nuclei with
prominent nucleoli
LOCATIONS OF PARAGANGLIOMAS
AORTICOPULMONARY MALIGNANT SALIVARY TUMORS
PARAVERTEBRAL
CHAIN
MORPHOLOGY/
• Organ of TUMOR REMARKS
• Near great vessels of PRESENTATION
Locations Zuckerkandl
head and neck • Most common site: Parotid
• Bladder (rare)
gland > minor salivary
Incidence • Less common • More common Muco- glands • Prognosis
Innervation • Sympathetic • Parasympathetic epidermoid • Mucus-secreting cells depends on the
Chromaffin carcinoma (muco-) + squamous cells (- grade of tumor
• Positive • Often negative
stain epidermoid) + intermediate
• Familial paragangliomas: cells
o Multiple Endocrine Neoplasia 2 (Pheochromocytomas) • Recurrence is
• Most common site: minor
• Morphology: common
(palatine) glands
General • Nests (zellballen) with vascular septa • Distant
• Patterns:
Morphology • Usually none-to-little atypia & mitosis metastasis:
Adenoid o Cribriform: most
• Salt-and-pepper chromatin nuclei bone, liver,
cystic common form
Chief cells • (+) neuroendocrine markers: Synaptophysin, brain
carcinoma • Small cells with scant
Chromogranin, Neuron-specific enolase • Worse
cytoplasm, and
Sustentacular • Network of spindle-shaped stromal cells prognosis in
hyperchromic nuclei
cells • (+) S-100 protein minor salivary
• Perineural invasion
glands
16. GASTROINTESTINAL TRACT • Location: Antimesenteric side

• Lining: Intestinal-type
• Congenital anomalies • Small intestine and Colon
• May have ectopic pancreatic or gastric tissue
• Esophagus • Anus
o May cause ulceration of adjacent mucosa → bleeding, pain
• Stomach • Appendix
QUICK SHEET:
MECKEL DIVERTICULUM RULE OF 2
CONGENITAL ANOMALIES • 2% of the population
ATRESIA • Most found within 2 feet (60 cm) of the ileocecal valve
TRACHEOESOPHAGEAL FISTULA WITH ESOPHAGEAL ATRESIA • ~2 inches (5cm) long
• Abnormalities in partition of trachea and esophagus by • 2 times more common in males
• 2 years old when symptomatic
tracheoesophageal septum
• Most common type: Type C, distal TEF with proximal Meckel diverticulum is an important differential diagnosis in patients
esophageal atresia) > A > H (or E) > D > B (see below) where acute appendicitis is considered. This is particularly true if we are
• Clinically: aspiration, suffocation, pneumonia, severe fluid and talking about pediatric patients.
Dr. Elomina
electrolyte imbalances
PYLORIC STENOSIS
• Congenital hypertrophic pyloric stenosis
o 3-5x more common in males
o Associations:
§ Turner syndrome (45 XO), Trisomy 18
§ Erythromycin/Azithromycin exposure in 1st 2 weeks of life
• Morphology
o Hypertrophic muscularis propria of the pyloric region
TRACHEOESOPHAGEAL FISTULA WITH ESOPHAGEAL ATRESIA
Figure 39.8 Schwartz’s Principles of Surgery, 11th ed. 2019 • Clinically: New-onset regurgitation, nonbilious vomiting,
feeding abnormalities, and olive-shaped abdominal mass
Aspiration can happen either by vomiting (in atretic lesions without
fistula), or through the fistulous tract. Pneumonia is the consequence of • Treatment: Myotomy
aspiration. Lesions that impair enteral nutrition leads to fluid and In the book, it says hyperplasia of the muscularis propria of the pyloric
electrolyte imbalances. region. I find it inconsistent with the name of the disease, though. So, I
Dr. Elomina
took the liberty of writing hypertrophy of the muscularis propria.
IMPERFORATE ANUS Dr. Elomina
• Most common form of congenital intestinal atresia

• Failure of cloacal membrane involution HIRSCHSPRUNG DISEASE
• Clinically: failure to pass meconium • Absence of Myenteric (Auerbach) and Submucosal (Meissner)
plexuses due to abnormal migration of neural crest cells or
DIAPHRAGMATIC HERNIA, OMPHALOCELE, AND premature death
GASTROSCHISIS • Mutations : RET mutations
DIA PHRAGMATIC HERNIA • Morphology
o Aganglionic segment (variable length): constricted
• Incomplete diaphragm development → herniation of
o Normal segment: dilated (megacolon)
abdominal contents into the thoracic cavity → may lead to
o Rectum is always affected
pulmonary hypoplasia
• Absence of ganglion cells within the affected segment
• Types
o Acetylcholinesterase: IHC stain to assess ganglion cells
o Bochdalek (more common): posterolateral defect, left-sided
o Intraoperative frozen section to confirm presence of
o Morgagni: anteromedial defect
Ganglion cells at anastomotic margin
OMPHALOCELE AND GASTROSCHISIS • Clinical manifestations
o Failure to pass meconium, explosive passage of flatus and
OMPHALOCELE
feces if facilitated
• Failure of viscera to return during physiologic herniation (6- o Abdominal distention
10th week AOG) with concurrent incomplete closure of the o Complications: Enterocolitis, Fluid and electrolyte
abdominal musculature imbalance. Perforation → Peritonitis
• Herniation of abdominal viscera through an enlarged umbilical
ring
o Visceral organs (including liver) are enclosed in a sac ESOPHAGUS
GASTROSCHISIS ESOPHAGEAL OBSTRUCTION
• Herniation of abdominal viscera (usually, only intestines are • Causes:
involved) directly into the amniotic cavity o Functional (Motility disorders)
o Defect involves all layers of abdominal wall o Mechanical (Anatomic obstruction)
Between omphalocele and gastroschisis, omphalocele is the one • Main symptom: Dysphagia
associated with chromosomal abnormalities, and as a consequence, it FUNCTIONAL ESOPHAGEAL OBSTRUCTION
is usually associated with other abnormalities. Gastroschisis tends to be DISEASE DEFINITION
an isolated abnormality. Nutcracker • High-amplitude contractions of the distal
Dr. Elomina
esophagus esophagus
ECTOPIA Diffuse • “Corkscrew esophagus”
• Ectopic tissues have normal function, but because they are in an Esophageal • Repetitive simultaneous normal-amplitude
ectopic position, they can cause disease Spasm contractions of the distal esophageal smooth
o Gastric tissue in upper third of esophagus (Inlet patch) (DES) muscle
§ Dysphagia, esophagitis, Barrett esophagus, • High resting pressure or incomplete relaxation
LES
Adenocarcinoma in isolation or together with nutcracker
dysfunction
o Pancreatic tissue in esophagus and stomach esophagus and DES
§ Inflammation and scarring → obstruction • Sequelae: False Diverticula due to ↑ wall stress
o Gastric tissue in small bowel and colon Epiphrenic • False diverticulum above the LES
§ Peptic ulceration → occult bleeding • False diverticulum above the UES
MECKEL DIVERTICULUM • Due to cricopharyngeus
Pharyngoesophageal
dysfunction
• Most common congenital anomaly of the GI tract (Zenker)
• Regurgitation, halitosis (from
• True diverticulum: All 3 layers present accumulated food)
• Failed involution of vitelline/omphalomesenteric duct
MECHANICAL ESOPHAGEAL OBSTRUCTION
EXAMPLE DEFINITION
• Luminal narrowing
• Causes
Stenosis
o Benign: GERD, irradiation, caustic injury
o Malignant: Esophageal Ca
• Semi-circumferential ledge-like mucosal
protrusions
Esophageal
o Plummer-Vinson syndrome (triad): BARRETT ESOPHAGUS
mucosal
§ Upper esophageal webs Figure 13.14A. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 508.
webs
§ Iron deficiency anemia
§ Glossitis, cheilosis ESOPHAGEAL CARCINOMA
• Circumferential protrusions thicker than SQUAMOUS CELL
Esophageal FEATURE ADENOCARCINOMA
webs, and may contain all three layers of the CARCINOMA
rings
esophagus Incidence • More common • Less common
(Schatzki
o A rings: ABOVE GEJ • Tobacco and
rings)
o B rings: SCJ of lower esophagus alcohol • Chronic GERD
• Diet low in fresh • Tobacco
ACHALASIA fruits and • Radiation
• Triad: vegetables exposure
1. Incomplete LES relaxation • Hot drink ingestion • Helicobacter pylori
2. Increased LES tone Risk factors • Previous radiation (some serotypes
3. Esophageal aperistalsis • HPV associated with
• Etiology • Caustic esophageal atrophic gastritis):
o Primary: Degeneration of NO-producing neurons injury PROTECTIVE, due
o Secondary: Chagas disease (T. cruzi) • Achalasia to decreased acid
• Clinical manifestations: Dysphagia, Difficulty in belching, • Plummer-Vinson secretion
Chest pain syndrome
Common
• Middle third • Distal third
ESOPHAGITIS AND RELATED DISORDERS site
LACERATIONS Precursor • Squamous • Dysplasia in
FEATURES lesion dysplasia Barrett esophagus
• Longitudinal mucosal tears near GEJ • Most common: • Intestinal type
• Associated with severe retching or vomiting Well- and (Most common)
secondary to acute alcohol intoxication Moderately o Gland-forming
Mallory- • Failure of esophageal muscle relaxation differentiated and usually
Weiss Tear preceding the antiperistaltic contractile wave Morphology Squamous cell produces mucin
→ reflux of gastric contents → tearing of carcinoma • Signet ring type
esophageal wall • Verrucous • Poorly
• Presents with hematemesis carcinoma differentiated (like
• Transmural rupture & tearing of distal • Basaloid carcinoma SCLC of the lung)
esophagus • Clinical manifestations
Boerhaave
• Leaking of esophageal contents → severe o Dysphagia and odynophagia
syndrome
mediastinitis o GI bleed (Hematemesis)
• Clinically: severe chest pain, shock (mimics MI) o Obstruction
• Most common cause: GERD o Symptoms of GERD in Adenocarcinoma
• Pathogenesis: transient LES relaxation o Constitutional symptoms suggestive of malignancy (e.g.
• Risk factors: Alcohol, Tobacco, CNS depressants, profound weight loss)
Hiatal hernia, ↑ intraabdominal pressure
Reflux • Prognosis
• Morphology: eosinophils in squamous mucosa,
esophagitis o Deeper depth of invasion: Poor prognosis
basal zone hyperplasia, elongation of lamina
o Lymph node metastasis: Poor prognosis
propria papillae
• Clinical manifestations: heartburn, dysphagia,
§ Spread depends on location of the primary tumor
regurgitation • Upper third: Cervical nodes
• Middle third: Mediastinal, Paratracheal, Tracheobronchial
Esophageal pathologies usually mimic the chest pain of MI, because the nodes
esophagus and the heart share the same visceral pain area.
Dr. Elomina • Lower third: Gastric and Celiac nodes
ESOPHAGEAL VARICES
• Dilation of esophageal portocaval anastomosis: esophageal
branch of left gastric vein and azygos, due to portal ESOPHAGEAL CARCINOMA
hypertension https://qrs.ly/excmdwf
• Causes
o Most common cause: Liver cirrhosis, secondary to alcoholic
liver disease
o Second most common cause: Hepatic Schistosomiasis STOMACH
• Morphology: Dilated mucosal and submucosal veins ACUTE GASTRITIS AND GASTROPATHY
• Most dreaded complication: Bleeding • Mucosal, inflammatory response
Gastritis o Acute gastritis: neutrophilic infiltrate
BARRETT ESOPHAGUS o Chronic gastritis: mononuclear infiltrate
• Complication of chronic GERD characterized by intestinal Gastropathy • Rare or absent inflammatory cells
metaplasia within the squamous epithelium • Common pathogenesis
• Increased risk of esophageal adenocarcinoma o Imbalance between mucosal protective mechanisms and
• Morphology: injurious stimuli
Gross • Red, velvety mucosa
• Intestinal metaplasia (presence of Goblet cells)
• Dysplasia can be present: Grading depends on
Microscopic
degree of cytologic atypia and architectural
abnormality
HELICOBACTER PYLORI GASTRITIS
• Gram-negative, microaerophilic, urease-positive, helical
bacterium, motile by lophotrichous flagella
• Virulence factors:
Flagella • Allows movement through viscous mucus
• Converts urea → NH3 (ammonia); elevates
Urease
gastric pH → allows H pylori growth
Adhesins • Allows adherence to foveolar epithelial cells
• Associated with multifocal atrophic gastritis
CagA
→ gastric adenocarcinoma
PATHOGENESIS OF GASTROPATHY AND GASTRITIDES

STRESS-RELATED MUCOSAL DISEASE (SRMD)

DISEASES ASSOCIATED WITH H. pylori INFECTION
• Notable entities: Reference: Jameson, JL et al. Harrison’s Principles of Internal Medicine, 19th ed. 2015.
• Seen in patient with shock, sepsis, trauma
Stress
• ↓ intravascular volume → splanchnic
ulcers HELICOBACTER PYLORI
vasoconstriction → ↓ mucosal blood flow
GASTRITIS
Curling
• Proximal duodenal ulcers seen in burns https://qrs.ly/fdcmdwj
ulcers
• Esophageal, gastric, duodenal ulcers in patients
Cushing with intracranial pathology AUTOIMMUNE ATROPHIC GASTRITIS
ulcers • Direct vagal stimulation → hypersecretion of
• Features
gastric acid
o Antibodies to parietal cells and intrinsic factor that can be
MORPHOLOGY detected in serum and gastric secretions
• Multiple lesions found in different locations, with blood vessel o Reduced serum pepsinogen I concentration
thickening & absent scarring o Endocrine cell hyperplasia
• Healing by re-epithelialization: Since erosion only involves o Vitamin B12 deficiency
mucosa o Defective gastric acid secretion (achlorhydria)
In contrast with SRMDs, Peptic ulcers are solitary, and are often located • Pathophysiology
in the antrum. o Autoimmune destruction of parietal cells
Dr. Elomina § HCl: Achlorhydria with consequent hypergastrinemia
§ IF: Vitamin B12 deficiency
CHRONIC GASTRITIS o CD4+ T-cells directed against parietal cell components;
• Most common cause of chronic gastritis: Helicobacter pylori autoantibodies against H+,K+-ATPase (proton pump) and IF
gastritis o Typically spares the antrum
• H. pylori gastritis: multifocal atrophic gastritis
• Most common cause of diffuse atrophic gastritis: autoimmune AUTOIMMUNE
gastritis (< 10% of cases of chronic gastritis) ATROPHIC GASTRITIS
• Autoimmune gastritis: most common form of gastritis in https://qrs.ly/7vcmdwl
patients without H. pylori infection
MAIN TYPES OF CHRONIC GASTRITIS

FEATURE H. PYLORI-ASSOCIATED AUTOIMMUNE
CLINICAL
Acid production • ↑ to slightly ↓ • ↓
Gastrin • N to ↑ • ↑ to markedly ↑
Serology • Antibodies to H. pylori • Antibodies to parietal cells (Proton pump and IF)
• Peptic ulcer, adenocarcinoma, MALToma • Atrophy, pernicious anemia, adenocarcinoma,
Sequelae
carcinoid tumor
Associations • Low SES, poverty, residence in rural areas • Autoimmune disease: thyroiditis, DM, Graves
MORPHOLOGY
Location • Antrum • Body
Inflammation • Superficial, in lamina propria • Deep, in gastric glands
Inflammatory infiltrate • PMNs, subepithelial plasma cells • Lymphocytes, Macrophages
• In H. pylori corpus-predominant atrophic gastritis: • Diffuse and extensive
Chief cell loss (Atrophy)
Patchy distribution (Multifocal atrophic gastritis)
Other lesions • Hyperplastic/inflammatory polyps • Neuroendocrine hyperplasia
Table 17.8. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 (Modified)
PEPTIC ULCER DISEASE • Clinical manifestation: Burning epigastric pain
• Chronic mucosal ulceration affecting duodenum or stomach o Perforated ulcers: Referred pain to back, LUQ, or chest (can
• Common causes: H. pylori, NSAIDs, cigarette smoking mimic MI), pneumoperitoneum
• Epidemiology • Most common complication: Bleeding
o Incidence of PUD decreases with decreasing prevalence of H. o Other complications: Perforation and Obstruction
pylori infection
o Increasing incidence of PUD from NSAID use in patients >60
years
GASTRIC VS. DUODENAL ULCERS GASTRIC ADENOCARCINOMA
FEATURE GASTRIC (GU) DUODENAL (DU) • Risk factors
• Mucosal o Chronic atrophic gastritis (corpus-predominant atrophic
• Antral-
atrophy (Corpus- gastritis (H. pylori) and Autoimmune atrophic gastritis
predominant
Associations predominant o Ingestion of N-nitroso compounds and benzo[a]pyrene
gastritis caused
gastritis caused by • Most common site: Antrum; lesser > greater curvature
by H. pylori, NSAIDs
H. pylori, AIG)
• Types (Lauren classification): Intestinal, Diffuse infiltrative
Gastric acid
• Decreased • Increased • Most important prognostic factors: depth of invasion,
secretion
nodal/distant metastases
• With meals or
Timing of • Several hours
shortly after
epigastric pain after meals LAUREN CLASSIFICATION OF GASTRIC CARCINOMAS
meals
Nocturnal DIFFUSE
• Usually absent • Usually present INTESTINAL
awakening INFILTRATIVE
Association with • Mutations that cause
• Loss-of-function
gastric • Yes • No increase in WNT
Mutations mutations of CDH1
adenocarcinoma signaling pathway (APC
(E-cadherin) gene
etc.)
• Morphology
• Linitis plastica
o Usually solitary (80%) • Bulky, exophytic
(leather bottle
o Round to oval, sharply punched-out defect masses
Gross appearance):
o Mucosal margin level with surrounding mucosa • Ulcerative,
Thickened stiff wall
§ Heaped-up margins: suspect malignancy infiltrative masses
with flattened rugae
HISTOLOGY
• Glandular
Architecture
structures lined by • Dyscohesive cells
and
dysplastic intestinal- • Signet-ring cells
Cytology
type epithelial cells
• Intracellular: Apical • Intracellular: Signet-
mucin vacuoles ring cells
Mucin
• Extracellular: Gland • Extracellular mucin
lumina lakes
Clinical manifestations of gastric cancer are typically a combination of
obstruction and constitutional symptoms. In diffuse infiltrative cancers,
you usually have a non-distensible stomach on EGD.
Dr. Elomina
MORPHOLOGY OF PEPTIC ULCER LYMPHOMA
• Most common: Extranodal Marginal Zone B-cell Lymphoma
HYPERTROPHIC GASTROPATHIES
• Mucosa-associated lymphoid tissue (MALT) is normally absent in
• Diseases characterized by giant “cerebriform” enlargement of the stomach, but can be “induced” in chronic gastritis e.g. H. pylori
rugal folds due to epithelial hyperplasia without inflammation o H. pylori-dependent MALT lymphomas are responsive to H.
pylori eradication (no chromosomal translocations)
• Diffuse foveolar hyperplasia + protein losing o MALT lymphomas with chromosomal translocations
Ménétrier
enteropathy involving MLT and BCL10 (stimulus-independent) are not
disease
• due to excessive TGF-α secretion responsive to H. pylori eradication
Zollinger- • Parietal cell hyperplasia + consequent acid • Generally low-grade tumors, but can transform into DLBCL
Ellison hypersecretion secondary to a gastrin- (Richter phenomenon): H pylori eradication is ineffective if
syndrome secreting tumor → peptic ulceration
Richter phenomenon occurs
• Morphology
GASTRIC POLYPS • Lymphocytic infiltrates in lamina propria
• The risk of a more ominous consequence in polyps increases • Lymphoepithelial lesions: neoplastic
with SIZE Histology lymphocytes surrounding gastric glands
• Polyps with a genetic basis (e.g. familial fundic gland polyps, • Reactive follicles and plasmacytic
gastric adenomas) have malignant potential differentiation
MORPHOLOGY/ • CD19, CD20 (+) (B-cell origin)
POLYP REMARKS Immuno-
PRESENTATION • CD5, CD10 (-)
• Associated with H pylori
phenotype
• CD43 (+) in 25%
infection
• Leads to reactive NEUROENDOCRINE NEOPLASMS
Inflammatory/
hyperplasia in response • Most common
hyperplastic
to injury gastric polyp • Tumors of neuroendocrine origin
polyp • Most common site: GIT, particularly small intestine (40%)
• Irregular, cystically
dilated, foveolar glands • Morphology
• Inflamed polyps o Submucosal or intramural firm masses (Intense desmoplasia)
• PPI use → ↓ gastric acid
• Associated with
→ Can cause bowel kinking and obstruction
secretion → ↑ gastrin → o IHC: Synaptophysin (+), Chromogranin (+)
Fundic gland proton pump
parietal cell overgrowth • Prognosis
polyps inhibitor (PPI)
• Minimal to absent
use o Degree of differentiation
inflammation
o Mitosis and proliferative index
• Associated with
• Can present as chronic gastritis o Location
Gastric § Midgut NETs (Jejunum and Ileum): Multiple and aggressive
dysplastic (low-grade or with atrophy &
adenoma
high-grade) intestinal Because NETs are “endocrine” tumors, they produce hormones that
metaplasia dominate the clinical picture of the patient e.g., carcinoid syndrome. In
the intestine, the hormones are metabolized by the liver and may not
GASTRIC TUMORS cause symptoms. Exceptions include a large primary tumor size that can
overwhelm the metabolizing capacity of the liver, or metastatic tumors,
• Most common malignancy: Adenocarcinoma (90%) because the hormones they produce bypass the liver.
• Most common site of extranodal lymphomas: Stomach Dr. Elomina
• Most common mesenchymal tumor of the abdomen:

Gastrointestinal stromal tumor (GIST)
TOPNOTCH MEDICAL BOARD PREP PATHO MAIN DIGITAL HANDOUT BY KEVIN ELOMINA, MD Page 59 of 103
GASTROINTESTINAL STROMAL TUMOR (GIST) PERSISTENT WITH FASTING
• Associations Secretory • Isotonic stools as seen in Cholera
o Carney triad: GIST, paraganglioma, pulmonary chondroma • Purulent, bloody stools as seen in Amebic
Exudative
o Neurofibromatosis Type 1 dysentery (painful, bloody, small-volume)
• Cytogenetic origin: Interstitial cells of Cajal CHOLERA
• Genetic mutation: Tyrosine kinase activation (KIT) • Etiologic agent: Vibrio cholerae
• Morphology o Gram-negative, facultative anaerobic, comma-shaped
o Spindle cell type: Thin, elongated cells bacterium
o Epithelioid type: Epithelial-like cells o Toxin-producing strains infected with a virulence phage
o Mixed • Pathophysiology
o IHC: CD117(+) o Cholera toxin → ↑ ADP ribosylation of stimulatory G protein →
GISTs are notorious for producing large masses, and so patients tend to
↑ cAMP
present with a palpable abdominal mass, sometimes with consequent § Opens CFTR channel → ↑ Chloride secretion into the lumen
obstruction. Because the mucosal surface overlying the tumor can § ↓ Na and Cl reabsorption
ulcerate, patients may also have evidence of GI bleeding. o ↑ in Na, Cl, and HCO3 levels in the lumen → ↑ osmotic force in lumen
Dr. Elomina → water is drawn into the lumen → watery diarrhea
SMALL INTESTINE AND COLON • Clinical manifestations
o Rice water stools with fishy odor
INTESTINAL OBSTRUCTION o Signs of dehydration and volume depletion
• Most common cause: Hernia
AMEBIC DYSENTERY
• Most common cause in children <2 years old: Intussusception
• Etiologic agent: Entamoeba histolytica
• Symptoms: Abdominal pain, distention, vomiting, and
• Common sites affected: Cecum and ascending colon
constipation
• Pathophysiology:
o Ingestion of cyst (Infective stage, resistant of gastric acid) →
excystation in colon → trophozoites → enterocyte apoptosis,
crypt and lamina propria invasion
§ Flask-shaped ulcer: narrow necked, broad-based ulcers
§ Clinical manifestation: Dysentery
• Complications
o Amebic liver abscess: Trophozoites penetrate splanchnic
vessels and embolize to the liver
o Dissemination into other organs (heart, lung, kidneys, brain)
INFLAMMATORY BOWEL DISEASE
• Chronic condition resulting from inappropriate mucosal activation
• Crohn disease (CD) and Ulcerative colitis (UC)
• Main differences between CD and UC
o Bowel wall involvement: CD: transmural, UC: mural
o Organ involvement: CD: any part of GI tract, UC: colon and
DIFFERENT FORMS OF INTESTINAL OBSTRUCTION rectum
Figure 17.23. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 • Both typically present at a young age (teens and early 20s)
• Common extraintestinal manifestations: migratory
ISCHEMIC BOWEL DISEASE polyarthritis, ankylosing spondylitis, uveitis, skin lesions
• Bowels are hollow organs with multiple blood supply • Most feared long-term complication of UC and colonic CD:
o Pattern of injury: Hemorrhagic infarction (Red infarct) Colitis-associated neoplasia
• Most common site: Colon • Common histologic changes: inflammatory infiltrates, crypt
o Watershed areas (termination of blood supply): Splenic abscesses, crypt distortion, and pseudopyloric epithelial
flexure, rectosigmoid metaplasia
o Surface epithelium: Most vulnerable to ischemic damage • Paneth cell metaplasia: Paneth cells in left colon (normally
among the layers of the intestine absent) in CD
§ Findings: Sloughing off of surface epithelium with • Noncaseating granulomas: hallmark of CD
hypoproliferative crypts CD UC
• Types MACROSCOPIC
o Mucosal Bowel region • Ileum + colon • Colon only
o Mural: Mucosa and submucosa Distribution • Skip lesions • Diffuse
o Transmural: All three layers Stricture • Yes • Rare
§ Usually caused by acute vascular obstruction, secondary to Wall appearance • Thick • Thin
thrombosis or embolism MICROSCOPIC
• Atherosclerosis: Most important risk factor for Inflammation • Transmural • Limited to mucosa
thrombosis Pseudopolyps • Moderate • Marked
• Heart: Most common source of emboli • Superficial, broad-
Ulcers • Deep, knife-like
• Clinical manifestation based
o Sudden, cramping left lower abdominal pain, tenesmus, Lymphoid
• Marked • Moderate
hematochezia reaction
Fibrosis • Marked • Mild to none
o Complications: Shock, Perforation, Stricture (chronic
Serositis • Marked • Mild to none
ischemia)
Granulomas • Yes (~35%) • No
DIARRHEA AND INFECTIOUS ENTEROCOLITIS Fistulae/sinuses • Yes • No
DIARRHEA CLINICAL
• Increase in stool mass, frequency typically >200 g/day • Yes (in colonic
Perianal fistula • No
disease)
• Categories:
Fat/vitamin
RELIEVED BY FASTING • Yes • No
malabsorption
• Due to osmotic force by unabsorbed solutes Malignant • With colonic
Osmotic • Yes
• Seen in Lactase deficiency potential involvement
• Failure of nutrient absorption Recurrence after
• Common • No
• Steatorrhea: bulky, greasy, stools surgery
Malabsorptive
• Seen in Celiac disease: Cell-mediated immune Toxic megacolon • No • Yes
enteropathy on exposure to gliadin (in gluten) Table 17.8. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
Basically, IBDs are autoimmune disease targeting your gastrointestinal FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
tract. As such, they are usually associated with other autoimmune • Multiple colorectal adenomas as teenagers
manifestations. Make sure to study this table, because it is high yield.
Dr. Elomina o Extracolonic adenomas (Ampulla of Vater, Stomach)
o Extracolonic manifestation: Congenital hypertrophy of
SIGMOID DIVERTICULAR DISEASE retinal pigment epithelium
• Mutation: Adenomatous polyposis coli (APC) gene (Ch. 5)
• False diverticula (mucosal and submucosal outpouchings in
• Diagnosis: At least 100 polyps
focal areas of weakness i.e. where blood vessels penetrate the
• Adenocarcinoma develops in 100% of untreated patients often
bowel wall, coupled with ↑ intraluminal pressure)
before 30 and nearly always by age 50
o Muscularis propria absent
• Complications: Inflammation (diverticulitis, colitis), Fibrosis Remember that APC loss is also the genetic basis of gastric adenomas, and this
and strictures, Perforation explains why FAP patients also manifest with adenomas in the stomach.
Dr. Elomina
Clinically, diverticulitis can present with “left-sided appendicitis”. HEREDITARY NON-POLYPOSIS COLON CANCER (HNPCC)
Perforated diverticula can present with acute abdomen. • Familial clustering of colorectum, endometrium, stomach, ovary,
Dr. Elomina
ureters, brain, small bowel, hepatobiliary tract, pancreas, and
POLYPS skin
• Non-neoplastic: Hyperplastic (HP), inflammatory, and • Mismatch repair genes: MSH2, MLH1
hamartomatous • Amsterdam criteria (3-2-1 rule): Verified Lynch Syndrome-
• Neoplastic: Adenomas; further classified into architectural associated cancers in:
forms: tubular, villous, tubulovillous, and sessile serrated o 3 members (at least one should be a first-degree relative of the
lesions (SSLs) other two, and FAP should have been ruled out already)
o At least 2 generations
NON-NEOPLASTIC POLYPS o At least 1 diagnosed under age 50
• Benign lesions with serrated architecture Loss of DNA repair capability consequently leads to high mutational
secondary to delayed shedding of surface burden and carcinogenesis. The fact that Lynch syndrome manifests with
Hyperplastic carcinomas elsewhere means that microsatellite instability is part of the
epithelial cells
polyp (HP) molecular pathogenesis of these extra-colorectal malignancies.
• Must be differentiated with SSL: both have
Dr. Elomina
serrated architecture (see table below)
HAMARTOMATOUS POLYPS COLORECTAL ADENOCARCINOMA
• Most common site: Rectum • Most common malignancy of the GI tract
• Sporadic (as retention polyp): solitary, benign • Risk factors
• AD Juvenile polyposis syndrome: o Dietary factors: low fiber, high carbohydrate and fat diet
Juvenile o Often multiple o NSAIDs: protective, due to decreased synthesis of PGE2
polyp o With risk for malignant transformation
(responsible for epithelial proliferation)
o Extraintestinal lesions: Pulmonary AVMs
• Molecular genetics (Nice-to-know)
• Morphology: mixed inflammatory infiltrate
with cystically dilated glands o Adenoma-carcinoma sequence (80%)
• Autosomal dominant (AD) inheritance
§ Early mutational event: Biallelic loss of APC → adenomas →
• Most common site: Small Intestine other mutations → carcinomas
• Multiple GI hamartomatous polyps & § Associated with colorectal adenomas
Peutz- o Microsatellite instability (MSI)
mucocutaneous hyperpigmentation
Jeghers § Associated with SSLs
• Increased risk for malignancy in other sites
polyp
• Morphology: Arborizing networks of Recall from Neoplasia module: APC is also known as the “gatekeeper
connective tissue, smooth muscle, lamina of colonic neoplasia”
Dr. Rubio
propria and normal-looking glands
RIGHT AND LEFT-SIDED COLON CANCERS
RIGHT-SIDED LEFT-SIDED
NEOPLASTIC POLYPS
• Iron deficiency
COLORECTAL ADENOMA • Change in bowel
Clinical anemia,
• Presence of dysplasia: nuclear hyperchromasia, elongation, manifestations
habits, bowel
weakness and
and stratification obstruction
fatigue
• Size: Most important characteristic that relates to malignancy
• Bulky, exophytic • Annular “napkin-
risk (> 4 cm) Gross
masses ring” configuration
o Other factors: Architecture (villous), Degree of dysplasia
(high-grade) • Adenocarcinoma (glandular structures
• Intramucosal carcinoma: Dysplasia extending to lamina lined by dysplastic columnar epithelial
cells seen in adenomas) with strong
propria and muscularis mucosa (but not beyond muscularis Histology
desmoplastic response (Most common)
mucosae)
• Mucin-producing (Poor prognosis)
SESSILE SERRATED LESION (SSL) • Signet ring cell-type (Rare)
• Serrated lesions with malignant potential • Prognostic factors: Depth of invasion, Lymph node metastases
• Most common site of metastases: Liver
MORPHOLOGY OF SERRATED LESIONS
Mucinous carcinomas of the colon are associated with poorer prognosis
HYPERPLASTIC because they are MSI-high tumors.
SSL
POLYP (HP) Dr. Elomina
Common
location
• Left colon • Right colon ANUS
Serrated • Limited to upper HEMORRHOIDS
• Entire gland
architecture third of the crypt INTERNAL EXTERNAL
Dysplasia • Absent • Persistently ↑ venous pressure on
• Yes (Elephant- hemorrhoidal plexuses
Lateral growth • No Pathology
feet glands) • May be associated with portal
Malignant hypertension (anorectal varices)
• None • Yes
potential Hemorrhoidal • Superior • Inferior
plexus hemorrhoidal hemorrhoidal
FAMILIAL TUMOR SYNDROMES involved plexus plexus
• Familial adenomatous polyposis (FAP) Location
• Hereditary non-polyposis colon cancer (HNPCC) (Lynch relative to • Above • Below
syndrome) dentate line
• Stratified COMMON LIVER FUNCTION TESTS
Lining • Intestinal-type squamous, non- LIVER FUNCTION SERUM MEASUREMENT
keratinizing • AST (SGOT)
Hepatocyte
• Usually absent, • ALT (SGPT)
integrity
Pain except when • Usually present • LDH
thrombosed • Bilirubin (Total, Direct, and Indirect)
Histology • Dilated submucosal vessels Biliary excretory
• Alkaline phosphatase
function
• γ-glutamyl transpeptidase (GGT)
TUMORS OF ANAL CANAL • Albumin
• Type of epithelium determines the kind of tumors that arise in Hepatocyte • PT
the anal canal and its usual location synthetic function • aPTT
o Upper third: Intestinal • Ammonia
o Middle third: Transitional
o Lower third: Stratified squamous non-keratinizing
• Condyloma acuminata: associated with low-risk HPVs LIVER FAILURE
• Carcinomas • Most severe form of liver disease occurring in 80-90%
o Squamous cell carcinoma parenchymal loss
§ Associated with high-risk HPVs • Causes:
o Adenocarcinoma o Acute: Sudden massive hepatic destruction
o Basaloid (from basal cells of transitional zone) o Chronic: Insidious, progressive liver injury (More common)
§ May be associated with mucinous differentiation o Acute on chronic: Acute injury superimposed on a late-stage
chronic disease, or acute flare of a chronic disease
APPENDIX
ACUTE LIVER FAILURE
ACUTE APPENDICITIS
• Conditions
• Luminal obstruction → stasis of luminal contents and
o No pre-existing liver disease
impaired venous outflow → inflammation
o Encephalopathy and coagulopathy
o Causes of obstruction
o Occurs within 26 weeks post initial insult
§ Fecalith (most common), gallstone, tumor, mass of worms,
periappendiceal lymphoid hyperplasia • Clinical manifestations: Jaundice and cholestasis
• Histologic criterion: PMNs in muscularis propria • ↑ NH3: impaired neurotransmission,
Hepatic cerebral edema
• Complication: Gangrenous appendicitis → rupture →
suppurative peritonitis encephalopathy • (+) confusion to coma
• (+) Asterixis: flapping tremor
Coagulation • Impaired synthesis of coagulation
TUMORS
defects factors
• Most common: Well-differentiated NET (carcinoid) • Kidney failure in liver failure patients
o Usually found at the tip without intrinsic kidney dysfunction
o Benign behavior
• Systemic vasodilation → renal
• Mucinous tumors Hepatorenal
hypoperfusion → RAAS activation →
o Clinical significance: Pseudomyxoma peritonei (Mucinous syndrome
renal afferent arteriolar
ascites) - Occurs when the appendix is ruptured vasoconstriction → ↓ GFR
Aside from the adnexae, the appendix is one of the organs that you should • RAAS activation → sodium retention
also investigate if you have a female patient with mucinous ascites. Portal • Increased resistance to portal blood
Dr. Elomina
hypertension flow
• Laboratory findings
17. LIVER AND GALLBLADDER o Initial increase in ALT and AST
LIVER • Cholestatic disease § Due to hepatocyte destruction
• Generalities • Circulatory disorders
o Decrease in ALT and AST late in the course
• Liver failure • Nodules and Tumors
• Infectious disorders GALLBLADDER
§ Deceptive; not always an indicator of recovery
• Autoimmune hepatitis • Congenital anomalies § May indicate decreased residual hepatocyte mass
• Drug- and toxin-induced • Cholecystitis
hepatitis • Carcinoma QUICK SHEET:
• Fatty liver disease ACUTE LIVER FAILURE CAUSES (ABCDEF)
• Inherited liver disease • A: Acetaminophen (most common drug), hepatitis A, autoimmune hepatitis
• B: Hepatitis B
• C: Hepatitis C, cryptogenic
GENERALITIES • D: Drugs/toxins, hepatitis D
• Most of liver diseases are chronic, except Acute liver failure • E: Hepatitis E, esoteric causes (Wilson disease, Budd-Chiari syndrome)
• Responses to injury • F: Fatty change of the microvesicular type (fatty liver of pregnancy,
• Steatosis (fatty change) valproate, tetracycline, Reye syndrome)
• Cholestasis
Reversible • Ballooning: Cell swelling, cytoplasmic clearing CHRONIC LIVER FAILURE AND CIRRHOSIS
• Mallory hyaline: Clumped intermediate filaments
• Common causes: Chronic HCV > HBV, Alcoholic liver disease,
seen in steatohepatitis
and NAFLD
• Necrosis: Usually occurs in ischemic injury
• Cirrhosis: Diffuse transformation of the liver into regenerating
• Apoptosis: Usually in viral hepatitides
Irreversible parenchymal nodules, surrounded by dense bands of scar,
o Councilman bodies: acidophilic apoptotic
bodies
with variable degrees of vascular shunting
• • Additional morphologic findings
Regeneration: via replication of existing
hepatocytes around the injury o Ductular reactions increase with advancing stage of disease
§ Ductular reactions incite some of the scarring
o Ductular reaction: Differentiation of oval cells
o Regression of fibrosis may happen, but is uncommon
(stem cells) into duct-like structure containing
Repair • Clinical aspects
multipotent cells; occurs when replicative limit
has been reached o Jaundice with pruritus
• o Hyperestrinism
Scar formation: activation of stellate cells of Ito
§ Palmar erythema, spider angiomas, hypogonadism,
(Vitamin A storage cells) to highly fibrogenic
myofibroblasts (post-injury) gynecomastia (in men), HPO axis abnormalities (in women)
o Portal hypertension
PORTAL HYPERTENSION • Chronic hepatitis
• ↑ resistance to portal blood flow o Interface hepatitis: inflammation that crosses the limiting
• Most common cause: Cirrhosis (85%) plate → injury of periportal hepatocytes
• Major outcomes (APES) o Scarring, Cirrhosis (usually happens late in course)
o Ascites o Repair (stem cell activation i.e. ductular reactions)
o Formation of Portosystemic shunts Hepatitis B • Ground-glass hepatocytes
o Hepatic Encephalopathy Hepatitis C • Lymphoid follicles, bile duct injury, & steatosis
o Congestive Splenomegaly
• Main pathophysiologic derangements
o Sinusoidal remodeling and intrahepatic shunting (A→V): ↑
resistance at the level of the sinusoids
o Hyperdynamic circulation: splanchnic vasodilation (most
important mediator: NO)
§ Hyperdynamic circulation in pulmonary circulation →
hepatopulmonary syndrome
§ Also, part of pathophysiology of hepatorenal syndrome
ASCITES
• Excess fluid in peritoneal cavity
• Most common cause: Cirrhosis
• Usual characteristics: Serous, <3 g/dL protein (mostly
albumin), serum : ascitic fluid albumin gradient ≥ 1.1 g/dL MORPHOLOGIC FINDINGS IN ACUTE AND CHRONIC HEPATITIS
Memory device for Hepatitis B and C-specific findings:
PORTOSYSTEMIC SHUNTS BaGaGa: Hepatitis B = Ground-glass hepatocytes
• Opening of portocaval anastomoses: CaLaBaSa: Hepatitis C = Lymphoid follicles, Bile duct injury, and Steatosis
- Eugene G. Odoño, MD, DPSP, (2016)
1. Left gastric vein, azygos: esophagogastric varices On a personal note, I owe a lot to this memory device as a resident. It’s
§ Important cause of mortality always asked in our in-service exams. HAHAHA
2. Superior rectal veins, middle and inferior rectal veins: Dr. Elomina
anorectal varices/hemorrhoids
3. Periumbilical veins and abdominal wall collaterals: caput
medusae
4. Retroperitoneum
• ↑ shunting of blood to the systemic circulation
o ↑ NH3 in systemic circulation: hepatic encephalopathy
HEPATOPULMONARY SYNDROME
• ~ 30% of cases with cirrhosis and portal hypertension
• Hyperdynamic circulation in the pulmonary circulation →
inadequate perfusion of lung → VQ mismatch→ hypoxia
• Platypnea: dyspnea on upright position; hypoxia preferentially
occurs on upright position
Simply put, hyperdynamic circulation means that there isn’t enough
blood flowing to other organs because of splanchnic vasodilation. The NATURAL HISTORY OF HBV INFECTION
hypoperfusion of those other organs is central to the pathogenesis of Figure 18.9. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
hepatopulmonary and hepatorenal syndromes. Most cases of hepatitis lead to recovery. In cases of acute hepatitis, death is
Dr. Elomina usually secondary to acute liver failure. Uncommonly, acute infection
progresses to chronic hepatitis (the frequency also depends on what type of
PORTOPULMONARY HYPERTENSION hepatitis virus one is infected with), then it can progress to cirrhosis and
• Pulmonary hypertension arising in liver disease and portal hepatocellular carcinoma, which are common causes of death in these
hypertension patients.
Dr. Elomina
o Due to excessive pulmonary vascular remodeling FOUR CLINICAL SYNDROMES
• Clinically, exertional dyspnea and clubbing of the fingers • Acute asymptomatic infection with recovery
o Presence of antibodies, or elevated LEs
INFECTIOUS DISORDERS • Acute symptomatic infection with recovery
VIRAL HEPATITIS • Chronic hepatitis
o Symptomatic, biochemical, serologic evidence of infection > 6
ETIOLOGY months
• Hepatitis A,B,C,D, and E • Acute liver failure
o The vowels are transmitted via fecal-oral route, and never
Hepatitis serology will be discussed in Medical Microbiology and IM handouts
cause chronic (AcutE), except chronic HEV in Dr. Rubio
immunocompromised hosts
§ HEV can also cause severe hepatitis in pregnant patients AUTOIMMUNE HEPATITIS
o The consonants (B,C,D) are parenterally transmitted and • Chronic progressive hepatitis
cause chronic disease • Shares common traits of autoimmune diseases:
§ HDV needs HBV in order to cause disease o Genetic predisposition
§ Between HBV and HCV, HCV is more associated with chronic o Formation of autoantibodies
liver disease (>80%) o Responsive to immunosuppressive therapy
§ Both are associated with development of Hepatocellular • More common in females
carcinoma (HCC) TYPES OF AUTOIMMUNE HEPATITIS
FEATURE TYPE 1 TYPE 2
MORPHOLOGY • More common
• Acute and chronic viral hepatitides both have mononuclear Incidence • More common
in children
infiltrates • ANA
o Hepatitis A: more prominent plasma cells • Anti-SMA
Circulating • Anti-LKM-1
• Portal inflammation: hallmark of chronic viral hepatitis • Anti-SLA/LP
antibodies • Anti-ACL-1
• Acute hepatitis: focal to massive injury: necrosis or apoptosis • AMA
o Councilman (acidophil) bodies (antimitochondrial)
DRUG- AND TOXIN-INDUCED HEPATITIS • Pathogenesis

• Mechanisms of injury: o ↑ Hepatic fat accumulation secondary to conditions that ↑
o Generation of reactive metabolites (via CYP450 enzymes) lipogenesis
(Most common) § Lipid-laden hepatocytes become more sensitive to
o Hypersensitivity response to drug and its metabolites injurious stimuli → hepatocyte loss (necrosis, apoptosis),
• Two types of toxins inflammation → scarring
o Predictable: dose-dependent • Diagnostic criteria of NASH
§ Acetaminophen (NAPQI metabolite is hepatotoxic) o Steatosis (≥ 5% of hepatocytes)
o Lobular inflammation
• Most common cause of ALF needing transplantation in US
o Ballooned hepatocytes
o Idiosyncratic: dose-independent (Most common)
§ Most common drugs implicated: Antimicrobials
• Morphology
o Can mimic morphology of any other pathology
o Centrizonal necrosis
§ Because CYP450 enzymes are more active in this zone
FATTY LIVER DISEASE

ALCOHOLIC LIVER DISEASE
• 80 g/day: Threshold for developing Alcoholic Liver Disease
(ALD)
o Other factors
§ Gender: Females are more susceptible
§ Ethnicity and Genetic factors
§ Presence of concurrent liver pathology: More susceptible
• AST is more elevated in ALD (in contrast with other forms of
chronic liver disease where ALT is more elevated)
MORPHOLOGIC FORMS OF ALCOHOL-INDUCED LIVER INJURY NATURAL HISTORY OF NAFLD

FORM FEATURES Adapted from Figure 18.22. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
• Macrovesicular steatosis (Most common) INHERITED LIVER DISEASES

Steatosis • Alcoholic foamy degeneration: Microvesicular HEMOCHROMATOSIS
steatosis
• Excessive iron absorption and deposition into liver and
Alcoholic • Ballooned hepatocytes with Mallory hyaline pancreas (most common organs), heart, joint, and other organs
hepatitis • Necro-inflammatory activity o Triad:
• Pericellular or perisinusoidal “chicken wire” § Micronodular cirrhosis (200-fold rick for HCC)
Fibrosis fibrosis → Micronodular cirrhosis “Laennec § Diabetes mellitus
cirrhosis” (Most common) § Abnormal/skin pigmentation
• Forms:
• Adult: HFE mutations (Ch. 6)
Hereditary
• Juvenile: Hepcidin, Hemojuvelin
hemochromatosis
mutations
Secondary • Acquired causes, most commonly
hemochromatosis due to multiple blood transfusions
• Morphology:
o Hemosiderin deposition in tissues:
• Prussian blue (+) hemosiderin granules →
MACROVESICULAR STEATOSIS Liver
Figure 19.28. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 744.
fibrosis → micronodular cirrhosis
• Interstitial fibrosis, parenchymal atrophy →
Pancreas
DM
Heart • Enlarged with Hemosiderosis → fibrosis
Skin • ↑ Melanin and Hemosiderin → slate-gray skin
Joints • Pseudogout (with ↑ Ca pyrophosphate deposition)
Pituitary • ↓ testosterone & gonadotropins → testicular atrophy
• Clinical manifestations are findings referrable to dysfunction of
affected organs
HEPATOCYTE BALLOONING WITH MALLORY HYALINE
Figure 19.31A. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 746.
HEMOSIDERIN GRANULES IN THE LIVER IN HEREDITARY

HEMOCHROMATOSIS, PERL PRUSSIAN BLUE STAIN
PERICELLULAR “CHICKEN WIRE” FIBROSIS, TRICHROME STAIN WILSON DISEASE

Figure 19.33B. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 747.
• Autosomal recessive disorder characterized by impaired Cu
NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) excretion into bile and incorporation to ceruloplasmin
• Fatty liver not attributed to alcohol or any other secondary • Mutation: ATP7B mutation (Ch13)
cause of hepatic fat accumulation • Organs affected: Liver, Brain (Basal nuclei), and Eye
o Non-alcoholic steatohepatitis (NASH): NAFLD with • ↑ Tissue Cu, ↓ serum ceruloplasmin, ↑ urinary Cu excretion
inflammation • Morphology:
§ Morphology similar with ALD Liver • Variable morphology: steatosis to cirrhosis
§ ↑ risk of fibrotic liver disease Brain • Putaminal atrophy: Movement disorders
• Most common cause of chronic liver disease in the US • Kayser-Fleischer ring: Green-to-brown Cu
Eyes
• Associated with Metabolic syndrome deposits in Descemet membrane in corneal limbus
INHERITED HYPERBILIRUBINEMIAS
DISEASE DEFECT
UNCONJUGATED HYPERBILIRUBINEMIA
Crigler-Najjar Type 1 • Severe UGT1A1 deficiency
Crigler-Najjar Type 2 • UGT1A1 deficiency, but with some
Gilbert syndrome residual activity
DISEASE DEFECT
CONJUGATED HYPERBILIRUBINEMIA
KAYSER-FLEISCHER RING
https://www.wilsonsdisease.org/about-wilson-disease/kayser-fleischer-rings • Autosomal recessive
α-1-ANTITRYPSIN DEFICIENCY
Dubin-Johnson • MRP2 mutation → impaired
syndrome transport of non-bile salt organic
• Most commonly diagnosed inherited hepatic disorder in (Dark liver) anions at canalicular membranes
infants and children
• (+) Black liver discoloration (
• Autosomal recessive disorder of protein folding → ↓ α1AT
• Autosomal recessive
• Pathogenesis & Morphology:
Rotor syndrome • Impaired storage of conjugated
• Misfolded α1AT accumulates in hepatocytes → bilirubin in hepatocytes
triggers unfolded protein response → hepatocyte death
Liver by apoptosis If you noticed, most unconjugated hyperbilirubinemias involve UGT1A1.
This is because UGT1A1 is involved in bilirubin conjugation. Conjugated
• Cirrhosis, PAS-positive, diastase-resistant hyaline
hyperbilirubinemias on the other hand have no problem conjugating
globules bilirubin; instead, they have a problem of handling and transporting
• ↓ α1AT → ↑ protease activity → panacinar conjugated bilirubin. In keeping with non-toxicity of conjugated bilirubin,
Lung
emphysema Dubin-Johnson and Rotor syndrome are clinically innocuous.
• Increased risk of HCC (because of associated cirrhosis) Dr. Elomina
LARGE BILE DUCT OBSTRUCTION
• Causes:
CHOLESTATIC DISEASE
• Stones, Biliary tree and pancreatic head
HYPERBILIRUBINEMIA Adults
malignancy, Strictures
FORMS OF HYPERBILIRUBINEMIA • Biliary atresia, Cystic fibrosis, Choledochal
UNCONJUGATED CONJUGATED Children
cysts
(INDIRECT) (DIRECT) Autoimmune • Primary sclerosing cholangitis
• Hepatocellular • Morphology
• Hemolysis disease o Proximal duct dilation, Portal edema, Ductular reaction
• Disorders of • Bile duct injury o Pericholangitis: Neutrophilic infiltrates around ductules
Causes
defective • Biliary obstruction § Ascending cholangitis: neutrophils in bile duct epithelium
conjugation • Disorders of bile and lumina
secretion • Complications
Albumin o Ascending cholangitis: Secondary bacterial infection of
• Tightly bound • Loosely bound
binding biliary tree
Excretion § Charcot triad: 1. Fever, 2. Jaundice, 3. RUQ pain
through • No • Yes o Biliary cirrhosis
urine § Fibrosis secondary to chronic obstruction
Water
• Insoluble • Soluble
solubility NEONATAL CHOLESTASIS
Toxicity • Toxic • Non-toxic • Prolonged conjugated hyperbilirubinemia in the neonate
Prominent • Kernicterus • Causes
• Tea-colored urine
clinical (Neurologic o Obstructive: Extrahepatic biliary atresia (EHBA)
• Acholic stools
findings manifestations) o Non-obstructive
Morphology § Alagille syndrome: Cholestasis and paucity of bile ducts
• Green-brown bile plugs in hepatocytes and canaliculi § Metabolic disorders: Galactosemia, Niemann-Pick disease
o Feathery degeneration: Swollen, foamy cytoplasm of § Nonsyndromic causes: α1AT deficiency, bile acid synthesis
hepatocytes due to accumulation of bile salts and transport defects
Clinical manifestations: § Idiopathic neonatal hepatitis
• Jaundice/Icterus: yellow discoloration of skin/sclerae • Cause must be distinguished
o Bilirubin level: 2-2.5 mg/dL (Hyperbilirubinemia) o Kasai procedure (treatment of choice of EHBA) may adversely
o Kernicterus: deposition of unconjugated bilirubin in the CNS affect patients with other causes
• Pruritus, Skin xanthomas EXTRAHEPATIC BILIARY ATRESIA
• Malabsorption of fat-soluble vitamins (ADEK) • Complete or partial obstruction of the extrahepatic biliary tree
• ↑ Serum Alkaline phosphatase and γ-glutamyltransferase within the first 3 months of life
(GGT) • Hallmark: Inflammation and fibrosis of the hepatic or common
The toxicity of unconjugated hyperbilirubinemia is because of its highly bile ducts
lipophilic nature that facilitates its deposition in cells. The brain, in
particular, is an organ that is rich in lipids, and so is a prominent target AUTOIMMUNE CHOLANGIOPATHIES
of unconjugated bilirubin deposition, called Kernicterus. • Autoimmune disorders of intrahepatic bile ducts
Dr. Elomina
PHYSIOLOGIC JAUNDICE OF THE NEWBORN • Increased risk for malignant tumors
• Main diseases
• Unconjugated hyperbilirubinemia secondary to inadequate
o Primary biliary cholangitis (PBC)
UGT1A1 activity in newborns
o Primary sclerosing cholangitis (PSC)
• Breastmilk has bilirubin deconjugating enzymes → contribute
to unconjugated hyperbilirubinemia
AUTOIMMUNE CHOLANGIOPATHIES
FEATURE PRIMARY BILIARY CHOLANGITIS PRIMARY SCLEROSING CHOLANGITIS
Sex • 90% Female • 70% Male
Associated • Sjögren syndrome (70%), Hashimoto Thyroiditis,
• Inflammatory Bowel Disease (70%)
conditions Scleroderma
Serology • 95% AMA (+) • 65% ANCA (+)
Radiology • Normal • Strictures and beading of large bile ducts
Bile ducts
• Small to medium-sized intrahepatic • Extrahepatic and large intrahepatic
involved
FEATURE PRIMARY BILIARY CHOLANGITIS PRIMARY SCLEROSING CHOLANGITIS
• Florid duct lesion: Lymphocytic and/or
granulomatous bile duct destruction • Acute and chronic inflammation → “onion-skin” fibrosis and
• Cirrhosis with elongated cirrhotic nodules (“garland- stricture → luminal obliteration
Histologic pearls
shaped”) • Lithiasis in proximal dilated segments
• Nodular regenerative hyperplasia: Regenerative • Biliary cirrhosis (because of obstruction)
nodules without fibrosis
Diagnosis • Liver biopsy • Radiologic imaging of biliary tree (beading of contrast medium)
Sequelae • Increased risk for HCC • Increased risk for cholangiocarcinoma
CIRCULATORY DISORDERS HEPATIC VENOUS OUTFLOW OBSTRUCTION

BUDD-CHIARI SYNDROME
• Liver enlargement, pain, and ascites secondary to hepatic vein
thrombosis
• Causes: Same pathologies that can cause thrombosis
NODULES AND TUMORS

QUICK SHEET:
• Most common benign tumor: Cavernous Hemangioma
• Most common liver tumor of early childhood: Hepatoblastoma
• Most common tumor involving the liver: Metastases
• Most common primary malignant tumor: Hepatocellular Carcinoma
(HCC)
• Second most common primary malignant tumor: Cholangiocarcinoma
(CCA)
HEPATOCELLULAR NODULES & TUMORS
LESION FEATURES
• Non-neoplastic (nodular) lesion most
common in adult women
• Morphology:
o Well-demarcated, poorly encapsulated
Focal nodular
o Central scar containing thick-walled
hyperplasia
o Prominent ductular reaction
• Angiography: Hypervascular with dense
capillary blush
FORMS AND CLINICAL MANIFESTATIONS OF HEPATIC
• Liver scan: Normal to increased uptake
CIRCULATORY DISORDERS
Figure 18.40. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 • Benign neoplasm in young women
• Associated with OCP and anabolic steroid
use, obesity, and metabolic syndrome
HEPATIC • Morphology:
Hepatocellular
CIRCULATORY DISORDERS o Discrete mass with areas of hemorrhage
adenoma
o Hepatocytes with architectural and cytologic
https://qrs.ly/3gcmdxj
features ranging from benign to atypical
• Angiography: Hypovascular
• Liver scan: No uptake
IMPAIRED BLOOD INFLOW
• Preoperative differentiation between FNH and HCA is possible because of
HEPATIC ARTERY COMPROMISE
their difference in imaging, particularly in their contrast uptake. This is
• Hepatic infarcts are uncommon because of the liver’s dual blood because FNH is a vascular lesion, in keeping with its pathogenesis.
supply, but it happens in combined portal vein & hepatic • It is also important to differentiate FNH and HCA because FNH is non-
artery thrombosis neoplastic, while HCA has definite malignant potential.
• Causes: Tumor, Vasculitis (PAN), Sepsis Dr. Elomina
• Morphology: Anemic (white) infarct or Hemorrhagic (red) HEPATOCELLULAR CARCINOMA (HCC)

infarct (Hemorrhagic infarcts can happen in the liver because of • Chronic liver disease with cirrhosis: Most common setting and
dual blood supply) emergence of HCC
• Morphology:
PORTAL VEIN OBSTRUCTION AND THROMBOSIS o Precursor lesions: Large cell change, Small cell change,
• Causes of extrahepatic portal vein obstruction and thrombosis Dysplastic nodules (more ominous)
o Idiopathic o Gross: Single to multiple masses or diffuse liver infiltration
o Hypercoagulable states (Myeloproliferative neoplasia, o Histology:
Malignancy) § Variable architecture
o Tumor (HCC with portal vein invasion) • Pseudoglandular architecture is potentially problematic
o Cirrhosis (with associated portal vein thrombosis) § Well-differentiated to poorly differentiated cells
• Schistosomiasis: Most common cause of small portal vein • Laboratory features
obstruction o Tumor marker: α-fetoprotein
o Imaging: Early enhancement in arterial phase → rapid
IMPAIRED INTRAHEPATIC BLOOD FLOW venous washout (Contrast CT scan)
• Causes: • Behavior and Prognosis
o Cirrhosis (Most common cause) o Poor prognosis by convention
o Sickle cell anemia § Underlying liver disease (Chronic liver disease)
o Disseminated intravascular coagulation § Intrinsic resistance to chemotherapy
o Eclampsia o Metastases: Hematogenous, most commonly to lung
o Diffuse intrasinusoidal metastatic tumor (with concurrent Since HCC can be architecturally heterogeneous, IHCs may be needed to
thrombosis) demonstrate hepatocellular origin. The pseudoglandular pattern of
• Peliosis hepatis: Sinusoidal dilation secondary to impaired growth, in particular, is problematic because cholangiocarcinomas also
efflux of hepatic blood appear glandular in appearance. To make matters worse, there are
metastatic carcinomas that can also assume the same appearance.
o Blood-filled cystic spaces either unlined or lined by sinusoidal Dr. Elomina
endothelial cells
MALIGNANT BILIARY TUMORS A solitary lesion does not always equate to a primary liver tumor. In the
• Nomenclature same manner, not all multiple tumors are metastases.
Dr. Elomina
o Intrahepatic cholangiocarcinoma (IHCA): Intrahepatic biliary tree
o Biliary adenocarcinoma (BA): Extrahepatic bile ducts GALLBLADDER
• Risk factors CONGENITAL ANOMALIES
o Developmental disorders: Fibropolycystic liver disease • Most common: folded fundus “Phrygian cap”
o Inflammatory disorders: Primary sclerosing cholangitis, • Agenesis
Opisthorchis, Clonorchis infestation, Primary hepatolithiasis • Ectopia
o Liver diseases (IHCA): HBV, HCV, NAFLD • Choledochal cysts
• Location • True “biliary atresia”: Hypoplastic narrowing of the biliary
o BA: Perihilar (Klatskin tumor) (Most common), common bile duct channels”
• Morphology
o Well- to moderately differentiated Adenocarcinoma
o Abundant fibrous stroma, Lymphovascular and perineural
CHOLELITHIASIS (GALLSTONES)
invasion common • Most common biliary tract disease
• Clinical manifestations • Risk factors (Memory device: 3Fs: Female, Fat, Forty)
o IHCA: Incidental finding on imaging, cholestatic profile, liver o Female sex and Estrogen exposure
mass o Advancing age
o BA: Biliary obstruction o Obesity and rapid weight loss
• Prognosis: Dismal • Clinical manifestations
o Usually has lymph node metastasis at presentation o Asymptomatic
o Poor chemotherapy response o Epigastric or RUQ pain after a fatty meal
• Complications
METASTASIS
o Colic, Cholecystitis, Obstructive cholestasis, and Pancreatitis
• Common sites: Colon, Breast, Lung, and Pancreas o Gallstone ileus (Bouveret syndrome)
• Virtually any cancer from the body § Large stone erodes directly into adjacent small bowel
• Single or multiple hepatic nodules
TYPES OF STONES
CHOLESTEROL PIGMENT
1. Supersaturation of bile with cholesterol
• ↑ Calcium salts of unconjugated bilirubin from increased hemolysis, ileal dysfunction
2. Hypomotility
Pathogenesis or bypass, and biliary tract infections: E. coli, A. lumbricoides, C. sinensis
3. Accelerated cholesterol crystal nucleation
o β-glucuronidase: breaks down bilirubin glucuronides → ↑ unconjugated bilirubin
4. Mucus hypersecretion
• Pale yellow, round to ovoid, finely • Black: In sterile GB
granular, hard external surface o Small, numerous, friable stones with spiculated, molded surface
Morphology
• Cholesterolosis: Mucosal cholesterol- • Brown: Infected GB, with Ca salts of fatty acids
laden macrophages o Laminated, soft, soap- or grease-like consistency
• Usually radiolucent (may be radiopaque if • Black: Radiopaque
Radiolucency
with sufficient CaCO3) • Brown: Radiolucent
CHOLECYSTITIS
ACUTE CHOLECSYSTITIS CHRONIC CHOLECYSTITIS
• Calculous (90%): Obstruction of neck or
cystic duct by stone • Most common: Calculous (>90%)
Pathogenesis
• Acalculous: Ischemia (Cystic artery has • Conditions promoting stone formation also promote chronic inflammation
no collateral circulation)
• Mononuclear cells in GB wall
Morphology • Neutrophils in GB wall
• Rokitansky-Aschoff sinuses: Mucosal outpouchings
• Empyema: Pus in GB lumen • Porcelain GB: Extensive dystrophic calcification
• Gangrenous: Black, necrotic, may have • Hyalinizing cholecystitis: Extensive fibrosis
Notable
perforations • Xanthogranulomatous cholecystitis: Massively thickened wall, shrunken, nodular,
forms
• Emphysematous: Infection with gas- chronically inflamed, with necrosis and hemorrhage, and xanthoma cells
forming organisms • Hydrops: Atrophic, dilated with clear secretions
• Clinical manifestations: Agenesis • Due to homozygous PDX1 mutation
o Acute calculous: Progressive epigastric or RUQ pain, fever, • Common sites: stomach, duodenum, jejunum,
Ectopia
anorexia, tachycardia, nausea, and vomiting Meckel diverticulum, ileum
o Chronic calculous: Recurrent epigastric or RUQ pain
PANCREATIC CARCINOMA
CARCINOMA • One of the cancers with the highest mortality rates
• Primarily a disease of older people
• Most common malignancy of the extrahepatic biliary tract
• Smoking: Most important environmental risk factor
• More common in women
• KRAS (Ch 12): most frequently mutated oncogene
• Most important risk factor: Gallstones
• Clinical manifestations:
• Morphology
• Usually presents with obstructive jaundice
o Grossly: Infiltrating (looks like chronic cholecystitis),
Location at the • Courvoisier sign: palpable, enlarged,
Exophytic
head nontender GB, mild jaundice
o Most common histology: Adenocarcinoma
• Most common location (60%)
• Usually detected late: tumor has already invaded the liver
Location at body
• Usually clinically apparent
& tail
18. PANCREAS • Migratory superficial vein
Trousseau
• Congenital anomalies thrombophlebitis
syndrome
• Pancreatitides • Paraneoplastic syndrome
• Pancreatic carcinoma Tumor marker • CA 19-9
• Morphology:
CONGENITAL ANOMALIES o Ductal adenocarcinoma, usually moderately or poorly
• Most common congenital anomaly differentiated
Pancreatic • Failure of fusion of fetal pancreatic ducts → o Lymphovascular and perineural invasion (even early
divisum bulk of parenchyma drained by small duct of cancers)
Santorini → ↑ risk of chronic pancreatitis
o Intense desmoplasia
Annular
• Causes duodenal obstruction (usually 2nd part) • Prognosis: Dismal (usually unresectable at diagnosis)
pancreas
For the two forms of pancreatitis, you focus on the main pathology. Acute pancreatitis involves inflammation because of pancreatic destruction. The
inflammatory reaction can be so severe that it can cause a “sepsis-like” picture. Like I said before, the words “chronic” and “fibrosis” go together. When something
is fibrosed, it is not functional. In chronic pancreatitis, you deal with the effects of decreased pancreatic reserve (be it exocrine (malabsorption) or endocrine
(DM)), because of fibrosis and atrophy of the pancreatic parenchyma.
Dr. Elomina
PANCREATITIDES
ACUTE CHRONIC
• Reversible pancreatic parenchymal injury associated
with inflammation • Prolonged inflammation of the pancreas associated with irreversible
Definition • Pathology: inappropriate release and activation of destruction of exocrine parenchyma, fibrosis, and, in the late stages,
pancreatic enzymes, which destroy pancreatic tissue the destruction of endocrine parenchyma
and elicit an acute inflammatory reaction
• Most common etiology: Long-term alcohol abuse
Common • Common etiologies: Alcoholism and Pancreatic duct
• Other etiologies: long-standing duct obstruction (stones or
etiologies obstruction (e.g. gallstones)
neoplasms), autoimmune injury, and hereditary pancreatitis
• Microvascular leak and edema • Fibrosis, atrophy and dropout of acini, and variable dilation of
• Enzymatic fat necrosis pancreatic ducts
Morphological
• Acute inflammation • Chronic inflammation
hallmarks
• Destruction of pancreatic parenchyma • Atrophied, hyperplastic, or metaplastic (squamous) ductal epithelium
• Destruction of blood vessels and interstitial hemorrhage • Islets usually spared, but are lost in advanced disease
Common • Epigastric pain (sudden, severe, boring, radiating to • Acute pancreatitis
clinical the back) • Pancreatic insufficiency (Malabsorption)
manifestations • SIRS, shock, elevated amylase and lipase • Diabetes mellitus
19. KIDNEY
• Clinical manifestations of renal • Cystic diseases of the kidney
disease • Obstructive uropathy and
• Glomerular diseases Urolithiases
• Tubulointerstitial diseases • Tumors
• Vascular diseases
CLINICAL MANIFESTATIONS OF RENAL DISEASE

• Increase in BUN & creatinine
• Pre-renal: Renal hypoperfusion
Azotemia
• Renal: Intrinsic diseases of the kidney
• Post-renal: Urine flow obstruction distal to kidney
Uremia • Azotemia + Clinical manifestations
• Rapid decline in GFR with concurrent dysregulation of fluid and electrolyte balance, and retention of
Acute kidney injury (AKI) metabolic waste products (Urea, Creatinine)
• Can present with oliguria or anuria
• Diminished GFR < 60 mL/min/1.73 m2 , present for ≥ 3 months, from any cause, and/or persistent
Chronic kidney disease (CKD)
albuminuria
End-stage renal disease (ESRD) • Terminal stage of uremia with GFR <5% of normal
• Polyuria (Concentrating urine is a function of tubules)
Renal tubular defects • Nocturia
• Electrolyte disturbances (Reabsorption and secretion of substances are functions of tubules)
Urinary tract infection • Pyuria & bacteriuria
Nephrolithiasis • Spasms of severe pain (renal colic), hematuria, recurrent stone formation
GLOMERULAR DISEASES
GLOMERULAR RESPONSE TO INJURY
HYPERCELLULARITY BM THICKENING HYALINOSIS/SCLEROSIS
Type of response • Acute • Chronic • Chronic
• Proliferation of cells (Mesangial, • Deposition of electron-dense
• Hyalinosis: Deposition of
Endothelial cells) material (Immune complex etc.)
homogenous eosinophilic material
Pathogenesis • Infiltration of Leukocytes • ↑ Synthesis of CHON component of GBM
• Sclerosis: Deposition of collagen
• Crescent formation (Epithelial • Formation of additional layers of BM
(also eosinophilic)
cells + WBCs) matrices
Special stains • None • PAS • Masson-Trichrome
Example • PSAGN • Membranous nephropathy • FSGS
DEFINITION OF TERMS Chronic Renal • Azotemia → uremia progressing for
TERM DEFINITION Failure months to years
Focal • Involves SOME glomeruli Isolated Urinary • Glomerular hematuria and/or
Diffuse • Involves ALL glomeruli Abnormalities subnephrotic proteinuria
Segmental • Involves a PORTION of a glomerulus
Global • Involves the WHOLE glomerulus
NEPHRITIC SYNDROME
Mesangial • Involves only the mesangial region
• Pathogenesis:
GLOMERULAR SYNDROMES o Glomerular inflammation → loss of integrity of glomerular
SYNDROME MANIFESTATIONS filtration barrier → hematuria > proteinuria
• Hematuria, azotemia, variable o → obliteration of capillary lumen → decreased GFR → Oliguria
Nephritic syndrome and Azotemia
proteinuria, edema, and hypertension
Rapidly Progressing • Acute nephritis, proteinuria, and acute o → fluid retention → Edema and Hypertension
Glomerulonephritis renal failure • Glomerular diseases presenting as Nephritic syndrome
• >3.5 g/day proteinuria, o Post-streptococcal acute glomerulonephritis (PSAGN)
Nephrotic syndrome hypoalbuminemia, hyperlipidemia, o Rapidly progressing glomerulonephritis (RPGN)/Crescentic
lipiduria GN
PSAGN FINDINGS I II III
• Prototype glomerular disease of immune complex etiology • Crescents → Obliteration of urinary space and
LM
(Type III HS) compression of glomerular tuft
• Most common cause of nephritic syndrome in children • Ruptures in the GBM
• Non-suppurative sequelae of GABHS infection • “Lumpy bumpy” • No
EM
• Nephritogenic strains of GAHBS (M12, 4, and 1 in 90%) - appearance of detectable
GBM deposits
FINDINGS PSAGN • Linear • Granular • Negative
• Enlarged, hypercellular glomeruli IF immune immune immune
• Crescent formation in severe cases deposits deposits deposits
Light Microscopy
• Capillary lumina obliteration
(LM)
• Tubulointerstitial edema and RPGN TYPE I (GOODPASTURE SYNDROME)
inflammation, with RBC casts FEATURE GOODPASTURE SYNDROME
Electron • Antibodies against the non-collagenous domain
• Subepithelial humps on GBM
Microscopy (EM) of α3 chain of Collagen Type IV (common antigen
Immuno- • Granular deposits of IgG, C3, and sometimes Pathology in alveoli and GBM) → necrotizing hemorrhagic
fluorescence (IF) IgM in the mesangium and along the GBM interstitial pneumonitis and RPGN
• Anti-GBM disease: Limited to the kidneys
CLINICAL ASPECTS • May affect any age, but most commonly 20s
CHILDREN ADULTS Epidemiology • Male preponderance
• ↑Anti-Streptococcal titers (ASO or anti • Most patients are active smokers
Important Usual clinical • 20s, Male, active smoker, with hemoptysis and
DNase B, depending on the antecedent
laboratory picture renal failure
infection)
findings
• ↓ C3 and other complement components
Azotemia • Usually absent • Usually present
Recovery • >95% • 60%
Progression to
NEPHRITIC SYNDROME
• Less likely • More likely https://qrs.ly/gacmdyr
CGN or RPGN
ASO is for pharyngeal infections; Anti DNase B is for pyoderma.
Dr. Elomina
NEPHROTIC SYNDROME
RAPIDLY-PROGRESSING GLOMERULONEPHRITIS
• Pathogenesis
• Syndrome of progressive loss of renal function, characterized o Index event: Loss of integrity of filtration barrier → ↑
by nephritic syndrome often with severe oliguria permeability → Proteinuria → hypoalbuminemia → edema
• Histologic hallmark: presence of “crescents” (crescentic GN) § → ↓ Globulins → susceptibility to infections
o Crescents: Proliferation of parietal epithelial cells admixed § → Loss of anticoagulant proteins (antithrombin III) →
with leukocytes infiltrating the glomerulus hypercoagulable state
• 3 types, according to underlying immune mechanism o Collateral increase in hepatic lipoprotein synthesis →
TYPE PATHOGENESIS COMMON DISEASES hyperlipidemia → lipiduria
• Presence of antibodies • Anti-GBM disease • Glomerular diseases presenting as Nephrotic syndrome
I against glomerular basement • Goodpasture o Minimal Change Disease (Lipoid nephrosis)
membrane syndrome o Focal segmental glomerulosclerosis (FSGS)
• PSAGN o Membranous nephropathy/glomerulopathy
• Complication of immune-
• Lupus nephritis o Membranoproliferative glomerulonephritis (MPGN Type I)
II complex mediated
• HSP o Dense deposit disease (MPGN Type II)
glomerular injury
• Berger disease
• Pauci-immune (presence of
III • ANCA vasculitides
ANCA)
MOST IMPORTANT PRIMARY GLOMERULAR LESIONS PRESENTING WITH NEPHROTIC SYNDROME

MCD* MGN* FSGS*
Epidemiology • Most common cause in children • Second most common in adults • Most common cause in adults
Azotemia • Usually absent • Usually absent • Usually present
Steroid-responsive • Usually Yes • Usually No • Variable
• HIV
• SLE, thyroiditis
• Sickle cell anemia
Association with other • Children: Respiratory infections • Infections (HBV, HCV, T. pallidum,
• Obesity
diseases • Adults: HL, NHLs, leukemias Schistosoma, Plasmodium)
• Secondary event (e.g. IgA
• Lung, Colon CA, Melanoma
nephropathy)
• Prophylactic immunization, • Penicillamine, Captopril, Gold,
Association with drugs • Heroin
NSAIDs NSAIDs
MORPHOLOGY
• Collapsed capillary loops and
hyalinosis
• ↑ Mesangial matrix (in affected
• Uniform diffuse thickening of
Light Microscopy (LM) • Normal glomerulus and nonaffected segments)
the capillary wall
• Collapsing glomerulopathy:
Collapse of entire glomerular tuft
o In HIV-associated nephropathy
• Subepithelial deposits along the • Diffuse effacement of foot processes
Electron Microscopy • Uniform and diffuse effacement of
GBM (spike and dome appearance) • Focal epithelial cell detachment
(EM) foot processes of the podocytes
• Effacement of foot processes and GBM denudation
Immunofluorescence
• None • Granular immune complex deposits • Immune deposits in sclerotic areas
(IF)
* - MCD: Minimal change disease; MGN: Membranous nephropathy; FSGS: Focal segmental glomerulosclerosis
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN)
DENSE DEPOSIT DISEASE
MPGN TYPE I
(MPGN TYPE II)
Immune complex
• Yes • No
deposition
Complement activation • Classical and alternative • Alternative
• SLE, HBV and HCV infection, endocarditis, infected AV shunts,
Association with other
chronic visceral abscesses, HIV, Schistosomiasis, α1-antitrypsin -
diseases
deficiency, lymphoid neoplasms (CLL)
• Nephritic and/or nephrotic syndrome
Clinical presentation
• ~ 50% of patients progress to ESRD
MORPHOLOGY
• Large, hypercellular glomeruli with mesangial cell proliferation
• Variable (Mesangioproliferative or
Light Microscopy (LM) and ↑ mesangial matrix
inflammatory with focal crescents)
• Thickened GBM “double-contour” “tram-track” appearance
Electron Microscopy • Lamina densa permeated by a ribbon-like
• Subendothelial electron-dense deposits
(EM) extremely electron-dense structure
Immunofluorescence • Granular C3 deposits WITH IgG and early complement • Granular or linear C3 deposits
(IF) components (C1q and C4) WITHOUT IgG and early complement
OTHER GLOMERULONEPHRITIDES
FEATURE IGA NEPHROPATHY (BERGER DISEASE) HENOCH-SCHÖNLEIN PURPURA (HSP)
• IgA deposition in the mesangial regions (Localized to
Pathology • Systemic IgA deposition
kidneys)
• Most common type of glomerulonephritis • Most common in children 3-8 years old
Epidemiology
worldwide • Severe manifestation in adults
• Older children and young adults, gross hematuria
• Purpuric skin lesions, abdominal pain and intestinal
after a respiratory or GI or GU tract infection
Usual clinical picture bleeding, and arthralgias along with renal abnormalities
• Secondary IgA nephropathy: Celiac disease and liver
following RTI
disease
MORPHOLOGY
• Mesangioproliferative GN: Mesangial widening and endocapillary proliferation
Light Microscopy (LM) • Focal proliferative GN → FSGS (on healing)
• Focal crescenting GN
Electron Microscopy • Mesangial electron-dense deposits
(EM)
Immunofluorescence • Mesangial deposition of IgA, often with C3 and properdin and smaller amounts of IgG or IgM
(IF) • Usually absent early complement components
NEPHROTIC SYNDROME
https://qrs.ly/hscmdz4
HEREDITARY NEPHRITIS
FEATURE ALPORT SYNDROME
Pathology • Defective assembly of Type IV collagen
• Autosomal (Ch2 and Ch13)
Genetics
• X-linked
• Eyes: lens dislocation, posterior
Usual clinical
cataracts, corneal dystrophy
picture and
• Ears: nerve deafness
prognosis
• Kidney: hematuria → CKD
MORPHOLOGY PATHOPHYSIOLOGY OF ACUTE TUBULAR INJURY/NECROSIS
• Glomerulosclerosis, vascular sclerosis,
Light Microscopy ISCHEMIC ATI TOXIC ATI
tubular atrophy, and interstitial fibrosis
(LM) Distribution of
(late) • Patchy • Extensive
• Alternating foci of GBM thickening and necrosis
Electron thinning Length of affected
• Short • Long
Microscopy (EM) • Basket-weave appearance: splitting segment
and lamination of lamina dense • Proximal
• Proximal
convoluted
Affected straight tubule
TUBULOINTERSTITIAL DISEASES tubule
segments • Ascending limb
• Ascending limb
• Acute tubular injury/necrosis • Acute pyelonephritis/UTI of Henle’s loop
of Henle’s loop
• Tubulointerstitial nephritis • Chronic pyelonephritis
Casts in DCT and
• (+) • (+)
Collecting duct
ACUTE TUBULAR INJURY/NECROSIS
• Acute renal failure and often, but not invariably, morphologic TUBULOINTERSTITIAL NEPHRITIS
evidence of tubular injury, in the form of necrosis of tubular • Inflammatory injuries of the tubules and interstitium
epithelial cells • Often insidious in onset
• Most common cause of AKI • Principal clinical manifestation: Azotemia
• Types: • Hallmarks
o Ischemic: Due to renal hypoperfusion o Absence of nephritic or nephrotic syndrome
o Toxic: Direct toxic effects to tubules o Presence of defects in tubular function
§ Endogenous: Substance innate to body (hemoglobin, § Inability to concentrate urine
myoglobin, Ig light chains (Bence-Jones protein), § Salt wasting
bile/bilirubin) § Metabolic acidosis (↓ acid excretion)
§ Exogenous: Drugs, contrast, heavy metals, organic solvents § Isolated defects in tubular reabsorption and secretion
ACUTE TIN CHRONIC TIN VASCULAR DISORDERS
Interstitial NEPHROSCLEROSIS
• Present • Absent
edema
• Sclerosis of renal arterioles and small arteries
Fibrosis • Absent • Present
• Associations: Advancing age, Hypertension, Diabetes
Atrophy • Absent • Present
• Pathogenesis
Predominant
• Neutrophils • Mononuclears o Endothelial injury → Medial and intimal thickening
leukocytic
and eosinophils (Lymphocytes) o Extravasation of plasma proteins and ↑ basement membrane
infiltrates
matrix deposition → Hyalinization
o Consequence: Luminal narrowing → ischemia →
PYELONEPHRITIS AND URINARY TRACT INFECTION parenchymal loss
• Inflammation affecting tubules, interstitium, and renal pelvis • Morphology:
• Epidemiology: Gross • Smaller than normal kidneys
o More common in females (in the absence of instrumentation findings • Leather, granular external surface
and in 1-40 years old) • Hyaline arteriolosclerosis
o More common in males with advancing age due to prostatic • Fibroelastic hyperplasia (interlobular & arcuate
hypertrophy Histologic arteries)
• Risk factors: findings • Glomerular collapse, sclerosis of Bowman space,
o Obstruction o Pre-existing renal lesions periglomerular fibrosis
o Instrumentation o Diabetes • Tubular atrophy, interstitial fibrosis
o Vesicoureteral reflux o Immunosuppression • Clinical manifestations
• Etiopathogenesis: o Uremia and renal insufficiency is uncommon, EXCEPT
Most common • Gram (-) enteric bacilli § African patients
organisms • E coli (most common), Proteus, etc. § Malignant hypertension
Most common § Diabetes
• Ascending pathway
route
RENAL ARTERY STENOSIS
• Urethral colonization → ascending infection
Initiating event • Pathogenesis: Stenosis → Renal ischemia → ↑ RAAS activity →
to urinary bladder
• Vesicoureteral reflux: Incompetent Secondary Hypertension
vesicoureteral orifice • Causes
• Intrarenal reflux: Reflux of urine to renal o Most common: Atherosclerosis (usually in males)
Reflux parenchyma through papillae o Second most common: Fibromuscular dysplasia
mechanisms o Upper & lower poles: most commonly § In females, younger age groups (3rd-4th decade)
affected due to flattened & concave tips → • Morphology
most common location of scars in chronic o Diffuse ischemic atrophy with mild arteriolosclerosis in
pyelonephritis ipsilateral kidney
• Types: o Severe arteriolosclerosis in contralateral kidney
FEATURE ACUTE CHRONIC Because of the stenosis in the ipsilateral kidney, its vessels are protected
• Infection (Fever, • Renal insufficiency from the hypertension that it causes, hence the mild arteriolosclerosis.
Clinical However, because of the decrease in blood supply in the ipsilateral kidney,
CVA tenderness, • Hypertension
manifestations ischemic changes are more diffuse. Meanwhile, the poor vessels of the
Pyuria) • Repeated APN
contralateral kidney suffer from great hemodynamic stress from the
• Chronic
Type of • Suppurative hypertension.
(mononuclear) Dr. Elomina
inflammation (Neutrophilic)
with fibrosis
• Extensive RENAL INFARCTS
• Overlying • Kidneys are susceptible to infarction due to Limited collateral
Scarring • In areas of healing deformed calyces circulation & Extensive blood flow to kidneys
and flattening of • Most common cause: Embolism (from cardiac mural thrombus)
papillae • Morphology: White infarct (coagulative necrosis)
• Ischemic and
Glomerular • Inflammation and
hypertensive
changes necrosis when severe CYSTIC DISEASES OF THE KIDNEY
changes
Tubular • Inflammation • Thyroidization • AD (adult) polycystic kidney disease (ADPKD)
changes • Necrosis • Atrophy • AR (childhood) polycystic kidney disease (ARPKD)
• Papillary necrosis
• Secondary FSGS →
Complications • Pyonephrosis
ESRD
• Perinephric abscess
To summarize, the main feature of Acute pyelonephritis is inflammation
and necrosis, while the main feature of Chronic pyelonephritis is the
consequence of fibrosis secondary to chronic inflammation.
Dr. Elomina
TUBULOINTERSTITIAL NEPHRITIS CAUSED

BY DRUGS AND TOXINS
• Second most common cause of AKI
ACUTE DRUG-INDUCED INTERSTITIAL NEPHRITIS
• Pathogenesis: Type I or Type IV Hypersensitivity to self-
antigens modified by drugs, which are otherwise non-
immunogenic
• Clinical manifestations: 2-40 days after drug exposure
o Fever, Eosinophilia, Rash
o Renal abnormalities
§ Hematuria, Mild proteinuria, leukocyturia (may be
eosinophils), AKI
• Withdrawal of offending drugs causes recovery, but it is slow
NSAID-INDUCED NEPHROPATHY
• COX-2: expressed in human kidneys (COX-2-specific NSAIDs PATHOGENESIS OF POLYCYSTIC KIDNEY DISEASE
may not cause gastric upset, but affect kidneys) Figure 20.42. Robbins and Cotran Pathologic Basis of Disease, 10 ed. 2020 th
UROLITHIASES
• More common in men; Peak onset at 20-30 years
POLYCYSTIC KIDNEY DISEASE • Calcium stones: Most common
https://qrs.ly/fqcmdzd • Supersaturation: Most important determinant of stone formation
• Classic clinical manifestation: Painful hematuria
FEATURE ADPKD ARPKD MALIGNANT TUMORS

• PKD1 (polycystin-1, • Most common: Renal cell carcinoma
• PKHD1
Ch16) • Second most common: Wilms tumor
Mutation (fibrocystin,
• PKD2 (polycystin-2, • Third most common: Urothelial carcinomas of the pelvicalyceal
Ch6)
Ch4) system
• Renal mass • Portal
Clinical
• Hematuria, Pain hypertension RENAL CELL CARCINOMA
presentation
• Chronic kidney disease • Splenomegaly • Epidemiology
• Congenital o More common in elderly (6th to 7th decade)
• Liver cysts hepatic o More common in men
Associated • Intracranial berry fibrosis (in • Risk factors: Smoking: Most important risk factor
anomalies aneurysms patients who o Others:
• Mitral valve prolapse survived § Diseases: Obesity, Hypertension, ESRD, CKD, acquired cystic
infancy) disease, Tuberous sclerosis
Most § Substances: Unopposed estrogen therapy, asbestos,
• Coronary or
common • Renal failure petroleum, heavy metals
hypertensive heart
cause of (in infancy)
disease (40%)
death
RENAL CELL CARCINOMA
OBSTRUCTIVE UROPATHY https://qrs.ly/l9cmdzg
EFFECTS OF OBSTRUCTION
• Increased susceptibility to infections & stone formation
• Permanent renal atrophy (Hydronephrosis/Obstructive uropathy)
COMMON UROLITHS
CALCIUM
STRUVITE URIC ACID CYSTINE
OXALATE
Urine pH • Acidic • Basic • Acidic • Acidic
• Hypercalcemia • Hyperuricemia
Associated • Proteus infections
• Hypercalciuria • Diseases with rapid cell • Cystinuria
conditions • Urease (+): Urea → NH3 → ↑ pH
• Hyperoxaluria turnover (leukemias)
Radiologic • Opaque, but difficult to
• Opaque • Opaque • Lucent
appearance visualize than Ca stones
• Colorless, coffin-lid appearance
Morphology • Colorless, small, • Yellow, red brown to • Colorless, hexagonal
• Staghorn calculi: large stones
(Urinalysis) octahedron brown, rhombic plates
occupying renal calyces
* - Magnesium ammonium phosphate/Triple phosphate
COMMON HISTOLOGIC TYPES OF RENAL CELL CARCINOMA

CLEAR CELL PAPILLARY CHROMOPHOBE
Incidence • 70-80% • 10-15% • 5%
• Intercalated cells of collecting
Cytogenetic origin • Proximal tubule cells • Distal tubule cells
ducts
• Birt-Hogg-Dubé syndrome
• Hereditary leiomyomatosis and renal (BHD: folliculin)
Autosomal • Von Hippel-Lindau (VHL) cell cancer syndrome (FH): FH-deficient o Skin (acrochordons)
Dominant syndrome: Renal cysts, leiomyomas and papillary RCC o Pulmonary cyst or blebs
Syndromes bilateral renal cell carcinoma • Hereditary papillary carcinoma (MET): o Renal tumors (varied
Multiple bilateral papillary tumors histology, not restricted to
chromophobe)
• Cells with abundant clear or • Sheets of pale eosinophilic
• Papillary formations
Histology granular cytoplasm, which cells, often with a perinuclear
• Psammoma bodies may be present
contains glycogen and lipids halo
• Triad: Hematuria, Flank pain, Mass
Clinical
manifestations • Paraneoplastic syndrome: Polycythemia, hypercalcemia, hypertension, hepatic dysfunction, feminization or
masculinization, Cushing syndrome, eosinophilia, leukemoid reactions, and amyloidosis
• Renal vein invasion common → Metastasis is common before being symptomatic
Behavior
• Sites: Lung (>50%), Bone (33%), Regional nodes, Liver, Adrenal glands, Brain
CLEAR CELL RENAL CELL CARCINOMA PAPILLARY RENAL CELL CARCINOMA

Figure 24.26. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1028. Figure 24.28B. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1029.
BENIGN CONDITIONS THAT MIMIC BLADDER CANCER
• Malakoplakia
Inflammatory lesions
• Polypoid cystitis
• Cystitis glandularis and cystitis cystica
Metaplastic lesions • Squamous metaplasia
• Nephrogenic adenoma
MALAKOPLAKIA
• Chronic inflammatory reaction secondary to acquired defects in
CHROMOPHOBE RENAL CELL CARCINOMA
Figure 24.36. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1031. phagocyte function
• Setting: Chronic bacterial infection, Immunosuppression
20. LOWER URINARY TRACT Gross
• Soft, yellow, slightly raided mucosal plaques
findings
AND MALE GENITAL TRACT • Large, foamy macrophages
LOWER URINARY TRACT MALE GENITAL TRACT Histologic
• Michaelis-Gutmann bodies: laminated
• Ureter • Penis findings
mineralized concretions in phagolysosomes
• Urinary bladder • Testis/Epididymis
• Urethra • Prostate POLYPOID CYSTITIS
• Usual setting: indwelling catheters (irritation of bladder
URETER mucosa)
• Submucosal edema throws the urothelium into polypoid
CONGENITAL ANOMALIES projections (may be mistaken for papillary urothelial Ca)
• Ureteropelvic junction obstruction: Most common cause of
METAPLASTIC LESIONS
hydronephrosis in infants and children LESION PATHOLOGY
o More common in males, mostly bilateral; associated with
Cystitis • Urothelial (Brunn) nests in lamina propria
other congenital anomalies (contralateral renal agenesis) glandularis o CG: Cuboidal to columnar epithelial
TUMORS (CG) and metaplasia (can be a precursor to
cystitis adenocarcinoma)
• Primary ureteral tumors are rare
cystica (CC) o CC: Cystic spaces lined by flattened urothelium
• Mesenchymal tumors: Most common benign tumors
• Non-keratinizing squamous metaplasia in
• Urothelial carcinoma: Most common primary malignant response to injury
tumor Squamous
• Multifocal and extensive keratinizing
• Concurrent urothelial carcinoma of bladder or renal pelvis metaplasia
squamous metaplasia: precursor of squamous
carcinoma (S haematobium)
OBSTRUCTION
• Implantation of renal tubular epithelial cells in
• Unilateral: Proximal intrinsic or extrinsic causes (stones, Nephrogenic sites of bladder mucosal erosion
tumor) adenoma • Papillary architecture and downward growth
• Bilateral: Distal causes (nodular prostatic hyperplasia) (can be mistaken for carcinoma)
• Sequelae: Hydroureter, Hydronephrosis, Pyelonephritis
NEOPLASMS OF THE URINARY BLADEDER
URINARY BLADDER UROTHELIAL NEOPLASMS
CONGENITAL ANOMALIES • Most common bladder neoplasms
VESICOURETERAL REFLUX • More common in males and advancing age
• Most common and most serious congenital anomaly of the • Flat or papillary lesions that are precursors to invasive
urinary bladder, due to predisposition to infection urothelial carcinoma
(pyelonephritis) and scarring • Risk factors:
DIVERTICULA o Smoking (most important) o Cyclophosphamide
• Congenital, or acquired (due to obstruction: BPH, tumors) o Arylamines (2- o Irradiation
• Sequelae: Infections, stones, carcinoma Naphthylamine)
o Long-term analgesic use
BLADDER EXSTROPHY • Clinical manifestations
• Anterior abdominal wall and bladder defect i.e. bladder o Painless hematuria (Most common)
communicates directly with abdominal surface o Frequency, Urgency, Dysuria
• Sequelae: Infections, Colonic glandular metaplasia, ↑ risk of o Obstruction → pyelonephritis or hydronephrosis
Adenocarcinoma
• Ranges from benign to frankly
• Associated with Epispadias Noninvasive papillary
malignant lesions
URACHAL ANOMALIES tumors
• More common than flat tumors
• Total patency → Fistula between bladder and umbilicus Noninvasive flat
• Partial patency → Urachal cyst → Adenocarcinoma • Considered high-grade tumor
tumors
• Malignant urothelial neoplasms invading at
INFLAMMATION Invasive least the lamina propria
ACUTE AND CHRONIC CYSTITIS urothelial • T1: lamina propria invasion
• More common in women due to shorter urethra carcinoma • T3: muscularis propria invasion (Detrusor
• Risk factors: Similar to those of pyelonephritis (obstruction, muscle) → ↓ survival rate
immune deficiency, instrumentation) • Cytologically malignant cells on a flat urothelium
• Most common etiology: Coliforms (similar to pyelonephritis) o Full-thickness dysplasia
Carcinoma
• Clinical manifestations: o Pagetoid spread: Scattered malignant cells
in situ
o Frequency, hypogastric or suprapubic pain, dysuria in an otherwise normal urothelium
o Dyscohesive cells → ↑ shedding in the urine
COMMON MORPHOLOGIC PATTERNS OF CYSTITIS
PATTERN FINDINGS/ASSOCIATIONS
OTHER TUMORS OF THE URINARY BLADDER
• EPITHELIAL TUMORS
Mucosal hyperemia, neutrophilic
Acute cystitis
infiltrate, exudate Squamous cell • Can be secondary to chronic bladder
Chronic cystitis • Mononuclear infiltratecarcinoma irritation & infection (S haematobium)
Hemorrhagic • Viruses: Adenovirus, BK virus • Arises in urachal remnants&
cystitis
Adenocarcinoma
• Drugs: Cyclophosphamide intestinal metaplasia
Emphysematous • Gas-filled vesicles in wall
Small cell • Similar to small cell CA in other sites
cystitis • In C. perfringens carcinoma • Very aggressive
MESENCHYMAL TUMORS
• Most common benign mesenchymal
Leiomyoma
tumor of the urinary bladder
• Most common sarcoma of the
Leiomyosarcoma
urinary bladder in adults
Embryonal
• Most common sarcoma of the
Rhabdomyosarcoma
urinary bladder in children
(Sarcoma botryoides)
KOILOCYTOSIS IN CONDYLOMA ACUMINATUM
SECONDARY TUMORS Figure 28.8B. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1178.
• Common sources: Cervix, uterus, prostate, rectum SQUAMOUS CARCINOMA IN SITU

• Lymphomas (part of systemic disease) PENILE INTRAEPITHELIAL NEOPLASIA (PeIN)
OBSTRUCTION • Malignant squamous lesions confined to the epithelium by an
intact basement membrane
Most common • Males: nodular prostatic hyperplasia • Types:
causes • Females: cystocele of the bladder • Associated with high-risk HPV (HPV 16)
HPV-related
• Smooth muscle hypertrophy → thickened Undifferentiated • No evidence of squamous differentiation
wall PeIN • Bowen disease, Bowenoid papulosis
• Trabeculation: enlargement of individual Non-HPV-
Morphology muscle fibers • Associated with balanitis xerotica
related
• Diverticula formation obliterans
Differentiated
• Extreme dilation → wall attenuation • Has evidence of squamous differentiation
PeIN
(acute cases)
UNDIFFERENTIATED PeIN
URETHRA BOWENOID
BOWEN DISEASE
INFLAMMATION (URETHRITIS) PAPULOSIS
• Associated with prostatitis (men) and cystitis (women) Age group • Older men • Younger age
• Infectious: • Shaft and scrotum:
o Gonococcal: N gonorrhoeae Solitary thickened,
o Non-gonococcal: C trachomatis, Ureaplasma urealyticum gray-white, opaque • Multiple, reddish-
Gross
• Non-infectious: plaque brown papules
o Reactive arthritis (Reiter syndrome): Arthritis, • Glans: Velvety red
Conjunctivitis, Urethritis lesion
• Dysplastic squamous cells
TUMORS AND TUMOR-LIKE CONDITIONS Histology • Loss of orderly maturation
URETHRAL CARUNCLE • Numerous mitosis (with atypical forms)
Precursor
• Inflamed granulation tissue covered with friable, intact mucosa; • Almost always never
to
may ulcerate and bleed • Yes • Spontaneously
invasive
TUMORS regresses
carcinoma
• Benign epithelial tumors: Squamous and Urothelial papillomas, The number of lesions clinches the diagnosis between Bowen disease and
Inverted urothelial papillomas, Condylomas Bowenoid papulosis. Make sure to make the correct diagnosis because
• Primary carcinomas: Rare Bowen is an established preinvasive lesion.
o Proximal urethra: Urothelial carcinoma Dr. Elomina
o Distal urethra: HPV-related Squamous cell carcinoma INVASIVE SQUAMOUS CELL CARCINOMA
o Adenocarcinoma: Rare; usually occurs in females • Risk factors:
o Poor hygiene o Cigarette smoking
PENIS o High-risk HPV (HPV o Chronic inflammatory
16,18) conditions
CONGENITAL ANOMALIES • Circumcision offers protection
HYPOSPADIAS AND EPISPADIAS • Molecular pathogenesis: HPV-encoded proteins inactivate
• Malformation of urethral groove → abnormal opening on major tumor suppressor genes
ventral (hypospadias) or dorsal (epispadias) shaft E6 • Inactivation of p53; Stimulates telomerase expression
• Hypospadias more common • Inactivation of RB → ↑p16 (cyclin-dependent kinase
• Consequences: Infections, and in some, infertility E7
inhibitor)
PHIMOSIS • Common sites: Glans, inner surface of prepuce near coronal
• Foreskin orifice too small to permit normal retraction sulcus
• Most commonly a result of scarring from infections • Histologic types:
• Favors development of infections, and possibly cancer • HPV-related; poorly differentiated,
Basaloid SCCA
aggressive course
BALANOPOSTHITIS SCCA, usual type • Non-HPV-related; most common
• Infection of glans and prepuce • Non-HPV-related; well-differentiated,
Verrucous CA
favorable prognosis
• Agents: Candida albicans, anaerobic and pyogenic bacteria,
Gardnerella • Clinical manifestations
• Consequence of poor local hygiene in uncircumcised males o Slowly growing, locally invasive penile lesion
o Smegma: Desquamated epithelial cells, sweat, and debris o Inguinal node metastasis may occur early
TUMORS OF THE PENIS

PENILE INVASIVE
CONDYLOMA ACUMINATUM SQUAMOUS CELL CARCINOMA
• Benign, sexually transmitted wart caused by low-risk HPVs https://qrs.ly/elcmelb
o HPV 6 (more common) & HPV 11
• Common location: Coronal sulcus and inner surface of prepuce
• Histology
o Papillomatosis, acanthosis with orderly maturation,
hyperkeratosis, and no atypia
o Koilocytosis: Perinuclear cytoplasmic vacuolization
TESTIS AND EPIDIDYMIS OTHER INFLAMMATORY CONDITIONS

Mumps • More common in post-pubertal males
CRYPTORCHIDISM
orchitis • Occurs a week after parotitis
• Complete or partial failure of the intra-abdominal testes to • Obliterative endarteritis with perivascular
descend into the scrotal sac Syphilis lymphocytes, plasma cells
• Unilateral in most of cases (75%) • Gumma formation
• Most common location of undescended testis: Inguinal canal • Clinical presentation:
• Most common phase of arrest: Inguinoscrotal (4-7th month AOG) o Tender mass with or without fever
• Morphology (histologic changes evident as early as 2 years old) Granulomatous
o Painless mass (mimics testicular tumor)
(autoimmune)
o Changes can be seen in contralateral descended testis • Morphology:
orchitis
o Also seen in testicular atrophy o Non-caseating granulomas in
§ Loss of spermatogonia → only Sertoli cells are seen seminiferous tubules
§ Basement membrane thickening
§ Increase in interstitial stroma
TESTICULAR TORSION
§ Prominent Leydig cells • True urologic emergency
• Clinical significance • Twisting of spermatic cord → Impaired venous drainage →
o Trauma, Inguinal hernias, Infertility Congestion → Hemorrhagic infarction
o Testicular cancer • Golden period: 6 hours
§ Like histologic changes in cryptorchidism, cancer may also • Types:
develop in contralateral descended testis Neonatal • Occurs in utero or shortly after birth
torsion • No associated anomaly
INFLAMMATORY CONDITIONS • Occurs in adolescents
“Adult”
• Due to “bell-clapper deformity” → bilateral
• Inflammation: Common in epididymis torsion
anatomic defect increasing testicular mobility
• Tumors: Common in testis
• Gonorrhea and TB: first affect epididymis; testis may be TESTICULAR TUMORS
involved through extension • Most common cause of painless testicular enlargement
• Syphilis: first affects testis o Any testicular mass should be considered neoplastic unless
proven otherwise
NON-SPECIFIC ORCHITIS AND EPIDIDYMITIS • Germ cell (95%) and sex cord-stromal (5%)
• Causes depend on age GERM CELL TUMORS
o Children: Gram (-) rods, usually with genitourinary
• Cryptorchidism – most important associated condition
abnormality
• Practical classification
o Sexually active men < 35 years: C trachomatis, N gonorrhoeae
o Seminomatous tumors (SGCTs): better prognosis
o UTI in men > 35 years: E. coli, Pseudomonas
o Non-seminomatous tumors (NGSCTs): usually unfavorable
• Pathogenesis: Ascending or lymphatic spread of UTI
prognosis
• Morphology
o Acute suppurative inflammation → fibrous scarring → can
TESTICULAR GERM CELL TUMORS
cause sterility
https://qrs.ly/akcmelo
o Sparing of Leydig cells: androgen production relatively
unaffected
GERM CELL TUMORS
SEMINOMA EMBRYONAL CARCINOMA YOLK SAC TUMOR CHORIOCARCINOMA
• Prepubertal: Most common
Type • Pure embryonal testicular GCTs in infants
• Pure choriocarcinoma (Rare)
and/or • Most common GCT carcinoma or as a and children up to 3 years
or component of mixed GCTs
incidence component of mixed GCTs • Postpubertal: usually occurs
as component of mixed GCTs
Peak
• 4th decade • 20-30s • Prepubertal: Pediatric -
incidence
• Large polyhedral cells, with • Variable architecture • Schiller-Duval • Atypical cyto- and
clear cytoplasm, central • Highly anaplastic (with (glomeruloid) bodies: syncytiotrophoblasts
Histology nuclei with prominent tumor giant cells) Central blood vessel without villi formation
nucleoli • Lymphovascular enveloped by tumors cells • Hemorrhage, Necrosis
• Lymphocytic infiltrate invasion (LVI) • (+) AFP • (+) hCG
• More aggressive than • Prepubertal: Excellent • Highly malignant
Behavior • Favorable
seminomas prognosis • Widespread metastasis
Testicular and ovarian teratomas have different predictors of biologic
behavior. In the testis, as previously mentioned, it is the patient’s age. In
the ovary, it is the presence of the immature component that determines
the prognosis. That is why testicular teratomas are classified into
prepubertal and postpubertal types, while ovarian teratomas are
classified into mature and immature teratomas.
Dr. Elomina
TERATOMAS WITH SOMATIC-TYPE MALIGNANCY
SCHILLER-DUVAL BODY IN YOLK SAC TUMOR • Non-germ cell malignancy arising in a teratoma (Squamous
Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 10th ed. 2011. cell carcinoma, mucin-secreting adenocarcinoma, sarcoma)
o Non-germ cell malignant component is chemoresistant
TESTICULAR TERATOMA The non-germ cell malignancy is chemoresistant to therapy for germ cell
• Germ cell tumors composed of elements derived from >1 germ tumor but may respond to agents for the somatic-type malignancy itself.
cell layer As long as the somatic-type malignancy remains confined within the
• Second most common testicular tumor in infants and children testis, it does not affect prognosis.
Dr. Elomina
o In adults, usually occurs as a component of mixed GCTs MIXED GERM CELL TUMOR
• Patient’s age: Most important predictor of biologic behavior • 60% of testicular tumors
o Prepubertal type: Benign • Second most common GCT in adults
o Postpubertal type: Malignant • Common combinations:
• Histology o Teratoma, embryonal carcinoma, yolk sac tumor
o Mature elements (Adult tissues) o Seminoma with embryonal carcinoma
o Immature elements (Fetal or embryonic tissues) o Embryonal carcinoma with Teratoma
TUMOR MARKERS IN TESTICULAR GERM CELL TUMORS • Estrogens
Functional • No
• Clinical utility: initial evaluation, staging, assessment of • Androgens
tumor burden, monitoring response to therapy • Gynecomastia
Clinical
MARKER USE • Sexual precocity in • Testicular swelling
presentation
LDH • Assesses of tumor burden children
AFP • Characteristically produced by yolk sac tumor • Large, round or
• Product of syncytiotrophoblasts polygonal cells with • Tumor cells arranged
hCG abundant granular in trabeculae forming
• Characteristically seen in choriocarcinoma
Histology cytoplasm and round cord-like structures
SEX-CORD-STROMAL TUMORS central nucleus and tubules (resemble
• Histologic types • Crystalloids of seminiferous tubules)
o Leydig cell tumor (LCT) Reinke (25%)
o Sertoli cell tumors (SST) TESTICULAR LYMPHOMA
• Most cases display a benign behavior (~90%)
• Most common testicular neoplasm in men > 60 years of age
COMMON SEX-CORD-STROMAL TUMORS • Most common form: DLBCL
LCT SST • Behavior: Aggressive tumors (disseminated at diagnosis)
• Klinefelter syndrome § Commonly bilateral with spermatic cord involvement
• Carney complex
• Cryptorchidism § Frequent CNS involvement
Associated • Peutz-Jeghers
• Hereditary
conditions syndrome
leiomyomatosis and
• FAP
RCC syndrome
PROSTATE
PROSTATITIS
COMMON FORMS OF PROSTATITIDES
ACUTE BACTERIAL
CHRONIC BACTERIAL PROSTATITIS CHRONIC ABACTERIAL PROSTATITIS
PROSTATITIS
Epidemiology - - • Most common
Etiology • E. coli, G(-) rods, enterococci, staphylococci -
• Low back pain, dysuria, perineal and
• Fever, chills, dysuria • Signs and symptoms of chronic
suprapubic discomfort
Diagnostic clues • Tender, boggy prostate bacterial prostatitis
• May be asymptomatic
on DRE • (-) History of recurrent UTI
• (+) History of recurrent UTI
ACUTE BACTERIAL
CHRONIC BACTERIAL PROSTATITIS CHRONIC ABACTERIAL PROSTATITIS
PROSTATITIS
WBC in prostatic
• > 15/HPF, without pyuria • >10/HPF
secretions
Bacterial culture • Positive • Negative
The clinical presentation of acute prostatitis is more akin to acute infection with systemic signs like fever. That’s something that you don’t see in your chronic
prostatitis. Chronic bacterial and a bacterial prostatitis may present clinically the same, but evidence of infection sets them apart
Dr. Elomina
BENIGN AND MALIGNANT PROLIFERATIVE LESIONS • Genetic: Race (African Americans), Family history of prostate
cancer in first-degree relatives, Inherited mutations
• Most common site of prostatic
Peripheral adenocarcinoma • Environmental: Diet (Charred red meats, animal fat)
zone • Allows it to be palpable during digital MORPHOLOGY
exams • Precursor lesion: Prostatic intraepithelial neoplasia (PIN)
• Most common site of benign prostatic • Prostatic adenocarcinoma = Prostatic acinar adenocarcinoma
Transitional o Tightly packed, simple, small glands with single layer of
hyperplasia (BPH)
zone cuboidal or low columnar epithelium
• Most often produces urinary obstruction
• Both NPH and prostatic adenocarcinoma are diseases of elderly § Nuclear enlargement with prominent nucleoli
males (>50 years old) and are associated with androgens § Pleomorphism (variation) not marked
§ Mitosis uncommon
BENIGN PROSTATIC HYPERPLASIA Normally, your prostatic glands have an inner luminal layer and an outer
• Most common benign prostatic disease in men > 50 years old basal layer of cells. In cancer, your outer basal layer cells are absent.
Dr. Elomina
• NOT a premalignant lesion BEHAVIOR
• Pathogenesis: • Metastasis:
o Dihydrotestosterone (DHT): ultimate mediator of prostatic o Lymphatic: Obturator → Para-aortic nodes
growth o Hematogenous: Batson plexus → Bones (Axial skeleton)
§ Formed by Type 2 5-α-reductase (expressed only in (Blastic lesions)
prostatic stromal cells) § Common sites (descending order of frequency): Lumbar
o DHT interacts with androgen receptors found in prostatic spine, proximal femur, pelvis, thoracic spine, ribs
epithelial and stromal cells → stromal cell proliferation and
longer epithelial cell survival PROGNOSTIC FACTORS
o Estrogens (ER-α) have proliferative effects on prostate cells • Grade and Stage: Most important prognostic factors
• Morphology: Stromal (fibromuscular) and Epithelial (glandular) • Gleason system: Grading system used for prostatic
hyperplasia → nodularity (Hallmark) adenocarcinomas
• Clinical manifestations: Urinary obstruction, and/or infection o 5 patterns from well- to poorly differentiated
o Basic rule of scoring: Most dominant pattern + Second most
PROSTATIC ADENOCARCINOMA dominant pattern (Order is important)
• Most common cancer in men in the US • WHO Contemporary prostate cancer grading system (2016)
• Second most common cause of cancer-related death following o 5 groups based on Gleason grades
lung cancer o Each of the five groups has different prognosis
• Most common genetic alteration: ETV1-TMPRSS2 Order in Gleason scoring is important because it is prognostically
rearrangement significant, as evidenced by WHO grade group 2 (3+4) and 3 (4+3), which
RISK FACTORS both have Gleason score of 7, but have different survival rates.
Dr. Elomina
• Advancing age
• Androgen excess
CLINICAL FEATURES VULVA
• Localized: Asymptomatic or palpable nodule on DRE with ↑
Prostate-specific antigen (PSA)
BARTHOLIN CYST
• Advanced: Urinary obstruction or Bone pain (if with • Cystic dilation of the Bartholin gland due to duct obstruction
metastasis) • Lining: Transitional or Squamous epithelium
• May be infected (adenitis) → Abscess formation
PROSTATE-SPECIFIC ANTIGEN (PSA)
• Biopsy is indicated in patients > 40 years to rule out
• Synthesized in the epithelial cells of the prostate gland
malignancy
• Normal reference range: 0-4 ng/mL
SCREENING GUIDELINES FOR PROSTATE CANCER
• Start of screening: 45 years old NON-NEOPLASTIC EPITHELIAL DISORDERS
• Components: DRE and baseline PSA • Not premalignant lesions but associated with vulvar cancer
AGE PSA and DRE RECOMMENDATION o Lichen sclerosus: slightly ↑ risk for developing vulvar cancer
• PSA < 1 ng/mL • Repeat testing q 2-4 o Squamous hyperplasia: at margins of vulvar cancer
• DRE normal years • Common clinical presentation: Leukoplakia
45-75 • PSA 1-3 ng/mL • Repeat testing q 1-2 SQUAMOUS
FEATURE LICHEN SCLEROSUS
years • DRE normal years HYPERPLASIA
• PSA > 3 ng/mL • Thinning of the • Acanthosis
• Biopsy
• Very suspicious DRE epidermis • Mitosis
• PSA <4 ng/mL • Basal cell • Hyperkeratosis
• DRE normal • Repeat testing q 1-4 degeneration • Dermal lymphocytic
• (-) indications for years Histology • Hyperkeratosis infiltrate
>75 years
biopsy • Sclerotic changes of
• PSA ≥ 4 ng/mL superficial dermis
• Biopsy
• Very suspicious DRE • Dermal lymphocytic
Reference: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Oncology. Prostate Cancer
Early Detection, Version 2.2019, May 31, 2019 (Adapted) infiltrate
VULVAR INTRAEPITHELIAL NEOPLASIA (VIN) AND
21. FEMALE GENITAL TRACT VULVAR SQUAMOUS CELL CARCINOMA
• Infections • Fallopian tubes VULVAR SQUAMOUS CELL CARCINOMA
• Vulva • Ovary
• Most common histologic type of vulvar cancer
• Vagina • Gestational and placental
• Cervix disorders • Behavior
• Body of Uterus & Endometrium o Lymphatic spread: Inguinal → Pelvic → Iliac → Peri-aortic
o Hematogenous spread: Lungs, liver, etc.
INFECTIONS • Prognostic factors: Tumor size, Depth of invasion, Lymphatic
invasion
LOWER GENITAL TRACT INFECTIONS HPV-RELATED Non-HPV-RELATED
PRESENTATION ETIOLOGIC AGENT(S) Incidence • 30% • 70%
• Gardnerella vaginalis • High-risk HPV • Chronic epithelial
• N gonorrhoeae Pathogenesis
infection irritation
Discharge • C trachomatis
Patient age • 60 years • 75 years
• C albicans
• T vaginalis • Basaloid
Histology • Keratinizing
• Herpes simplex virus • Warty
Genital ulcers • H ducreyi Precursor
• Classic VIN • Differentiated VIN
• K granulomatis lesion
Mass formation • Human papillomavirus Your penile and vulvar cancers have similar classification, pathogenesis, histology,
and precursor lesions. Classic VIN is similar with undifferentiated PeIN, while
differentiated VIN is similar with differentiated PeIN. Warty carcinomas are
PELVIC INFLAMMATORY DISEASE
architecturally similar to condylomas but have malignant cytology.
• Infection that begins in vulva/vagina that ascends to involve Dr. Elomina
most of the structures in the female genital system
EXTRAMAMMARY PAGET DISEASE
• Clinical manifestations: pelvic pain, adnexal tenderness, fever,
vaginal discharge • Similar to Paget Disease of breast clinically and histologically
• Etiology: • Not associated with underlying invasive cancer (unlike
• Common cause of PID (most serious Mammary Paget Disease)
complication of gonorrhea in women)
N gonorrhoeae • Initial infection mostly involves the VAGINA
endocervical mucosa → ascends to involve DEVELOPMENTAL ANOMALIES
the adnexal structures → less inflammation
C trachomatis • Another well-recognized cause of PID Septate • Failure of Müllerian duct fusion
• Staphylococci, streptococci, coliforms & vagina • Associated with DES exposure in utero
C perfringens • Areas of columnar mucinous epithelium
• Secondary to puerperal infections Vaginal (endocervical-like)
Polymicrobial
• Modes of transmission: instrumentation, adenosis • Associated with DES exposure in utero
surgical procedures, induced abortion, via • Associated with Clear cell CA of vagina
lymphatics → more inflammation Gartner
• Remnant of the Wolffian (mesonephric) duct
duct cyst
GONOCOCCAL PID
MORPHOLOGY NEOPLASTIC LESIONS
General • Intense acute inflammatory infiltrates with
morphology intracellular Gram-negative diplococci • Stromal polyps, leiomyomas,
Benign tumors
Cervix • Acute and chronic cervicitis hemangiomas
Endometrium • Usually spared Carcinoma
• Acute suppurative salpingitis → Pyosalpinx
spreading from • Most common malignant tumor
(Pus in the lumen) → Chronic salpingitis cervix
Fallopian • Second most common malignant tumor
(Scarring) + Fimbrial fusion → Hydrosalpinx Primary
tube • Almost all are HPV-related
(accumulation of secretions and tubal squamous cell
distention) • Most common site: posterior wall at
carcinomas
Ovary • Salphingo-oophoritis → tubo-ovarian abscess ectocervico-vaginal junction
• Grape-like (Botryoid) clusters of mass BODY OF THE UTERUS AND ENDOMETRIUM
seen in the young (<5 years) DYSFUNCTIONAL UTERINE BLEEDING
• Histology: embryonal
• AUB without an organic (structural) cause
rhabdomyoblasts
• Most common cause: Anovulatory cycle
o Tennis racket-like, small cells
Sarcoma o Unopposed estrogen stimulation due to failure of ovulation
o Cambium layer: concentration of
botryoides i.e. no corpus luteum and progesterone → endometrial
neoplastic cells beneath intact
proliferation → bleeding
epithelium
o Histology: Menstrual-like endometrium (eosinophilic
• Can cause death via penetration into
epithelial metaplasia and stromal breakdown) without
peritoneal cavity or urinary tract
progesterone-mediated changes (the endometrium appears
obstruction
proliferative)
CERVIX ENDOMETRITIS
• Rare because endocervix protects it from ascending infections
ENDOCERVICAL POLYPS
• Chronic endometritis is clinically significant (unlike chronic
• Can be a cause of irregular vaginal bleeding (post-coital) cervicitis)
• Fibrous stroma lined by endocervical-type epithelium, ACUTE CHRONIC
usually with inflammation • Chronic PID
• Post-partum or
• Retained products of
Associated miscarriage (with
PREMALIGNANT AND MALIGNANT conception
conditions retained products of
NEOPLASMS OF THE CERVIX • IUDs
conception)
• High-risk HPVs: most important factor in the development of • Tuberculosis
cervical cancer: HPV 16 (60%) > HPV 18 (10%) • Stromal acute
Morphology • Stromal plasma cells
inflammation
CERVICAL INTRAEPITHELIAL NEOPLASIA ENDOMETRIOSIS AND ADENOMYOSIS
(SQUAMOUS INTRAEPITHELIAL LESIONS)
• Endometriosis: presence of ectopic endometrial tissue outside
• Two-tiered classification currently used: low- and high-grade the uterus (most common location: ovaries)
squamous intraepithelial lesion (SIL)
• Adenomyosis: presence of endometrial tissue within the
DYSPLASIA/CIS CIN SIL (CURRENT)
myometrial wall
Mild dysplasia CIN I LSIL
Moderate dysplasia CIN II ENDOMETRIOSIS ADENOMYOSIS
Severe dysplasia HSIL • Severe
CIN III • Menometrorrhagia,
dysmenorrhea,
Carcinoma in situ dysmenorrhea,
Adapted from Table 22.1. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 Clinical dyspareunia, pelvic
dyspareunia,
MORPHOLOGY presentation pain, infertility
premenstrual pelvic
• Nuclear atypia • Menstrual
pain
• Koilocytic atypia: Nuclear atypia with cytoplasmic “halos” irregularities
• Grade: expansion of immature cells from basal layer • Red blue to yellow-
• Symmetrically
o LSIL: confined to lower third of epithelium brown nodules
enlarged corpus with
• Chocolate cysts
o HSIL: expansion to upper two-thirds of epithelium thickened
Gross (Endometriomas):
Nuclear atypia is characterized by nuclear enlargement, myometrium and/or
findings Cysts filled with
hyperchromasia, coarse chromatin pattern, and pleomorphism. multiple blood lakes
chocolate brown
Dr. Elomina within the
NATURAL HISTORY material (Ovary)
myometrium
• Adhesions
• LSIL is not treated as a premalignant lesion (Often regresses)
• Endometrial glands
• HISL has high risk for progression to carcinoma
• Endometrial and stroma at least
LESION REGRESS PERSIST PROGRESS* Histologic
glands and/or one low-power field
LSIL 60% 30% 10% to HSIL findings
stroma from the endo-
HSIL 30% 60% 10% to CA myometrial junction
* - Progression within 2-10 years
Table 22.2. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 PATHOGENESIS
The basis for the two-tiered classification is because the management is also • Regurgitation theory (Retrograde menstruation)
two-tiered. For LSILs, because it is not treated as a premalignant lesion, • Metastatic theory (Benign metastasis)
Theories
observation may suffice. Meanwhile, HSILs require surgical intervention. • Metaplastic theory (Coelomic metaplasia)
Dr. Elomina
• Extrauterine stem/progenitor stem cell theory
CERVICAL CANCER
• CIN + invasion beyond the basement membrane ENDOMETRIAL POLYP
• Various histologic types, but most are associated with high- • Exophytic masses that project into endometrial cavity
risk HPVs o Histology: Polypoid lesion with endometrial glands
o Squamous cell carcinoma (80%) embedded in a fibrous stroma
o Adenocarcinoma (15%) o Clinically silent or present with AUB and infertility
o Adenosquamous and Neuroendocrine carcinoma (5%) • Seen in patients on Tamoxifen
• Most common cause of death: complications secondary to • Rarely give rise to carcinomas
urinary tract obstruction (ureteral obstruction, pyelonephritis,
uremia)
ENDOMETRIAL HYPERPLASIA
• Distant metastasis: Liver, Lungs, Marrow, etc. • Important cause of AUB, and precursor to endometrial
carcinoma (Type I)
• Risk factors: Prolonged estrogenic stimulation
CERVICAL CANCER STAGING o Obesity, Menopause, PCOS, Functioning granulosa cell tumor,
https://qrs.ly/w5cmeni Ovarian cortical stromal hyperplasia, Estrogen replacement
therapy
• Molecular pathogenesis:
o PTEN inactivation (in 20% of cases): Tumor suppressor gene
that inhibits PI3K/AKT pathway
• Classification and Morphology:
• ↑ gland/stromal ratio, focal glandular crowding,
Typical
cytologically bland epithelial cells
• ↑ cytologically atypical epithelial cells
Atypical
• ↑ risk of endometrial carcinoma
ENDOMETRIAL CARCINOMA MALIGNANT MIXED MÜLLERIAN TUMOR

• Most common invasive cancer of the female genital tract (CARCINOSARCOMA)
• Important differential diagnosis for post-menopausal • Mixed epithelial and mesenchymal tumors, both of which are
bleeding malignant
• Has 2 broad types: Type I (endometrioid) & Type II (serous, clear • Staged as carcinomas, because it is a first and foremost, a
cell, malignant mixed Mullerian tumor – MMMT) carcinoma (that gained the ability to differentiate into
• Stage: Most important prognostic factor mesenchymal elements)
• Metastasis usually contains only epithelial components
ENDOMETRIAL STROMAL TUMORS

• Adenosarcoma: Benign endometrial glands embedded in a
malignant-looking stroma
o Can present as polypoid masses (important to differentiate
between large endometrial polyps)
• Pure endometrial stromal tumors
o Benign: Endometrial stromal nodule (ESN)
o Malignant: Endometrial stromal sarcoma (ESS) (Low-grade or
High-grade)
• Your adenosarcoma can be likened to Phyllodes tumor of the breast.
• Your pure endometrial stromal tumors can have overlapping features
with myometrial tumors, and difficulties may be resolved by IHC,
because smooth muscle cells and endometrial stromal cells have a
MOLECULAR PATHOGENESIS OF ENDOMETRIAL CARCINOMA
Figure 22.24. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 different marker expression profile.
Dr. Elomina
TYPE I TYPE II
(ENDOMETRIOID) (NON- MYOMETRIAL TUMORS
ENDOMETRIOID) • Leiomyoma: Most common tumor in women
Age o Malignant transformation is rare
• 55-65 • 65-75
(years) • Leiomyosarcoma: Arises de novo (not from leiomyomas)
Mutation • PTEN • TP53 o Hematogenous route of metastasis to lungs, bone, brain
• Unopposed
estrogen MORPHOLOGY OF MYOMETRIAL TUMORS
Clinical • Atrophy
• Obesity LEIOMYOMA LEIOMYOSARCOMA
setting • Thin physique • Well-
• Hypertension • Bulky, fleshy masses that
• Diabetes circumscribed,
invade the uterine wall
• Serous endometrial Gross unencapsulated
• Polypoid masses that project
grayish-white
Precursor • Hyperplasia intraepithelial into the uterine lumen
tumors
carcinoma
HISTOLOGY
• Indolent • Aggressive
Atypia • Usually absent • Usually present
Behavior • Spread via • Intraperitoneal and Mitotic
lymphatics lymphatic spread • None to low • High
Table 22.4. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 (adapted)
figures
Necrosis • Absent • Usually present
I think the most important distinction that you have to remember
between Type I and Type II carcinomas is their biologic behavior, with
Type II carcinomas being more aggressive i.e. high stage at presentation. FALLOPIAN TUBES
We have a saying in the pathology world, especially in gynecologic
• Common lesions: Inflammation and cysts
pathology, “serous is serious.”
Dr. Elomina o Salpingitis: Suppurative (Most common: gonococcus,
MOPHOLOGY OF ENDOMETRIAL CARCINOMAS followed by Chlamydia), Tuberculous
ENDOMETRIOID SEROUS § Consequence: Infertility and ectopic pregnancy (due to
scarring)
• Glandular, Papillary, • Papillary,
Architecture o Cyst: Paratubal cysts (tubal-like epithelial lining)
Solid Glandular
• Rare lesions: Tumors
Cytologic atypia • Mild to moderate • Marked
o Serous tubal intraepithelial carcinoma (STIC)
Squamous § Precursor lesion of high-grade serous carcinoma
differentiation § Found in patients with germline BRCA1 mutations
• Based on solid, non- § Usually found in the fimbriated end of the fallopian tube
• Automatically
Grading squamous growth
high-grade
and nuclear grade
OVARY
There are two morphologic clues to distinguish endometrioid and serous.
Endometrioid carcinomas are usually associated with squamous
CYSTS
differentiation and Serous carcinomas have a seriously ugly cytology. CYSTIC FOLLICLES (≤ 2 cm)/FOLLICLE CYST (> 2 cm)
Dr. Elomina
• Lining
o Inner granulosa cells, may be flattened due to pressure
atrophy
ENDOMETRIAL CARCINOMA STAGING
o Outer theca cells with pale cytoplasm (luteinization)
https://qrs.ly/fvcmfsd • If pronounced luteinization (hyperthecosis): Hyperestrinism
and secondary endometrial abnormalities
LUTEAL CYST (Corpus luteum cyst)

• Lining: Luteinized granulosa cells
• May rupture and cause peritoneal reaction
POLYCYSTIC OVARIAN SYNDROME (PCOS) (Stein-Leventhal

syndrome)
• Complex endocrine disorder characterized by
ENDOMETRIAL ENDOMETRIOID CARCINOMA WITH SQUAMOUS hyperandrogenism, menstrual abnormalities, polycystic
DIFFERENTIATION (L) AND SEROUS CARCINOMA (R) ovaries, chronic anovulation, and decreased fertility
Figure 33.34A and 33.37B. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1312-1313.
• Associated with obesity, Type 2 DM, and premature MORPHOLOGY OF OVARIAN TERATOMAS
atherosclerosis MATURE IMMATURE
• Numerous cystic follicles or follicle cysts that enlarge the • Cystic mass lined by skin-
ovaries Architecture like structures (dermoid • Solid
cyst)
OVARIAN TUMORS • Tissues from different origin
• Neuroepithelium
(skin and adnexa), cartilage,
• Most are benign (80%) Histology (small, round, blue
bone, thyroid, and neural
• Incidence of malignancy increases with age cells)
tissues
• Major groups (4) Biologic
o Surface epithelial (most common), Germ cell, Sex cord- • Benign • Malignant
behavior
stromal, Metastatic
• Presentation: Mass effect, tumor invasion, or hormone
elaboration (e.g. vaginal bleeding in granulosa cell tumor)
SURFACE EPITHELIAL TUMORS

• Histologic types: serous (most common), mucinous,
endometrioid, clear cell
• General morphology: benign, borderline, malignant forms
o Borderline tumors are distinguished from benign tumors by MATURE TERATOMA (L) AND IMMATURE TERATOMA (R)
Figure 35.72 and 35.69. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1397-1398.
presence of atypia and more complex architecture
o Atypia and architectural complexity increase as you go from MONODERMAL TERATOMA
borderline to carcinoma • Teratomas with one type (1) of tissue
o Carcinomas are distinguished from borderline and benign
• Almost always unilateral
tumors by presence of stromal invasion
• If functional, can produce symptoms related to hormone excess
• Most women present with high-stage disease
Struma ovarii • Contains mature thyroid tissue
• CA-125: tumor marker to monitor recurrence/progression
• Causes carcinoid syndrome (flushing,
Carcinoid diarrhea, bronchospasms)
MORPHOLOGY/
TYPE REMARKS tumor • If bilateral, exclude metastatic intestinal
PRESENTATION
carcinoid
• Has tubal-like
epithelium (ciliated
SEX-CORD-STROMAL TUMORS
cuboidal to columnar) • Mostly benign
Serous • Sertoli-Leydig cell tumors can also occur in the ovary (see
• Frequent ovarian (60%)
surface involvement Chapter 21, under Germ cell tumors)
• Usually bilateral • Usually unilateral
• Has mucinous epithelium • Clinical manifestations attributed to mass effect and hormone
• Mostly benign production
(intestinal-like)
(80%)
• Rare ovarian surface o Estrogen: Granulosa cell tumors, Fibrothecomas, Thecomas,
Mucinous • Associated with
involvement and rarely, Sertoli-Leydig cell tumors
pseudomyxoma
• Usually unilateral, large § Symptoms depend on age group
peritonei
masses • Pre-pubertal: Precocious puberty
• Mostly • Reproductive age: Abnormal uterine bleeding
• Resembles endometrium
malignant • Post-menopausal: Post-menopausal bleeding
• Bilateral in 40%, usually
Endometrioid • Can coexist with o Androgen: Sertoli-Leydig cell tumors
signifies extension
endometriosis,
beyond genital tract GRANULOSA CELL FIBROMA,
endometrial CA
TUMOR THECOMA
• Rare
• Meigs syndrome (Ovarian
• Has large cells with • Mostly tumor, Hydrothorax,
Clear cell abundant clear malignant Clinical
• Hyperestrinism Ascites)
cytoplasm • Associated with syndrome
• Hyperestrinism (if with
endometriosis thecomatous component)
• Small, cuboidal to • Fibroblast-like cells
GERM CELL TUMORS polygonal cells (Fibroma)
• Generally histologically similar with testicular counterparts (so • Call-Exner bodies: • Plump spindle cells
Histology
only a few diseases will be discussed under this section) Gland-like (Thecoma)
structures filled with • Mixture of both cells
• Like testicular GCTs, age provides an important diagnostic clue acidophilic material (Fibrothecoma)
o Children and Younger women: Immature teratomas, Yolk sac Biologic • Low-grade
tumor • Benign
behavior malignancy
o Reproductive age: Mature cystic teratomas, Dysgerminomas
• Most common ovarian GCT: Mature cystic teratoma METASTASIS
• Most common primary: Müllerian: Uterus, Fallopian tube,
TERATOMA Contralateral Ovary, Pelvic peritoneum
• Presence of immature component (neuroepithelium): Major • Most common extra-Müllerian primary: Breast, GIT,
determinant of biologic behavior Hepatobiliary tract
o Main difference from testicular teratomas • Pseudomyxoma peritonei (PMP) from appendiceal mucinous
o Hence, the diagnosis is either mature teratoma or immature neoplasms
teratoma (immature teratoma is graded based on amount of • Krukenberg tumor: Signet ring cell carcinoma from GIT (most
neuroepithelium present) commonly gastric) metastatic to both ovaries
• Anti-N-methyl-D-aspartate (NMDA) encephalitis
o Paraneoplastic syndrome characteristically associated with GESTATIONAL TROPHOBLASTIC TUMORS
teratomas (but not solely with teratomas) HYDATIDIFORM MOLE
o Autoimmune disorder that attacks the NMDA receptors of the • Histologic hallmark: Cystic swelling of the chorionic villi with
limbic system trophoblastic proliferation
§ Production of anti-NMDA antibodies by teratoma cells
• Clinical significance
o Pathologic finding: Inflammatory limbic encephalitis
o One of top differentials for bleeding in the first half of
o Clinical manifestations: psychosis, seizures, coma
pregnancy (together with abortion and ectopic)
o Precursor to persistent molar disease (invasive mole) and
gestational choriocarcinoma (complete mole)
• Types: Complete, Partial, Invasive MYOEPITHELIAL CELLS
• Pathogenesis • General rules:
o Complete: Chromosome duplication of paternal chromosomes o Myoepithelial cells are PRESENT in BENIGN lesions and in situ
Diploid karyotype → (46XX) carcinomas (In in situ carcinomas, myoepithelial cells are
o Partial: Dispermy and a haploid ovum → Triploid karyotype present in the duct where it is contained)
(69XXX or 69XXY) o Myoepithelial cells are ABSENT in INVASIVE carcinomas
PARTIAL
COMPLETE MOLE
MOLE CLINICAL MANIFESTATIONS OF BREAST DISEASE
• 69 XXX Pain • Usually benign
Karyotype • 46 XX
• 69 XXY Inflammation • Usually infectious, or inflammatory CA
CLINICAL MANIFESTATIONS Palpable
Diagnosis • Missed abortion • Molar gestation • Cysts, fibroadenomas, carcinomas
masses
Uterine size • Smaller for dates • Larger for dates Nipple • Suspect cancer, if spontaneous, unilateral &
Theca-Lutein cysts • Rare • Uncommon discharge bloody
Initial hCG levels • <100,000 mIU/mL • >100,000 mIU/mL
Medical
complications*
• Rare • Uncommon MAMMOGRAPHIC FINDINGS IN BREAST DISEASE
Rate of subsequent Benign • Rounded densities
• 1-5% of cases • 15-20% of cases features • Large, regular, few, non-clustered calcifications
GTN**
PATHOLOGY Malignant • Irregular densities
Embryo-Fetus • Often present • Absent Features • Small, irregular, numerous clustered calcifications
Amnion, Fetal
• Often present • Absent
erythrocytes BENIGN MIMICS OF BREAST CANCER
Villous edema • Focal • Widespread DISEASE -
Trophoblastic PATHO-
• Slight to severe • Marked HISTORY HISTOLOGY
proliferation PHYSIOLOGY
CLUES
Trophoblastic Infection with
• Mild • Marked ACUTE
atypia pyogenic • Acute suppurative
* - Anemia, hyperthyroidism, hyperemesis gravidarum, preeclampsia, and MASTITIS
organisms (S. inflammation
infection Post-partum
aureus)
** - Gestational trophoblastic neoplasia DISEASE -
Reference: Cunningham et al. Williams Obstetrics, 24th ed. 2014 PATHO-
INVASIVE MOLE HISTORY HISTOLOGY
PHYSIOLOGY
• Infiltrative molar lesion that penetrates the uterine wall CLUES
• Clinical presentation: Vaginal bleeding, Uterine enlargement • Dilated ducts filled
Accumulation of with lipid-laden
and possible rupture
DUCT ECTASIA secretions with macrophages
possible rupture • Rupture: Chronic
GESTATIONAL CHORIOCARCINOMA
inflammation, fibrosis
• Malignant neoplasm of trophoblastic cells derived from a • Acute: Hemorrhagic
previous normal or abnormal pregnancy Action of blood
FAT NECROSIS fat necrosis
• Behavior: Rapidly invasive, widely metastasizing, BUT and tissue lipase
Trauma/Surgery • Chronic: Calcifications,
responsive to chemotherapy of fat
Fibrosis
o Ovarian choriocarcinomas: Generally unresponsive to LYMPHOCYTIC • Lymphocytic infiltrate
chemotherapy due to absence of tumoral paternal antigens MASTOPATHY Autoimmune • Dense collagenous
• Both invasive mole and gestational choriocarcinoma demonstrate
DM Type 1, damage to ducts stroma
infiltrative growth, but invasive mole forms chorionic villi, while Autoimmune and lobules • Duct and lobule
gestational choriocarcinoma does not. thyroid disease atrophy
• Gestational choriocarcinomas contain paternal antigens that the immune These are inflammatory disorders that can mimic a malignant process.
system recognizes as foreign. Therefore, the immune system helps eliminate Acute mastitis can present with an inflamed breast, and in these cases, an
these tumor cells, which contributes to their susceptibility to important differential would be inflammatory carcinoma. Duct ectasia,
chemotherapeutic agents. Ovarian choriocarcinomas are exclusively fat necrosis, and lymphocytic mastopathy may mimic cancer because of
composed of maternal antigens, and so they escape immune surveillance. the fibrosis that can present as a palpable mass. There are clues in the
Dr. Elomina
history that can raise suspicion of these diseases.
Dr. Elomina
22. BREAST
• Functional anatomy and • Benign mimics of breast cancer EPITHELIAL LESIONS AND TUMORS
histology • Epithelial lesions and tumors
• Clinical manifestations of breast • Fibroepithelial tumors
EPITHELIAL LESIONS
disease • Other tumors • Divided into 4 categories with respective risks of developing
• Mammographic findings in • Diseases of the male breast invasive carcinoma
breast disease ALR
CATEGORY RR*
FUNCTIONAL ANATOMY AND HISTOLOGY (%)**
Non-proliferative breast changes 1 3
FUNCTIONAL ANATOMY Proliferative breast disease without
FEATURES LESIONS 1.5-2.0 5-7
atypia
STRUCTURAL UNIT
Proliferative breast disease with atypia 4-5 13-17
Large duct • Large duct papilloma Carcinoma in situ 8-10 25-30
Terminal Duct-Lobular • Epithelial hyperplasia * - Relative risk: Risk compared to women without any risk factors
Unit (TDLU) • DCIS, invasive carcinoma ** - Absolute lifetime risk: Percentage of patients expected to develop invasive
STROMA carcinoma if untreated
Interlobular • Angiosarcoma, Hemangioma Table 23.1. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020
Intralobular • Fibroadenoma, Phyllodes tumor

NON-PROLIFERATIVE BREAST CHANGES
FIBROCYSTIC CHANGES
BASIC HISTOLOGY
• Cystic change
• Nipple and superficial portions of major ducts o Dilated lobules filled with brown or blue fluid (blue-dome
o Keratinizing stratified squamous epithelium cysts) and calcifications
• Ductal system and TDLU o Lining: flattened atrophic or (+) apocrine metaplasia
o 2 Types of epithelial cells: INNER LUMINAL cells, OUTER • Fibrosis: Cyst rupture → chronic inflammation → fibrosis
MYOEPITHELIAL cells • Adenosis: Increase in number of acini per lobule
PAPILLARY NEOPLASMS
• Range from benign to malignant entities
o Classification depends on presence of myoepithelial cells
• Malignant entities in themselves are associated with favorable
prognosis i.e. Encapsulated papillary carcinoma, Solid papillary
carcinoma
• Invasive papillary carcinoma is very rare (Always rule out
metastasis)
FIBROCYSTIC CHANGES
(Figure number unrecalled). Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 10th ed. 2011. INTRADUCTAL PAPILLOMA
PROLIFERATIVE BREAST DISEASE WITHOUT ATYPIA • Papillary fronds with fibrovascular cores growing in a dilated
duct
• Increase in both luminal and myoepithelial
cells in a duct • Epithelial hyperplasia and apocrine metaplasia frequent
Epithelial
hyperplasia • Irregular lumens in periphery • Clinically, bloody nipple discharge if stalk goes infarction
• Important differential: DCIS
• Clinical, radiologic, and histologic mimic of BREAST CARCINOMA
invasive cancer • Most common and deadly malignancy of women globally
Sclerosing • Risk factors:
• Increase in acini with central stromal
adenosis o Gender (Female)
fibrosis
• Compression of central acini → solid cords o Age (Advancing age)
• Combination of epithelial hyperplasia, o Lifetime exposure to estrogen (Nulliparity, Early menarche,
sclerosing adenosis, and papilloma Late menopause, Primiparity at > 35 y.o.)
Complex • Radial sclerosing lesion (Radial scar) o Genetic inheritance (BRCA1/2, Strong family history)
sclerosing o Radiologic, gross, and histologic mimic of o Environmental and Lifestyle factors (Radiation, High alcohol
lesion invasive cancer consumption, Physical inactivity)
o Central nidus of entrapped glands in a • Important genes (most important BRCA1, BRCA2): most
hyalinized stroma common genes implicated for single gene familial breast cancers
(80-90%)
PROLIFERATIVE BREAST DISEASE WITH ATYPIA • More associated with ovarian malignancy (BRCA1 >
BRCA1 BRCA2)
Atypical • = DICS – full duct involvement (Ch17) • May be poorly differentiated, triple-negative breast
ductal • Has monomorphic cells cancers (TNBC)
hyperplasia • Sometimes has cribriform appearance BRCA2 • Associated with male breast cancer
• = LCIS, but <50% involvement of acini in a (Ch13) • May be ER-positive
Atypical lobule • Receptor tyrosine kinase that promotes cell
HER2 /
lobular • Has monomorphic, LOOSELY COHESIVE proliferation
ERBB2
hyperplasia CELLS (similar with LCIS, ILC) • Amplification → overexpression
(Ch17)
• Associated with poorer prognosis
• Loss of E-cadherin → discohesive, loos cells
CDH1 • Encodes for E-cadherin
Your ADH and ALH are basically your “hilaw” na DCIS and LCIS, (Ch16) • Loss of expression is seen in ALH, LCIS, ILC
respectively.
Dr. Elomina MOLECULAR TYPES OF BREAST CARCINOMA
• Based on estrogen and progesterone receptors (ER/PR), and
HER2 status
• Clinical significance
o Determines amenability to specific therapies
o Prognostic staging
MOLECULAR TYPES OF BREAST CARCINOMA
LUMINAL TRIPLE NEGATIVE BREAST CANCER
HER2-ENRICHED
A B (TNBC)
• ER(+) • HER2(+) • ER(-)
Phenotype
• HER2(-) • ER, PR (+/-) • HER2(-)
Frequency • 40-55% • ~10% • ~20% • ~15%
Proliferation index
• Low • High • Usually High
(Ki-67)
• HER-2 targeted therapy • Chemotherapy, Immunotherapy
Treatment • Hormonal therapies (Tamoxifen)
(Trastuzumab) (PD-L1 inhibitors)
• Clinicopathologic correlates: CARCINOMA IN SITU
o HER2-enriched and TNBCs are common in the younger age TYPE MORPHOLOGY/PRESENTATION
group, while incidence of luminal cancers increases with age • Malignant epithelial cells within ducts
o Luminal cancers are usually well- to moderately (myoepithelial layer is present)
differentiated with Luminal A cancers responding better to • Can present with a mass (periductal fibrosis)
therapy than Luminal B Ductal • Can be detected mammographically as calcifications
o HER2-enriched and TNBCs are often poorly differentiated carcinoma • Histology:
with aggressive biological behavior in situ o Architectural patterns (Solid, cribriform,
o Some special types of invasive breast carcinoma fall under a (DCIS) papillary, micropapillary)
specific molecular type, and therefore it dictates the biologic o Mild to severe nuclear atypia
behavior of a particular special type o Comedo DCIS: high-grade nuclei, central
necrosis
MOLECULAR • Malignant epithelial cells reaching nipple skin
SPECIAL HISTOLOGIC TYPES without basement membrane violation
TYPE Paget
• Clinically, eczematous nipple lesion
Luminal • Lobular, Mucinous, Tubular, Papillary disease of
• Palpable, poorly differentiated mass in 50-60% cases
HER2 • Apocrine, Micropapillary the nipple
o Most patients without a mass have an underlying
enriched DCIS
• Invasive breast carcinoma (no special type) Lobular • Discohesive growth of malignant cells due to E-
TNBC
with medullary pattern, Metaplastic carcinoma cadherin loss (same with ALH, ILC)
in situ • Cells are monomorphic with mild atypia
(LCIS) • Almost always an incidental finding
Important differential diagnoses for Paget disease include: 1. Melanoma FIBROADENOMA (FA)
and 2. Squamous cell carcinoma. Immunohistochemical studies may be
needed for cases without adequate history and PE. • Proliferation of both epithelial and stromal elements
Dr. Elomina o Epithelial: may be surrounded by stroma (pericanalicular) or
SUMMARY OF CARCINOMA IN SITU be compressed by stroma forming slit-like spaces
DCIS LCIS (intracanalicular); may be atrophic with age
Basement membrane • Intact o Stromal: myxoid (bluish violet); resembles normal
Disruption of lobules • Yes • No intralobular stroma
Architectural variation • Yes • No • Frequently multiple, and bilateral
• Usually absent, Clinical • Occur in younger women (20s and 30s)
Necrosis and • Present, thus features • Hormonally responsive: grown in size during
thus (-)
secretory activity (+)calcifications pregnancy, regresses after menopause
calcifications
Involvement of the • No (Pagetoid Histology in • Stroma: densely hyalinized
• Yes (Paget) older women • Epithelium: atrophic
nipple skin spread)
Bilaterality • 10-20% • 20-40%
Hormonal status • Variable • ER, PR(+),HER2(-) PHYLLODES TUMOR (PT)
• Stromal component more predominant than epithelial
INVASIVE (INFILTRATING) CARCINOMA component → leaf-like stromal projections
TYPE MORPHOLOGY/PRESENTATION • Phyllodes tumor is distinguished from fibroadenoma on the
• Most common type (2/3 of breast CA) basis of: high cellularity, higher mitotic rate, nuclear
• Hard mass due to prominent desmoplasia pleomorphism, stromal overgrowth, infiltrative borders
Invasive breast • Parameter of Nottingham histologic
• Occur in older women (40s and 50s)
CA, no special grading system (1-3) (increasing grade)
• Mostly benign (low-grade): occasionally recur
type (IBC-NST) o Decreasing tubule formation
locally but do not metastasize
o Increasing nuclear pleomorphism Clinical
• Malignant (high-grade): usually recur, can spread
o Increasing mitotic figures features
hematogenously (only stromal component)
• Soft mass, due to minimal desmoplasia
• Lymphatic spread is rare regardless of grade:
• Well-circumscribed
axillary node dissection is contraindicated
• Better prognosis
Medullary CA • Histology:
o Sheets of large cells with pleomorphic
nuclei & prominent nucleoli (high-grade)
o Presence of lymphoplasmacytic infiltrate
o Non-infiltrative (pushing) borders
• Rarely present with a mass due little
Invasive
desmoplasia
lobular
• Indian filing of tumor cells
carcinoma
• Dyscohesive cells due to loss of E-cadherin FIBROADENOMA (L); PHYLLODES TUMOR (R)
(ILC)
• Usually have mild atypia Figure 36.30A. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1448.; Figure 36.34A.
Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1450.
TYPE MORPHOLOGY/PRESENTATION
SUMMARY OF FIBROEPITHELIAL TUMORS
• Well-circumscribed and soft
Mucinous CA • Has small islands of cells in pools of mucin FEATURE FA PT
• Usually have mild atypia CLINICAL/GROSS
• Has squamous & mesenchymal-looking Age • Younger • Older
Metaplastic CA Size of lesion • Smaller • Larger
elements
• Reserved as a clinical diagnosis • Well- • Well-circumscribed
Borders
• Important differential in inflamed breast circumscribed to infiltrative
Inflammatory (erythematous, edematous) MICROSCOPIC
CA • Peau d’ orange: thickened skin due to • Epithelial =
Proliferation • Stromal > Epithelial
edematous breast, secondary to dermal Stromal
lymphatic space plugging Stromal
• Lower • Higher
cellularity
PROGNOSTIC FACTORS IN BREAST CARCINOMA Atypia • None to mild • Variable
• Anatomic Stage: 1. Tumor size (cm) (T), 2. Lymph node Mitosis • Rare to absent • Variable
metastasis (N), 3. Distant metastasis (M)
o Lymph node metastasis: Most important prognostic factor OTHER TUMORS
in the absence of distant metastasis TYPE EXAMPLES
• Prognostic stage: Integration of molecular tumor • Benign: Myofibroblastomas, Lipomas,
characteristics with anatomic stage Fibromatosis
o Histologic Grade Mesenchymal
• Malignant: Angiosarcoma (sporadic or
o ER, PR, and HER2 status post-radiation)
o Gene expression profiling • Most common: B-cell NHLs
• Locally advanced disease (poor) Hematolymphoid
• T-cell implant-associated lymphomas (Rare)
• Lymphovascular invasion (poor) Cutaneous • Similar to tumors found in non-breast skin
• Inflammatory carcinoma (poor) Metastasis • Melanomas, Ovary
• Response to neoadjuvant chemotherapy
o Tumor regression (better) vs. absence of tumor regression (worse)
DISEASES OF THE MALE BREAST
o TNBCs and HER2-enriched cancers may respond better to
chemotherapy GYNECOMASTIA
o Luminal cancers rarely respond to chemotherapy, but are • Clinically, unilateral/bilateral areolar swelling
responsive to endocrine therapy • Histology
o Epithelial hyperplasia of duct lining
FIBROEPITHELIAL TUMORS o Dense collagenous stroma
o Rare lobule formation
• Fibroadenoma and Phyllodes tumor
o Fibroadenoma: Most common benign tumor of the female
breast MALE BREAST CANCER
• Cytogenetic origin: Intralobular stromal cells • Aside from Klinefelter syndrome, risk factors are similar to
• Common genetic mutation: Somatic mutations in MED12 (X female breast cancer
Chromosome) • Clinically, palpable subareolar mass and/or nipple discharge
• Usually luminal HYPOPITUITARISM
• High-stage at diagnosis: • Occurs at approximately 75% parenchymal loss
o Locally advanced (less adipose tissue) • Most cases are destructive processes directly involving the
o Axillary LN and distant metastasis are common anterior pituitary
o Hypopituitarism + evidence of posterior pituitary dysfunction:
23. ENDOCRINE SYSTEM almost always hypothalamic in origin
• Pituitary diseases • Diseases of the Endocrine pancreas • Loss of hormonal function proceeds in an ordered manner
• Thyroid diseases • Adrenal gland diseases o GH and gonadotropin (FSH and LH) (lost first) → TSH and
• Parathyroid • Multiple Endocrine Neoplasia (MEN) ACTH → prolactin (lost last)
diseases syndromes • Causes:
o Tumors/mass o Genetic defects
lesions o Ischemic pituitary necrosis
ENDOCRINE PATHOLOGY o TBI/SAH and Sheehan syndrome
https://qrs.ly/9ncmfuy o Pituitary (postpartum)
surgery/radiation o Empty sella syndrome
o Pituitary apoplexy o Inflammatory/infection
PITUITARY DISEASES
CLINICAL MANIFESTATIONS OF PITUITARY DISEASE CLINICAL MANIFESTATIONS OF HYPOPITUITARISM
DEFICIENT
• Hyperpituitarism – Hormone excess HORMONE
• Hypopituitarism – Hormone deficiency GH • Growth failure in children (pituitary dwarfism)
• Mass effect • Amenorrhea, infertility (females)
o Sellar abnormalities, Visual field defects, Increased ICP FSH and LH • Decreased libido, impotence, loss of pubic and
o Pituitary apoplexy axillary hair (males)
• Because of the location of pituitary gland, its enlargement can impinge TSH • Hypothyroidism
on the optic chiasm leading to visual field defects, and it can cause ACTH • Hypoadrenalism
increase in ICP because it’s in the very rigid cranial vault. Prolactin • Failure of postpartum lactation
• Pituitary apoplexy is a sudden onset of neurologic impairment because MSH • Pallor
of a rapidly enlarging adenoma (because of hemorrhage).
Dr. Elomina In primary empty sella syndrome, there is a sellar diaphragm defect where the
arachnoid and CSF herniate into the sella turcica and impinge the pituitary. In
HYPERPITUITARISM secondary empty sella syndrome, either the contents of the sella are removed
iatrogenically or by a pathologic process e.g., infarction.
• Most common cause of hyperpituitarism: functional anterior Dr. Elomina
pituitary adenoma
• 1 cm: limit size to determine micro/macroadenomas POSTERIOR PITUITARY SYNDROMES
• More commonly diagnosed early (due to endocrine effects) • Causes
• Most common: Prolactin cell adenoma (30%) o CNS disease: Head trauma, tumors, inflammatory disorders of
• Second most common: Somatotroph adenoma the hypothalamus and pituitary, and surgical complications
o Renal disorders: Obstruction, vascular disorders, ischemia
CLINICAL MANIFESTATIONS OF HYPERPITUITARISM o Neoplasms: Small cell lung carcinoma
CELL TYPE HORMONE CLINICAL MANIFESTATIONS o Drugs
• Galactorrhea and amenorrhea
Lactotroph • Prolactin (females) SYNDROME PATHOLOGY CAUSES
• Sexual dysfunction, infertility Central Diabetes
• Gigantism (children) • ADH deficiency • CNS disorders
Somatotroph • GH Insipidus
• Acromegaly (adults) Nephrogenic • Unresponsiveness of • Drugs
• Cushing syndrome Diabetes Insipidus renal tubules to ADH • Renal disorders
Corticotroph • ACTH
• Nelson syndrome* • SCLC
Thyrotroph • TSH • Hyperthyroidism SIADH • ADH excess
• CNS disorders
• Hypogonadism
Gonadotroph • FSH, LH • Mass effect
CRANIOPHARYNGIOMA
• Hypopituitarism
*-development of large, destructive pituitary adenomas post-adrenalectomy • Hypothalamic suprasellar tumor
for treatment of Cushing syndrome • Origin: Vestigial remnants of Rathke pouch
• Bimodal age incidence: 5-15 years and 65 years
PITUITARY ADENOMA • Clinical manifestations: Mass effect and Hypopituitarism
• Most common type of pituitary adenoma (compression atrophy of normal pituitary parenchyma)
Nonfunctioning • Prognosis: Generally favorable
• Usually macroadenomas at the time of
adenomas o Transformation to Squamous cell carcinoma is rare and
diagnosis
Prolactin- usually happens after irradiation
• Most common type of functional TYPE and
secreting MORPHOLOGY
pituitary adenoma MUTATION
adenoma
• Stratified squamous epithelium with
Nonfunctioning pituitary adenomas are usually macroadenomas at peripheral palisading embedded in a
the time of diagnosis because clinical features are not apparent until Adamantinomatous
spongy reticulum
tumor mass effects occur. • CTNNB1 (β-
Dr. Rubio • Compact, lamellar “wet” keratin
catenin)
MORPHOLOGY • Dystrophic calcification
• Uniform, polygonal cells in sheets and cords • Cyst formation with “machine oil” fluid
• Sparse reticulin network (vs. normal pituitary parenchyma) Papillary • Solid sheets and papillae lined by well-
• Immunohistochemistry required to determine specific type • BRAFV600E differentiated squamous epithelium
Adamantinomatous craniopharyngioma looks like Ameloblastoma, and
PITUITARY CARCINOMAS Papillary craniopharyngioma looks like Squamous papilloma.
Dr. Elomina
• Atypical adenomas + Metastases (CSF/systemic)
• Usually functional: ACTH (42%), PRL (33%)
In pituitary carcinomas, the requirement for diagnosis is metastasis.
Dr. Elomina
THYROID GLAND FORMS OF HYPOTHYROIDISM

CRETINISM MYXEDEMA
HYPERTHYROIDISM
• Infancy to early • Late childhood to
Age
childhood adult
↑ Thyroid
hormones • Mental retardation • Slowing of physical
• Coarse facial and mental activity
features • Overweight
Secondary
Clinical • Protruding tongue • Hypercholesterolemia
Primary (Thyroid
pathology,
(Extrathyroid findings • Umbilical hernia • Nonpitting edema
pathology,
↓TSH)
↑TSH) • Coarse facial features
• Macroglossia
• Deepening of voice
Diffuse Toxic
Hyperplasia
Hyperfunctional
multinodular
Hyperfunctional
TSH-secreting
pituitary
• Accumulation of
(Graves disease) thyroid adenoma
85%
Goiter adenoma matrix substances
Notable (GAGs and hyaluronic
DEFINITION OF TERMS histologic - acid) in skin,
• Thyrotoxicosis: Hypermetabolic state caused by ↑ thyroid features subcutaneous tissue,
hormone levels in the blood and a number of
• Hyperthyroidism: Thyrotoxicosis secondary to thyroid gland visceral sites
hyperfunction
COMMON CLINICAL MANIFESTATIONS THYROIDITIS
• Increased basal metabolic rate (Hypermetabolic state) • Inflammatory diseases of the thyroid gland
o Warm, flushed skin, Heat intolerance, Hyperhidrosis, Weight o Hashimoto thyroiditis (Struma lymphomatosa)
loss despite increased appetite o Subacute lymphocytic (Painless) thyroiditis (Postpartum
• Cardiac manifestations: One of the earliest and most consistent thyroiditis)
features o Granulomatous (De Quervain thyroiditis, Painful)
o Tachycardia, Arrhythmia (atrial fibrillation), Heart failure o Riedel thyroiditis
• Sympathetic nervous system overactivity § Extensive fibrosis of the thyroid and contiguous neck
o Tremors, Hyperactivity, Insomnia, Diarrhea structures (May simulate a malignant process)
• Thyroid hormone levels vary in the course of the disease
HYPOTHYROIDISM
o Thyrotoxicosis (due to release of pre-formed thyroid
hormones) → Hypothyroidism
↓ Thyroid • Common clinical manifestation: Thyroid enlargement
hormones
o Painful: Granulomatous thyroiditis
o Painless: Hashimoto and Subacute lymphocytic
• Complications
Primary (Thyroid Secondary o Persistent hypothyroidism: Hashimoto and some cases of
pathology, ↑TSH)
More common
(Extrathyroid
pathology, ↓TSH)
subacute lymphocytic thyroiditis
o Development of autoimmune diseases: Hashimoto
o Development of neoplasms (Marginal zone B-cell lymphoma,
Papillary thyroid carcinoma): Hashimoto
Congenital
Autoimmune Iatrogenic Hypothalamic
(Iodine
(Hashimoto (Surgery and and pituitary
deficiency*,
thyroiditis)** Radiation) failure
Genetic)
* Most common cause of congenital hypothyroidism worldwide

** Most common cause of hypothyroidism in iodine-sufficient areas
COMMON THYROIDITIDES
HASHIMOTO SUBACUTE LYMPHOCYTIC GRANULOMATOUS
• T-cell mediated injury • Autoantibodies against thyroid
• Antigen-mediated immune damage to
Pathology • Autoantibodies against thyroglobulin peroxidase
follicular cells (by cytotoxic T cells)
and thyroid peroxidase • Family history of autoimmunity
• Most common cause of hypothyroidism • May occur in the post-partum period
Remarks • History of URTI prior to thyroiditis
in iodine-sufficient areas (only in 5% of cases)
HASHIMOTO SUBACUTE LYMPHOCYTIC GRANULOMATOUS
• Hürthle cell changes • Neutrophils (early) → lymphocytic
• Presence of lymphocytic infiltration w/ • Presence of lymphocytic infiltration w/ infiltration (late)
Histology
germinal centers germinal centers • Granulomas (w/ multinucleated
• Presence of fibrosis (intracapsular only) giant cells)
GRAVES DISEASE • Ophthmalopathy: Deposition of GAGs,

• Most common cause of endogenous hyperthyroidism lymphocytic infiltration → Fibrosis (Orbit
GRAVES DISEASE and EOMs)
1. Hyperthyroidism • Dermopathy (Pretibial myxedema): Dermal
Triad 2. Ophthalmopathy → Exophthalmos thickening (due to deposition of GAGs and
3. Dermopathy lymphocytic infiltration)
• Type II Hypersensitivity You cannot see ophthalmopathy and dermopathy in other causes of
• Autoantibodies against TSH receptor thyrotoxicosis, which makes them good clues to clinch the diagnosis of
Graves.
1. TSI (Thyroid stimulating Ig): mimics TSH
Pathology Dr. Elomina
actions (most common)
2. TSH receptor blocking Ig (TSB): results in GOITERS
hypothyroidism • Thyroid enlargement, caused by impaired thyroid hormone
• Thyroid gland: Diffuse hypertrophy and synthesis
hyperplasia o Clinical presentation: symptoms referable to mass effect
Morphology o Scalloped colloid • Most common cause: Iodine deficiency
o Interstitial lymphoid infiltrates (T cells > B • Multinodular goiters can produce very large glands that can be
cells) with germinal centers mistaken for malignancy
• Incidence of malignancy is low
Impaired synthesis of thyroid hormones MORPHOLOGY
Most common cause: Iodine deficiency TYPE HISTOLOGY
• Papillary fronds with fibrovascular cores
Papillary
• Optically clear nuclei (Orphan Annie nuclei)
Compensatory increase in TSH (RET/PTC,
• Calcifications (Psammoma bodies)
BRAF)
• Propensity for lymphatic metastasis
Enlargement of the thyroid gland Follicular • Cytologically similar to normal follicular cells
(trophic effects of TSH on thyroid) (RAS, PAX8- invading thyroid capsule and vasculature
PPAR- • Diffuse Hürthle change (Oncocytic type)
1. Euthyroid state (compensated) gamma) • Propensity for hematogenous metastasis
2. Hypothyroid state (decompensated) • Pleomorphic giant cells (osteoclast-like
Anaplastic
multinucleated giant cells)
PATHOPHYSIOLOGY OF GOITER (TP53)
• Spindle-shaped cells (sarcomatous appearance)
PHASES OF GOITER • Sheets of polygonal cells in an amyloid stroma
Medullary
(stains w/ Congo red)
HYPERPLASTIC COLLOID INVOLUTION (RET)
• Associated with MEN2A, MEN2B
• Sufficient iodine intake
Inciting • Trophic effects of
• ↓ Thyroid hormone
event TSH on gland
demand
PARATHYROID DISEASES
• Diffuse, symmetrical • Brown, glassy, HYPERPARATHYROIDISM
Gross
enlargement translucent cut surface • Hyperfunctioning of the parathyroid gland
Follicular Primary • Adenoma (most common) > Hyperplasia >
• Columnar • Flattened and cuboidal
epithelium Carcinoma
Colloid • Less abundant • Abundant • As compensation to chronic hypocalcemia
In hyperplastic phase, because there is decrease in thyroid hormone levels, TSH Secondary • Renal failure (most common), steatorrhea,
levels increase, and it causes the gland to undergo hyperplasia. In colloid Vitamin D deficiency, inadequate dietary Ca2+
involution phase, sufficient intake of iodine blocks release of thyroglobulin, • Persistent PTH secretion after correction of
Tertiary
causing it to be stored within the follicle, consequently distending it. hypocalcemia (post-renal transplant)
Dr. Elomina
TYPES
CLINICAL MANIFESTATIONS OF PRIMARY
GOITER MORPHOLOGY/PRESENTATION HYPERPARATHYROIDISM
Diffuse • More common in areas of iodine SYSTEM FINDINGS
nontoxic insufficiency and intake of goitrogens Renal • Nephrolithiasis, nephrocalcinosis
(simple) (Cassava; contains thiocyanate)
• Constipation, nausea, peptic ulcers,
• Irregular enlargement of the thyroid Gastrointestinal
pancreatitis, gallstones
• Resulted from repeated hyperplastic &
Multinodular CNS • Depression, lethargy, seizures
colloid phases → nodularity
Neuromuscular • Weakness, fatigue
• Unencapsulated nodular architecture
Cardiac • Aortic and/or Mitral valve calcifications
Toxic • Autonomous nodule in a long-standing
multinodular multinodular goiter QUICK SHEET:
(Plummer • Clinically presents w/ hyperthyroidism CLINICAL PANIFESTATIONS OF SYMPTOMATIC PRIMARY
syndrome) • Has no ophthalmopathy, dermopathy HYPERPARATHYROIDISM
“Stones, Thrones, Bones, Groans, Psychiatric Overtones”
Stones – Kidney Stones
NEOPLASMS Thrones – polyuria (and polydipsia)
• Clinically: Solitary thyroid nodule (STN) Bones – Bone Pain
• <1% of STNs are malignant Groans – weakness, constipation, abdominal / flank pain
Psychiatric overtones – confusion, hallucinations, irritability, etc.
• Solitary nodule
First Aid for the USMLE Step 1 2020
Clinical factors • Young, male patient
favoring malignancy • History of radiation therapy Skeletal system changes
• Non-functional nodule “cold nodules” Von • Increased osteoclast activity
Recklinghausen • Peritrabecular fibrosis
FOLLICULAR ADENOMA bone disease • Cystic brown tumor formation
• Shares morphologic features with adenomatous nodule and • Microfractures w/ hemorrhages → repair
Osteoporosis
follicular carcinomas via brown fibrous ingrowth “brown tumor”
• Adenomas are generally not precursors of carcinomas, but they • Osteoclast dissecting through bony
Dissecting
share the same genetic abnormalities trabeculae of cancellous bone →
Osteitis
peritrabecular fibrosis
• Usually nonfunctional, but some present with thyrotoxicosis
• Morphology: Looks like “normal” follicular epithelial cells SECONDARY HYPERPARATHYROIDISM
o Tumor is enclosed by an intact, well-formed capsule • Bone changes usually milder than primary (renal
o Absent capsule: Adenomatous nodule osteodystrophy)
o Capsular and vascular invasion: Follicular carcinoma • Metastatic calcification in blood vessels → ischemic injury
(calciphylaxis)
CARCINOMA
PARATHYROID NEOPLASMS
• Most common: Papillary > Follicular
• Adenomas and carcinomas can be grossly (well-encapsulated)
• Second most common: Follicular and cytologically similar (uniform, polygonal cells)
• Most arise from thyroid follicular epithelium, except Medullary o Metastases and local invasion: reliable criteria for
(Parafollicular C cells) malignancy
• Medullary thyroid CA (MTC): Associated with MEN2A, MEN2B
o Clinically present with paraneoplastic syndromes (VIP,
ACTH) and high levels of Calcitonin (w/o hypocalcemia)
HYPOPARATHYROIDISM
• Prognosis depends on type: • Causes
• Papillary thyroid CA o Surgically induced (Most common)
Favorable prognosis o Autoimmune
• Minimally invasive follicular CA
• Widely invasive follicular CA o Single gene defects
Unfavorable prognosis • Medullary thyroid CA o Congenital absence (part of DiGeorge syndrome)
• Anaplastic thyroid CA o Pseudohypoparathyroidism: end-organ resistance to PTH
(genetic defects)
§ Normal PTH levels with symptoms of PTH deficiency
CLINICAL MANIFESTATIONS OF HYPOPARATHYROIDISM Diagnosis of PanNETs heavily relies on the symptomatology that can be
SYSTEM FINDINGS explained by the hormones that these tumors elaborate.
Dr. Elomina
• Tetany (neuromuscular irritability)
Neuromuscular COMMON PanNETs
Chvostek and Trousseau sign
INSULINOMA GASTRINOMA
• Emotional instability, anxiety and
• Hypergastrinemia
Mental depression, confused state, hallucinations, • Hyperinsulinism
• Zollinger-Ellison
frank psychosis • Whipple Triad
syndrome
• Calcifications of basal ganglia, Parkinsonian- 1. Hypoglycemia
1. Pancreatic islet cell
CNS like movement disorders, Increased ICP with (<50 mg/dL)
Clinical tumor
papilledema 2. Neuroglycopenic
syndrome 2. Hypersecretion of
Ocular • Calcification of lens, cataract formation symptoms
gastric acid
Cardiac • Conduction defect (QT prolongation) 3. Relief upon parenteral
3. Severe peptic
glucose
ulceration (may occur
administration
DISEASES OF THE ENDOCRINE PANCREAS in jejunum)
Location • Pancreas • Gastrinoma triangle
DIABETES MELLITUS Biologic
• Group of metabolic disorders sharing the common feature of • Usually benign • Usually malignant
behavior
hyperglycemia • May recapitulate normal pancreatic islets
Histology • Even malignant tumors can be encapsulated
• Amyloid deposition (in insulinomas)
OTHER RARE PanNETs
TUMOR HORMONE PRESENTATION
α-cell • Mild DM, necrolytic migratory
• Glucagon
tumors erythema, anemia
δ-cell • DM, cholelithiasis,
• Somatostatin
tumors steatorrhea, hypochlorhydria
• Vasoactive • WDHA syndrome: Watery
VIPoma intestinal diarrhea, hypokalemia,
peptide achlorhydria
Pancreatic-
polypeptide • Pancreatic • Mass lesions
secreting polypeptide • No endocrine effects
tumors
CLINICAL MANIFESTATIONS OF DIABETES MELLITUS • Carcinoid syndrome: Facial
Figure 24.33. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 Pancreatic
• Serotonin flushing, diarrhea,
carcinoid
bronchoconstriction
PATHOPHYSIOLOGY
OF DIABETES MELLITUS
ADRENAL GLAND
https://qrs.ly/flcmfw9
HYPERADRENALISM
TYPES • Glucocorticoids: Cushing syndrome
TYPE I DM TYPE II DM • Mineralocorticoids: Hyperaldosteronism
Insulin • Sex steroids: Androgenital/virilizing syndromes
• Absolute deficiency • Relative deficiency
Deficiency CUSHING SYNDROME
• Insulin resistance, • Most common cause overall: Exogenous steroids (“Iatrogenic”)
Pathogenesis • β-cell destruction
• β-cell dysfunction • Most common endogenous cause: ACTH-secreting pituitary
• Insulitis adenoma (Cushing disease)
Pathology (lymphocytic • Amyloid deposition
• Common clinical presentation: abdominal striae, obesity,
infiltration in islets)
dorsocervical fullness (buffalo hump), moon facies
IMPORTANT POINTS ON PATHOGENESIS OF TYPE 2 DM • Laboratory features: ↑ 24-hour urine free cortisol
• Triad: Genetic, environmental, and proinflammatory state (not o ACTH-independent: ↑ cortisol → ↓ ACTH
autoimmune) o ACTH-dependent: ↑ ACTH → ↑ cortisol
• Most important environmental factor: Central/visceral obesity § Pituitary (Cushing disease) or ectopic (SCLC)
→ ↑ Adipokines → IL-1 release and action on sites of insulin ACTH-INDEPENDENT ACTH-DEPENDENT
action → Insulin resistance • Neoplasm: Atrophic
adjacent parenchyma
COMPLICATIONS OF DIABETES MELLITUS
Adrenal and contralateral • Bilateral diffuse or
• Hypoglycemia (most common) morphology gland nodular hyperplasia
Acute
• Diabetic ketoacidosis (DKA) • Iatrogenic: Bilateral
complications
• Hyperosmotic hyperglycemic state (HHS) cortical atrophy
• Coronary heart disease (MI: most common Pituitary • Crooke-hyaline change: homogenous, paler
Macrovascular cause of death), Peripheral arterial disease, morphology cytoplasm of ACTH-secreting cells
disease Cerebrovascular disease
• Hallmark: accelerated atherosclerosis The adrenal morphology is explained by the trophic effect of ACTH on the
adrenal gland i.e., the gland undergoes hyperplasia under ACTH influence.
• Retinopathy, Nephropathy, Neuropathy
In ACTH-independent Cushing, ACTH is decreased because of negative
• Hallmark: diffuse BM thickening & leaky feedback on the pituitary, so both adrenals become atrophic because of the
capillaries loss of trophic effect of ACTH on the adrenals. In ACTH-dependent Cushing,
Microvascular
• Glomeruli: Nodular glomerulosclerosis both adrenals become hyperplastic because of ACTH influence.
disease
(Kimmelstiel-Wilson lesion) Dr. Elomina
• Tubular: Pyelonephritis, Necrotizing papillitis HYPERALDOSTERONISM

• Nerve: Glove & Stocking pattern (most common) • Intrinsic adrenocortical defect
Primary • Most common cause: bilateral
PANCREATIC NEUROENDOCRINE TUMORS (PanNETs) hyperaldosteronism idiopathic hyperaldosteronism
(Conn syndrome) • Neoplasm: Adrenal adenoma >
• Rare (2% of pancreatic tumors) Adrenocortical carcinoma
• Most common: Insulinomas • Decreased renal perfusion:
• If insulinoma, more probably benign (others: malignant) Secondary Nephrosclerosis, Renal artery stenosis,
• Unequivocal criteria for malignancy: metastases, vascular hyperaldosteronism Arterial hypovolemia
invasion, and local infiltration • Pregnancy: Estrogen-induced ↑ in renin
• Common clinical manifestations: Hypertension, Hypokalemia Hyper-
• Laboratory features: ↑ Plasma aldosterone pigmentation
o Primary: ↑ Aldosterone → ↓ Renin • AIA: Irregularly
o Secondary: ↑ Renin → ↑ Aldosterone Adrenocortical shrunken adrenals • Variable, depending
Morphology with lymphoid on ACTH deficiency
In primary hyperaldosteronism, you have an excess in aldosterone, which infiltrates
causes decreased plasma renin activity (because the RAAS system does ACTH • Negative • Positive
not need to be activated). In secondary hyperaldosteronism, for example stimulation test (no ↑ in cortisol) (↑ in cortisol)
renal stenosis, there is a constant state of renal hypoperfusion that fools
the kidneys that the body has decreased effective circulating volume. The Hyperpigmentation in Addison disease is secondary to the collateral
RAAS system is activated, hence the increased plasma renin activity. increase in MSH that accompanies the increase in ACTH in response to
Dr. Elomina low adrenal cortisol output. Recall the components of POMC!
ADRENOGENITAL SYNDROMES Dr. Elomina
• Part of Cushing disease ADRENAL NEOPLASMS

o Adrenal androgen production is dependent on ACTH ADRENOCORTICAL NEOPLASMS
• Adrenocortical neoplasms • Functional neoplasms cause hyperadrenalism
• Congenital adrenal hyperplasia o Hypercortisolism & hyperaldosteronism: seen in adenomas
CONGENITAL ADRENAL HYPERPLASIA o Virilization: seen in carcinomas
• Enzyme blocks in steroidogenesis → ↓ cortisol and ↑ androgens • Carcinomas predominate in children
→ ↑ ACTH → Adrenal hyperplasia ADENOMA CARCINOMA
• Most common: 21-hydroxylase deficiency (90%) • Large, poorly
o Classic salt-wasting type: Total deficiency demarcated with
• Well-circumscribed,
BIOCHEMICAL necrosis, hemorrhage,
CLINICAL MANIFESTATIONS Gross yellow (lipid-rich),
ABNORMALITY and cystic change
small masses
Glucocorticoid • Hypoglycemia • Small masses (can look
deficiency • Cardiovascular collapse like adenomas)
Mineralocorticoid • Salt-wasting HISTOLOGY
deficiency • Cardiovascular collapse • Eosinophilic to
• Well-differentiated
Androgen excess • Virilization vacuolated cytoplasm,
Cells cells to bizarre
ORGAN MORPHOLOGY reminiscent of normal
monstrous giant cells
adrenocortical cells
• Bilaterally enlarged, brown, w/
Adrenal thickened cortex • Minimal “endocrine • Moderate to markedly
Atypia
• Lipid-depleted cells atypia” anaplastic
Pituitary • Corticotroph hyperplasia Mitosis • Inconspicuous • Marked
Necrosis • Absent • Marked
The adrenals are depleted of their lipids because they are made into adrenal
androgens. The corticotroph hyperplasia is a response to the decrease in PHEOCHROMOCYTOMA
glucocorticoids. The corticotrophs in the pituitary feel like they need to work • Cytogenetic origin: chromaffin cells of medulla
extra to produce ACTH hoping to see an increase in cortisol. • Releases catecholamines
Dr. Elomina
• Morphology
o Zellballen (nests of cells surrounded by sustentacular cells)
ADRENOCORTICAL INSUFFICIENCY o Salt and pepper chromatin
(HYPOADRENALISM) o Metastasis: Only reliable criterion for malignancy
PRIMARY ACUTE ADRENOCORTICAL INSUFFICIENCY • Clinical manifestation: Hypertension (predominant)
• Settings • Triad: Diaphoresis, Headaches, Palpitations
o Crisis in patients with chronic adrenocortical insufficiency • Laboratory findings: ↑ Urinary excretion of free catecholamines
o Rapid withdrawal of steroids in patients maintained on and metabolites (vanillylmandelic acid (VMA) and
steroids metanephrines)
o Massive adrenal hemorrhage
QUICK SHEET:
§ Waterhouse-Friedrichsen syndrome: bilateral adrenal
PHEOCHROMOCYTOMA - “Rule of 10s”
hemorrhage as a complication of disseminated bacterial
• 10% are extra-adrenal
infection (N. meningitidis and other highly virulent organisms) • 10% are bilateral
• Acute adrenocortical insufficiency in patients with chronic adrenocortical • 10% are biologically malignant
insufficiency happens when the patient experiences an increased demand for • 10% are not associated with hypertension
glucocorticoids (e.g., sepsis), which when matched with decreased capability • Additional: 25% have germline genetic mutations
to produce steroids (because of the background chronic adrenocortical
insufficiency), can lead to cardiovascular collapse.
• Steroid therapy decreases ACTH and the adrenals become atrophic. MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES
Sudden withdrawal of steroids in these patients means losing their only • Group of inherited diseases resulting in proliferative lesions of
source of glucocorticoids, and they go in crisis. multiple endocrine tumors
Dr. Elomina
OTHER TYPES OF ADRENOCORTICAL INSUFFICIENCY o MEN1: Wermer syndrome
PRIMARY CHRONIC o MEN2A: Sipple syndrome
SECONDARY o MEN2B
(ADDISON DISEASE)
• Autoimmune • Pituitary and • Differences of MEN-associated tumors from sporadic
adrenalitis (AIA) hypothalamic failure counterparts
Etiology (Most common) • Chronic o Younger age of onset
• Infections glucocorticoid o Multiple endocrine organs involved at the same time
• Metastases therapy (synchronous) or at different times (metachronous)
Hormone • Mineralocorticoid • Glucocorticoid o Asymptomatic stage of hyperplasia precedes the tumor
deficiency • Glucocorticoid • Androgen o More aggressive and recurrent
MEN1 MEN2
Mutation • MEN1 • RET (MEN2A and MEN2B have distinct mutations)
• Pituitary: Most common: Prolactinomas • Common lesions
• Parathyroid: Most common: Primary o Pheochromocytoma
hyperparathyroidism Pancreas (PanNET) o Medullary thyroid carcinoma
Syndrome
o Most common: Pancreatic Polypeptide • MEN2A: Parathyroid hyperplasia
o Most common types that produce hypersecretory • MEN2B: Neuromas, Ganglioneuromas, Marfanoid
states: Insulinoma, Gastrinoma habitus
24. SKIN CLINICAL ASPECTS

• Definition of microscopic lesions • Clinical: ABCDE: Asymmetry, Irregular Borders, Variegated
• Disorders of pigmentation and melanocytes Color, Increasing Diameter, Evolution
• Epithelial Lesions (Benign, Adnexal, Premalignant, Malignant) • Diagnosis: Histopathology, Immunohistochemistry
• Inflammatory dermatoses o Melanocytic markers: S-100 (Neural crest cell marker), Melan
• Blistering diseases A and HMB-45 (Melanocytic markers)
• Skin infections • Treatment: Surgery (Wide excision) and Immunotherapy
o Immune checkpoint inhibitors (like in TNBCs)
DEFINITION OF MICROSCOPIC LESIONS
PROGNOSTIC FACTORS
Acanthosis • Diffuse, epidermal, hyperplasia
• Premature keratinization within cells • Tumor depth (Breslow thickness): Thinner is favorable
Dyskeratosis o Distance between superficial granular cell layer and deepest
below stratum granulosum
intradermal tumor involvement
Hypergranulosis • Hyperplasia of stratum granulosum
• Mitoses (Favorable: <1/mm2)
Hyperkeratosis • Thickening of the stratum corneum
• Evidence of tumor regression (Favorable: absence of
• Keratinization with retained nuclei in regression and ulceration)
Parakeratosis the stratum corneum
• Tumor infiltrating lymphocytes (TILs) (Favorable: brisk TILs)
• Normal in mucous membranes
• Gender
Spongiosis • Intercellular edema of the epidermis • Location (Central body or extremity)
• Nodal status
DISORDERS OF PIGMENTATION AND
MELANOCYTES BENIGN EPITHELIAL LESIONS
NEVI SEBORRHEIC KERATOSES
• Pigmented nevus, Mole • Benign, but can be mistaken for melanomas grossly (small
Melanocytic
• Grossly & histologically benign-looking pore-like ostia impacted w/ keratin)
nevus
• Clinical significance: Cosmetic • Leser-Trélat sign: Rapid increase in seborrheic keratoses
• Grossly & histologically worrisome (atypia) o Paraneoplastic syndrome of GI malignancies
Dysplastic • Clinical significance: Direct precursor of o Tumor cells produce TGF-α → keratinocyte stimulation
nevus melanoma, marker of increased • Morphology:
melanoma o Exophytic and well-demarcated lesion
o Basaloid cells with variable pigment production
MALIGNANT MELANOMA (MM) § Irritated SK: (+) Squamous eddies
• Most deadly of all skin cancers o Hyperkeratosis: Exuberant keratin production
• Risk factors: Sun exposure (most important risk factor), o Horn cysts: Small keratin-filled cysts
Dysplastic nevus syndrome (AD, multiple dysplastic nevi, & o Invagination cysts: Invaginations of keratin into the mass
melanoma)
ACANTHOSIS NIGRICANS
• Thickened, hyperpigmented skin with a “velvet-like” texture in
flexural areas
• Cutaneous marker of benign and malignant conditions
o Benign conditions (More common): Obesity and DM
o Malignant conditions: GI malignancies
• Morphology
o Undulation of epidermis and dermal papillae
o Hyperkeratosis
o Basal cell hyperpigmentation WITHOUT melanocytic
hyperplasia
FIBROEPITHELIAL POLYP
• Acrochordon, Squamous papilloma, Skin tag
• Fibrovascular cores w/ benign squamous epithelium
KERATINOUS CYSTS
TUMOR PROGRESSION SEQUENCE IN MELANOMA • Cystic invaginations of the hair follicle epithelium
• Complication: Rupture → Inflammation
Melanocytes are neural crest cell-derived cells located apart from each
other in the stratum basale. Melanocytic hyperplasia that allows them to TYPES OF KERATINOUS CYSTS
be adjacent to each other is called lentigo. Atypia starts from dysplastic
EPIDERMAL PILAR
nevus, but here, the atypical cells are confined within the epidermis. In early
melanomas, there is only superficial dermal involvement, and in advance • Follicular
melanomas, the involvement goes deeper that it can reach the vessels, which infundibular cyst • Trichilemmal
Other name
means acquirement of metastatic potential. • Epidermal inclusion cyst
Dr. Elomina
cyst
GROWTH PHASES OF MELANOMA
• Infundibulum • Isthmus
RADIAL VERTICAL Origin in follicle
(upper portion) (middle portion)
• Epidermal, superficial
Involvement • Deep dermis Granular layer in
dermis • Present • Absent
lining
• Superficial spreading
Specific (Most common) Keratin • Loose, lamellated • Compact
• Nodular
types • Lentigo maligna
• Acral lentiginous ADNEXAL TUMORS
Metastatic • Tumors that arise from cutaneous appendages
• No • Yes
potential
• Numerous entities
• Large cells, with irregular nuclei contours
• Clinical significance: Some benign adnexal tumors may be
Cytology • Clumped chromatin at nuclear periphery
mistaken for Basal cell carcinoma
• Prominent eosinophilic (red) nucleoli
Prognosis • More favorable • Less favorable
PREMALIGNANT AND MALIGNANT LESIONS ACUTE INFLAMMATORY DERMATOSES

ACTINIC KERATOSIS • Wheals: ↑ dermal microvascular permeability
• Angioedema: involvement of deeper dermis &
• Hyperkeratotic lesion that occurs in sun-damaged skin subcutaneous fat
• Premalignant lesion to squamous cell carcinoma Urticaria • Mechanisms: Mast-cell and IgE
• Risk factors: Sun exposure, ionizing radiation, industrial dependent/independent processes
hydrocarbons, arsenicals • Morphology: Superficial dermal edema, Sparse
• Morphology superficial perivenular mononuclear infiltrate
o Hyperkeratosis → Cutaneous horn • CD4+ T-cell mediated hypersensitivity to either
o Parakeratosis Acute contact antigens or internal circulating Ags
o Atypical dyskeratotic cells in basal layer eczematous • Forms: Allergic contact, Atopic, Drug-related,
o Solar elastosis: Blue-gray elastic fibers in dermis dermatitis Photoeczematous, Primary irritant
• Cardinal histologic change: Spongiosis
SQUAMOUS CELL CARCINOMA ERYTHEMA MULTIFORME
• Second most common tumor arising on sun-exposed skin • Associated conditions: Infections (HSV, Mycoplasma), Drugs,
• Risk factors: Most important: Sun exposure Cancers, Collagen vascular diseases
o Immunosuppression (↑ susceptibility to HPV 5 and 8) • Pathogenesis: CD8+ T-cell mediated process, split occurring at
o Disorders of DNA repair (Xeroderma pigmentosum) epidermal-dermal junction
o Industrial carcinogens (tars, oils) • Spectrum:
o Chronic ulcers and draining osteomyelitis Steven-Johnson syndrome • <10% TBSA involvement
o Old burn scars SJS-TEN overlap • 10-30% TBSA involvement
o Arsenicals Toxic epidermal necrolysis • >30% TBSA involvement
o Ionizing radiation • Morphology: Targetoid lesions
• Associated syndromes
o Epidermodysplasia verruciformis CHRONIC INFLAMMATORY DERMATOSES
§ Autosomal recessive • Cell-mediated (CD4+, CD8+) autoimmune dermatitis →
§ ↑ susceptibility to cutaneous Squamous cell carcinomas increased epidermal cell proliferation
• Behavior • Most common sites: Elbows, Knees, Scalps,
Intergluteal cleft
o Has metastatic potential
• Salmon-colored plaques, w/ silver-white scales
o Less aggressive than mucosal Squamous cell carcinomas
o Auspitz sign: pinpoint bleeding on lifting of scales
due to dilated tortuous vessels
BASAL CELL CARCINOMA Psoriasis o Koebner phenomenon: lesions post-trauma
• Most common invasive cancer in humans • Morphology:
o Test tubes in a rack appearance: Acanthosis with
• Risk factors: Most important: Sun exposure
elongation of rete ridges
o Immunosuppression o Munro microabscesses: Neutrophils w/
o Disorders of DNA repair (Xeroderma pigmentosum) parakeratotic stratum corneum
• Associated syndrome o Spongiform pustules of Kogoj: Neutrophils in
o Nevoid basal cell carcinoma syndrome (Gorlin syndrome) spongiotic foci of the superficial epidermis
§ Autosomal dominant: PTCH inactivation • Classically involves region w/ high density of
§ Multiple BCCs, Medulloblastomas, Ovarian fibromas, OKCs sebaceous glands
• Behavior: Locally aggressive, Metastasis is very rare • Dandruff: seborrheic dermatitis of scalp
Seborrheic • Morphology: spongiotic (acute) → acanthotic
MORPHOLOGY OF COMMON EPIDERMAL MALIGNANCIES dermatitis (chronic) pattern
SQUAMOUS CELL BASAL CELL o Follicular lipping: Mounds of parakeratosis
CARCINOMA CARCINOMA containing PMNs and sebum at the ostia of hair
• Pearly papules with follicles
telangiectasia → • 6Ps: pruritic, purple, polygonal, planar, papules,
plaques
• Plaques to nodules extensive ulceration
Gross o Wickham striae: white dots/lines on papules
with ulceration (rodent ulcer) • Pathogenesis: CD8+ T-cell mediated hypersensitivity
• May show • Koebner phenomenon is observed
pigmentation Lichen
• Clinical significance: Development of SCCA
planus
• Atypical squamous • Morphology:
cells involving full • Nests of basaloid o Hyperkeratosis & Hypergranulosis
thickness of (looks like cells in o Sawtoothing of epidermal-dermal junction
epidermis with basal layer) cells with o Civatte (colloid) bodies: Anucleate, necrotic basal
Histology cells incorporated into inflamed papillary dermis
dermal invasion peripheral
• Keratin pearl palisading It is postulated that trauma exposes a yet to be characterized antigen to
formation • Stromal retraction which to body reacts against to produce the lesions. This is the basis of
Koebner phenomenon seen in psoriasis.
• Dyskeratotic cells Dr. Elomina
INFLAMMATORY DERMATOSES BLISTERING DISEASES

ACUTE CHRONIC INFLAMMATORY BLISTERING DISEASES
Duration • Days to weeks • Months to years • Autoimmune injury to skin components that results in
• Inflammatory formation of vesicles and bullae
infiltrates • Changes in o Pemphigus
(mononuclear) epidermal growth § Pemphigus vulgaris: Most common
General
• Edema (atrophy or § Paraneoplastic pemphigus: in Non-Hodgkin Lymphomas
changes
• Variable epidermal, hyperplasia) or o Bullous pemphigoid
vascular or dermal fibrosis o Dermatitis herpetiformis
subcutaneous injury § Associated with Celiac disease
• Urticaria • Psoriasis
• Acute eczematous • Seborrheic INFLAMMATORY
Examples
dermatitis dermatitis BLISTERING DISEASES
• Erythema multiforme • Lichen planus https://qrs.ly/crcmfx9
In chronic inflammatory dermatoses, there is an epidermal reaction seen (in
response to the injury), which is absent in acute inflammatory disorders
Dr. Elomina
INFLAMMATORY BLISTERING DISEASES
PEMPHIGUS VULGARIS BULLOUS PEMPHIGOID DERMATITIS HERPETIFORMIS
Target compound and • Bullous pemphigoid Ags • Reticulin (fibrils at anchor
• Desmoglein (desmosomes)
structure (hemidesmosomes) epidermis to superficial dermis)
Location of blisters • Suprabasilar • Subepidermal
Antibodies • IgG • IgG • IgA
• Mainly intercellular squamous
Deposit location (IF) • Basement membrane • Tips of dermal papillae
region
• Fibrin and neutrophils at tips of
• No acantholysis
Histologic changes • Acantholysis dermal papillae
• Basal cell layer vacuolization
• Basal cell layer vacuolization
Nikolsky sign • Positive • Negative • Negative
NON-INFLAMMATORY BLISTERING DISEASES 25. BONES, JOINTS, AND SOFT TISSUE
EPIDERMOLYSIS BULLOSA BONES JOINTS
• Defects in either keratin (simplex, most common), laminin and • Developmental disorders • Osteoarthritis
BPAGs (junctional), and Type VII collagen (dystrophic) • Metabolic bone disease • Rheumatoid arthritis
• Fractures • Seronegative
PORPHYRIA • Osteonecrosis spondyloarthropathies
• Inherited defects in heme metabolism • Osteomyelitis • Infectious arthritis
• Blocks late in heme synthesis lead to sun-induced skin damage • Tumors • Crystal-induced arthritis
SOFT TISSUE TUMORS
SKIN INFECTIONS BONES

• Viruses DEVELOPMENTAL DISORDERS
o Verrucae: HPV DYSOSTOSES
o Molluscum contagiosum: MCV poxvirus • Localized disruption of migration and condensation of
o Varicella, Herpes Zoster: Varicella-Zoster virus mesenchyme
• Bacteria DEFECT EXAMPLES
o Impetigo: Streptococcus pyogenes, Staphylococcus aureus Complete absence of bone • Aplasia
o Acne vulgaris: Propionibacterium acnes Extra bones or digits • Supernumerary digits
• Fungi: Agents of superficial and cutaneous mycosis (Malassezia • Syndactyly
furfur and the dermatophytes) (will not be covered) Abnormal bone fusion
• Craniosynostoses
DYSPLASIA
SELECTED SKIN INFECTIONS
INFECTION MORPHOLOGIC • Global disorganization of bone/cartilage
• Morphology: Papillomatous epidermal FIBROBLAST GROWTH FACTOR 3
Verrucae – HPV
hyperplasia w/ koilocytic change ACHONDROPLASIA
• Morphology: Pink, pearly, firm papule • Most common skeletal dysplasia and major cause of dwarfism
w/ umbilicated center • Autosomal dominant: gain-of-function mutations in FGF3 →
Molluscum
• Curd-like material can be expressed inhibition of endochondral growth
contagiosum –
from the umbilication • Thanatophoric dysplasia: most common lethal form of dwarfism
MCV
• Hallmark: Molluscum body: Ellipsoid, o Usual cause of death: Respiratory insufficiency
Cytoplasmic inclusion in keratinocytes TYPE I COLLAGEN
• Varicella: Acute infection with VZV OSTEOGENESIS IMPERFECTA "BRITTLE BONE DISEASE"
• Zoster: Latent infection with VZV • Most common inherited disorder of connective tissue
• Hallmark: Intraepidermal vesicles w/ • Usually, Autosomal Dominant
Intranuclear inclusions in • Fundamental abnormality: Extreme skeletal fragility due to
keratinocytes too little bone
• Complications: • Four major types: Type 2: Most lethal (fractures in utero)
Varicella & o Post-herpetic neuralgia: most
common In OI patients, you can see the characteristic “blue sclera” because the
Zoster – VZV abnormal collagen fibers of sclera allow the underlying uvea to be
o Ramsay-Hunt syndrome: Facial visualized.
paralysis (Geniculate nucleus Dr. Elomina
involvement) METABOLIC PATHWAYS
o Herpes Zoster Ophthalmicus: OSTEOPETROSIS "MARBLE BONE DISEASE"
Reactivation at Ophthalmic division of • Most are autosomal recessive
Trigeminal nerve → can lead to o Impaired osteoclast function → Excessive bone formation
blindness § Deposited bone is woven
• Clinical lesion: Honey-colored crusting • Albers-Schönberg disease: Mild autosomal dominant form
• Microscopic hallmark: Neutrophil • Morphology
accumulation beneath stratum o Absence of medullary canal: Bone marrow failure with
Impetigo
corneum extramedullary hematopoiesis
• Impetigo contagiosa: S pyogenes o Erlenmeyer flask deformity: Bulbous ends of long bones
• Impetigo bullosa: S aureus Osteoclasts have an osteoclast resorption pit where the actual bone
• Histologic hallmark: Comedogenesis resorption occurs. Normal function of this structure relies on its adequate
• Open comedones: Small follicular acidification. Most of the mutations in osteopetrosis target enzymes
papules w/ central black keratin plug needed for acidification of the osteoclast resorption pit.
Dr. Elomina
Acne vulgaris – (melanin oxidation)
P acnes • Closed comedones: No visible plug METABOLIC BONE DISEASE
• Acne conglobata: Severe form of acne OSTEOPENIA AND OSTEOPOROSIS
with sinus tract formation & dermal • Osteopenia: decreased bone mass
scarring • Osteoporosis: Severe osteopenia, enough to increase risk of
fractures
• Bone resorption exceeds formation
• Most common forms: Senile and postmenopausal
• Hallmark: Histologically normal bone, but ↓ in quantity
OSTEONECROSIS
• Most common causes: Trauma, Steroids
• Morphology:
o Medulla more commonly affected (due to lack of collateral
circulation)
o Subchondral infarcts
• Sequelae: Collapse of necrotic bone, fracture
OSTEOMYELITIS
PYOGENIC OSTEOMYELITIS
• Route of infection: Hematogenous, extension, direct implantation
• Causative agents:
o S. aureus: Most common (80-90%)
o E. coli, Pseudomonas, Klebsiella: GUT infections & IV drug users
o H. influenzae, GBS: Neonates
PATHOPHYSIOLOGY OF SENILE AND POSTMENOPAUSAL o Salmonella: Sickle cell disease
OSTEOPOROSIS • Location dependent on osseous vascular circulation
Adapted from Figure 26.9. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 o Neonates: Metaphyses and/or epiphyses
RICKETS AND OSTEOMALACIA o Older Children: Metaphyseal
o Adult: Epiphyses and Subchondral regions
• Manifestations of Vitamin D deficiency
• Morphology
o Rickets: Children
o Subperiosteal abscesses
o Osteomalacia: Adults
o Draining sinuses: Secondary to developing bone abscess
• Decreased mineral content of bone
o Sequestrum: Dead bone
o Involucrum: Newly developed bone around dead bone
HYPERPARATHYROIDISM
• Clinical manifestations:
• Biologic effects of PTH: ↑ Ca2+ levels o Systemic symptoms related to infection
o Bone: Osteoclast activation → Bone resorption o Pain over infected bone
o Kidneys o Radiograph: Lytic focus with surrounding sclerosis
§ ↑ Ca2+ tubular reabsorption
§ ↑ PO43- excretion (PTH = Phosphate trashing hormone) MYCOBACTERIAL OSTEOMYELITIS
§ ↑ Vitamin D synthesis → ↑ Intestinal Ca2+ absorption and ↑ • More destructive and more resistant to control
Bone Ca2+ mobilization • Involves spine in 40% of cases (Tuberculous spondylitis, Pott
• For detailed morphology, see Endocrine system disease): Kyphoscoliosis and neurologic manifestations
RENAL OSTEODYSTROPHY TUMORS

• Skeletal changes in chronic renal failure (including dialysis) • Dictum: Look at patient’s age and the location of tumor!
o Osteopenia/osteoporosis • In general, when a bone tumor occurs in younger patients, it is
o Osteomalacia most likely benign; in older patients, it is most likely malignant
o Secondary hyperparathyroidism o Exceptions include malignant bone tumors that peak in
o Growth retardation pediatric age group: Osteosarcoma and Ewing sarcoma
• Pathophysiology • Most common primary malignant tumors (excluding
o Renal tubular acidosis → Systemic acidosis → ↑ Bone hematologic): Osteosarcoma > Chondrosarcoma > Ewing
demineralization and Osteomalacia sarcoma
o Poor Ca2+ reabsorption + Poor PO43- excretion → ↑ PTH → ↑ • Common clinical manifestations: Mass, Pain, Fracture
Bone resorption
o ↓ Vitamin D synthesis and dysregulation of Ca2+- PO43-
BONE-FORMING TUMORS
homeostasis between kidney and bone
OSTEOID OSTEOMA AND OSTEOBLASTOMA
PAGET DISEASE (OSTEITIS DEFORMANS) • Benign tumors common in 10-20 years old
• Increased, but disordered and structurally unsound bone • Malignant transformation is rare
• Mosaic pattern of lamellar bone: “jigsaw puzzle” Morphology: Haphazardly interconnecting trabeculae of woven
• Clinical aspects bone WITH osteoblastic rimming (Reactive bone around lesion)
o Primarily a disease of elderly, presents as bone pain OSTEOID OSTEOMA OSTEOBLASTOMA
o Most common bones: Axial skeleton, Proximal femur Size • < 2 cm • > 2 cm
o Complications • Appendicular
• Axial skeleton
§ High-output failure: Pagetic bone as AV shunt skeleton
• Posterior spine
§ Most dreaded complication: Osteosarcoma and Location • Most common:
(Lamina and
fibrosarcoma Femur or Tibial
pedicle)
cortex (50%)
Significant bone involvement may cause high-output cardiac failure
Pain relieved
because the AV shunts in Pagetic bone. Afterload is decreased (decreased • Yes • No
by NSAIDs
TPR because the blood bypasses arterioles) and preload is increased
(increased venous return), hence the high cardiac output. Reactive bone
Dr. Elomina • Marked • Less pronounced
formation
FRACTURE HEALING • Radiofrequency

Treatment • En bloc excision
ablation
TIME PROCESS
• Breakage of bone OSTEOSARCOMA
0-1 day • Ruptured blood vessels → Hematoma formation • Bimodal age incidence: Most occur in <20 years old (75%)
→ Fibrin mesh • Most common location: Metaphysis of long bones (Knee i.e.
TIME PROCESS distal femur, proximal tibia (50%))
• ↑ Progenitor cells → ↑ Osteoblasts and • Radiographic findings: Periosteal lifting (Codman triangle),
Osteoclasts infiltrative borders (Sunburst appearance),
0-2 weeks
• Soft tissue callus/Procallus formation • Morphology
(not yet good for weight bearing)
o Cytologically malignant cells
2-3 weeks • Bony callus (Woven bone) o Bone formation (usually lace-like pattern) (Diagnostic)
3 weeks- o Abundant cartilage: Chrondroblastic osteosarcoma
• Lamellar bone formation
months
CARTILAGE-FORMING TUMORS GIANT CELL TUMOR OF BONE (OSTEOCLASTOMA)

OSTEOCHONDROMA • Benign, but locally aggressive
• Most common benign bone tumor: Adolescence, early • Pathogenesis: Tumor cells have ↑RANKL levels (promotes
adulthood osteoclast maturation) → ↑↑ bone resorption (localized)
• Most commonly solitary • Common age group: 3rd-5th decade
• Common location: Metaphyseal (near growth plate of long • Most common: Epiphyses of long bones (around the knee)
bones): Knee > Pelvis, Scapula, Ribs • Histology: Mononuclear cells with osteoclast-like giant cells
• Morphology: Cartilage cap: w/ Underlying bone and marrow
CHONDROMA
FIBROUS DYSPLASIA
• Benign tumor that shows features of localized developmental
• Benign tumor of hyaline cartilage that occurs in bones of
arrest of bone
endochrondral origin
o Monostotic or Polyostotic: depending on number of bones
o Enchrondroma: Intramedullary
involved
§ Most common intraosseous cartilage tumor
o Juxtacortical: Bone surface o Polyostotic diseases are more ominous
§ Presents at an earlier age, clinically problematic, and can
• Age: 20-50 years
transform into sarcoma
• Location: Metaphysis of hand and foot bones
• Associated diseases
• Associations: Ollier and Maffucci syndrome
o Mazabraud syndrome: Polyostotic FD + Soft tissue myxomas
Maffucci syndrome: Spindle cell hemangiomas, and brain
o McCune-Albright syndrome: Polyostotic FD + Café-au-lait
gliomas
spots + Precocious puberty
CHONDROSARCOMA, CONVENTIONAL TYPE • Morphology: Curvilinear trabeculae of woven bone WITHOUT
• Second most common malignant-producing tumor of bone osteoblastic rimming
• Age: Usually a disease of elderly (>40 years) • The buzz word here is “Chinese characters” appearance of bony
• Common location: Axial skeleton (pelvis, shoulder, ribs) trabeculae.
• Morphology: Anaplastic chondrocytes with varying cellularity, • Osteoblastic rimming is characteristically absent in FD, while it is
atypia, and mitosis (Basis for three-tier grading) present in Osteoid osteoma/Osteoblastoma.
Dr. Elomina
• Grade is a prognostic factor
METASTASIS
TUMORS OF UNKNOWN ORIGIN
• Most common skeletal malignancy
EWING SARCOMA
• Pathways of spread: Direct extension, Lymphatic or
• Second most common group of bone sarcomas in children hematogenous dissemination, Intraspinal seeding (via
• Most common mutation: t(11;22) EWSR1-FLI1 fusion gene Batson plexus)
• Age: <20 years old • Sources:
• Common location: Diaphysis of lone bones (femur), o Adults: Prostate, Breast, Kidney, and Lung
• Manifestations: Painful, mass with systemic symptoms o Children: Neuroblastoma, Wilms tumor, Osteosarcoma,
• Radiographic findings: Lytic lesion Ewing sarcoma, Rhabdomyosarcoma
o Periosteal reaction: Onion-skin reactive bone deposition • Radiographic appearance:
• Morphology: o Blastic: Prostate
o Small, round blue cells in scant fibrous stroma o Lytic: Kidney, Lung, GIT, Melanoma
o Homer-Wright rosettes may be seen o Mixed
JOINTS
FEATURE OSTEOARTHRITIS RHEUMATOID ARTHRITIS
Primary
• Mechanical injury to articular cartilage • Autoimmunity
abnormality
Role of • May be secondary; Inflammatory mediators • Primary: Cartilage destruction is caused by CD4+ T cells and
inflammation exacerbate cartilage damage antibodies reactive with joint antigens
Joints involved • Primarily weight-bearing (knees, hips) • Often begins with small joints of fingers → multiple joints
• Cartilage degeneration and fragmentation • Pannus: Mass of edematous synovium, inflammatory cells,
• Bone eburnation: Polished ivory appearance of granulation tissues, and fibrosis → invasion and destruction of cartilage
exposed subchondral bone due to friction • Severe chronic inflammation
Pathology
• Bone spurs (Osteophytes) • Joint fusion (Ankylosis)
• Subchondral cysts • Rheumatoid nodules: Necrotizing granulomas (Fibrinoid
• Minimal inflammation necrosis)
• Various: Rheumatoid factor, Anti-citrullinated peptide
Serum antibodies • None
antibody
Extra-articular
• No • Yes (Lungs, Heart, Other organs)
involvement
Systemic symptoms • Absent • Present (can precede joint involvement)
Physical • Bouchard nodes: Osteophytes at PIP • Swan neck deformity: PIP Hyperextension, DIP flexion
examination • Heberden nodes: Osteophytes at DIP • Boutonniere deformity: PIP Flexion DIP Hyperextension
SERONEGATIVE SPONDYLOARTHROPATHIES REACTIVE ARTHRITIS

• Common characteristics: • Arthritis, Nongonococcal urethritis, Conjunctivitis
o Absence of rheumatoid factor • Mono- or oligoarticular arthritis days to weeks post-infection
o Sacroiliac joint involvement, ligamentous attachments o Yersinia, Salmonella, Shigella, Campylobacter, Clostridium
o Association with HLA-B27 difficile, Chlamydia
o Bony proliferation → Ankylosis Memory device for Reactive arthritis: “Can’t see, can’t pee, Can’t climb a tree.”
Dr. Elomina
• Pathogenesis: T-cell hypersensitivity against uncharacterized
microbial against cross-reacting with MSS antigens
CRYSTAL-INDUCED ARTHRITIS
ANKYLOSING SPONDYLITIS • Pathogenesis: Crystal deposition incites an inflammatory
response that destroys the articular cartilage
• Destruction and bony ankylosis of Sacroiliac and Vertebral
apophyseal joints • Crystals
o Monosodium urate (MSU) (Gout), Calcium pyrophosphate
• Clinical manifestations: Lower back pain and spinal immobility
dihydrate (CPPD) (Pseudogout), Basic calcium phosphate
CRYSTAL-INDUCED ARTHRITIS
GOUT PSEUDOGOUT
• Hyperuricemia • Idiopathic
o ↑ Production • Genetic mutations
§ Enzyme defects (Lesch-Nyhan syndrome) • Secondary causes
§ ↑ Nucleic acid turnover (Leukemia) o Previous joint damage
Causes
o ↓ Excretion o Hyperparathyroidism
§ Chronic kidney disease o Hemochromatosis
o Hypomagnesemia
o Hypothyroidism
• Usually monoarticular • Mono- or polyarticular
Joint involved
• Most common: 1st MTP of big toe • Most common: Knee
• NSAIDs, colchicine • No known treatment
Treatment
• Uric acid-lowering agents
MORPHOLOGY
Shape • Needle-shaped • Rhomboid
Polarizing Microscopy • Negatively birefringent • Positively birefringent
Inflammation • More intense • Less intense
PATTERNS OF GOUT TUMORS OF SMOOTH MUSCLE
FORM MORPHOLOGY
• Most common neoplasm in women
• Intense neutrophilic inflammation with Leiomyoma
• Common site: Uterus
Acute scattered mononuclears
arthritis • Usually in deep soft tissues of extremities
• MSU crystals in synovium and cytoplasm of
& retroperitoneum
neutrophils Leiomyosarcoma
• Atypical eosinophilic spindle cells,
• Deposition of urate on articular surface →
Chronic prominent necrosis
pannus formation → cartilage destruction →
tophaceous
juxta-articular bone erosions
arthritis
• Fibrous or bony ankylosis 26. PERIPHERAL NERVOUS SYSTEM
• Pathognomonic hallmark AND SKELETAL MUSCLE
Tophi • Large aggregate of urate crystals surrounded PERIPHERAL NERVES SKELETAL MUSCLE
by foreign body giant cells • Generalities of PNS injury • Inflammatory myopathies
• Urate crystals in renal medullary • Neuropathies • Muscular dystrophies
Urate
interstitium and tubules • Neuromuscular junction
nephropathy
• Nephrolithiasis and pyelonephritis diseases
PERIPHERAL NERVE SHEATH TUMORS
SOFT TISSUE TUMORS
PERIPHERAL NERVES
GENERALITIES GENERALITIES OF PNS INJURY
CLINICAL ASPECTS PERIPHERAL NERVE
• Benign and malignant neoplasms exist; both presents as a mass STRUCTURES AFFECTED
INJURY
• Most sarcomas occur in adults, except for some that Axonal neuropathy • Axons
predominantly afflict children (e.g. Rhabdomyosarcoma) Demyelinating
• Schwann cells and myelin
neuropathy
CLINICAL CHARACTERISTICS OF SOFT TISSUE TUMORS • Neurons with secondary axonal
Neuronopathy
BENIGN SARCOMAS damage
Location • Usually superficial • Usually deep-seated Axonal and demyelinating neuropathies can be electrophysiologically
Size at distinguished. Axons are responsible for signal transmission, so when you
• Usually small • Usually large
presentation have axonal loss, it will manifest with decrease in signal amplitude. The
Rate of growth • Usually slow • Usually fast organization of myelin along the axon results in increased conduction
velocity (Recall your saltatory conduction in neurophysiology) because the
PATHOLOGIC ASPECTS signals jump from one node of Ranvier to the other. So, when you have
• Cytogenetic origin: Pluripotent mesenchymal stem cells demyelination, it will manifest with decrease in conduction velocity.
• Can demonstrate differentiation or undifferentiated Dr. Elomina
• Sarcomas are graded using a system using three parameters: PATTERNS OF INVOLVEMENT DISTRIBUTION
1. Differentiation, 2. Mitosis, and 3. Necrosis Mononeuropathy • Single nerve
Polyneuropathy • Multiple nerves (symmetric)
TUMORS OF ADIPOCYTIC DIFFERENTIATION Mononeuritis multiplex • Several nerves (asymmetric)
LIPOMA Polyradiculoneuropathy • Multiple nerve roots
• Most common soft tissue tumor of adulthood
• Encapsulated mass of mature adipocytes NEUROPATHIES
LIPOSARCOMA • Chronic inflammatory demyelinating
poly(radiculo)neuropathy (CIDP): Most common chronic
• Most common sarcoma of adulthood
acquired peripheral neuropathy
• Histologic clue to adipocytic differentiation: Lipoblasts
• DM: Most common cause of peripheral neuropathy
• Charcot-Marie Tooth (CMT) disease: Most common inherited
TUMORS OF SKELETAL MUSCLE peripheral neuropathy
DIFFERENTIATION
RHABDOMYOSARCOMA GUILLAIN-BARRÉ SYNDROME
• Common histologic subtypes in pediatric age group • Acute, Symmetric ascending demyelinating
• Almost all are malignant polyradiculoneuropathy
• Numerous spaces lined by discohesive, • Pathogenesis: T-cell mediated hypersensitivity with antibody
Alveolar
uniform, round tumor cells component against peripheral nerves → demyelination
• Most common subtype (50%) • Associations: Campylobacter jejuni, Mycoplasma pneumoniae
• Mixture of primitive round & spindle cells, and CMV, EBV, prior vaccination
Embryonal differentiated cells w/ rhabdomyoblasts • Morphology
(pink cells w/ cross-striations) o Inflammation of peripheral nerves: perivenular and
• Sarcoma botryoides: best prognosis endoneurial mononuclear inflammation
Pleomorphic • Usually affect adults, and are fatal o Segmental demyelination with axonal damage if severe
• Clinical manifestation SKELETAL MUSCLE DISEASES
o Ascending paralysis and areflexia → respiratory muscle
paralysis
INFLAMMATORY MYOPATHIES
o ↓ Nerve conduction velocity DERMATOMYOSITIS POLYMYOSITIS
o CSF: Albuminocytologic dissociation: ↑ protein, little • Juvenile (most common
pleocytosis Age/ inflammatory myopathy)
• Usually adult
associations • Adults: usually a
paraneoplastic syndrome
CHRONIC INFLAMMATORY DEMYELINATING
• Myalgias + Proximal weakness → Distal
POLY(RADICULO)PATHY (CIDP) Weakness
weakness (Late)
• Symmetric mixed sensorimotor polyneuropathy ≥ 2 months DERMATOMYOSITIS POLYMYOSITIS
• Pathogenesis: T-cell mediated hypersensitivity with antibody • Heliotrope rash: Periorbital
component against molecules expressed at Schwann cell-axon lilac discoloration
junction and in noncompact areas of myelin Skin changes • Gottron papules: Dusky • None
• Histology: Recurrent demyelination and remyelination red patches over knuckles,
associated with Schwann cell proliferation knees and elbows
• Responsive to steroids • CD8+ T cell-
• Immunologic damage to
mediated
Pathogenesis small blood vessels (Type I
DIABETIC NEUROPATHY damage to
interferon response)
muscle
• Pathogenesis:
Mononuclear • Perimysial
o ↑ Advanced glycation end products → protein dysfunction • Endomysial
infiltrate • Perivascular
and inflammation
Pattern of • Random,
o ↑ Sorbitol → ↓ NADPH → ↑ Susceptibility of neurons to • Perifascicular
atrophy Patchy
oxidative damage
o Ischemic damage of nerves as a consequence of vascular
disease MUSCULAR DYSTROPHIES
• Morphology DUCHENNE BECKER
o Axonal neuropathy Defect (dystrophin • Total • Truncated version
o Hyaline arteriolosclerosis of endoneurial arterioles on X chromosome) absence (reduced activity)
• Clinical manifestations Onset and • Early-onset • Late-onset
o Distal symmetric sensorimotor neuropathy: Numbness, loss phenotype • More severe • Milder
of pain sensation, difficulty with balance, & paresthesias / • Musculoskeletal
dysethesias o Pelvic girdle weakness → shoulders
§ Abnormal discharge from damaged nerves Symptoms o Pseudohypertrophy of lower leg muscles
o Diabetic autonomic neuropathy • Cardiac: Arrhythmias, cardiomyopathy
§ Postural hypotension • CNS: Mental retardation
§ Incomplete bladder emptying → recurrent infections • Early
§ Sexual dysfunction o Segmental myofiber degeneration and
regeneration admixed with atrophic
myofibers
CHARCOT-MARIE-TOOTH DISEASE
Histology o Preserved fascicular architecture
• Genetically and pathologically diverse, with axonal and • Late
demyelinating forms o Fatty replacement and endomysial
• CMT1: Most common subtype type fibrosis
o Onset: Second decade of life o Distorted fascicular architecture
o Form: Slowly progressive distal demyelinating sensorimotor Dystrophin IHC • Absent • Reduced
neuropathy
Dystrophin can also be found in the heart and in the brain, which is the reason
• CMT2 (Most common subtype of CMT2: CMT2A) why these muscular dystrophies present with cardiac and CNS abnormalities.
o Onset: Early childhood Dr. Elomina
o Form: Axonal neuropathy

PERIPHERAL NERVE SHEATH TUMORS
NEUROMUSCULAR SYSTEM DISEASES • Mostly show evidence of Schwann cell differentiation
LAMBERT EATON o S-100 protein is positive in neural crest cell-derived cells
MYASTHENIA (Schwann cells, melanocytes, etc.)
MYASTHENIC
GRAVIS (MG)
SYNDROME (LEMS) • Sporadic or associated with familial tumor syndromes
• Antibody-mediated hypersensitivity • Benign: Neurofibromas, Schwannomas
Pathogenesis
(Type II) • Malignant: Malignant Peripheral Nerve Sheath Tumor (MPNST)
• Thymoma • Neuroendocrine • Common clinical presentation: Mass and Mass effect
Associations • Thymic carcinoma of the
hyperplasia lung (Most common) SCHWANNOMA
• Postsynaptic ACh • Presynaptic Ca • Mutation: NF2 (Merlin) (Ch22) inactivation
Auto-
receptor channel → blocked • Morphology: Well-circumscribed, encapsulated
antibodies
(Most common) release of ACh o Biphasic appearance
Weakness § Antoni A: Cell-dense areas with spindle cells arranged in
• No (Muscle strength
with • Yes (Fluctuating) fascicles with nuclear palisading
increases with activity)
exertion • Verocay bodies: Cell-free areas due to nuclear palisading
• Common: EOMs § Antoni B: Cell-poor areas with prominent myxoid stroma
(Diplopia and • Locations
Muscle • Usually,
Ptosis) o Vestibular Schwannoma: Cerebellopontine angle (attached to
groups extremities
• May be vestibular branch of CN VIII
generalized o Intradural: Sensory nerves preferentially affected (dorsal
• Decrement in • Increase in muscle roots and CN V branches)
Electro-
muscle response response with o Extradural: Large nerve trunks and soft tissue
physiologic
with repeated repeated
studies
stimulation stimulation
NEUROFIBROMA MALIGNANT PERIPHERAL NERVE SHEATH

• Heterogeneous cell composition: TUMOR
o Neoplastic Schwann cells: S-100(+), Spindle cells: CD34 (+) • Sarcoma arising in:
• Mutation: NF1 (Ch17) inactivation → unbridled RAS activation o An anatomic compartment of a major nerve or a pre-
→ tumorigenesis existing nerve sheath tumor, OR in an NF1 patient
• Morphology: • Morphology: Just like any other sarcoma
• Well-circumscribed, unencapsulated o Atypia, Mitosis, Necrosis (in High-grade MPNSTs)
Superficial • Heterogeneous cell population embedded in a o Divergent differentiation is common
cutaneous collagenous stroma w/ “Shredded carrot” § Malignant Triton tumor: (+) Rhabdomyoblastic
appearance differentiation
• “Bag of worms” appearance: Consequence of
Plexiform expansion and thickening of multiple nerve
fascicles by the tumor
• Clinical significance: In NF1 patients, plexiform neurofibromas
can transform into MPNSTs
27. CENTRAL NERVOUS SYSTEM
• Cellular pathology of CNS • Trauma • Demyelinating diseases
• Cerebral edema, hydrocephalus, increased ICP and • Cerebrovascular diseases • Neurodegenerative diseases
herniation • Infections • Toxic and acquired metabolic diseases
• Malformations • Prion diseases • Tumors
• Perinatal brain injury
CELLULAR PATHOLOGY OF THE CNS

CELL BASIC FUNCTION REACTION TO INJURY
• Cell death
o Acute neuronal injury (Red neuron)
Neuron • Information transmission § Intense eosinophilia, Shrinkage of cell, Nuclear pyknosis, Loss of Nissl substance
o Subacute and Chronic neuronal injury (Degeneration)
§ Cell death by apoptosis with reactive gliosis
• Metabolic buffer • Hyperplasia, Hypertrophy (Gliosis: Most important pathologic marker of CNS injury)
Astrocytes
• Barrier function (BBB) • Reactive atypia (Gemistocytic astrocytes: Large, atypical bright pink cells)
• Hyperplasia
Microglia • Resident macrophages • Aggregation around necrotic foci (Microglial nodules) or cell bodies of dying neurons
(Neuronophagia)
Oligodendrocytes • Myelination • Cell death → Demyelination
Ependymal cells • Lining of ventricles • No specific pattern
CEREBRAL EDEMA, HYDROCEPHALUS, RAISED TYPES OF HYDROCEPHALUS

VENTRICULAR
INTRACRANIAL PRESSURE, AND HERNIATION HYDROCEPHALUS DEFINITION
DILATION
CEREBRAL EDEMA Noncommunicating • Obstructed
• Result of increased fluid leakage from blood vessels and injury • Localized
(obstructive) ventricular system
to various cells of the CNS • Ventricles
CLINICAL Communicating communicate w/ • Generalized
EDEMA ↑ PATHOGENESIS
SITUATIONS subarachnoid space
• ↑ Vascular • Inflammation, • ↑ CSF as compensation
Hydrocephalus ex • Not
Vasogenic • ECF permeability and tumors to decreased
vacuo applicable
BBB disruption • Hypoxic injury parenchyma
• Cellular swelling
Cytotoxic • ICF (because of Na-K • Hypoxic injury
INCREASED INTRACRANIAL PRESSURE
ATPase failure) • Monro-Kellie doctrine
o When brain tissue increases in volume (mass lesions), CSF
resorption and decrease in cerebral blood flow occur as
HYDROCEPHALUS
compensatory mechanisms
• Accumulation of excessive CSF within the ventricular system • Herniation
o Presentation depends on the state of closure of cranial sutures o Displacement of the brain tissue past rigid dural folds or
§ Head enlargement (not closed), ↑ ICP (closed) through openings in the skull because of increased ICP
HERNIATION SYNDROMES
FEATURE SUBFALCINE TRANSTENTORIAL TONSILLAR
Herniating part • Cingulate • Medial aspect of temporal lobe • Cerebellar tonsils
Herniation through • Under the falx cerebri • Across tentorium cerebelli • Foramen magnum
• CN III
Compressed
• ACA and branches • PCA • Brainstem
structure
• Contralateral cerebral peduncle
• Ipsilateral mydriasis, impaired ocular movements
• Cardiac and
• PCA infarcts
Effects • ACA infarcts respiratory
• Ipsilateral hemiparesis
depression
• Hemorrhagic lesions in midbrain and pons (Duret hemorrhages)
MALFORMATIONS • Extrusion of malformed brain tissue through a

Encephalocele midline cranial defect
NEURAL TUBE DEFECTS • Common location: Occiput
• Most common CNS malformations • Failure of the closure of the anterior neural
• Risk factor: Folate deficiency tube
DISEASE DEFINITION Anencephaly • Absence of most of brain and calvarium
Spinal • Most common neural tube defect • Area cerebrovasculosa: Flattened remnant of
dysraphism • Asymptomatic bony defect (spina bifida disorganized brain tissue
(Spina bifida) occulta)
• Extension of the spinal cord and meninges
Myelo-
through a vertebral column defect
meningocele
• Meningocele: Meninges only
FOREBRAIN ANOMALIES TRAUMATIC VASCULAR INJURY

DISEASE DEFINITION SUBDURAL
EPIDURAL HEMATOMA
• Incomplete separation of the HEMATOMA
cerebral hemispheres across the Age/Onset • Middle age • Extremes of age
midline • Slowly evolving
Holoprosencephaly o Associated with Trisomy 13 • Rapidly evolving neurologic
Clinical
o Manifestations: Cyclopia, neurologic symptoms symptoms
picture
Arrhinencephaly (Absence of with lucid intervals • Often delayed
olfactory cranial nerves) onset
• Absence of white matter bundles that • Arterial
• Most common: middle • Venous:
Agenesis of corpus carry cortical projections from one Blood source
meningeal artery bridging veins
callosum hemisphere to another
(from pterion fracture)
• May be found in normal individuals
Plain CT-scan • Crescent-shaped
• Lentiform density
appearance density
POSTERIOR FOSSA ANOMALIES
DISEASE DEFINITION SPINAL CORD INJURY
ARNOLD-CHARI MALFORMATION LEVEL CLINICAL MANIFESTATIONS
• Low-lying cerebellar tonsils extend down Thoracic or
into the vertebral canal • Paraplegia
Type I lower
• Symptomatic: Hydrocephalus, Medullary • Quadriplegia
compression Cervical
• Respiratory compromise (diaphragm
lesions
• Small posterior fossa paralysis): in lesions above C4
• Misshapen cerebellar tonsils with
downward extension of vermis through the CEREBROVASCULAR DISEASES
Type II
foramen magnum
• Hydrocephalus CEREBRAL ISCHEMIA
• Lumbar meningomyelocele • Excitotoxicity: Inappropriate release of excitatory
Dandy- • Enlarged posterior fossa (Absence or neurotransmitter (glutamate) → ↑ Ca2+ influx in neurons (via
Walker hypoplasia of cerebellar vermis) NMDA receptors) → neuronal damage
malformation • Cystic dilatation of the fourth ventricle GENERAL MORPHOLOGIC FINDINGS IN CNS ISCHEMIA
PHASE MICROSCOPIC FINDINGS
Acute • Red neuron, Cytotoxic and vasogenic edema
PERINATAL BRAIN INJURY
Subacute • Liquefaction, Microglial proliferation, Gliosis
DISEASE DEFINITION
Healed • Gliosis
• Nonprogressive neurologic motor deficits
Hemorrhagic
(dystonia, spasticity, ataxia/athetosis, • Blood extravasation and resorption
Cerebral palsy infarctions
paresis) occurring during prenatal and
perinatal periods (usually hypoxic insults) • In global cerebral ischemia, the changes tend to be diffuse
LESIONS ASSOCIATED WITH PRETERM INFANTS • In global cerebral ischemia, because of the different
• Most often near developing thalamus and susceptibilities of different areas of the brain, the area of
Germinal neuronal loss and gliosis is irregular → laminar necrosis
caudate
matrix
• May extend into ventricular system or
hemorrhage FOCAL CEREBRAL ISCHEMIA
subarachnoid space
• Supratentorial periventricular white matter • Reduction or cessation of blood flow to a localized area of brain
Periventricular infarcts due to arterial occlusion or hypoperfusion
leukomalacia • Multicystic encephalopathy: Large cystic • Causes: Embolism, Thrombosis, Vasculitis
lesions involving both gray and white matter • Non-hemorrhagic or Hemorrhagic infarct
o Hemorrhagic conversion
TRAUMA § After spontaneous or therapeutic removal of obstruction
• Trauma to skull, parenchyma, vasculature, and spinal cord
LACUNAR INFARCTS
• Sequelae
• Small cavitary infarcts associated with Hypertension
o Post-traumatic hydrocephalus and epilepsy
o Chronic traumatic encephalopathy (dementia pugilistica) • Common sites: Putamen (Most common), Globus pallidus,
o Psychiatric disorders Thalamus, Internal capsule, Deep white matter, Caudate nucleus,
Pons
PARENCHYMAL INJURIES GLOBAL CEREBRAL ISCHEMIA
CONCUSSION • Causes
• Clinical syndrome of altered consciousness secondary to head o Generalized reduction of cerebral perfusion
injury § Cardiac arrest, Shock, Severe hypotension
o Decreased oxygen carrying capacity of blood
CONTUSION (BLUNT), LACERATION (PENETRATING) § CO poisoning
• Most common sites of contusion: Frontal lobes along orbital • Neurons most sensitive to ischemia
ridges and Temporal lobes o Pyramidal layer of hippocampus (CA1: Sommer sector)
• Coup (same side), Contrecoup (opposite side) o Cerebellar Purkinje cells
o Pyramidal cells of cerebral cortex
DIFFUSE AXONAL INJURY
• Finding: Axonal swellings, focal hemorrhagic lesions BORDERZONE (“WATERSHED”) INFARCTS
• Found in 50% of patients who develop coma post-trauma • Infarcts in areas that lie at borders of arterial territories
• Most common area: ACA-MCA border zone
OLD TRAUMATIC LESIONS
• Depressed, retracted, yellowish brown patches involving the INTRACRANIAL HEMORRHAGE
crests of gyri (plaque jaune) • Risk factors/Causes
• Can become epileptic foci o Hypertension: Deep parenchymal hemorrhage
o Cerebral amyloid angiopathy: Lobar hemorrhage
• Morphology
o Basically the same with hemorrhagic infarction
HYPERTENSIVE INTRAPARENCHYMAL HEMORRHAGE VASCULAR MALFORMATIONS
• Common sites: Putamen (Most common), Thalamus, Pons, • Arteriovenous malformations
Cerebellar hemispheres (Rare) • Cavernous malformations
If you notice, hypertension usually affects the basal nuclei and subcortical o Significant risk of hemorrhage and neurologic symptoms
white matter. This is because hypertension preferentially affects vessels • Capillary telangiectasia
supplying those areas. These vessels have a background arteriolosclerosis. • Venous angiomas
Dr. Elomina
ARTERIOVENOUS MALFORMATION
CEREBRAL AMYLOID ANGIOPATHY • Most clinically significant vascular malformation
• Amyloidosis (Aβ) of leptomeningeal and cortical vessels → • Epidemiology: 10-30 years, More common in males
weakening of the vessel wall • Common clinical presentation: Seizure disorder, Intracerebral
hemorrhage, Subarachnoid hemorrhage
The amyloid in cerebral amyloid angiopathy is the same amyloid
associated with Alzheimer disease • Most common site: Posterior branches of MCA
Dr. Elomina
MORPHOLOGY
MALFORMATION MICROSCOPIC FINDINGS
SUBARACHNOID HEMORRHAGE
• Large blood vessels separated by gliotic
• Most common cause: Ruptured saccular “berry” aneurysm tissue
• Saccular aneurysm: Most common type of intracranial Arteriovenous • Blood vessels show abnormalities
aneurysm malformation (Fragmentation of internal elastic lamina,
o Most common location: ACA-ACoA junction (40%) Medial hyalinosis)
• Associations • (+) Shunting
o Mendelian disorders: ADPKD, Ehlers-Danlos syndrome type • Distended, loosely organized, back-to-
IV, Neurofibromatosis type 1, Marfan syndrome, back vascular channels without
Fibromuscular dysplasia, Coarctation of the aorta intervening brain tissue
Cavernous
o Smoking • Blood vessels have collagenous walls of
malformation
o Hypertension varying thickness
• Morphology • Most common site: Cerebellum
o Aneurysm wall and neck: Absent smooth muscle and internal • (-) Shunting
elastic lamina
CNS INFECTIONS
§ Layers present: Thickened hyalinized intima and
adventitia • Mechanism of injury
• Clinical presentation: “Worst headache of my life” → syncope o Direct injury
• Consequences o Indirect (by inflammation)
o Ischemic injury: May cause vasospasm of cerebral vessels o Immune-mediated
o Meningeal fibrosis from healing may cause CSF outflow • Routes of infection
obstruction o Hematogenous (Most common)
o Direct implantation (Trauma)
o Local extension (Infections from nearby structures)
o Retrograde transport (VZV and Rabies virus)
TYPES OF MENINGITIS
FEATURE ACUTE PYOGENIC ACUTE ASEPTIC TUBERCULOUS MENINGITIS
• Enteroviruses most common
• Infants: E. coli and group B streptococci
identifiable agent (80%)
Common • Adolescents and young adults: N.
• Bacterial, Rickettsial • M tuberculosis
causes meningitidis
• Autoimmune
• Elderly: S. pneumoniae, L. monocytogenes
• Chemical (Ruptured epidermoid cyst)
CSF FINDINGS
• Viral: Lymphocytic
Pleocytosis • Neutrophils (can be purulent) • Mononuclear
• Chemical: Neutrophils
Sugar ↓↓ N ↓ or N
Protein ↑ ↑ ↑↑
Culture (+) (-) (+) for Mtb
MORPHOLOGY FINDINGS CLINICAL MANIFESTATIONS
ACUTE PYOGENIC MENINGITIS • Systemic signs of infection
• Leptomeningeal exudate • Meningeal irritation: Nuchal rigidity, (+) Brudzinsky and Kernig
Gross signs
• Congested meningeal vessels
• Neutrophils in subarachnoid space and • Neurologic impairment: Headache, Changes in sensorium
around leptomeningeal vessels
• Ventriculitis: Extension to ventricular BRAIN ABSCESS
system • Localized focus of necrosis of brain tissue with accompanying
Histology • Cerebritis: Extension to brain inflammation
• Vasculitis → Venous thrombosis → • Predisposing conditions
o Acute bacterial endocarditis
Secondary infarction
o Congenital heart disease (R→L shunts)
• Leptomeningeal fibrosis (Healing) → o Chronic pulmonary sepsis (Bronchiectasis)
Hydrocephalus o Systemic disease with immunosuppression
TUBERCULOUS MENINGOENCEPHALITIS • Most common agents: staphylococci, streptococci
• Exudate in basal cisterns & near cranial • Morphology
Gross
nerves o Central focus of liquefactive necrosis
• Caseating granulomas o Marked vasogenic edema (because of neovascularization in the
• Obliterative endarteritis of subarachnoid surrounding granulation tissue)
vessels → Infarction o Healing: Collagenous capsule with surrounding reactive gliosis
Histology • Adhesive arachnoiditis (Healing) → with gemistocytic astrocytes
Hydrocephalus • Clinical manifestations
• Tuberculomas: Distinct masses (can o Mass effect: Neurologic symptoms, ↑ ICP
o Abnormal CSF findings
present as a space-occupying lesion)
• Complications
o Extension: Ventriculitis, Meningitis, Venous sinus thrombosis
o Herniation
NEUROSYPHILIS
MENINGOVASCULAR PARETIC TABES DORSALIS
Common sites of • Meninges on the base of the
• Cerebral cortex (frontal lobe) • Sensory axons in dorsal roots
involvement brain
• Progressive cognitive impairment with • Locomotor ataxia, Areflexia
Clinical findings • Chronic meningitis mood alterations → severe dementia • Joint damage (Charcot joints)
(general paresis of the insane) • Lightning pains
• Obliterative endarteritis • Neuronal loss • Axonal loss and demyelination of
Histologic (Heubner arteritis) • Microglial proliferation dorsal roots
findings • Perivascular plasma cells • Gliosis • Dorsal column atrophy
• Gummas • Iron deposits (perivascular, neuropil)
OTHER MENINGITIDES PROTOTYPES OF NEURODEGENERATIVE DISEASES
ORGANISM HISTOLOGIC FINDINGS ANATOMIC LOCATION CLINICAL CONDITION
• Hemorrhagic necrotizing encephalitis Cortex • Dementias
HSV (Temporal and orbital gyri of frontal lobe) Basal Ganglia and Brainstem • Parkinsonism
• Cowdry Type A inclusion bodies Spinal cord and Cerebellum • Ataxia
• CMV inclusion-bearing cells
Motor neurons • Muscle atrophy
• Subacute encephalitis involving subependymal
regions (hemorrhagic necrotizing
CMV PRION DISEASES
ventriculoencephalitis and choroid plexitis)
• In utero: Microcephaly, Periventricular • Rapidly progressive neurodegenerative disease
calcification o Cellular protein conversion to an abnormal variant →
• Neuronophagia of the anterior-horn motor neurodegenerative disease
Poliomyelitis
neurons of the spinal cord • Prion proteins: Resistant to protease digestion, can self-
• Widespread neuronal degeneration most propagate, and can spread
severe in brainstem • Most common prion disease: Creutzfeldt-Jakob disease
• Negri bodies: Cytoplasmic, round to oval, CREUTZFELDT-JAKOB DISEASE
Rabies
eosinophilic inclusions in pyramidal neurons
• Peak incidence: 7th decade
of the hippocampus and Purkinje cells of the
cerebellum
• Onset: Progressive dementia and involuntary jerks on sudden
stimulation (Startle myoclonus)
• Microglial nodules, multinucleated giant cells,
HIV • Uniformly fatal (Mean survival = 7 months)
sometimes foci of necrosis, and reactive gliosis
• Patchy to confluent white matter injury • Morphology
• Demyelination and axonal loss o Spongiform transformation of cerebral cortex and deep
JC virus gray matter (Pathognomonic)
• Glassy amphophilic intranuclear inclusions in
oligodendrocytes o Kuru plaques: Extracellular deposits of Congo Red and PAS
• Expanded perivascular (Virchow-Robin) (+) aggregated abnormal protein, usually in cerebellum
Cryptococcus spaces containing aggregates of organisms
without significant inflammation or gliosis ALZHEIMER DISEASE
• Most common cause of dementia in older adults
DEMYELINATING DISEASES • Slow, unrelenting course, impaired higher intellectual functions
• Diseases characterized by preferential damage to myelin with • Pneumonia: Usual terminal event
relative preservation of axons • Morphology:
• Mechanisms of demyelination o Cortical atrophy (Most pronounced in frontal, temporal, and
o Immune: Multiple sclerosis (most common demyelinating parietal lobes)
disorder) o Neuritic plaques (Aβ): focal, spherical collections of dilated,
o Oligodendrocyte infection: Progressive multifocal tortuous, neuritic processes around a central amyloid core
encephalopathy (JC polyomavirus) o Neurofibrillary tangles (tau): Cytoplasmic bundles of
o Genetic: Leukodystrophies filament in neurons
§ Correlates more with degree of dementia
§ Not specific for AD
MULTIPLE SCLEROSIS
• Autoimmune demyelinating disorder characterized by distinct
episodes of neurologic deficits, separated in time, attributable
PARKINSON DISEASE
to patchy white matter lesions that are separated in space • Loss of Dopaminergic neurons in Substantia Nigra
• Cell-mediated (Mainly CD4+) hypersensitivity to myelin sheath • Dementia with Lewy Bodies: Parkinson + Dementia
• Clinical aspects: • Triad: Tremor, Rigidity, Bradykinesia
o Common initial manifestation: Unilateral involvement of the • Morphology
optic nerve (optic neuritis) o Pallor of substantia nigra and locus coeruleus
o CSF findings: Moderate pleocytosis, mildly elevated protein, o Lewy body (α-synuclein): Cytoplasmic, eosinophilic,
↑ IgG, Oligoclonal IgG bands (CSF electrophoresis) inclusion with a dense core surrounded by a pale halo
• Morphology: Multiphasic sclerotic plaques o Dementia with Lewy Bodies: Lewy bodies in cortical and
§ Active plaque: Evidence of ongoing myelin breakdown brainstem neurons
§ Inactive plaque: Myelin depletion with and gliosis
§ Shadow plaque: Evidence of partial and incomplete HUNTINGTON DISEASE
remyelination • Loss of striatal neurons that dampen motor output →
excessive motor output (generalized jerky, dystonic movements
NEURODEGENERATIVE DISEASES (chorea) → bradykinesia and rigidity (later)
• Progressive loss of neurons that are functionally related • Dementia: due to cortical neuronal loss
• Accumulation of protein aggregates • Pneumonia: Most common cause of death
DISEASE PROTEIN AGGREGATES • Morphology
o Cortical atrophy (Most common: Frontal lobe)
Alzheimer disease • Aβ, Tau
o Caudate & Putaminal atrophy with loss of striatal neurons
Parkinson disease • Tau, α-synuclein
o Huntingtin aggregates in cortical and striatal neurons
Huntington disease • Polyglutamine aggregates
Amyotrophic lateral sclerosis • TPD-43, FUS
FRIEDREICH ATAXIA • WHO Classification of CNS tumors integrates morphology and

• Autosomal recessive disorder characterized by progressive molecular data in order to provide prognostically relevant
ataxia, spasticity, weakness, sensory neuropathy, and diagnoses
cardiomyopathy o WHO Grade (I-IV) reflects biologic behavior
• Symptoms usually surface in the first decade of life
• Pathogenesis: GAA trinucleotide repeat expansion (Ch9) → ↓ ASTROCYTOMAS
frataxin → ↓ mitochondrial oxidative phosphorylation • Two broad types:
• Morphology o Infiltrating astrocytomas: Infiltrative borders on
o Spinal cord: Axonal loss and gliosis neuroimaging (More common in adults)
o Neuronal degeneration of motor cortex, brainstem, o Localized astrocytomas: Well-defined borders on
cerebellum, spinal cord neuroimaging
o Heart
§ Enlarged with pericardial adhesions INFILTRATING ASTROCYTOMAS
§ Multifocal destruction of myocardial fibers with • Diffuse astrocytoma (WHO II/IV)
inflammation and fibrosis • Anaplastic astrocytoma (WHO III/IV)
• Glioblastoma (WHO IV/IV)
AMYTROPHIC LATERAL SCLEROSIS
• Loss of upper motor neurons and lower motor neurons WHO CLASSIFICATION OF INFILTRATING ASTROCYTOMAS
o Consequence: Denervation of Skeletal muscles → weakness TYPE GRADE MORPHOLOGY
and atrophy Diffuse II • Atypia
• Pathogenesis: SOD1 (Ch21) mutation Anaplastic III • Atypia + Mitosis
• Morphology: Predominantly motor involvement • Atypia + Mitosis + (Microvascular
Glioblastoma IV
o Upper motor neurons: Cerebral cortex Proliferation or Necrosis)
§ Atrophic BA 4,6 (Precentral gyrus)
o Lower motor neurons: Brainstem and Spinal cord GLIOBLASTOMA
§ Thinned anterior roots • High-grade infiltrating astrocytoma with the following defining
§ Loss of motor neurons and cranial nerve motor nuclei features:
§ Bunina bodies: PAS(+) cytoplasmic inclusions seen in o Necrosis: Palisading of tumor cells around necrosis
remaining neurons o Microvascular proliferation: Glomeruloid proliferation of
§ Corticospinal tract degeneration endothelial cells
PILOCYTIC ASTROCYTOMA (WHO I/IV)

TOXIC AND METABOLIC DISEASES
• Localized low-grade glioma usually found in children in the
INSULT FINDINGS
infratentorial area e.g., cerebellum
• Wernicke encephalopathy: Ataxia,
confusion, ophthalmoplegia (ACO) • Neuroimaging: Well-defined solid or cystic mass with solid
o Hemorrhage and necrosis of the component (mural nodule)
mammillary bodies • Morphology
Thiamine o Low to moderately cellular with biphasic architecture
• Korsakoff syndrome: Confabulation,
deficiency § Compact fibrillary areas: Bipolar cells with hair-like
Hallucination, Amnesia (CHA)
o Cystic space with hemosiderin-laden processes
macrophages in dorsomedial nucleus of § Loose microcystic areas: Multipolar cells
the thalamus o Rosenthal fibers: Eosinophilic, corkscrew-shaped inclusions
• Subacute combined degeneration o Eosinophilic granular bodies
Cobalamin
o Degeneration of ascending and descending
deficiency
spinal tracts
• Simulates ischemic injury
Hypoglycemia • Most susceptible neurons: Large cortical
pyramidal neurons
Hyperglycemia • No significant changes
• Alzheimer Type II cells in cortex, basal
Hepatic nuclei, and subcortical gray matter
encephalopathy o Astrocytes with large nuclei and scant PILOCYTIC ASTROCYTOMA
cytoplasm Figure 43.64. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 1995.
• Coagulative necrosis → gliosis

• Vascular fibrinoid necrosis → sclerosis OLIGODENDROGLIOMA (WHO II/IV)
Radiation
• Axons and cell bodies: Dystrophic • Distinct genetic mutation: IDH1 and concurrent 1p19q
mineralization codeletion
• Neuroimaging: Well-demarcated lesions usually in cortex and
TUMORS subcortical white matter
• In children, most are Infratentorial • Morphology
• In adults, most are Supratentorial o Fried-egg appearance of cells: Regular cells with spherical
• Most common tumor: Metastases nuclei with finely granular chromatin surrounded by a clear
• Most common primary: Gliomas halo of vacuolated cytoplasm
o Gliomas: Astrocytomas, Oligodendrogliomas, Ependymomas o Delicate “chicken wire” vascular network
• Clinical aspects o Calcifications
o Symptoms related to mass effect o Perineuronal satellitosis in cortical tumors
o Symptoms depend on location of the tumor
o Any CNS neoplasm, if situated in critical brain areas, may have
lethal consequences
PATHOLOGIC EVALUATION OF CNS TUMORS

• Always check the patient’s age
• Always look at the neuroimaging findings (Location, Borders, OLIGODENDROGLIOMA
Cystic/Solid)
o Age and neuroimaging findings alone can greatly reduce the
number of differential diagnoses
EPENDYMOMA (WHO II/IV) FAMILIAL TUMOR SYNDROMES

• Common location depends on age TUBEROUS SCLEROSIS COMPLEX
o 4th ventricle: First two decades of life • Autosomal dominant
o Spinal cord: Adults and Neurofibromatosis Type 2 patients o Loss of function of TSC1 (Ch9) and TSC2 (Ch16)
• Morphology • Hamartomatous cortical tubers and subependymal nodules →
o Gland-like round or elongated structures lined by cells with Subependymal giant-cell astrocytomas (SEGA)
fibrillary process and bland-appearing nuclei • Renal angiomyolipoma, Retinal glial hamartomas, Pulmonary
o Perivascular pseudorosette: Perivascular nuclear free zone lymphangioleiomyomatosis, Cardiac rhabdomyomas, Liver,
composed of thin ependymal processes radiating toward the Kidney, and Pancreatic cysts, and Skin tumors (Angiofibromas,
central blood vessel Subungual fibromas)
NEUROFIBROMATOSIS
• Autosomal dominant disorders
NF TYPE 1 NF TYPE 2
• Neurofibromas
• MPNSTs
• Optic nerve gliomas • Bilateral eight
EPENDYMOMA • Other glial tumors and nerve
hamartomatous lesions Schwannomas
• Pheochromocytomas • Multiple
MEDULLOBLASTOMA (WHO IV/IV) Components
• Pigmented iris nodules Meningiomas
• Malignant embryonal tumor of the cerebellum (Lisch nodules) • Ependymomas
• Predominantly afflicts children • Cutaneous (Commonly
• Morphology (Classic type) hyperpigmented intraspinal)
o Small, round, blue cells with Homer-Wright pseudorosettes macules (Café au lait
(as in Neuroblastoma) spots)
o Highly proliferative (Mitosis and Ki-67 index)
• Common complication: Dissemination to CSF 28. EYE
• Radiosensitive
• Orbit • Sclera • Uvea
• Eyelid • Cornea • Retina and Vitreous
• Conjunctiva • Anterior segment • Optic nerve
ORBIT
PROPTOSIS
MEDULLOBLASTOMA, CLASSIC TYPE
Figure 43.108. Goldblum et al. Rosai and Ackerman’s Surgical Pathology, 11th ed. 2018. p. 2001. • Forward displacement of the eye
• Issues: Cosmetic, Chronic corneal exposure to air → Ulceration
PRIMARY CNS LYMPHOMA (presence of pain, due to presence of pain fibers in the cornea)
• Most common CNS neoplasm in immunocompromised • Forward displacement
individuals Axial • Seen in Graves ophthalmopathy, Optic nerve
• Most common subtype: DLBCL tumors
o In immunosuppressed patients, usually EBV (+) • Lacrimal gland inflammation/neoplasm →
Positional
• PDL1 overexpression in immunocompetent patients inferomedial globe displacement
o Potential target of immune checkpoint inhibitors If the pathology is contained within the cone made by the rectus muscles,
it will result in axial proptosis. Graves ophthalmopathy involves the EOMs,
MENINGIOMA and gliomas and meningiomas arise in the optic nerve. These structures
are within the aforementioned cone.
• Predominantly affects adults Dr. Elomina
• Cytogenetic origin: Meningothelial cells of arachnoid

TUMORS OF THE ORBIT
• Neuroimaging: Dural-based masses
• Histologically heterogeneous (most are WHO I/IV) • Most common primary tumor of the orbit
• Atypical Meningioma (WHO II/IV): More mitotic activity, with • Childhood: Capillary hemangioma,
Vascular
propensity to invade other structures Lymphangioma (unencapsulated)
tumors
• Morphology (WHO I/IV types) • Adult: Encapsulated Cavernous
o Meningothelial meningioma (syncytial): whorled clusters of hemangioma
cells in groups without visible cell membranes Encapsulation is important in assessment of orbital tumors, because it
o Psammomatous meningioma: Numerous Psammoma bodies can limit the differential diagnoses i.e., there are only few encapsulated
orbital tumors (Pleomorphic adenoma of lacrimal gland, Dermoid
cyst, and Schwannoma).
Dr. Elomina
EYELID
Blepharitis • Inflammation of the eyelid
• Lipogranuloma of the eyelid due to
Chalazion obstruction of sebaceous ducts → lipid
extravasation → granuloma formation
MENINGOTHELIAL MENINGIOMA Basal cell CA • Most common malignancy of the eyelid
METASTASES TO BRAIN CONJUNCTIVA

• Most common sources: Lung, Breast, (Melanoma), Kidney, GIT, CONJUNCTIVITIS
Morphology: • Clinically, redness and itching
o Sharply demarcated masses, often at the junction of gray and • Most cases of bacterial and viral conjunctivitis do not scar
white matter, usually surrounded by a zone of edema • Chlamydia trachomatis (trachoma) → Significant
o Meningeal carcinomatosis: Lung and Breast carcinomas conjunctival scarring
• Consequence of scarring: Dry eye (due to loss of goblet cells → ↓
Mucin to which the tear film adheres)
PINGUECULA AND PTERYGIUM ENDOPHTHALMITIS AND PANOPHTHALMITIS
• Submucosal conjunctival elevations that arise in sun-exposed ANTERIOR CHAMBER EXUDATES
areas of the conjunctiva • Secondary to ↑ vascular permeability of ciliary body vessels
• Biopsy is done to rule out precursors of actinic damage- • Sequelae:
related malignancies (Squamous cell carcinoma, Melanoma)
Keratic • Exudates adhering to corneal
PINGUECULA PTERYGIUM
precipitates endothelium
Histology • Submucosal fibrovascular connective tissue
• Anterior synechiae between iris &
Pathogenesis • Actinic (sun-induced) damage
trabecular meshwork
Corneal invasion • No • Yes
Synechiae • Leads to ↑ IOP
Visual problems • No • Astigmatism
(fibrous • Posterior synechiae between iris &
CONJUNCTIVAL NEOPLASMS adhesions) anterior surface of lens
• Most common site: Limbus • Leads to fibrous metaplasia of lens (due
• Eyelid and conjunctivae are rich in lymphatics to ↓ aqueous humor exposure)
• Common malignancies: ENDOPHTHALMITIS
o Squamous cell carcinomas
• Inflammation within the vitreous humor
o Melanomas (Metastasis → Parotid & Submandibular nodes)
o Endogenous: Hematogenous delivery of infection
o Exogenous: From environment (access through wound)
SCLERA
PANOPHTHALMITIS
• Has intrinsically poor wound healing because of low vascularity
• Inflammation involving the retina, uvea, sclera, and orbit
Necrotizing • Immune deposition w/in sclera
scleritis • Seen in Rheumatoid arthritis
• Occurs due to optical Tyndall effect (brown UVEA
color of uvea appears blue) • Components: Iris, Ciliary Body, Choroid
• Seen in Osteogenesis imperfecta, Staphyloma, o Choroid: One of the most richly vascularized tissues in the
Congenital melanosis coli human body
Blue sclera
• Staphyloma: Zone of scleral ectasia line by
uveal tissue (due to ↑ intraocular pressure) UVEITIS
• Congenital melanosis coli: Heavily • Inflammation of the tissues that comprise the uvea
pigmented congenital uveal nevus o Infectious: P. jirovecii, M. tuberculosis, T. gondii
o Autoimmune: Seen in systemic autoimmune diseases
CORNEA o Idiopathic: Sarcoidosis
• Cornea: Main refractive surface of the eye (contributed 2/3 of NEOPLASMS
the total refractive power of the eye: 40 out of 60 diopters) • Most common intraocular malignancy
• Distortion of the corneal contour → astigmatism Metastasis
• Mostly found in choroid (due to rich
• Corneal thinning → cone-shaped cornea to uvea
vascularity)
• Seen in Down syndrome, Marfan syndrome, & Uveal • Most common primary intraocular malignancy
Atopic diseases melanoma in adults (vs. retinoblastoma in children)
Keratoconus
• Morphology: Corneal thinning w/ breaks in
• Most common location containing metastases
Bowman layer, Corneal hydrops (effusion of Liver
aqueous humor into Descemet membrane)
of uveal melanomas
In a patient with histologically confirmed metastatic melanoma in the
KERATITIS AND ULCERS
liver without any obvious primary, investigate for uveal melanoma.
• Notable organisms: HSV (granulomatous reaction in Descemet Dr. Elomina
membrane), VZV (in Herpes zoster), Acanthamoeba, other RETINA AND VITREOUS
bacterial and fungal organisms RETINAL DETACHMENT
• Inflammation → Collagenase activation: Accelerates
• Separation of neurosensory retina from the retinal pigment
dissolution of corneal stroma
epithelium (RPE)
• Hypopyon: Collection of pus in anterior chamber
• Clinical significance: Ophthalmologic emergency
o Exudates leak from iris and ciliary body vessels into anterior
• Types: Rhegmatogenous (RRD) and Non-rhegmatogenous
chamber
(NRRD)
RRD NRRD
ANTERIOR SEGMENT Full-thickness
• Yes • No
CATARACT retinal defect
• Opacification of the lens → absence of the ROR in fundoscopy • Any disorder with
• Vitreous travels
• Causes: increased
through full-
o Systemic diseases (Galactosemia, DM, Wilson disease) exudation that
thickness retinal
Pathogenesis accumulates
o Drugs (Corticosteroids), Radiation, Trauma defect and dissects
between the RPE
o Age-related (nuclear sclerosis) between RPE and
and neurosensory
§ Urochrome deposition → brown lens (distorted perception of neurosensory retina
retina
blue color)
RETINAL VASCULAR DISEASE
GLAUCOMA
HYPERTENSIVE RETINOPATHY
• Diseases characterized by distinctive changes in visual field and
optic nerve cup • Arteriolosclerosis (Copper or silver wiring)
• Most are associated with ↑ IOP o Vein occlusion in areas where arteries and veins cross
o Normal or low-tension glaucoma: Characteristic optic nerve and • Cotton-wool spots: Collections of cytoid bodies around infarcted
visual field changes without increased IOP nerve fiber retinal layer
OPEN-ANGLE ANGLE-CLOSURE o Cytoid bodies: Accumulation of mitochondria around swollen
Trabecular ends of damaged axons
meshwork • Yes • No • Malignant hypertension: Retinal and choroidal vessel damage
access o Choroidal vessels
• Peripheral zone of the § Elschnig pearls: Focal choroidal infarcts
• ↑ Resistance to § Non-rhegmatogenous retinal detachment: Secondary
iris adheres to the
aqueous humor damage of RPE → Exudate accumulation
Pathogenesis trabecular meshwork
outflow in open
→ ↓ egress of aqueous o Retinal vessels
angle
humor § Macular star: Spoke-like exudate in outer plexiform layer
↑ IOP • Yes • Yes
DIABETIC RETINOPATHY TUMORS
• Reliable indicator of DM in the eye: Thickening of basement RETINOBLASTOMA
membrane of epithelium of pars plicata of ciliary body • Most common primary intraocular malignancy in children
• 40% of patients have a germline mutation in one RB allele
TYPES OF DIABETIC RETINOPATHY
• Leukocoria: Common presentation (“White ROR”)
NONPROLIFERATIVE PROLIFERATIVE
• Morphology:
• Thickening of BM of • Retinal o “Small, round blue cells” (small, round cells with
retinal blood vessels neovascularization:
Histologic • Microaneurysms
hyperchromatic nuclei)
Vessels have already
changes • Exudates in outer o Flexner-Wintersteiner rosettes and fleurettes: Tumor cells
reached internal
plexiform layer encircling a central lumen (photoreceptor differentiation)
limiting membrane
• Mainly because of neovascularization Remember: RB mutations can lead to retinoblastoma & osteosarcoma.
Dr. Rubio
o Retinal detachment: Non-rhegmatogenous → RETINAL LYMPHOMA
Rhegmatogenous (with severe traction caused • Aggressive tumor involving RPE & Neurosensory retina
by neovascular membrane on the retina)
Sequelae • Most common type: DLBCL
o Neovascular glaucoma: Neovascular
membrane causes anterior synechiae → Angle- • Brain involvement via the optic nerve
closure glaucoma
• Clinically: Visual loss OPTIC NERVE
OPTIC NERVE EDEMA
VASCULAR OCCLUSION SYNDROMES
• Swelling of the optic nerve head
• Central retinal artery occlusion (CRAO) o Unilateral: due to Nerve compression
o Ophthalmologic emergency o Bilateral (Papilledema): due to Increased ICP
• Central retinal vein occlusion (CRVO) • Morphology: Swollen & hyperemic optic nerve head
FEATURE CRAO CRVO
• Occurs in ischemia
Ischemia e.g., CRA
• May occur with or GLAUCOMATOUS OPTIC NERVE DAMAGE
without ischemia • Diffuse loss of ganglion cells and thinning of retinal nerve
Atherosclerosis
• Hollenhorst fiber layer
• Ischemic: • Atrophic, cupped optic nerve (in advanced cases)
plaques: Fragments
Neovascularization of
of atherosclerotic • Pediatric cases:
retina, optic nerve head,
plaque lodged in o Buphthalmos: Diffuse eye enlargement
Histologic and iris (angle-closure
retinal circulation o Megalocornea: Enlargement of cornea
findings glaucoma)
• Cherry-red spot in o Staphyloma: Thinning of the sclera
• Non-ischemic:
macula with diffuse
Hemorrhages, Exudates,
retinal pallor in total
Macular edema OPTIC NEURITIS
occlusion
• Loss of vision secondary to demyelination of the optic nerve
• Multiple sclerosis: One of the most important causes
DEGENERATIVE DISEASES
AGE-RELATED MACULAR DEGENERATION (ARMD)
PHTHISIS BULBI
• Types:
• a.k.a. “End Stage Eye Disease”
• Drusen formation in Bruch membrane &
Dry ARMD • Atrophic eye with internal disorganization
geographic RPE atrophy
Wet ARMD • Choroidal neovascularization • Causes: Trauma, Inflammation, Chronic retinal detachment, etc.
• Histology:
RETINITIS PIGMENTOSA o Ciliochoroidal effusion: Presence of blood between ciliary
body and sclera and choroid and sclera
• X-linked, AR, or AD disorder due to apoptosis of rods & cones
o Cyclitic membrane: Presence of membrane from one aspect of
§ Apoptosis of Rods: Nyctalopia
ciliary body to the other
§ Apoptosis of Cones: Central visual acuity impairment
o Chronic retinal detachment
• Morphology: o Optic nerve atrophy
o Waxy pallor of the optic disc o Intraocular bone: Due to Osseous metaplasia of the RPE
o Accumulation of retinal pigment around blood vessels o Thickened sclera (usually the posterior portion)
o Hypotony: ↓ IOP
END OF PATHOLOGY

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TOPNOTCH MEDICAL BOARD PREP PATHOLOGY PHASE X DIGITAL HANDOUT BY DR. PATRICK A. MABUGAT
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PATHOLOGY – PHASE X
Topnotch Medical Board Preparation Incorporated. Any violation and or infringement,
whether intended or otherwise shall be subject to legal action and prosecution to the full
By Patrick A. Mabugat, RMT, MD
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10 HI-YIELD TOPICS
1. HYPERSENSITIVITY
trends and feedback. Please buy all recommended review books and other materials listed • HYPERSENSITIVITY = INJURIOUS IMMUNE REACTIONS
below.
• excessive or harmful reaction an antigen
Type Immune Mechanisms Histopathologic Lesions Prototypical Disorders

Production of IgE antibody → immediate Vascular dilation, edema,
Anaphylaxis; allergies;
Immediate (type I) release of vasoactive amines and other smooth muscle contraction,
bronchial asthma (atopic
hypersensitivity mediators from mast cells; later mucus production, tissue injury,
forms)
recruitment of inflammatory cells inflammation

Production of IgG, IgM → binds to antigen Phagocytosis and lysis of cells;
Antibody-mediated Autoimmune hemolytic
on target cell or tissue → phagocytosis or inflammation; in some diseases,
(type II) anemia; Goodpasture
lysis of target cell by activated complement functional derangements
hypersensitivity syndrome
or Fc receptors; recruitment of leukocytes without cell or tissue injury

Deposition of antigen-antibody complexes
Systemic lupus erythematosus;
Immune complex- → complement activation → recruitment of
Inflammation, necrotizing some forms of
mediated (type III) leukocytes by complement products and Fc
vasculitis (fibrinoid necrosis) glomerulonephritis; serum
hypersensitivity receptors → release of enzymes and other
sickness; Arthus reaction
toxic molecules

Cell-mediated Activated T lymphocytes → (1) release of Perivascular cellular infiltrates; Contact dermatitis; multiple
(type IV) cytokines, inflammation and macrophage edema; granuloma formation; sclerosis; type I diabetes;
hypersensitivity activation; (2) T cell-mediated cytotoxicity cell destruction tuberculosis
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2. ATHEROSCLEROSIS
• KEY PROCESSES:
• INTIMAL THICKENING + LIPID ACCUMULATION
• Lipid accumulated by macrophages through a variety of
scavenger receptors (distinct from the LDL receptor):
MODIFIED LDL
• Because the modified lipoproteins cannot be completely
degraded, chronic ingestion leads to the formation of lipid-filled
macrophages called: FOAM CELLS
• Atherosclerotic plaques are susceptible to the following

pathologic changes:
1. Rupture, ulceration, erosion - thrombosis
2. Hemorrhage into a plaque
3. Atheroembolism
4. Aneurysm formation
3. SEX CHROMOSOMAL DISEASES

KLINEFELTER SYNDROME
• Two or more X chromosomes and one or more Y
chromosomes.
• Most frequent forms of genetic disease involving the sex
• Yellow white and encroach on the lumen of the artery; chromosomes, most common causes of hypogonadism in
superimposed thrombus over ulcerated plaques is red brown. the male.
• Plaques vary in size; can coalesce to form larger masses. • Most consistent finding in Klinefelter’s: hypogonadism
• Atherosclerotic lesions are patchy, usually involving only a
portion of any given arterial wall, therefore looking
“eccentric”
• Most extensively involved

vessels: Lower abdominal aorta
> coronary arteries > popliteal
arteries > internal carotid
arteries > vessels of the circle
of Willis.
• Abdominal aorta is typically
involved to a much greater
degree than the thoracic aorta
• Vessels of the upper
extremities, mesenteric and
renal arteries, except at their
ostia are spared.
• Most tend to have a consistent
degree of atherosclerotic
burden, however severity of
disease in one arterial
distribution does NOT always
predict its severity in another.
TURNER SYNDROME 5. GERD
• Complete or partial monosomy of the X chromosome
GASTROESOPHAGEAL REFLUX DISEASE
• Most common sex chromosome abnormality in females.
• Characterized primarily by: hypogonadism in phenotypic
females
• Most frequent cause of
esophagitis, most common
outpatient GI diagnosis: Reflux
of gastric contents
• Most common cause of
gastroesophageal reflux:
Transient lower esophageal
sphincter relaxation
• Imbalances (excess or loss) of sex chromosomes are much
better tolerated than of autosomes.
• Due to: • Cause of gastroesophageal reflux:
o (1) lyonization or inactivation of all but one X o Swallow-induced lower esophageal sphincter relaxations
chromosome o Forceful opening of a relatively hypotensive lower
o (2) modest amount of genetic material carried by the Y esophageal (coughing, straining, or bending)
chromosome. • Other conditions that decrease lower esophageal sphincter tone
or increase abdominal pressure:
4. HIRSCHSPRUNG o Alcohol and tobacco use
o Obesity
CONGENITAL AGANGLIONIC MEGACOLON
o Central nervous system depressants
• Pathology: Premature arrest of migration of neural crest o Pregnancy
cells from cecum to rectum or when the ganglion cells o Hiatal hernia
undergo premature death o Delayed gastric emptying
• Distal intestinal segment lacks: Both the Meissner submucosal o Increased gastric volume
and the Auerbach myenteric plexus (“aganglionosis”). • Diagnostic of reflux esophagitis in biopsy:
o Basal zone hyperplasia (20%)
o Presence of eosinophils
• Appearance of aganglionic region: Normal or contracted

appearance.
• Appearance of normally innervated proximal colon:
Progressive dilation becoming massively distended • Complication of chronic GERD that is characterized by intestinal
(megacolon). metaplasia within the esophageal squamous mucosa: Barrett’s
esophagus
• Diagnosis: Documenting the absence of ganglion cells within the
affected segment = rectal suction biopsy
• Enzyme that is overexpressed in patients with Hirschsprung
disease: Acetylcholinesterase
• Clinical presentation: Failure to pass meconium in the

immediate postnatal period. Obstruction or constipation
follows.
• Major threats to life:
o Enterocolitis
o Fluid and electrolyte disturbances
o Perforation (cecum)
o Peritonitis
• Most esophageal adenocarcinomas arise from: Barrett • EBV-specific CD8+ cytotoxic T cells: Atypical lymphocytes
esophagus
• Antibodies produced by EBV-infected B cells that recognize

sheep, cow or horse red cells: Heterophile antibodies
• Heterophile positive: EBV
6. EPSTEIN BARR VIRUS

• EBV causes infectious • Heterophile negative: CMV
mononucleosis - benign, self-
limited lymphoproliferative
disorder
• Associated with: hairy
leukoplakia, lymphomas and
nasopharyngeal carcinoma
• Transmission: Close human • Sera + sheep RBC and look for agglutination = (+): Paul-Bunnel
contact (saliva during kissing) test
• Sera + bovine RBC and look for agglutination = (+): Monospot
• Main reservoir of infection: B cells test
• Receptor for EBV on B cells: CD21 (CR2) • Sera + bovine RBC, then + sheep RBC, if it does not agglutinate =
(+) Davidsohn’s differential
• EBV establishes latent infection, during which the virus persists
as an extrachromosomal episome • Type of Hodgkin lymphoma with the highest association with
EBV, poorest prognosis, and is the least common: Lymphocyte-
depleted
• Reactive condition marked by cytopenias and signs and
symptoms of systemic inflammation related to macrophage
activation (cytokine storm): Hemophagocytic
lymphohistiocytosis (macrophage activation syndrome)
o Most common trigger: Epstein-Barr virus
o If untreated, this picture can progress rapidly to multiorgan
failure, shock, and death
LYMPHOCYTE-DEPLETED HODGKIN LYMPHOMA (LEFT),

• Ability conferred by EBV upon normal lymphocytes derived HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (RIGHT)
from bone marrow: Immortalization
7. PSORIASIS
• Immune-mediated disease clinically characterized by
erythematous, sharply demarcated papules and rounded
plaques covered by silvery micaceous scale
• Traumatized areas often develop lesions of psoriasis: KOEBNER
PHENOMENON
• Features
o Stratum granulosum is thinned or absent, and extensive
overlying parakeratotic scale is seen
o Multiple, minute, bleeding points when the scale is lifted from
the plaque: AUSPITZ SIGN
8. PROSTATE CANCER
• Most common form of cancer in the men: Adenocarcinoma of
the prostate
• Common site: Peripheral zone, classically posterior
• Neutrophils form small aggregates within slightly spongiotic foci

of the superficial epidermis: SPONGIFORM PUSTULES (OF
KOGOJ) • Chief site of hematogenous
• Neutrophils form small aggregates within the parakeratotic spread occurs of prostate cancer:
stratum corneum: MUNRO MICROABSCESSES Bones (axial skeleton)
• Bones commonly involved:
lumbar spine > proximal femur >
pelvis > thoracic spine > and ribs
• Typical feature of bony
metastases that strongly point to
a prostatic origin: Osteoblastic
• DIAGNOSIS:
o Widely used to assist with the diagnosis and management of
prostate cancer: Measurement of serum PSA levels
o Digital rectal examination may detect some early prostatic
carcinomas because of their posterior location, but low
sensitivity and specificity
o Transrectal ultrasonography show characteristic findings in
TYPE OF PSORIASIS FEATURES those with cancerous prostates, but poor sensitivity and
• Most common variety; stable, specificity
slowly enlarging plaques, o Confirmatory: Transrectal needle biopsy
PLAQUE-TYPE • HISTOLOGIC FEATURES:
remain unchanged for long
periods of time o Well-defined, readily demonstrable gland patterns. In contrast
• Affects intertriginous regions, to benign glands, prostate cancer glands are more crowded
including the axilla, groin, o Lack branching and papillary infolding
INVERSE PSORIASIS submammary region, and navel; o Absent outer basal cell layer
it also tends to affect the scalp, o Pleomorphism not marked
palms, and soles. o Mitotic figures uncommon
• Small erythematous, scaling
GUTTATE PSORIASIS papules, frequently after upper
(ERUPTIVE PSORIASIS) respiratory tract infection with
β-hemolytic streptococci
• Characterized by fever lasting
several days, an accompanying
generalized eruption of
PUSTULAR PSORIASIS
sterile pustules, and a
background of intense
erythema PROSTATE-SPECIFIC ANTIGEN
• PSA is a product of prostatic epithelium and is normally secreted
TREATMENT OF PSORIASIS in the semen; androgen-regulated serine protease whose
Treatment for localized, plaque type Mid-potency topical function is to cleave and liquefy the seminal coagulum formed
psoriasis glucocorticoids after ejaculation
Treatment for widespread psoriasis Ultraviolet light • PSA is organ specific, but not cancer specific
Drug that should not be used for the • Serum levels of PSA are elevated to a lesser extent in BPH
treatment of psoriasis due to the than in prostatic carcinomas
potential for the development of life- Oral glucocorticoid • Free PSA is lower in men with prostate cancer (than in men with
threatening pustular psoriasis when BPH)
therapy is discontinued • Other factors that also increase serum PSA levels:
Treatment of choice of pustular o Prostatitis
Oral retinoids o Infarction of nodular hyperplasias
psoriasis in nonpregnant patients
o Instrumentation of the prostate
o Ejaculation
• Cutoff: 4 ng/mL
•
9. BENIGN BREAST TUMORS 10. SLE

• Most common benign tumor of the female breast: GENERAL FEATURES OF AUTOIMMUNE DISEASES
FIBROADENOMA • Autoimmune diseases tend to be chronic, sometimes with
• Usually present as a palpable mass in young women and as a relapses and remissions, and the damage is often progressive.
mammographic mass in older women. • The clinical and pathologic manifestations of an autoimmune
• The EPITHELIAL COMPONENT is hormonally responsive and disease are determined by: Nature of the underlying immune
there is typically an increase in size due to lactational changes response
during pregnancy.
SYSTEMIC LUPUS ERYTHEMATOSUS
• Hallmark: Production of autoantibodies
• Fundamental defect: Failure of mechanisms that maintain
self-tolerance
• Characterized by injury caused mainly by deposition of
immune complexes and binding of antibodies to various
cells and tissues
• Hypersensitivity type involved in immune complex deposition in
SLE: Type III hypersensitivity
• SLE predominantly affects women of childbearing age (17
through 55 years)
• Injury to the skin, joints, kidney, and serosal membranes is
prominent. Virtually every other organ in the body, however, may
FIBROADENOMA also be affected.
• Well-circumscribed, rubbery, grayish white nodules that bulge • The disease may be acute or insidious in its onset, and is
above the surrounding tissue and often contain slit-like spaces. typically a chronic, remitting and relapsing, often febrile,
• Delicate and often myxoid stroma resembles normal illness
intralobular stroma. AUTOANTIBODY IN SLE ASSOCIATION
• In older women, the stroma typically becomes DENSELY Double-stranded DNA Nephritis, specific for SLE
HYALINIZED and the EPITHELIUM ATROPHIC. U1-RNP
Smith Specific for SLE
Congenital heart block, neonatal
RO (SS-A)/LA (SS-B)
lupus
Phospholipid-protein
Antiphospholipid syndrome
complexes
Multiple nuclear antigens Found in other autoimmune diseases
AUTOANTIBODY IN RA ASSOCIATION
CCP Specific for rheumatoid arthritis
RF Not specific
AUTOANTIBODY IN
ASSOCIATION
SYSTEMIC SCLEROSIS
Diffuse skin disease, specific for
DNA topoisomerase 1
systemic sclerosis
Centromeric proteins Limited skin disease
Acute onset, scleroderma renal
RNA polymerase
crisis, cancer
PHYLLODES TUMORS • ANA staining most often indicative of

• are distinguished from fibroadenomas on the basis of: antibodies to double-stranded DNA:
o Higher cellularity Rim or peripheral staining
o Higher mitotic rate
o Higher nuclear pleomorphism
o Stromal overgrowth
o Infiltrative borders • LE cell – Any phagocytic leukocyte
(neutrophil or macrophage) with
degraded nuclear material
• Tart cell – Any phagocytic leukocyte

(neutrophil or macrophage) with
intact/viable nuclear material
• Extensive subendothelial deposits of

immune complexes (periodic acid-
Schiff stain) in lupus nephritis: Wire
loop lesions
CLASS DESCRIPTION
Class I Minimal mesangial
• Most phyllodes tumors are low-grade; these occasionally recur Class II Mesangial proliferative
locally but do not metastasize Class III Focal lupus nephritis
• Component of the Phyllodes tumor that may metastasize: Class IV Diffuse lupus nephritis
Stromal Class V Membranous nephropathy
Class VI Advanced sclerosing lupus nephritis
40 QUICK HITS
1. LIPOFUSCIN
• Insoluble pigment, lipochrome or “wear-and tear pigment.”
• Yellow-brown, finely granular cytoplasmic, often perinuclear,
pigment.
• Seen in cells undergoing slow, regressive changes; prominent in
the liver and heart of aging patients or patients with severe
malnutrition and cancer cachexia (atrophy)
• Physiologic adaptation for the massive growth of the uterus
during pregnancy: Hypertrophy of muscle fibers
3. HYALURONAN
• Proteoglycans form highly hydrated compressible gels
• In joint cartilage, proteoglycans provide a layer of lubrication
between adjacent boney surfaces
• Sine qua non of OA: Hyaline articular cartilage loss
• Telltale signs of previous episodes of pulmonary edema in

congestive heart failure: HEART FAILURE CELLS
• Due to red cells that within the alveolar spaces, where they are
digested by macrophages, which store the iron recovered from
hemoglobin in the form of: HEMOSIDERIN
• Organelle in which hemosiderin is found: LYSOSOME
4. AML
• Diagnosis of AML - based on the presence of at least 20%
myeloid blasts in the bone marrow.
• Auer rods, distinctive needle-like azurophilic granules
o Particularly numerous in AML with the t(15;17) (acute
promyelocytic leukemia).
2. METAPLASIA
• Replacement of one type of cell with another type
CHRONIC SMOKING
• Ciliated columnar epithelium > Stratified squamous epithelial
cells (most common)
5. CLL
• Most common leukemia of adults in the Western world: CLL
• CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND SMALL
LYMPHOCYTIC LYMPHOMA (SLL) - differ only in the degree of
peripheral lymphocytosis
• CLL - absolute lymphocyte count > 5000 per mm3.
GASTROESOPHAGEAL REFLUX • Pathognomonic for CLL: PROLIFERATION CENTERS
• Squamous epithelium of the esophagus > glandular (gastric or
intestinal) epithelium (more suited to acidic environment)
• SMUDGE CELLS – lymphocytes that are easily disrupted 9. DOWN SYNDROME
• Most common of the chromosomal disorders; major cause
of mental retardation
• 40% of the patients have congenital heart disease
• 10-fold to 20-fold increased risk of developing acute leukemia
• Virtually all older than age 40 develop neuropathologic changes
characteristic of Alzheimer disease
• Patients with Down syndrome have abnormal immune
responses that predispose them to serious infections
6. G6PD DEFICIENCY
• Oxidants cause both intravascular and extravascular hemolysis
• Exposure to oxidants causes the cross-linking of reactive
sulfhydryl groups on globin chains.
• HEINZ BODIES - Dark inclusions of denature hemoglobin within
red cells stained with crystal violet.
• HOWELL-JOLLY BODIES – Basophilic inclusions which are
remnants of nuclei
HEINZ BODIES (LEFT), HOWELL-JOLLY BODIES (RIGHT)
7. THROMBOTIC THROMBOCYTOPENIC
PURPURA 9. MATERNAL AGE AND TRISOMIES
• Deficiency of ADAMTS13, “vWF metalloprotease” - degrades • Risk of autosomal trisomies (13 – Patau, 18 – Edward, 21 – Down)
very high-molecular-weight multimers of von Willebrand factor increases with: INCREASING maternal age
(vWF)
• TTP pentad:
o Fever
o Microangiopathic hemolytic anemia
o Thrombocytopenia
o Renal failure
o Transient neurologic deficits
• HUS - distinguished from TTP by:
o Absence of neurologic symptoms
o Acute renal failure
o Frequent occurrence in children.
10. DERMATOMYOSITIS
• Clinical features: Heliotrope rash, Gottron sign, V sign, shawl
sign, mechanic’s hands
• Distinctive histologic feature: Perifascicular atrophy
Gastric carcinoma
Acanthosis nigricans Lung carcinoma
8. URACHUS VS EXSTROPHY Uterine carcinoma
Bronchogenic carcinoma
Dermatomyositis
Breast carcinoma
• Persistent urachus - the • Exstrophy - developmental

urachus (canal that failure in the anterior wall of
connects fetal bladder with the abdomen and bladder;
allantois) is normally the bladder either
obliterated after birth, but communicates directly
sometimes remains patent through a large defect with
in part or in whole. the surface of the body or
lies as an opened sac.
11. SCLERODERMA
• Distinguishing pathologic hallmark: Combination of widespread
capillary loss and obliterative microangiopathy, with fibrosis in
the skin and internal organs
• Most frequent extracutaneous complication of SSc : Raynaud’s
phenomenon - characterized by episodes of reversible
vasoconstriction
in the fingers and toes
• Hallmark that distinguishes SSc from other connective tissue
diseases : Skin thickening
13. LUNG CANCER

• Most common primary lung cancer – adenocarcinoma
• Strongest association with smoking – small cell carcinoma
12. MULTIPLE MYELOMA

• Overproduction of IgG by plasma cells
• CRAB
o HyperCalcemia • SPHERE of complications of
o Renal involvement lung cancer:
o Anemia o Superior vena cava/thoracic
o Bone lesions (punched out osteolytic lesions) outlet syndromes
• Inclusion bodies in the cytoplasm (Russel bodies) or nucleus o Pancoast tumor
(Dutcher bodies) usually found in atypical plasma cells (Mott o Horner syndrome
cells) o Endocrine (paraneoplastic)
o Recurrent laryngeal nerve
compression (hoarseness)
o Effusions (pleural or
pericardial
PARANEOPLASTIC SYNDROME OF SMALL CELL CANCER:

• ACTH (Cushing syndrome)
• ADH (SIADH)
• Antibodies against presynaptic Ca2+ channels (Lambert-Eaton
myasthenic syndrome) or neurons (paraneoplastic myelitis,
encephalitis, subacute cerebellar degeneration)
14. PRINCIPAL SUBGROUPS OF GLYCOGENESIS

• Hereditary deficiency of one of the enzymes involved in the
synthesis or sequential degradation of glycogen: Glycogen
• BENCE JONES PROTEIN Storage Diseases
o Ig light chains produced in excess in multiple myeloma • Enzyme involved in the hepatic form: Glucose-6-phosphatase
o (+) Heat test - precipitate forms at 40-60, disappears at 100 C, • Enzyme involved in the myopathic form: Muscle
and reappears at 40-60 phosphorylase
Clinicopathologic Specific Enzyme

Morphologic Changes Clinical Features
Category Type Deficiency
In untreated patients: failure to thrive, stunted growth,
hepatomegaly, and renomegaly
Hepatomegaly-intracytoplasmic
Hypoglycemia due to failure of glucose mobilization,
accumulations of glycogen and small
Hepatorenal- often leading to convulsions
amounts of lipid; intranuclear glycogen
vol Gierke Glucose-6- Hyperlipidemia and hyperuricemia resulting from
Hepatic type
disease phosphatase deranged glucose metabolism; many patients develop
Renomegaly-intracytoplasmic
(type I) gout and skin xanthomas
accumulations of glycogen in cortical
Bleeding tendency due to platelet dysfunction
tubular epithelial cells
With treatment: Most survive and develop late
complications (e.g., hepatic adenomas)
Painful cramps associated with strenuous exercise;
McArdle Skeletal muscle only-accumulations of myoglobinuria occurs in 50% of cases; onset in
Muscle
Myopathic type disease glycogen predominant in subsarcolemmal adulthood (>20 years); muscular exercise fails to raise
phosphorylase
(type V) location lactate level in venous blood; serum creatine kinase
always elevated; compatible with normal longevity
Mild hepatomegaly-ballooning of lysosomes Massive cardiomegaly, muscle hypotonia, and
Generalized
with glycogen, creating lacy cytoplasmic cardiorespiratory failure within 2 years; a milder adult
glycogenosis- Lysosomal
Miscellaneous pattern form with only skeletal muscle involvement, presenting
Pompe glucosidase
types Cardiomegaly-glycogen within sarcoplasm with chronic myopathy; enzyme replacement therapy
disease (acid maltase)
as well as membrane-bound available
(type II)
Skeletal muscle-similar to changes in heart
15. CO POISONING
• Acute poisoning by CO is generally a consequence of
accidental exposure or suicide attempt. • Cause of amebic liver abscess
• Most common source of intentional poisoning: Motor vehicle – penetration of splanchnic
• Hemoglobin has 200-fold greater affinity for CO than for vessel and embolization to
oxygen, and the resultant carboxyhemoglobin cannot carry O2 the liver
• In light-skinned individuals, acute poisoning is marked by
a characteristic generalized cherry-red color of the skin and
mucous membranes, which result from high levels of
carboxyhemoglobin.
19. CHICKENPOX
• Histologic finding of chickenpox: Intraepithelial vesicles with
intranuclear inclusions in epithelial cells at the base of the
vesicles
• May lead to destruction of the basal epidermal layer and residual
scarring: Bacterial superinfection of the vesicles
• Involvement of the geniculate nucleus causing facial paralysis:
Ramsay-Hunt syndrome (herpes zoster oticus)
16. ASBESTOS
• Markers of asbestos exposure: Asbestos bodies, ferruginous
bodies, asbestos plaques
• Pleural cancer associated with increased incidence among
people with heavy exposure to asbestos: Malignant
mesothelioma
20. V. CHOLERAE
17. ANOREXIA NERVOSA • Vibrio cholerae - comma-shaped, gram-negative bacteria that
VS BULIMIA NERVOSA cause cholera
• Mode of transmission: Contaminated drinking water (primarily),
NUTRITIONAL
DESCRIPTION COMPLICATIONS food
DISORDER
• Pathogenesis: Produce severe diarrhea by elaboration of an
• Severe PEM
enterotoxin
• Amenorrhea
Self-induced
• Mainstay of treatment of cholera: Oral rehydration (timely fluid
• Decreased thyroid
starvation,
Anorexia replacement)
resulting in
hormone
nervosa
• Decreased bone density
marked
weight loss
• Cardiac arrhythmia 21. ASCHOFF CELLS VS ANITSCHKOW CELLS
• Sudden death ASCHOFF BODIES
Patient binges • Electrolyte imbalance
Foci of T lymphocytes,
Bulimia on food and • Pulmonary aspiration
occasional plasma cells,
nervosa then induces • Esophageal and gastric
and plump activated
vomiting rupture
macrophages called
• Anorexia nervosa – highest death rate of any psychiatric Anitschkow cells
disorder
• Bulimia – more common than anorexia nervosa ANITSCHKOW CELLS
Macrophages that have
18. E. HISTOLYTICA abundant cytoplasm and
central round-to-ovoid
• Characteristic ulcer shape of Entamoeba histolytica: FLASK- nuclei in which the
SHAPED - Narrow neck and broad base chromatin condenses into a
central, slender wavy
ribbon (caterpillar cells)
• Subendocardial lesions, perhaps exacerbated by regurgitant
jets, can induce irregular thickenings in the left atrium called:
MacCallum plaques
22. COUGH 25. ACHALASIA

• CHRONIC COUGH – defined as cough persisting > 8 weeks • Triad of achalasia:
• Associated with obstructive lung diseases (asthma and o Incomplete LES relaxation
chronic bronchitis), as well as “nonrespiratory” diseases, such o Increased LES tone
as gastroesophageal reflux and postnasal drip o Aperistalsis of the
Wheeze Upper airway obstruction esophagus
Rhonchi Medium-sized airway obstruction • Primary achalasia is the result
Crackles Alveolar disease of: distal esophageal
Egophony and inhibitory
Abnormal sound transmission neuronal/ganglion cell,
whispered pectoriloquy
degeneration.
• Cause: Unknown; rare
23. EMPHYSEMA familial cases have been
• Type of emphysema that probably underlies many cases of described.
spontaneous pneumothorax in young adults: Distal acinar
(paraseptal) emphysema – also least common form
26. MALLORY-WEISS TEAR
• Longitudinal mucosal tears
near the gastroesophageal
junction: Mallory-Weiss
tears
• Most common association:
Severe retching or vomiting
secondary to acute alcohol
intoxication
PARASEPTAL EMPHYSEMA
27. PEPETIC ULCER LESIONS

TYPE OF
FEATURES
EMPHYSEMA • Classic description of peptic
Central or proximal parts of the acini ulcer: Sharply punched-out
Centriacinar are affected, distal alveoli are spared; defect
(centrilobular) Occurs predominantly in heavy • Characteristic of ulcers due to
emphysema smokers, often in association with cancers: Heaped-up margins
chronic bronchitis (COPD) • Most common form of peptic
Acini are uniformly enlarged from the ulcer disease: Chronic H.
Panacinar
level of the respiratory bronchiole to pylori induced antral
(panlobular)
the terminal blind alveoli; Associated gastritis (increased gastric acid
emphysema
with α1-antitrypsin deficiency secretion, decreased duodenal
Proximal portion of the acinus is bicarbonate secretion)
Distal acinar normal, distal part is predominantly
(paraseptal) involved; underlies many cases of
emphysema spontaneous pneumothorax in young
adults • Identification of perforation
Airspace into the peritoneal cavity:
Acinus is irregularly involved,
enlargement with Detection of free air under
invariably associated with scarring;
fibrosis (irregular the diaphragm on upright
clinically insignificant.
emphysema) radiographs of the abdomen
24. ASTHMA
• Fundamental abnormality in asthma: Exaggerated TH2
response to normally harmless environmental antigens 28. IMPERFORATE ANUS
• Microscopic finding of parts of the desquamated epithelium seen • Most common form of congenital intestinal atresia: Imperforate
in bronchi of asthmatic patients: Curschmann spirals anus
• Other findings: Creola bodies, Charcot-Leyden crystals • Due to: Failure of the cloacal diaphragm to involute
29. INSULINOMAS 34. AMYLOID PLAQUES

• Most common of • Fundamental abnormality in Alzheimer’s disease:
pancreatic endocrine Accumulation of 2 proteins (Aβ and tau) - likely as a result of
neoplasms: excessive production and defective removal
Insulinomas
• May produce
sufficient insulin to
induce clinically
significant
hypoglycemia
• 90% are benign
30. MINIMAL CHANGE DISEASE

• Most common of
pancreatic endocrine
neoplasms:
Insulinomas
• May produce
sufficient insulin to • Abnormality in Parkinson disease: Loss of pigmented neurons
induce clinically in the substantia nigra
significant • A-synuclein found in: Parkinson disease, Multiple systems
hypoglycemia atrophy
• 90% are benign
• Most common type of

glomerulonephritis worldwide: IgA
nephropathy (Berger disease)
• Characterized by: Prominent IgA Topnotch Phase 0 Pathology Handout by Dr. Kevin Elomina
deposits in the mesangial regions

+ recurrent hematuria 35. FRIEDRICH ATAXIA
• Diagnosis: Detection of glomerular
IgA deposition • Autosomal recessive disease due to a trinucleotide repeat
expansion characterized by progressive ataxia, spasticity,
weakness, sensory neuropathy, and a cardiomyopathy:
31. HEMORRHAGIC CYSTITIS Friedrich ataxia
• Causes of hemorrhagic cystitis: • Trinucleotide repeat: GAA
Cytotoxic antitumor drugs, • Found in the frataxin gene 9q13
(cyclophosphamide), adenovirus • Frataxin is essential for mitochondrial iron regulation, and its
• Persistence of the bacterial infection loss results in iron buildup with free radical damage
leads to chronic cystitis associated
with mononuclear inflammatory
infiltrates.
32. GYNECOMASTIA
• Only benign lesion seen with any frequency in the male breast:
Gynecomastia
• Clinical finding: Button-like subareolar enlargement and may be
unilateral or bilateral
• Microscopic features: Increase in dense collagenous
connective tissue associated with epithelial hyperplasia of the
duct lining with characteristic tapering micropapillae. Lobule
formation is almost never observed.
33. TYPE 1 DIABETES

• Fundamental immune
abnormality in type 1 diabetes:
Failure of self-tolerance in T
cells specific for islet antigen
• Type 2 diabetes - complex disease
that involves an interplay of
genetic and environmental
factors and a proinflammatory
state. Unlike type 1 diabetes,
there is no evidence of an
autoimmune basis.
36. DOPAMINERGIC TRACTS 39. NERVE COVERING FOR THE MUSCLES

NERVE
DESCRIPTION
COVERING
Endoneurium Surrounds axons within fascicles (innermost)
Perineurium Surrounds individual fascicles
Epineurium Surrounds nerve (outermost)
SYMPTOMS OF EXCESS
DOPAMINERGIC TRACT
ACTIVATION
Positive symptoms
Mesolimbic tract
(Hallucinations)
• Most important histopathologic indicator of CNS injury: Gliosis
Mesocortical tract Negative symptoms
- characterized by both hypertrophy and hyperplasia of
Nigrostriatal tract EPS and TD astrocytes
Tuberoinfundibular tract Hyperprolactinemia
37. MITOCHONDRIAL DISEASES

MITOCHONDRIAL DISEASE FEATURES
Recurrent episodes of acute
Mitochondrial neurologic dysfunction,
encephalomyopathy, lactic cognitive changes, and
acidosis, and stroke-like evidence of muscle
episodes (MELAS) involvement with weakness
and lactic acidosis
Myoclonus, a seizure
Myoclonic epilepsy and
disorder, and evidence of a
ragged red fibers (MERRF)
myopathy
Lactic acidemia, arrest of
psychomotor development,
Leigh syndrome feeding problems, seizures,
extraocular palsies, and
weakness with hypotonia
• Neurons with previously scant cytoplasm expands to a bright
pink, somewhat irregular swath around an eccentric nucleus,
from which emerge numerous stout, ramifying processes:
GEMISTOCYTIC ASTROCYTES
40. INFLAMMATORY MEDIATORS

Stimulates expression of
Macrophages,
endothelial adhesion molecules
TNF mast cells,
and secretion of other
T lymphocytes
cytokines; systemic effects
Macrophages,
endothelial Similar to TNF; greater role
IL-1
cells, some in fever
epithelial cells
Macrophages, Systemic effects (acute
IL-6
other cells phase response)
Macrophages,
endothelial Recruitment of leukocytes
cells, to sites of inflammation;
Chemokines
T lymphocytes, migration of cells in normal
38. ALS mast cells, tissues
• Most common form of motor other cell types
neuron disease: Amyotrophic Recruitment of neutrophils
IL-17 T lymphocytes
lateral sclerosis (Lou and monocytes
Gehrig’s disease)
• Amyotrophic lateral sclerosis “Hot T-Bone stEAK”
- progressive disorder; loss of IL-1: Fever (Hot)
upper motor neurons in the IL-2: Stimulates T-cells
cerebral cortex and lower IL-3: Bone
motor neurons in the spinal IL-4: Stimulates IgE production
cord and brainstem IL-5: Stimulates IgA production
IL-6: Stimulates aKute phase response
“Clean up on Aisle 8”
IL-8: Major chemotactic factor for neutrophils
“TGF-B and IL-10 Both atTENnuate”
TGF-B and IL-10 inhibit and attenuate the immune response
PARATOPE Recognizes and binds to an antigen
Region which is recognized by another

IDIOTOPE
antibody
IDIOTYPE Set of idiotopes
EPITOPE Part of an antigen which a paratope binds
• Most abundant antibody: IgG

• Able to cross the placenta: IgG
• Found in secretions: IgA
• Largest: IgM
• Allergic reactions: IgE
• Part of B cell receptor: IgD
• Destroy irreversibly stressed and abnormal cells, such as virus-

infected cells and tumor cells: Natural killer cells
END OF PATHOLOGY PHASE X
TOPNOTCH MEDICAL BOARD PREP PATHOLOGY PHASE 2 HANDOUT BY ROBERT GLEN R. ABESAMIS, MD, DPSP
A 20-year-old male visited his grandmother that takes care
The handouts, videos and other review materials, provided by Topnotch Medical Board of a lot of cats. During the visit, he inhales cat dander and
Preparation Incorporated are duly protected by RA 8293 otherwise known as the started to develop nasal congestion with nasal secretions.
Intellectual Property Code of the Philippines, and shall only be for the sole use of the person: Which of the following substances are is most likely the
a) whose name appear on the handout or review material, b) person subscribed to Topnotch
Medical Board Preparation Incorporated Program or c) is the recipient of this electronic culprit behind the patient’s symptoms?
communication. No part of the handout, video or other review material may be reproduced, A. IL-1
medium or machine-readable form, in whole or in part without the written consent of B. Histamine
Topnotch Medical Board Preparation Incorporated. Any violation and or infringement, C. Tumor necrosis factor
whether intended or otherwise shall be subject to legal action and prosecution to the full D. Bradykinin
A 45-year-old woman gives birth at 37 weeks to a small-for-
gestational-age male infant. Fetal ultrasound done reveals
DISCLOSURE an endocardial cushion defect, and polyhydramnios
responsibility of the person, whose name appears therein, that the handouts/review probably secondary to duodenal atresia. Upon birth, the
materials are not photocopied or in any way reproduced, shared or lent to any person or palms of the infant show a singular transverse crease only.
Which of the following malignancies is likely to develop in
8293. Topnotch review materials are updated every six (6) months based on the current this patient?
trends and feedback. Please buy all recommended review books and other materials listed A. Abdominal malignancies such as Wilms Tumor
below.
THIS HANDOUT IS NOT FOR SALE! B. Hematologic malignancies such as leukemia
C. Cardiac malignancies such as rhabdomyosarcoma
D. Liver malignancies such as hepatoblastoma
REMINDERS A 27-year old woman gave birth to a term infant after an
For Phase 2:
1. Finish the Phase 0 handout and Phase 1 video before proceeding to the
uncomplicated pregnancy. Initial physical examination
Phase 2 handout and video. reveals ambiguous genitalia. Chromosomal analysis
2. Phase 2 handouts are based on commonly used review books and reveals a karyotype of 46, XX. CT scan reveals internal
previous question feedback from students. genitalia consisting of a uterus, fallopian tubes and ovaries.
2. Answer the Pre-Test (Guide Questions) first prior to watching the video This clinical feature is most consistent with which of the
lectures. following conditions?
3. The guided content of the video lectures are in the 2nd part of the Phase A. True hermaphroditism
2 handouts and are meant to complement the video lecture. B. Male pseudohermaphroditism
C. Female pseudohermaphroditism
This handout is only valid for the September 2021 PLE batch. D. Androgen insensitivity syndrome
This will be rendered obsolete for the next batch Which of the following is the receptor needed by SARS-CoV-
since we update our handouts regularly. 2 virus to enter the cell?
A. ACE2 receptor
B. DPP4 receptor
PATHOLOGY – PHASE 2 C. APN receptor
D. 9-O-acetylated sialic acid
By Robert Glen R. Abesamis, MD A 5-year-old girl has a blotchy, reddish-brown rash on her
face, trunk and proximal extremities for 3 days. Physical
A 50-year-old female was found to have a blood pressure of exam reveals 0.3 to 0.5-cm ulcerated lesions on the oral
150/90 mm Hg during her annual physical check up. cavity mucosa and generalized tender lymphadenopathy.
Despite being prescribed medications, she never took any. The patient developed cough with minimal sputum
After a few years, which of the following cellular production. Which of the following complications are could
alterations in her heart would you expect to be present? occur later in life?
A. Hypertrophy A. Subacute subsclerosing encephalitis
B. Hyperplasia B. If pregnant, may have newborn with microcephaly
C. Atrophy C. West Nile Encephalitis
D. Metaplasia D. Mumps Encephalitis
Which of the following cytokines act to stimulate A biopsy of a lymph node showed cells with prominent
expression of endothelial adhesion molecular and intranuclear basophilic inclusions spanning one-half of the
secretion of other cytokines? nuclear diameter. Which of the following disease cells are
A. IL-12 a histologic findings in which of the following entities?
B. TNF A. Measles
C. IFN-gamma B. Cytomegalovirus
D. IL-17 C. Herpes Simplex Virus-1
Which of the following cells produce antibodies? D. Epstein-Barr Virus
A. B Lymphocytes A 10-year-old boy from Palawan was admitted due to
B. T Lymphocytes episodic fevers for 2 weeks. Last week, he developed
C. NK Cells severe headaches and became somnolent. The patient died
D. Mast Cells and an autopsy was done. The brain tissue revealed ring
A 30-year-old male incurs thermal burn injuries to 40% of hemorrhages surrounding blood vessels plugged with
his total burn surface area in an accidental fire while parasitized red cells. Which of the following organs is most
repairing a fuel tank. Physical examination shows that the likely to serve as reservoir for proliferation of the etiologic
trunk, neck and face are pink with blister formation and agent of this disease?
painful with touched. The skin of the arms is white and A. Lungs
anesthetic. After a few hours the BP of the patient went B. Spleen
down to 70/40 mm Hg. Which of the following conditions C. Liver
likely developed in this patient? D. Brain
A. Cardiogenic shock
B. Septic shock
C. Systemic inflammatory response syndrome
D. Neurogenic shock
Which of the following conditions is an example of
antibody-mediated hypersensitivity?
A. Anaphylaxis
B. Polyarteritis Nodosa
C. Inflammatory Bowel Disease
D. Acute Rheumatic Fever
TOPNOTCH MEDICAL BOARD PREP PATHOLOGY PHASE 2 HANDOUT BY ROBERT GLEN R. ABESAMIS, MD, DPSP Page 1 of 24
A pap smear of a 29-year-old female was found to have a A 10-year-old girl develops subcutaneous nodules over the
large, flagellated ovoid protozoan in her specimen skin of her arms and torso 3 weeks after a bout of acute
surrounded by dense inflammatory infiltrates. Clinical pharyngitis. She manifests with choreiform movements
history revealed that she had vulvovaginal discomfort, and begins to complain of pain in her knees and hips
dysuria and dyspareunia. Which of the following especially during movement. Chest auscultation reveals a
statements is true regarding the patient’s condition? friction rub. ASO antibody titers are elevated. Which of the
A. Colposcopy should show a “strawberry cervix” following statements are true regarding this condition?
B. This is caused by the MCV-1 virus. A. Acute rheumatic fever develops a few weeks after
C. If left untreated during pregnancy, it may cause group A streptococcal pharyngitis.
chorioamnionitis. B. The characteristic delay in symptom onset after
D. Diabetes mellitus, pregnancy and antibiotics can infection is usually between 5-6 weeks.
increase the risk of a symptomatic infection C. Damage to heart tissue may be caused by antibody
Which of the following metal pollutants can cause kidney and B cell-mediated reactions
damage and eventually osteoporosis and osteomalacia? D. Valvular lesions are characterized by large irregular
A. Lead masses on the valve cusps that can extend onto the
B. Cadmium chordae
C. Arsenic Which of the following histologic findings is seen in
D. Mercury Infective Endocarditis?
A 6-year-old child has had recurrent upper respiratory A. Loss of myocytes along with fatty infiltration and
infections for the past 3 months. The child is at the 55th fibrosis
percentile for height and the 35th percentile for weight. B. Foci of T-lymphocytes, occasional plasma cells and
Physical examination shows generalized edema, ascites, plump activated macrophages
muscle wasting and areas of desquamation of the skin C. Myofiber disarray
along the trunk and extremities. Laboratory findings are D. Friable, bulky, potentially destructive lesions
most likely to show which of the following findings? containing fibrin, inflammatory cells and bacteria
A. Presence of basophilic stippling on peripheral blood A 12-year-old boy was seen due to increasing abdominal
smear distention and pain for the past 3 days. Abdominal CT
B. Hypocalcemia shows a 7-cm mass along the ileocecal valve. Biopsy of the
C. Hypoalbuminemia mass reveals sheets of intermediate-sized cells with nuclei
D. Megaloblastic anemia having coarse chromatin, several nucleoli and many
A 4-month-old boy was brought to the pediatric emergency mitotic figures, apoptotic cells and interspersed benign
room due to a palpable abdominal mass. Aside from the macrophages. Cytogenetic analysis shows a t(8;14)
abdominal mass, the only other significant physical karyotype. Which of the infectious agents is likely present
examination finding is fever. An abdominal CT scan shows in this condition?
a 6-cm mass along the left adrenal gland. Biopsy of the A. Helicobacter pylori
tumor reveals sheets of small round blue cells, some B. Human Papillomavirus
arranged in rosettes. Which of the following laboratory C. Epstein-Barr Virus
markers will be elevated in this patient and is specific to D. Cytomegalovirus
the condition? A 10-year-old male is seen in the clinic due to joint
A. Homovanillic acid problems in the knees and ankles. His maternal uncle and
B. Lactate dehydrogenase male cousins also have the same condition. PE shows no
C. Alpha fetoprotein visible petechiae or purpura. Prothrombin time and
D. Beta-human chorionic gonadotropin bleeding time is normal but partial thromboplastin time is
A 45-year-old male is seen in the clinic due to fever, weight elevated. His CBC analytes along with the platelet count are
loss, hemoptysis and sinusitis. Laboratory tests reveal normal. Which of the following diagnosis is most likely?
elevation of serum antineutrophil cytoplasmic antibodies A. Disseminated Intravascular Coagulation
targeted against proteinase-3 and cavitary nodules. Which B. Von Willebrand Disease
of the following statements is true regarding this C. Vitamin K deficiency
condition? D. Hemophilia
A. Kidney lesions show membranoproliferative A 23-year-old female was seen in the clinic due to repeated
glomerulonephritis bouts of anemia despite intake of iron supplements
B. The lungs will contain chronic granulomatous (prescribed by previous doctor). CBC shows microcytic
inflammation with caseous necrosis hypochromic anemia with several target cells on the blood
C. This is a form of T-cell-mediated hypersensitivity smear. Serum iron, transferrin and ferritin are normal.
response to normally innocuous inhaled microbial or Which of the following is the likely diagnosis of the
environmental agents patient’s condition?
D. This is associated with atopy. A. Thalassemia
Which of the following represents episodic myocardial B. Anemia of chronic inflammation
ischemia caused by coronary artery spasm? C. Megaloblastic anemia
A. Crescendo angina D. Iron deficiency anemia
B. Stable angina Which of the following genetic abnormalities is seen in
C. Prinzmetal angina Polycythemia Vera?
D. Unstable angina A. Formation of BCR-ABL fusion gene
B. Activating mutation in JAK2
C. Presence of t(15;17)
D. Formation of BCL2-IGH fusion gene
A 30-year-old male suddenly developed severe dyspnea
with wheezing. Physical examination shows that he is
afebrile with a pulse of 97 bpm, respiratory rate of 32/min
and a blood pressure of 130/80 mmHg. CXR shows
increased lucency in all lung fields. Sputum cytology shows
Curschmann spirals, Charcot-Leyden crystals, eosinophils
and some hyphal elements. Which of the following is the
likely diagnosis of the patient’s condition?
A. Asthma
B. Pneumoconiosis
C. Bronchiectasis
D. Sarcoidosis
A 25-year-old male was admitted due to progressive A 63-year old male was admitted due to weight loss, small
dyspnea for the past 10 weeks. He is afebrile. CXR reveal stool caliber with occasional blood. Endoscopy revealed
bilateral pleural effusions and widening of the the presence of a mass at the level of the distal colon
mediastinum. Thoracentesis of the left side yielded 500 mL obstructing around 70-80% of the lumen. Biopsy revealed
of milky white fluid. Lab studies on the pleural fluid show infiltrating neoplastic glands. Which of the following genes
high protein content and microscopy shows many is the earliest mutated in the pathogenesis of this
lymphocytes with fat globules. Which of the following neoplasm?
conditions is likely the cause of these findings? A. SMAD2
A. Miliary tuberculosis with granulomatous pleuritis B. KRAS
B. Bacterial pneumonia with empyema C. TP53
C. Non-Hodgkin lymphoma with lymphatic obstruction D. APC
D. Congenital heart disease with congestive heart failure What is the percentage of alcoholics that progress to
A 57-year-old female had mild fever with cough for a week develop cirrhosis?
and improved for the next 10 days. However, she A. 10-15%
developed fever, cough, shortness of breath and malaise. B. 30-35%
Physical examination shows a febrile patient with C. 50-55%
inspiratory crackles. CXR shows bilateral patchy, small D. 70-75%
alveolar opacities while chest CT scan shows small, A 13-year-old male was seen in the clinic due to nerve
scattered ground-glass and nodular opacities. Biopsy of the deafness, dislocation of the left ocular lens and gross
areas involved show polypoid plugs of loose fibrous tissue hematuria. Electron microscopy reveals irregular foci of
and granulation tissue filling bronchioles, along with thickening and thinning of the glomerular basement
mononuclear cells infiltrating the surrounding tissue. She membrane with a “basket-weave” appearance of the
improves upon intake of corticosteroids. What is the likely lamina densa. Which of the following conditions is likely
diagnosis? the diagnosis of this patient?
A. Desquamative interstitial pneumonitis A. Alport syndrome
B. Hypersensitivity pneumonitis B. Poststreptococcal acute glomerulonephritis
C. Cryptogenic organizing pneumonia C. Minimal change disease
D. Bronchiectasis D. IgA Nephropathy
A 60-year-old non-smoker female has chronic A 5-year-old boy had honey-colored crusts on his face. The
nonproductive cough for 4 months along with loss of crusts were removed and initial gram stain studies show
appetite and weight loss. PE was unremarkable. CXR shows that the etiologic agent is a gram positive cocci. Antibiotics
a right peripheral subpleural mass. Based on these were given and the crusts resolved. However, he developed
information, if the patient has a lung cancer, which of the malaise, fever and was passing tea-colored urine 1 week
following types are most likely expected to develop? later. ASO titers were 1:1024. Which of the following
A. Adenocarcinoma statements is true regarding the patient’s disease?
B. Squamous cell carcinoma A. If a kidney biopsy is done, the glomeruli will be
C. Small cell carcinoma enlarged and hypercellular.
D. Carcinoid tumor B. This is an anti-GBM antibody-mediated disease.
Based on the question above, which of the following is the C. Serologic studies will reveal hyperlipidemia and
likely precursor lesion? lipiduria.
A. Squamous metaplasia D. Patient likely developed a form of nephrotic
B. Atypical adenomatous hyperplasia syndrome.
C. Pulmonary hamartoma A 40-year-old female was seen in the clinic due to lethargy
D. This lesion has no known precursor lesion. for around 4 months. Physical examination reveals a blood
An 8-year-old male was seen in the clinic due to bilateral pressure of 140/90. Laboratory findings show serum
pre-auricular masses of 2 days duration. The few days creatinine levels of 5.8 mg/dL (NV: 0.59 – 1.04 mg/dL),
prior, he has been experiencing fever, headache and hypocomplementemia and a negative ANA result.
malaise. Biopsy of the pre-auricular masses show an Urinalysis shows presence of blood and protein. Kidney
edematous interstitium and diffuse infiltration of biopsy shows hypercellular glomeruli with prominent
macrophages, lymphocytes and plasma cells, compressing ribbon-like deposits along the lamina densa of the
the acini and ducts. Which of the following complications glomerular basement membrane. What is the likely
are can occur after 1 week if left untreated? diagnosis of this patient?
A. Hepatitis A. Postinfectious glomerulonephritis
B. Epididymitis B. Rapidly progressive glomerulonephritis
C. Gastroenteritis C. Membranous nephropathy
D. Orchitis D. Dense deposit disease
Which of the following etiologic entities is known to cause A 45-year-old male was seen in the urologist’s clinic due to
achalasia? a bladder mass. A biopsy was done revealing neoplastic
A. Trypanosoma cruzi squamous cells. Which of the following is the likely risk
B. Cytomegalovirus factor present in the patient leading to the development of
C. Clostridium difficile his disease?
D. Schistosoma sp. A. Long exposure to cyclophosphamide
Which of the following findings should favor Ulcerative B. Exposure to aryl amines
Colitis over Crohn Disease? C. Tobacco Use
A. Presence of non-caseating granulomas D. Schistosoma haematobium infection
B. Deep, knife-like ulcers A 20-year-old G2P1 female was seen in the obstetricians
C. Mucosal inflammation clinic during her 2nd trimester due to small amount of
D. Marked serositis vaginal bleeding, and nausea and vomiting for the past 3
weeks. PE revealed that her uterus is large for her
supposed dates. Ultrasound examination revealed a
“snowstorm appearance” and no fetus was identified.
Curettage revealed a friable mass of cystic, grape-like
structures. Which of the following laboratory analytes is
likely to be elevated in the serum?
A. Alpha fetoprotein
B. Estradiol
C. Human placental lactogen
D. Human chorionic gonadotropin
A 51-year-old female is seen in the ENT clinic due to a A 6-year-old boy was brought by his mother due to multiple
painful neck mass, palpitations, weight loss and heat subcutaneous nodule along the right shoulder. Further
intolerance. Physical exam reveals a diffusely enlarged and physical examination shows multiple café-au-lait spots on
tender thyroid gland. Biopsy reveals lymphocytes, the skin as well. Biopsy of the subcutaneous nodule shows
macrophages, follicular cells and multinucleated giant multiple nerve fascicles that are expanded by infiltrating
cells. Which of the following is the likely diagnosis of the tumor cells resulting to a “bag-of-worms” appearance.
patient’s condition? Which of the following statements are true regarding this
A. Lymphocytic thyroiditis lesion?
B. Graves Disease A. Verocay bodies are also present in this lesion.
C. Hashimoto thyroiditis B. This lesion can become large and can mimic the
D. De Quervain thyroiditis appearance of Meissner corpuscles.
A 25-year-old female is seen in the clinic due to doubling of C. This lesion has a high risk of transforming to a
vision. Physical examination shows exophthalmos and malignant lesion.
weak extraocular muscle movement. There is a painless D. This lesion is associated with neurofibromatosis type 2.
diffuse enlargement of the thyroid gland but there is no A 58-year-old male was seen in the neurologist clinic due
lymphadenopathy. Which of the following laboratory to increasing difficulty in initiating voluntary movements
findings are expected in this patient? and inability to perform activities of daily living for 1 year.
A. Increased thyrotropin-releasing hormone level Physical examination shows difficulty in initiating
B. Decreased thyroid-stimulating hormone level movement but can easily follow if someone is walking
C. Very high levels of thyroid peroxidase autoantibodies ahead. Facies appear expressionless. When the patient
D. Decreased free thyroxine level died, autopsy revealed pallor of the substantia nigra and
A 50-year-old male was seen in the clinic due to a painless locus ceruleus. Which of the following additional clinical
anterior neck mass associated with difficulty in findings is compatible with these abnormalities?
swallowing. Other symptoms present include diarrhea and A. Ataxia with ambulation
flushing. Laboratory tests show elevation in serum B. Symmetric weakness in the extremities
calcitonin. Which of the following is the likely cell of origin C. Choreiform movements
of this lesion? D. Tremors at rest
A. Chief cells A biopsy of nerve from a patient with Lou Gehrig Disease
B. Oxyphil cells will show which of the following histologic findings?
C. Follicular cells A. Bunina bodies
D. Parafollicular C cells B. Lewy bodies
A 35-year-old female was seen in the emergency room C. Pick bodies
because she collapsed. A ventricular fibrillation was D. Negri bodies
detected and was then converted to a sinus rhythm. For the A 5-year-old boy died after brain herniation and an
past 3 months, she experienced palpitations, tachycardia, autopsy was conducted. Pertinent history included
tremors, diaphoresis and headache. Recently, her complaints of headaches for the past week along with
symptoms became worse with her BP measuring at 155/90 ataxia. A brain biopsy was done revealing sheets of small
mmHg. Physical examination is unremarkable. Which of round blue cells with some arranged in rosettes. A mass is
the following laboratory findings is likely present in this most likely present in which of the following locations?
patient? A. Basal ganglia
A. Increased serum free T4 B. Cerebellum
B. Increased urinary homovanillic acid level C. Cranial Nerve VIII
C. Increased urinary free catecholamines D. Fourth Ventricle
D. Decreased serum cortisol level
A 46-year-old female has had bilateral diffuse pain in the RATIONALE
thighs and shoulders for the past 6 weeks causing difficulty
from rising from the chair and climbing steps. A faint
violaceous rash developed around the orbits and on the A 50-year-old female was found to have a blood pressure of
skin of her knuckles. Physical revealed motor strength of 150/90 mm Hg during her annual physical check up.
4/5 in all extremities. Lab tests should ANA positive and Despite being prescribed medications, she never took any.
presence of Anti-Jo-1 antibodies. Which of the following After a few years, which of the following cellular
malignancies can cause this paraneoplastic condition? alterations in her heart would you expect to be present?
A. Uterine carcinoma A. Hypertrophy
B. Thymic carcinoma B. Hyperplasia
C. Breast carcinoma C. Atrophy
D. Acute promyelocytic leukemia D. Metaplasia
A biopsy of a right distal femoral mass from a 19-year-old CELL RESPONSE TO STRESS AND INJURIOUS STIMULI
male showed neoplastic cells with various shapes and sizes
with large hyperchromatic nuclei in a background of
neoplastic bone arranged in a “lace-like” pattern. Which of
the following mutated genes will cause a 1000-fold
increase of this condition?
A. INK4a
B. TP53
C. MDM2
D. RB
A 35-year-old woman has experienced malaise, fatigue,
and joint pain for the past 5 months. On physical
examination, the joint involvement is symmetric, and most
of the affected joints are in the hands and feet. The right
second and third digits have a “swan neck” deformity, and
there is ulnar deviation of both hands. Which of the
following laboratory findings is most likely to be reported
in this patient?
A. Positive Borrelia burgdorferi serologic test
B. Calcium pyrophosphate crystals in a joint aspirate
C. Serum positive for ACPA
D. Hyperuricemia
ADAPTATION DEFINITION STIMULUS MECHANISM EXAMPLES
PHYSIOLOGIC
• ↑ Functional • Myometrial hypertrophy in gravid uterus
↑ Organ/cell demand (hormonal stimulation)
HYPERTROPHY • ↑ Protein synthesis
SIZE • Hormonal • Muscle of bodybuilders (functional demand)
stimulation PATHOLOGIC
• LVH in hypertensive heart disease
• Growth factor-driven PHYSIOLOGIC
proliferation of • Pubertal breast changes (hormonal)
↑ NUMBER of • Hormonal
HYPERPLASIA mature cells or • Liver regeneration (compensatory)
cells • Compensatory
• ↑ Output of new cells PATHOLOGIC
from tissue stem cells • Endometrial hyperplasia (hormonal)
• ↓ Workload
• Denervation PHYSIOLOGIC
• ↓ Protein synthesis
• Ischemia • Embryonic atrophy (notochord and
↓ in cell size • ↑ Protein
ATROPHY • Malnutrition thyroglossal duct)
AND number degradation
• Loss of endocrine PATHOLOGIC
• Autophagy
stimulation • Senile atrophy of brain
• Pressure
• Squamous (Columnar to squamous; most
Differentiated
common): Vitamin A deficiency
cell type • Reprogramming of
METAPLASIA • Stress • Columnar: Barrett esophagus
replaced by stem cells
• Connective tissue: Myositis ossificans after
another cell type
intramuscular hemorrhage
MYOCARDIAL HYPERTROPHY CYTOKINES IN INFLAMMATION

• Stimuli: CYTOKINE PRINCIPAL PRINCIPAL ACTIONS
o Increased workload SOURCES IN INFLAMMATION
§ PRESSURE overload: Parallel formation of new sarcomeres IN ACUTE INFLAMMATION
→ hypertrophy (parameter: wall thickness) • Stimulates
§ VOLUME overload: Series formation of new sarcomeres → expression of
dilation (parameter: weight) endothelial adhesion
o β-adrenergic stimulation • Macrophages,
TNF molecules and
• Hypertrophied myocardium is metabolically demanding Mast cells, T cells
secretion of other
• No commensurate increase in blood supply cytokines
o Net effect: increased risk for ischemic injury and • Systemic effects
decompensation • Macrophages,
endothelial cells, • Similar to TNF;
IL-1
some epithelial greater role in fever
cells
• Systemic effects
• Macrophages,
IL-6 (Acute phase
other cells
response)
• Recruitment of
• Macrophages,
leukocytes to sites of
endothelial cells, T
Chemokines inflammation
cells, Mast cells,
• Migration of cells in
other cell types
normal tissues
• Recruitment of
IL-17 • T lymphocytes neutrophils and
monocytes
IN CHRONIC INFLAMMATION
• Dendritic cells, • Increased
IL-12
macrophages production of IFN-γ
• Activation of
Which of the following cytokines act to stimulate macrophages
expression of endothelial adhesion molecular and • T lymphocytes, NK
IFN-γ (increased ability to
secretion of other cytokines? cells
kill microbes and
A. IL-12 tumor cells)
B. TNF • Recruitment of
C. IFN-gamma IL-17 • T lymphocytes neutrophils and
D. IL-17 monocytes
CYTOKINES AND CHEMOKINES Which of the following cells produce antibodies?
• Cytokines: proteins produced by activated lymphocytes, A. B Lymphocytes
macrophages and dendritic cells, endothelial, epithelial, and B. T Lymphocytes
connective tissue cells that mediate and regulate immune and C. NK Cells
inflammatory reactions D. Mast Cells
• Chemokines: small (8 to 10 kD) proteins that act primarily as
chemoattractants for specific types of leukocytes
o Can be constitutively expressed (homeostatic) or inducible
(inflammatory)
CELLS IN THE IMMUNE RESPONSE • Derived from B lymphocytes
TYPE OF Plasma cells • Factories for producing
CELL NOTES
IMMUNITY antibodies
Epithelium • Antigen-presenting cells
Dendritic
(Skin, GI, • Acts as mechanical barrier • Initiating T-cell responses
cells
Respiratory) against protein antigens
Neutrophils • Phagocyte in the blood • Phagocytoses microbes
• Phagocyte in the blood and • Processes protein antigens
Macrophage
tissues and present peptide
• Captures protein antigens fragments to T cells
and displays for recognition • Key effector cells in certain
Macrophages
of T lymphocytes forms of cell-mediated
Dendritic immunity
• Has receptors that senses
cells
Innate microbes and cell damage • Phagocytoses and destroys
• Stimulated cytokine microbes opsonized by IgG
secretion or C3b
• Thought to be sources of A 30-year-old male incurs thermal burn injuries to 40% of
Innate
inflammatory cytokines at his total burn surface area in an accidental fire while
lymphoid
early part of immune repairing a fuel tank. Physical examination shows that the
cells
reaction trunk, neck and face are pink with blister formation and
• Recognizes and destroy painful with touched. The skin of the arms is white and
Natural
severely stressed or anesthetic. After a few hours the BP of the patient went
Killer (NK)
abnormal cells (virus- down to 70/40 mm Hg. Which of the following conditions
cells
infected and tumor cells) likely developed in this patient?
• Stimulates B lymphocytes to A. Cardiogenic shock
Helper T make antibodies B. Septic shock
Lymphocytes • Activate other leukocytes to C. Systemic inflammatory response syndrome
destroy microbes D. Neurogenic shock
Cytotoxic T THERMAL BURNS
• Kills infected cells
Adaptive Lymphocytes • Most common thermal injury
• Limits immune responses • Most common cause: fire or scalding
Regulatory T
• Prevent reactions against • Factors that determine outlook of burns
lymphocytes
self antigens o Depth
B • Only cells capable of o BSA (Recall BSA computation in Surgery)
lymphocytes producing antibodies o Internal injuries (from hot and toxic fume inhalation)
o Promptness of efficacy of therapy (Resuscitation and infection
control)
DEPTH OF BURNS
DEPTH DEEPEST EXTENT GROSS MICROSCOPIC
Superficial burns • Epidermis • Erythema of skin ---
Partial thickness • Dermis • Pink, mottled, with blisters • Coagulative necrosis: devitalized tissue
(2nd degree) • Painful • Inflammatory cells & exudation: around
Full thickness • Subcutaneous tissue and • White, charred, dry devitalized tissues
(3rd degree) deeper structures • Painless
USUAL CAUSES OF MORTALITY IN BURNS TYPES OF SHOCK

• Shock: From fluid shift to interstitial component, and SIRS SHOCK SETTING MECHANISM
• Sepsis: Burn site: fertile ground for infections • Myocardial
infarction • Failure of
o Serum (nutrients), decreased blood flow (impaired local
myocardial pump
inflammatory response) • Ventricular
resulting from
o Organisms: P. aeruginosa (Most common), MRSA, Candida rupture
intrinsic myocardial
• Respiratory insufficiency Cardiogenic • Arrhythmia
damage, extrinsic
o Direct effect of heat • Cardiac
compression, or
o Water-soluble gases may react with water and produce tamponade
obstruction to
acids/alkalis that cause inflammation → airway obstruction • Pulmonary outflow
o Lipid-soluble gases reach deeper airways → pneumonitis embolism
• Fluid loss (e.g.
SHOCK hemorrhage,
• Inadequate blood or
• State in which diminished cardiac output or reduced effective Hypovolemic vomiting,
plasma volume
circulating blood volume impairs tissue perfusion and leads to diarrhea, burns,
cellular hypoxia or trauma)
• General morphology: Hypoxic injury (Ischemic coagulative • Activation of cytokine
necrosis) • Overwhelming cascades
• Changes generally reversible if patient survives EXCEPT in Shock microbial • Peripheral vasodilation
neurons, myocytes associated infections and pooling of blood
with systemic • Superantigens • Endothelial
• Anaphylactic inflammation • Trauma activation/injury
o Systemic vasodilation and increased vascular permeability (Septic shock) • Burns • Leukocyte-induced
(mediator: histamine) secondary to an IgE-mediated • Pancreatitis damage
hypersensitivity reaction • DIC
• Neurogenic
Which of the following conditions is an example of
o Anesthetic accident or spinal cord injury with resultant loss of
antibody-mediated hypersensitivity?
vascular tone and peripheral pooling of blood
A. Anaphylaxis
B. Polyarteritis Nodosa
C. Inflammatory Bowel Disease
D. Acute Rheumatic Fever
MECHANISMS OF HYPERSENSITIVITY REACTIONS
Production of IgE antibody → immediate Vascular dilation, edema,
Anaphylaxis; allergies;
Immediate (type I) release of vasoactive amines and other smooth muscle contraction,
bronchial asthma (atopic
hypersensitivity mediators from mast cells; later mucus production, tissue injury,
forms)
recruitment of inflammatory cells inflammation
Production of IgG, IgM → binds to antigen Phagocytosis and lysis of cells;
Antibody-mediated Autoimmune hemolytic
on target cell or tissue → phagocytosis or inflammation; in some diseases,
(type II) anemia; Goodpasture
lysis of target cell by activated complement functional derangements
hypersensitivity syndrome
or Fc receptors; recruitment of leukocytes without cell or tissue injury
Deposition of antigen-antibody complexes
Immune complex- → complement activation → recruitment of
toxic molecules
Cell-mediated Activated T lymphocytes → (1) release of Perivascular cellular infiltrates; Contact dermatitis; multiple
(type IV) cytokines, inflammation and macrophage edema; granuloma formation; sclerosis; type I diabetes;
hypersensitivity activation; (2) T cell-mediated cytotoxicity cell destruction tuberculosis
o GIT: Hirschsprung disease, duodenal atresia

A 20-year-old male visited his grandmother that takes care o Acute leukemia: ALL or AML (Myeloid; acute
of a lot of cats. During the visit, he inhales cat dander and megakaryoblastic leukemia, most common)
started to develop nasal congestion with nasal secretions. o Neuronopathologic changes: Alzheimer disease
Which of the following substances are is most likely the o Abnormal immune responses: serious infections
culprit behind the patient’s symptoms?
A. IL-1
B. Histamine
C. Tumor necrosis factor
D. Bradykinin
TYPE I HYPERSENSITIVITY
• Commonly known as allergies (exogenous triggers)
• Key traits: Rapid; occurs in previously sensitized individuals;
IgE-mediated
• Two phases (with different effects and mediators)
o Immediate phase: vascular changes
o Late phase: leukocytic infiltration and tissue damage
§ Eosinophils: main cells
• IL-5: most potent eosinophil activating cytokine known; from
TH2 cells
• First exposure to allergen
o TH2 cell activation and production of IgE that binds to
basophils and mast cells
• Subsequent exposure to allergen
o Antigen binds to IgE on basophils and mast cells → mast cell
degranulation: mediators
• Vasoactive amines (Histamine), Arachidonic acid metabolites
→ Immediate response
• Cytokines and chemokines → Late response
• Morphology
o Vascular dilation, edema, smooth muscle contraction, mucus
production, tissue injury, inflammation
A 45-year-old woman gives birth at 37 weeks to a small-for-

gestational-age male infant. Fetal ultrasound done reveals
an endocardial cushion defect, and polyhydramnios
Image taken from: https://embryology.med.unsw.edu.au/embryology/index.php/Trisomy_21
probably secondary to duodenal atresia. Upon birth, the
palms of the infant show a singular transverse crease only.
A 27-year old woman gave birth to a term infant after an
Which of the following malignancies is likely to develop in
uncomplicated pregnancy. Initial physical examination
this patient?
reveals ambiguous genitalia. Chromosomal analysis
A. Abdominal malignancies such as Wilms Tumor
reveals a karyotype of 46, XX. CT scan reveals internal
B. Hematologic malignancies such as leukemia
genitalia consisting of a uterus, fallopian tubes and ovaries.
C. Cardiac malignancies such as rhabdomyosarcoma
This clinical feature is most consistent with which of the
D. Liver malignancies such as hepatoblastoma
following conditions?
DOWN SYNDROME (TRISOMY 21)
A. True hermaphroditism
• Most common of the chromosomal disorders; leading cause of B. Male pseudohermaphroditism
Mental Retardation C. Female pseudohermaphroditism
• Advanced maternal age: strong influence of occurrence D. Androgen insensitivity syndrome
• Causes: HERMAPHRODITISM
o Nondisjunction (95%)
• True hermaphroditism
o Robertsonian translocation (4%)
o Presence of both ovarian and testicular tissue
o Mosaicism (1%)
• Pseudo-hermaphroditism
• Advance maternal age: strong influence of occurrence
o Disagreement between phenotypic and gonadal sex
• Diagnostic clinical features: flat facial profile, oblique palpebral
• Genotypically male with female phenotype (Androgen
fissures, and epicanthic folds
insensitivity syndrome)
• Notable associations:
• Genotypically female with male phenotype (Androgenital
o Cardiac: Endocardial cushion defect, ostium primum defect,
syndromes)
ASDs, AV valve malformations, VSDs
Hermaphroditism
• True Hermaphrodite • Female • Male
(A.k.a. Ovotesticular disorder) Pseudohermaphrodite Pseudohermaphrodite
Genetic Sex • Usually 46, XX • 46, XX • 46, XY
Internal Phenotype (Histologic) • Has BOTH – called ovotestis • Female – Has ovaries, • Male – Has testis
fallopian tubes and uterus
External Phenotype • Ambiguous • Ambiguous or Male • Ambiguous or Female
Which of the following is the receptor needed by SARS-CoV-

2 virus to enter the cell?
A. ACE2 receptor
B. DPP4 receptor
C. APN receptor
D. 9-O-acetylated sialic acid
COVID-19 (SARS-COV-2)
• Virus: SARS-CoV-2
• Disease: COVID-19
• Important structural proteins:
Protein Purpose
• Entry to cell:
Responsible for receptor binding
Spike (S) Determines host range and cellular tropism o S protein binds to ACE2 receptors
o S protein requires proteolytic priming via TMPRSS2 (if on cell
Part of viral envelope
surface) or via cathepsin B or cathepsin L (if after endosomal
Envelope (E) Part of viral envelope
entry)
Membrane (M) Part of viral envelope
• Cellular tropism:
Nucleocapsid (N) Contains the RNA genome
o High levels of ACE2 and TMPRSS2 → alveolar type II cells, nasal
goblet and ciliated cells
o ACE2 positive cells in small intestine, gallbladder, kidneys,
testes, thyroid, adipose tissue, heart muscle, vagina, breast,
ovary and pancreas → multiorgan dysfunction
Reference: Synowiec A, Szczepański A, Barreto-Duran E, Lie LK, Pyrc K. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection. Clin Microbiol Rev. 2021 Jan 13;34(2):e00133-20. doi: 10.1128/CMR.00133-20. PMID: 33441314;
PMCID: PMC7849242.
A 5-year-old girl has a blotchy, reddish-brown rash on her
face, trunk and proximal extremities for 3 days. Physical
exam reveals 0.3 to 0.5-cm ulcerated lesions on the oral
cavity mucosa and generalized tender lymphadenopathy.
The patient developed cough with minimal sputum
production. Which of the following complications are could
occur later in life?
A. Subacute subsclerosing encephalitis
B. If pregnant, may have newborn with microcephaly
C. West Nile Encephalitis
D. Mumps Encephalitis
MEASLES
• Rash: Dilated skin vessels, edema, mononuclear perivascular
infiltrate
• Koplik spots (Pathognomonic): Necrosis, PMNs, and
neovascularization (opening of Stensen duct – near 2nd upper
molar)
• Lymphoid organs: Marked follicular hyperplasia, large germinal WARTHIN-FINKELDEY CELLS
Image from: https://alf3.urz.unibas.ch/pathopic/e/getpic-fra.cfm?id=003756
centers, (+) Warthin-Finkeldey cells
• Warthin-Finkeldey cells (Pathognomonic): Multinucleated A biopsy of a lymph node showed cells with prominent
giant cells with eosinophilic nuclear and cytoplasmic inclusions
intranuclear basophilic inclusions spanning one-half of the
(also in lung and sputum) nuclear diameter. Which of the following disease cells are
a histologic findings in which of the following entities?
A. Measles
B. Cytomegalovirus
C. Herpes Simplex Virus-1
D. Epstein-Barr Virus
VIRAL INFECTIONS A 10-year-old boy from Palawan was admitted due to
• Usually produces cytopathic-cytoproliferative reactions episodic fevers for 2 weeks. Last week, he developed
• Characterized by cell necrosis or cellular proliferation + sparse severe headaches and became somnolent. The patient died
inflammatory cells and an autopsy was done. The brain tissue revealed ring
• General morphology: hemorrhages surrounding blood vessels plugged with
o Inclusion bodies → from viral replication forming aggregates parasitized red cells. Which of the following organs is most
o Polykaryon formation → multinucleated cells formed via likely to serve as reservoir for proliferation of the etiologic
induction of cells by viruses agent of this disease?
A. Lungs
HISTOLOGIC FINDINGS OF VIRUSES B. Spleen
C. Liver
Type Virus Histologic Findings D. Brain
MALARIA
Warthin-Finkeldey Cells → • Etiologic agent: Plasmodium (P. falciparum, P. vivax, P. ovale, P.
multinucleated giant cells with malariae)
Measles
eosinophilic nuclear and • P. falciparum: MOST VIRULENT
RNA
cytoplasmic inclusions o High-level parasitemia
Virus
Interstitial edema + mononuclear o Infects ALL stages of RBCs
Mumps
cells o Sequestration: Infected RBCs stick to blood vessels
SARS-CoV-2 Diffuse alveolar damage in lungs o Cytoadherence/Rosetting: Infected RBCs stick to other RBCs
Cowdry Type A inclusions bodies § Sequestration and cytoadherence/rosetting cause vascular
Herpes Simplex occlusion → ischemia
→ pink to purple intranuclear
Virus
inclusion bodies • Other Plasmodium
Varicella Intraepithelial vesicles o Less virulent
DNA Large atypical cells with “Owl’s o Infect specific stage of RBCs
Cytomegalovirus § P. vivax and P. ovale: Young RBCs
Virus Eye nuclei”
Lymph node: May resemble — Hypnozoites: Liver forms; responsible for relapses
Epstein-Barr Reed-Sternberg cells of Hodgkin § P. malariae: Old RBCs
Virus Lymphoma → use EBER-ISH to • Diagnosis: Giemsa-stained thick and thin blood smears
confirm • In tissues: Hemozoin-
pigmented laden phagocytic
CYTOMEGALOVIRUS cells → gray or blackish
discoloration of involved
• Large, atypical cells with prominent
organs
intranuclear basophilic inclusions,
o Cerebral malaria (in P.
surrounded by a clear halo “Owl’s eye
falciparum): Dürck
inclusion”
granulomas
• Small basophilic inclusions in § Ring hemorrhages around a
cytoplasm vessel plugged with
• Focal necrosis with minimal parasitized red cells + small
inflammation focal inflammatory reaction
A pap smear of a 29-year-old female was found to have a A. Colposcopy should show a “strawberry cervix”
large, flagellated ovoid protozoan in her specimen B. This is caused by the MCV-1 virus.
surrounded by dense inflammatory infiltrates. Clinical C. If left untreated during pregnancy, it may cause
history revealed that she had vulvovaginal discomfort, chorioamnionitis.
dysuria and dyspareunia. Which of the following D. Diabetes mellitus, pregnancy and antibiotics can
statements is true regarding the patient’s condition? increase the risk of a symptomatic infection
LOWER GENITAL TRACT INFECTIONS A 6-year-old child has had recurrent upper respiratory
TYPE ORGANISMS NOTES infections for the past 3 months. The child is at the 55th
• Bacterial vaginosis; percentile for height and the 35th percentile for weight.
• Gardnerella vaginalis Physical examination shows generalized edema, ascites,
“Clue cells”
muscle wasting and areas of desquamation of the skin
• Ureaplasma • Seen in
urealyticum along the trunk and extremities. Laboratory findings are
Bacteria chorioamnionitis and
most likely to show which of the following findings?
• Mycoplasma hominis premature delivery
A. Presence of basophilic stippling on peripheral blood
• N. gonorrhoeae smear
• Cause of PID
• C. trachomatis B. Hypocalcemia
• HSV • HSV-2 > HSV-1 C. Hypoalbuminemia
• Molluscum D. Megaloblastic anemia
Viruses • MCV-2 is STI
contagiosum virus SEVERE ACUTE MALNUTRITION
• HPV • Causes SIL → SCCA • Previously called protein
• Pseudospores or energy malnutrition
Fungi • Candida albicans
hyphal elements (PEM)
• Trichomonas • Definition: Weight for
Parasites • STI; 3Ds
vaginalis height ratio that is 3
standard deviations
TRICHOMONAS VAGINALIS below the normal range
• Two forms: Marasmus
and Kwashiorkor
FEATURE MARASMUS KWASHIORKOR

• Weight ≤ 60% of
Definition and normal • Protein > caloric
cause • Caloric deprivation
deprivation
PROTEIN COMPONENT
Somatic protein
• Affected • Relatively spared
compartment
• Minimally
Visceral protein depleted • Affected (↓
compartment (normal albumin)
albumin)
FINDINGS
Growth failure • Present
Edema --- • Present
Loss of fat
Which of the following metal pollutants can cause kidney • More marked • Present
muscle atrophy
damage and eventually osteoporosis and osteomalacia?
Liver --- • Fatty liver
A. Lead
B. Cadmium • Findings common in Kwashiorkor, and
C. Arsenic are RARE in Marasmus
D. Mercury • Mucosal atrophy and loss of villi and
Small bowel
ENVIRONMENTAL POLLUTANTS: CADMIUM microvilli (and intestinal enzymes)
• Most common: disaccharidase
Mechanism • ROS production affecting kidneys, lungs
deficiency
Kidney
• Renal tubular damage → ESRD • Hypoplastic marrow (↓ precursors)
damage
• Anemia (variable morphology)
Lung Hematologic
• Increases risk for lung cancer • Thymic and lymphoid atrophy (more
damage
marked in Kwashiorkor)
Itai-itai • Osteoporosis and osteomalacia associated • Cerebral atrophy
disease with renal disease seen in postmenopausal Brain • ↓ Neurons
“ouch-ouch” Japanese women working in rice fields • Impaired white matter myelinization
ENVIRONMENTAL POLLUTANTS: OTHER METALS A 4-month-old boy was brought to the pediatric emergency
Metals Mechanism Clinical Features room due to a palpable abdominal mass. Aside from the
• Hema: Microcytic abdominal mass, the only other significant physical
• Interferes with Ca2+ examination finding is fever. An abdominal CT scan shows
hypochromic
metabolism a 6-cm mass along the left adrenal gland. Biopsy of the
anemia, basophilic
• Binding of sulfhydryl tumor reveals sheets of small round blue cells, some
stippling
Lead groups in proteins arranged in rosettes. Which of the following laboratory
• Children: CNS damage
• Inhibition of ALA markers will be elevated in this patient and is specific to
• Adults: Peripheral
dehydratase, the condition?
demyelinating
ferrochelatase A. Homovanillic acid
neuropathy
B. Lactate dehydrogenase
• Binding to sulfhydryl
• CNS damage C. Alpha fetoprotein
Mercury groups in proteins
• Kidney damage D. Beta-human chorionic gonadotropin
with high affinity
NEUROBLASTOMA
• Sensorimotor
neuropathy • Most common extracranial solid tumor of childhood; most
• Interference with • Prolonged QT wave frequently diagnosed tumor of infancy
mitochondrial → arrhythmias • Most common site: adrenal medulla (40%)
Arsenic • Clinically, abdominal masses (cross the midline), fever, and
oxidative • Alternating
phosphorylation hyperpigmentation weight loss; symptoms referable to metastases
and hyperkeratosis o Disseminated disease: cutaneous metastases (blueberry
in chronic exposure muffin baby)
o Commonly produces catecholamines • Syndromes:
§ Hypertension is less common o Angina pectoris (literally “chest pain”)
o Metastases route: lymphohematogenous o Myocardial infarction (MI)
§ Sites: Liver, Lung, Bones, and Bone marrow o Chronic IHD with heart failure
• Blastemal cells with mitosis, karyorrhexis, and atypia, in o Sudden cardiac death (SCD) (under Arrhythmias)
eosinophilic, fibrillary background (neuropil)
o ↑ Mitotic-karyorrhectic index is associated with unfavorable ANGINA PECTORIS
prognosis • Paroxysms of precordial chest discomfort due to myocardial
• Homer-Wright pseudorosettes: tumor cells around a central ischemia that is insufficient to cause myocyte necrosis
space filled with neuropil o Stable (typical): most common form; usually happens on
exertion
§ Increase in demand outweighs supply (demand problem)
o Prinzmetal: caused by coronary artery spasm
o Unstable (crescendo): prolonged, severe; may happen at rest
§ Plaque disruption and superimposed thrombosis, distal
embolization of thrombus and/or vasospasm
(supply problem)
A 10-year-old girl develops subcutaneous nodules over the

skin of her arms and torso 3 weeks after a bout of acute
pharyngitis. She manifests with choreiform movements
and begins to complain of pain in her knees and hips
especially during movement. Chest auscultation reveals a
friction rub. ASO antibody titers are elevated. Which of the
following statements are true regarding this condition?
A. Acute rheumatic fever develops a few weeks after
group A streptococcal pharyngitis.
B. The characteristic delay in symptom onset after
infection is usually between 5-6 weeks.
C. Damage to heart tissue may be caused by antibody
A 45-year-old male is seen in the clinic due to fever, weight and B cell-mediated reactions
loss, hemoptysis and sinusitis. Laboratory tests reveal D. Valvular lesions are characterized by large irregular
elevation of serum antineutrophil cytoplasmic antibodies masses on the valve cusps that can extend onto the
targeted against proteinase-3 and cavitary nodules. Which chordae
of the following statements is true regarding this RHEUMATIC FEVER
condition? • Acute, immunologically mediated, multisystem inflammatory
A. Kidney lesions show membranoproliferative disease classically occurring a few weeks after an episode of
glomerulonephritis Group A Streptococcal pharyngitis or pyoderma
B. The lungs will contain chronic granulomatous • Antibodies and CD4+ T-cells directed against Streptococcal M
inflammation with caseous necrosis proteins also recognize cardiac self-antigens “molecular
C. This is a form of T-cell-mediated hypersensitivity mimicry”
response to normally innocuous inhaled microbial • Sequelae: Rheumatic heart disease
or environmental agents
• Morphology
D. This is associated with atopy. o Aschoff bodies
GRANULOMATOSIS WITH ANGIITIS § T-lymphocytes
FEATURE GRANULOMATOSIS WITH ANGIITIS § Plasma cells
• Previously called Wegener’s § Anitschkow cells: Plump activated macrophages with
Epidemiologic granulomatosis slender, wavy ribbon chromatin (“caterpillar cells”)
significance • Widespread GPA looks like PAN + § Lesions can be seen in all layers of the heart (Pancarditis)
Pulmonary involvement
ANCA • PR3-ANCA (c-ANCA) RHEUMATIC HEART DISEASE
• Small and medium-sized vessels • Most commonly involved valve: Mitral
Vessel affected (prominent pulmonary involvement), o Aortic > Tricuspid > Pulmonic
may involve renal vessels • Cardinal changes: Leaflet thickening, commissural fusion and
• Persistent pneumonitis with bilateral shortening, and thickening and fusion of the tendinous cords
nodular and cavitary infiltrates (95%) o Fish mouth deformity
Prominent
• Chronic sinusitis (90%) § Calcification and fibrous bridging of valvular commissures
clinical
• Mucosal ulcerations of the nasopharynx o Verrucae
findings
(75%) § Small vegetations along lines of closure, overlying foci of
• Renal disease (80%) fibrinoid necrosis
• Acute necrotizing granulomas of o MacCallum plaques
respiratory tract § Subendocardial irregular thickenings due to regurgitant
Morphology • Necrotizing or granulomatous vasculitis jets
• Focal, segmental necrotizing GN often
crescentic GN Which of the following histologic findings is seen in
Infective Endocarditis?
Which of the following represents episodic myocardial A. Loss of myocytes along with fatty infiltration and
ischemia caused by coronary artery spasm? fibrosis
A. Crescendo angina B. Foci of T-lymphocytes, occasional plasma cells and
B. Stable angina plump activated macrophages
C. Prinzmetal angina C. Myofiber disarray
D. Unstable angina D. Friable, bulky, potentially destructive lesions
containing fibrin, inflammatory cells and bacteria
ISCHEMIC HEART DISEASE
INFECTIVE ENDOCARDITIS
• Related entities resulting from myocardial ischemia
(imbalance between myocardial supply and demand) • Microbial infection of heart valves and mural endocardium
• Most common cause: atherosclerosis of epicardial coronary • Vegetations: hallmark
arteries (Coronary artery disease) • Types: Acute and subacute
FEATURE ACUTE IE SUBACUTE IE BLEEDING DISORDERS: SUMMARY
• Viridans DISEASE PC BT PT PTT
• S. aureus (also
Common Streptococci Ehler-Danlos syndrome N N N N
common in IV drug
organisms • HACEK Immune thrombocytopenic purpura ↓ ↑ N N
users)
organisms Thrombotic thrombocytopenic purpura ↓ ↑ N N
Valves • Previously healthy • Diseased Bernard-Soulier disease ↓ ↑ N N
Tissue Glanzmann thrombasthenia N ↑ N N
• More pronounced • Less pronounced
destruction Von Willebrand disease N ↑ N ↑
Hemophilia N N N ↑
INFECTIVE ENDOCARDITIS: MORPHOLOGY Vitamin K deficiency N N ↑ ↑
• Vegetations: friable, bulky, potentially destructive lesions DIC ↓ ↑ ↑ ↑
containing fibrin, inflammatory cells, and bacteria or other INHERITED DISORDERS OF COAGULATION
organisms → may embolize (septic embolus)
• Von Willebrand Disease (VWD): Most common inherited
• Most commonly affected: aortic and mitral bleeding disorder
o Right valves in IV drug users
• Hemophilia: Most common hereditary disease associated with
• Large, irregular masses life-threatening bleeding
on the valve cusps that
FEATURE VWD HEMOPHILIA
may extend into chordae
• Autosomal (usually • X-linked
• Acute IE involves more Inheritance
dominant) recessive
tissue destruction than
subacute IE • Factor VIII
(Hemophilia A)
• Subacute IE: • Quantitative or
• Factor IX
granulation tissue at Abnormality qualitative depending
(Hemophilia B,
base on type
Christmas
disease)
A 12-year-old boy was seen due to increasing abdominal
Platelet
distention and pain for the past 3 days. Abdominal CT • PC: Normal • PC: Normal
number and
shows a 7-cm mass along the ileocecal valve. Biopsy of the • PF: Impaired • PF: Normal
function
mass reveals sheets of intermediate-sized cells with nuclei
having coarse chromatin, several nucleoli and many • Desmopressin (↑ vWF)
• Factor
mitotic figures, apoptotic cells and interspersed benign Treatment • Factor VIII and vWF
replacement
macrophages. Cytogenetic analysis shows a t(8;14) replacement
karyotype. Which of the infectious agents is likely present
in this condition? A 23-year-old female was seen in the clinic due to repeated
A. Helicobacter pylori bouts of anemia despite intake of iron supplements
B. Human Papillomavirus (prescribed by previous doctor). CBC shows microcytic
C. Epstein-Barr Virus hypochromic anemia with several target cells on the blood
D. Cytomegalovirus smear. Serum iron, transferrin and ferritin are normal.
BURKITT LYMPHOMA Which of the following is the likely diagnosis of the
• One of the fastest-growing human tumors patient’s condition?
A. Thalassemia
o Genetic basis: t(8;14) → MYC overexpression (Ch8) →
B. Anemia of chronic inflammation
expression of enzymes for aerobic glycolysis (Warburg
C. Megaloblastic anemia
metabolism) → c synthesis of building blocks for growth and
D. Iron deficiency anemia
cell division
IDA VS. ACI
• Associated with latent EBV infection
• Categories ANEMIA OF
IRON DEFICIENCY
o African (Endemic) Burkitt FEATURE CHRONIC
ANEMIA
§ Sites: Mandible, Ovaries, Kidneys, Adrenal INFLAMMATION
o Sporadic (Non-endemic) Burkitt • Common cause of
• Most common
§ Sites: Ileocecum, Peritoneum anemia in
Significance nutritional disorder
o HIV-associated hospitalized
in the world
• Morphology patients
o “Starry Sky” pattern: Non-neoplastic tingible-body • Chronic microbial
macrophages (Stars) dotting sheets of neoplastic lymphoid infections
cells (Sky) • Chronic immune
• Dietary lack
• Prognosis disorders
• ↓ Absorption
o Good response to intensive chemotherapy Causes • Neoplasms
• ↑ Requirement
o IL-6 → ↑ Hepcidin
• Chronic blood loss
→ ↓ Iron transfer
from storage pool
to bone marrow
• Microcytic,
hypochromic
Anemia • Poikilocytosis • Variable
(pencil cells: small,
A 10-year-old male is seen in the clinic due to joint elongated red cells)
problems in the knees and ankles. His maternal uncle and Serum Fe ↓ ↓
male cousins also have the same condition. PE shows no Transferrin
↑ ↓
visible petechiae or purpura. Prothrombin time and (TIBC)
bleeding time is normal but partial thromboplastin time is Ferritin ↓ ↑
elevated. His CBC analytes along with the platelet count are Serum
↓↓ ↓
normal. Which of the following diagnosis is most likely? Fe/TIBC
A. Disseminated Intravascular Coagulation • Loss of stainable Fe
B. Von Willebrand Disease from bone marrow
Marrow
C. Vitamin K deficiency macrophages ---
findings
D. Hemophilia (Prussian Blue
stain)
THALASSEMIA A 30-year-old male suddenly developed severe dyspnea
• ↓ synthesis of globin chains with wheezing. Physical examination shows that he is
o α-globin: α-thalassemia afebrile with a pulse of 97 bpm, respiratory rate of 32/min
§ α-globin: 2 copies of gene in Ch16 x 2 = 4 and a blood pressure of 130/80 mmHg. CXR shows
o β-globin: β-thalassemia increased lucency in all lung fields. Sputum cytology shows
§ β-globin: 1 copy of gene in Ch11 x 2 = 2 Curschmann spirals, Charcot-Leyden crystals, eosinophils
• The more globin chains absent, the more severe the clinical and some hyphal elements. Which of the following is the
manifestations likely diagnosis of the patient’s condition?
• Intrinsic cause, extravascular hemolysis A. Asthma
• Microcytic, hypochromic anemia B. Pneumoconiosis
• Anisocytosis (variation in size), poikilocytosis (variation in C. Bronchiectasis
shape) D. Sarcoidosis
• Protective against malaria BRONCHIAL ASTHMA
• Condition characterized by chronic airway inflammation and
THALASSEMIA SYNDROMES variable expiratory outflow obstruction
# AFFECTED o Atopic asthma: IgE-mediated (Type 1 hypersensitivity)
SYNDROME CLINICAL FEATURES o Non-atopic asthma: Not immunologically mediated
GENE
β-thalassemia § Noxious stimuli (pollutants, infections) can cause airway
hyperresponsiveness
• Severe
β-thalassemia
2 • Blood transfusion
major BRONCHIAL ASTHMA: MORPHOLOGY
required
• Occlusion of bronchi and bronchioles by thick tenacious mucus
• Severe
β-thalassemia plugs (in Status asthmaticus)
Variable • Regular transfusions not
intermedia • Curschmann spirals: extruded mucus plugs
required
• Charcot-Leyden crystals: eosinophilic crystals composed of
• Asymptomatic with mild galectin-10 (from eosinophils)
β-thalassemia
1 or absent anemia
minor • Eosinophils
• (+) red cell abnormalities
• Airway remodeling
α-thalassemia o Bronchial wall muscle hypertrophy (Airway wall thickening)
1 • Asymptomatic o Sub-basement membrane fibrosis (deposition of Type 1 and
Silent carrier
• No red cell abnormality Type 3 collagen)
α-thalassemia 2 • Asymptomatic o Increased vascularity
trait (minor) • Like β-thalassemia minor • Goblet cell hyperplasia (and submucosal gland hypertrophy)
3 • Severe
HbH disease • Like β-thalassemia
intermedia
Hydrops 4 • Lethal in utero without
fetalis transfusions
Which of the following genetic abnormalities is seen in

Polycythemia Vera?
A. Formation of BCR-ABL fusion gene
B. Activating mutation in JAK2
C. Presence of t(15;17)
D. Formation of BCL2-IGH fusion gene Eosinophils Curschmann Spirals Charcot-Leyden Crystals
Images from Pulmonary Cytopathology by Erozan YS and Ramzy I (2009)
POLYCYTHEMIA
• Abnormally high red cell count with increase in hemoglobin ASPERGILLOSIS
• Two types: • Can cause allergic disease in immunocompetent patients
o Relative: hemoconcentration (always rule out first) (asthmatics)
o Absolute: true increase in red cell mass • Aflatoxin: ↑ Risk of Liver Cancer
§ Primary: defect that produces red cells independent of EPO • Involvement:
stimulation (↓ EPO) o Allergic bronchopulmonary aspergillosis
— Most common: Polycythemia vera o Colonizing aspergillosis: Respiratory tract (in patients with
§ Secondary: increase in red cells secondary to high EPO cavitation)
levels due to other conditions (↑ EPO) o Invasive aspergillosis: Lung, other tissues (heart valves, brain)
— Cyanotic CHDs, High altitude, EPO-secreting tumors, etc.
ASPERGILLOSIS: MORPHOLOGY
POLYCYTHEMIA VERA • Mold: Fruiting bodies,
PARAMETER PV SEPTATE filaments,
JAK2 mutations • > 95% branching at ACUTE angles
Main abnormality • Increase in all cell lines (40°)
Transformation to AML • 1-2% • Colonizing: Aspergilloma
• Plethora (fungus ball) with sparse
• Hyperuricemia inflammation or chronic
Clinical presentation inflammation and fibrosis;
• Bleeding and thrombosis
MINIMAL or NO INVASION
• Pruritus and peptic ulcer
• Invasive:
• Basophilia
PBS findings o Hemorrhagic infarction:
• Large platelets
Angioinvasion
• Hypercellular marrow with o Lung: Necrotizing
Marrow findings increase in trilineage pneumonia with sharply
hyperplasia delineated, rounded, gray Images from Pulmonary Cytopathology by Erozan YS and
Ramzy I (2009)
foci and hemorrhagic
borders (Target lesions)
o Rhinocerebral forms
(same with that of Mucor)
A 25-year-old male was admitted due to progressive • Heart failure
dyspnea for the past 10 weeks. He is afebrile. CXR reveal (Most common)
Hydrothorax
bilateral pleural effusions and widening of the • Renal failure
mediastinum. Thoracentesis of the left side yielded 500 mL • Liver Cirrhosis
of milky white fluid. Lab studies on the pleural fluid show • Trauma
(Most common)
high protein content and microscopy shows many Non- Hemothorax
• Surgery
lymphocytes with fat globules. Which of the following Inflammatory
• Ruptured aortic aneurysm
conditions is likely the cause of these findings? • Thoracic duct trauma
A. Miliary tuberculosis with granulomatous pleuritis (Most common)
B. Bacterial pneumonia with empyema Chylothorax • Obstruction of a major
C. Non-Hodgkin lymphoma with lymphatic obstruction lymphatic duct by
D. Congenital heart disease with congestive heart failure malignancy
PLEURAL EFFUSION
• Pleural fluid; 15 mL normally, serous, acellular, clear fluid A 57-year-old female had mild fever with cough for a week
• Pleural effusion: excess fluid in pleural cavity and improved for the next 10 days. However, she
• Causes: developed fever, cough, shortness of breath and malaise.
CONDITION MECHANISM Physical examination shows a febrile patient with
Congestive Heart Failure ↑ Capillary hydrostatic pressure inspiratory crackles. CXR shows bilateral patchy, small
Pneumonia ↑ Capillary permeability alveolar opacities while chest CT scan shows small,
scattered ground-glass and nodular opacities. Biopsy of the
Nephrotic syndrome ↓ Capillary oncotic pressure
areas involved show polypoid plugs of loose fibrous tissue
Atelectasis ↑ Intrapleural pressure
and granulation tissue filling bronchioles, along with
Mediastinal carcinomatosis ↓ Lymphatic drainage
mononuclear cells infiltrating the surrounding tissue. She
improves upon intake of corticosteroids. What is the likely
TYPES OF PLEURAL EFFUSION diagnosis?
TYPE CHARACTERISTIC CONDITIONS A. Desquamative interstitial pneumonitis
• Inflammation of B. Hypersensitivity pneumonitis
pulmonary parenchyma
(Most common)
C. Cryptogenic organizing pneumonia
Serous,
• Radiation D. Bronchiectasis
Serofibrinous, CRYPTOGENIC ORGANIZING PNEUMONIA
• Autoimmune (RA, SLE)
Fibrinous
• Metabolic (Uremia) • Seen as a response to infection or inflammatory injury of the
• Neoplastic (Metastatic lungs
involvement of pleura) • Feature: Bronchiolitis obliterans
• Infections (Bacterial or • Associated with pneumonias, inhaled toxins, drugs, connective
Fungal)
tissue disease, GvH disease
Inflammatory • Contiguous spread from
intrapulmonary infection • Morphology: Masson bodies → Polypoid plugs of loose
Purulent organizing connective tissue within alveolar ducts
• Lymphohematogenous
dissemination • Can be treated with oral steroids for 6 months or longer
• Extension from a sub-
diaphragmatic infection A 60-year-old non-smoker female has chronic
• Hemorrhagic diatheses nonproductive cough for 4 months along with loss of
• Rickettsial diseases appetite and weight loss. PE was unremarkable. CXR shows
Hemorrhagic • Neoplastic involvement a right peripheral subpleural mass. Based on these
of pleura (Most
information, if the patient has a lung cancer, which of the
important)
following types are most likely expected to develop?
A. Adenocarcinoma
B. Squamous cell carcinoma
C. Small cell carcinoma
D. Carcinoid tumor
Based on the question above, which of the following is the
likely precursor lesion?
A. Squamous metaplasia
B. Atypical adenomatous hyperplasia
C. Pulmonary hamartoma
D. This lesion has no known precursor lesion.
COMMON LUNG CARCINOMAS

FEATURE ADENOCARCINOMA SQUAMOUS CELL SMALL CELL
Prevalence • Most common (50%) • 2nd most common (20%) • 3rd most common (15%)
Site • Peripheral • Central/hilar • Either
Association with • Yes but low (Most common type
• Yes • Almost always
tobacco smoke in never smokers)
Paraneoplastic • Hypercalcemia (PTH, PTHrP, PGE, • SIADH (ADH)
• Non-specific
syndromes Cytokines • Cushing syndrome (ACTH)
Clinical
• NSCLC • SCLC
classification
• Glandular differentiation (with • Keratinization (squamous pearls or chromatin and inconspicuous
different patterns) cells with intensely eosinophilic nucleoli
Morphology
• Mucin production (Invasive cytoplasm) • Extensive necrosis
mucinous adenocarcinomas) • Intercellular bridges • Azzopardi effect: Basophilic
staining of vascular walls
• Atypical adenomatous
• Squamous metaplasia → Squamous
Precursor lesion hyperplasia • No known pre-invasive lesion
dysplasia → carcinoma in situ
• Adenocarcinoma in situ
COMMON HISTOLOGIC VARIANTS An 8-year-old male was seen in the clinic due to bilateral
pre-auricular masses of 2 days duration. The few days
prior, he has been experiencing fever, headache and
malaise. Biopsy of the pre-auricular masses show an
edematous interstitium and diffuse infiltration of
macrophages, lymphocytes and plasma cells, compressing
the acini and ducts. Which of the following complications
are can occur after 1 week if left untreated?
A. Hepatitis
B. Epididymitis
C. Gastroenteritis
D. Orchitis
MUMPS
• Parotitis (bilateral in 70%): Interstitial edema and
mononuclear cell infiltration; focal epithelial damage from
neutrophils and necrotic debris in duct lumen
• Orchitis: Edema, mononuclear cell infiltration, hemorrhage;
compression of swollen testis against tunica albuginea →
infarction → scarring, atrophy, sterility (if severe)
• Pancreatitis
• Encephalitis: perivenous demyelination and perivascular
mononuclear cuffing
Which of the following etiologic entities is known to cause

achalasia?
A. Trypanosoma cruzi
B. Cytomegalovirus
C. Clostridium difficile
D. Schistosoma sp.
ACHALASIA
• Triad:
o Incomplete LES relaxation
o Increased LES tone
o Esophageal aperistalsis
• Etiology
o Primary: Degeneration of NO-producing neurons
o Secondary: Chagas disease (T. cruzi)
CARCINOID TUMOR • Clinical manifestations
o Dysphagia
• Low-grade malignant epithelial neoplasms of neuroendocrine
origin o Difficulty in belching
CHAGAS DISEASE (AMERICAN TRYPANOSOMIASIS)
o Obstruction: secondary to intraluminal growth
§ Cough, Hemoptysis, Infections • Heart (Dilated cardiomyopathy)
o Carcinoid syndrome: secondary to Serotonin and Bradykinin o Acute myocarditis: Myocardial cell necrosis, interstitial acute
§ Diarrhea, Flushing, Cyanosis inflammation
• Gross: o Chronic: Myocardial cell necrosis, interstitial chronic
o Rarely exceed 3-4 cm in size inflammation and fibrosis
o Intraluminal polypoid mass • Esophagus and Colon
mostly on mainstem bronchi o Dilation (No organisms in ganglia of Auerbach plexus)
o “collar-button” lesion
(penetration of bronchial Which of the following findings should favor Ulcerative
wall into the peribronchial Colitis over Crohn Disease?
tissue) A. Presence of non-caseating granulomas
• Histology B. Deep, knife-like ulcers
o Organoid, trabecular, C. Mucosal inflammation
palisading, ribbon, and D. Marked serositis
rosette-like arrangement of INFLAMMATORY BOWEL DISEASE
neoplastic cells • Chronic condition resulting from inappropriate mucosal
o Regular cells, uniform, activation
round nuclei, adequate • Crohn disease (CD) and Ulcerative colitis (UC)
cytoplasm • Main differences between CD and UC
o Rare mitotic activity o Bowel wall involvement: CD: transmural, UC: mural
o No necrosis o Organ involvement: CD: any part of GI tract, UC: colon and rectum
§ Atypical carcinoids: • Both typically present at a young age (teens and early 20s)
cytologic atypia, ↑ mitosis, • Common extraintestinal manifestations: migratory
and presence of necrosis polyarthritis, ankylosing spondylitis, uveitis, skin lesions
o Immunostains: Serotonin, • Most feared long-term complication of UC and colonic CD:
Neuron-specific enolase, Colitis-associated neoplasia
Bombesin, Calcitonin • Common histologic changes: inflammatory infiltrates, crypt
abscesses, crypt distortion, and pseudopyloric epithelial
metaplasia
• Paneth cell metaplasia: Paneth cells in left colon (normally
absent) in CD
• Noncaseating granulomas: hallmark of CD
FEATURE CD UC ULCERATIVE COLITIS
MACROSCOPIC
Bowel region • Ileum + colon • Colon only
Distribution • Skip lesions • Diffuse
Stricture • Yes • Rare
Wall • Thick • Thin
appearance
MICROSCOPIC
• Limited to
Inflammation • Transmural
mucosa
Pseudopolyps • Moderate • Marked
• Superficial,
Ulcers • Deep, knife-like
broad-based
Lymphoid
• Marked • Moderate
reaction
Fibrosis • Marked • Mild to none
Serositis • Marked • Mild to none
Granulomas • Yes (~35%) • No
Fistulae/sinuses • Yes • No
CLINICAL
• Yes (in colonic
Perianal fistula • No
disease)
Fat/vitamin
• Yes • No
malabsorption
Malignant • With colonic
• Yes
potential involvement
Recurrence
• Common • No
after surgery
Toxic
• No • Yes
megacolon
CROHN DISEASE
A 63-year old male was admitted due to weight loss, small

stool caliber with occasional blood. Endoscopy revealed
the presence of a mass at the level of the distal colon
obstructing around 70-80% of the lumen. Biopsy revealed
infiltrating neoplastic glands. Which of the following genes
is the earliest mutated in the pathogenesis of this
neoplasm?
A. SMAD2
B. KRAS
C. TP53
D. APC
COLORECTAL ADENOCARCINOMA FEATURE RIGHT-SIDED LEFT-SIDED
• Most common malignancy of the GI tract • Iron deficiency • Change in bowel
Clinical
• Risk factors anemia, weakness habits, bowel
manifestations
o Dietary factors: low fiber, high carbohydrate and fat diet and fatigue obstruction
o NSAIDs: protective, due to decreased synthesis of PGE2 • Bulky, exophytic • Annular “napkin-
Gross
(responsible for epithelial proliferation) masses ring” configuration
• Molecular genetics (Nice-to-know) • Adenocarcinoma (glandular structures
o Adenoma-carcinoma sequence (80%) lined by dysplastic columnar epithelial
§ Early mutational event: Biallelic loss of APC → adenomas → cells seen in adenomas) with strong
Histology
other mutations → carcinomas desmoplastic response (Most common)
§ Associated with colorectal adenomas • Mucin-producing (Poor prognosis)
o Microsatellite instability (MSI) • Signet ring cell-type (Rare)
§ Inherited mutations in one copy of mismatch repair genes +
inactivation of the other copy (due to mutation or epigenetic
silencing) → ↑ frequency of mutations → carcinogenesis
§ Associated with SSLs
ADENOMA-CARCINOMA SEQUENCE
MISMATCH REPAIR PATHWAY
What is the percentage of alcoholics that progress to HEREDITARY NEPHRITIS

develop cirrhosis? FEATURE ALPORT SYNDROME
A. 10-15% Pathology • Defective assembly of Type IV collagen
B. 30-35% • Autosomal (Ch2 and Ch13)
C. 50-55% Genetics
• X-linked
D. 70-75%
• Eyes: lens dislocation, posterior cataracts,
ALCOHOLIC LIVER DISEASE Usual clinical
corneal dystrophy
“Excessive alcohol (ethanol) consumption is the leading cause of picture and
• Ears: nerve deafness
liver disease in most Western countries. Alcohol accounts for 3.8% prognosis
• Kidney: hematuria → CKD
of deaths globally, making it the eighth highest risk factor for death
Light • Glomerulosclerosis, vascular sclerosis,
(fifth in middle-income countries and ninth in high-income
Microscopy tubular atrophy, and interstitial fibrosis
countries). There are three distinctive, albeit overlapping forms of
(LM) (late)
alcoholic liver injury: (1) hepatocellular steatosis or fatty change,
• Alternating foci of GBM thickening and
(2) alcoholic (or steato-) hepatitis, and (3) steatofibrosis (patterns Electron
thinning
of scarring typical for all fatty liver diseases including alcohol) up Microscopy
to and including cirrhosis in the late stages of disease (Fig. 18-18). • Basket-weave appearance: splitting and
(EM)
For some unknown reason, cirrhosis develops in only a small lamination of lamina dense
fraction of chronic alcoholics. The morphology of the three
interrelated forms of alcoholic liver disease is presented first, to
facilitate the later discussion of their pathogenesis.
Pathogenesis. Short-term ingestion of as much as 80 gm of alcohol

(six beers or 8 ounces of 80-proof liquor) over one to several days
generally produces mild, reversible hepatic steatosis. Daily intake
of 80 gm or more of ethanol generates significant risk for severe
hepatic injury, and daily ingestion of 160 gm or more for 10 to 20
years is associated more consistently with severe injury. Only 10%
to 15% of alcoholics, however, develop cirrhosis. Thus, other
factors must also influence the development and severity of
alcoholic liver disease.”
• 80 g/day: Threshold for developing Alcoholic Liver Disease (ALD)

o Other factors
§ Gender: Females are more susceptible
§ Ethnicity and Genetic factors
§ Presence of concurrent liver pathology: More susceptible
• AST is more elevated in ALD (in contrast with other forms of
chronic liver disease where ALT is more elevated)
FORM FEATURES A 5-year-old boy had honey-colored crusts on his face. The
crusts were removed and initial gram stain studies show
• Macrovesicular steatosis (Most common)
that the etiologic agent is a gram positive cocci. Antibiotics
Steatosis • Alcoholic foamy degeneration: Microvesicular
were given and the crusts resolved. However, he developed
steatosis
malaise, fever and was passing tea-colored urine 1 week
Alcoholic • Ballooned hepatocytes with Mallory hyaline later. ASO titers were 1:1024. Which of the following
hepatitis • Necroinflammatory activity statements is true regarding the patient’s disease?
• Pericellular or perisinusoidal “chicken wire” A. If a kidney biopsy is done, the glomeruli will be
Fibrosis fibrosis →→→ Micronodular cirrhosis enlarged and hypercellular.
“Laennec cirrhosis” (Most common) B. This is an anti-GBM antibody-mediated disease.
C. Serologic studies will reveal hyperlipidemia and
A 13-year-old male was seen in the clinic due to nerve lipiduria.
deafness, dislocation of the left ocular lens and gross D. Patient likely developed a form of nephrotic
hematuria. Electron microscopy reveals irregular foci of syndrome.
thickening and thinning of the glomerular basement POST-STREPTOCOCCAL ACUTE GLOMERULONEPHRITIS
membrane with a “basket-weave” appearance of the • Prototype glomerular disease of immune complex etiology
lamina densa. Which of the following conditions is likely (Type III HS)
the diagnosis of this patient?
• Most common cause of nephritic syndrome in children
A. Alport syndrome
• Non-suppurative sequelae of GABHS infection
B. Poststreptococcal acute glomerulonephritis
C. Minimal change disease • Nephritogenic strains of GAHBS (M12, 4, and 1 in 90%)
D. IgA Nephropathy
FINDINGS PSAGN IMPETIGO
• Enlarged, hypercellular glomeruli • Forms
• Crescent formation in severe cases o Impetigo contagiosa: S. pyogenes
Light • Endothelial cell swelling o Impetigo bullosa: S. aureus
Microscopy (LM) • Capillary lumina obliteration • Clinical lesion: Honey-colored crust
• Tubulointerstitial edema and • Superficial erosions from pustule rupture, covered with drying
inflammation, with RBC casts serum
Electron • Subepithelial humps on GBM • Characteristic microscopic finding: Accumulation of
Microscopy (EM) neutrophils beneath the stratum corneum
• Granular deposits of IgG, C3, and
Immuno- A 40-year-old female was seen in the clinic due to lethargy
sometimes IgM in the mesangium and
fluorescence (IF)
along the GBM for around 4 months. Physical examination reveals a blood
pressure of 140/90. Laboratory findings show serum
creatinine levels of 5.8 mg/dL (NV: 0.59 – 1.04 mg/dL),
hypocomplementemia and a negative ANA result.
Urinalysis shows presence of blood and protein. Kidney
biopsy shows hypercellular glomeruli with prominent
ribbon-like deposits along the lamina densa of the
FEATURE CHILDREN ADULTS glomerular basement membrane. What is the likely
Important • ↑ Anti-Streptococcal titers (ASO or anti DNase diagnosis of this patient?
laboratory B, depending on the antecedent infection) A. Postinfectious glomerulonephritis
findings • ↓ C3 and other complement components B. Rapidly progressive glomerulonephritis
Azotemia • Usually absent • Usually present C. Membranous nephropathy
D. Dense deposit disease
Recovery • > 95% • 60%
Progression
to CGN or • Less likely • More likely
RPGN
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
DENSE DEPOSIT DISEASE
FEATURE MPGN TYPE I
(MPGN TYPE II)
Immune complex
• Yes • No
deposition
Complement
• Classical and alternative • Alternative
activation
• SLE, HBV and HCV infection,
endocarditis, infected AV shunts,
Association with
chronic visceral abscesses, HIV, ---
other diseases
Schistosomiasis, α1-antitrypsin
deficiency, lymphoid neoplasms (CLL)
• Nephritic and/or nephrotic syndrome
Clinical presentation
• ~ 50% of patients progress to ESRD
• Large, hypercellular glomeruli with
• Variable
mesangial cell proliferation and ↑
Light Microscopy (Mesangioproliferative or
mesangial matrix
(LM) inflammatory with focal
• Thickened GBM “double-contour”
crescents)
“tram-track” appearance
• Lamina densa permeated Dense Deposit Disease
Electron Microscopy
• Subendothelial electron-dense deposits by a ribbon-like extremely
(EM)
electron-dense structure
• Granular C3 deposits WITH IgG and • Granular or linear C3
Immunofluorescence
early complement components (C1q deposits WITHOUT IgG and
(IF)
and C4) early complement
A 45-year-old male was seen in the urologist’s clinic due to OTHER NEOPLASMS OF THE BLADDER
a bladder mass. A biopsy was done revealing neoplastic • Squamous cell carcinoma
squamous cells. Which of the following is the likely risk o Risk factor: Chronic bladder irritation and infection
factor present in the patient leading to the development of (Schistosoma haematobium)
his disease? o Precursor lesion: Squamous dysplasia and CIS
A. Long exposure to cyclophosphamide • Adenocarcinoma
B. Exposure to aryl amines o Arises in urachal remnants and intestinal metaplasia
C. Tobacco Use • Small cell carcinoma
D. Schistosoma haematobium infection o Similar to small cell carcinomas in other sites
UROTHELIAL NEOPLASMS o Very aggressive
• Epidemiology
o More common in males and advancing age A 20-year-old G2P1 female was seen in the obstetricians
• Risk factors clinic during her 2nd trimester due to small amount of
vaginal bleeding, and nausea and vomiting for the past 3
o Smoking (most important)
o Arylamines (2-Naphthylamine) weeks. PE revealed that her uterus is large for her
supposed dates. Ultrasound examination revealed a
o Long-term analgesic use
“snowstorm appearance” and no fetus was identified.
o Heavy, long-term cyclophosphamide exposure
Curettage revealed a friable mass of cystic, grape-like
o Irradiation
structures. Which of the following laboratory analytes is
likely to be elevated in the serum?
o Painless hematuria (Most common)
A. Alpha fetoprotein
o Frequency, Urgency, Dysuria
B. Estradiol
o Obstruction with consequent pyelonephritis or
C. Human placental lactogen
hydronephrosis
D. Human chorionic gonadotropin
HYDATIDIFORM MOLE o Riedel thyroiditis
• Histologic hallmark: Cystic swelling of the chorionic villi with § Extensive fibrosis of the thyroid and contiguous neck
trophoblastic proliferation structures
• Clinical significance § May simulate a malignant process
o One of top differentials for bleeding in the first half of • Thyroid hormone levels vary in the course of the disease
pregnancy (together with abortion and ectopic) o Thyrotoxicosis (due to release of pre-formed thyroid
o Precursor to persistent molar disease (invasive mole) and hormones) → Hypothyroidism
gestational choriocarcinoma (complete mole) § Thyroid hormones return to normal levels in
• Types: Complete, Partial, Invasive Granulomatous and in some cases of subacute lymphocytic
• Pathogenesis thyroiditis
o Complete: Chromosome duplication of paternal chromosomes • Common clinical manifestation: Thyroid enlargement
Diploid karyotype → (46XX) o Painful: Granulomatous thyroiditis
o Partial: Dispermy and a haploid ovum → Triploid karyotype o Painless: Hashimoto and Subacute lymphocytic
(69XXX or 69XXY) • Complications
o Persistent hypothyroidism: Hashimoto and some cases of
HYDATIDIFORM MOLE: CHARACTERISTICS subacute lymphocytic thyroiditis
Feature Partial Mole Complete Mole o Development of autoimmune diseases: Hashimoto
Karyotype 69 XXX or 69 XXY 46 XX o Development of neoplasms (Marginal zone B-cell lymphoma,
Clinical presentation Papillary thyroid carcinoma): Hashimoto
Diagnosis Missed abortion Molar gestation
Uterine size Smaller for dates Larger for dates DE QUERVAIN (GRANULOMATOUS) THYROIDITIS
Theca-Lutein cysts Rare Uncommon FEATURE GRANULOMATOUS
Initial hCG levels <100,000 >100,000 Pathology • Antigen-mediated immune damage to
mIU/mL mIU/mL follicular cells (by cytotoxic T cells)
Medical History • History of URTI prior to thyroiditis
Rare Uncommon
complications* Inflammation • (+) PMNs → lymphocytes, activated
Rate of subsequent macrophages, plasma cells
1-5% of cases 15-20% of cases
GTN** Hürthle cell
* - Anemia, hyperthyroidism, hyperemesis gravidarum, • Absent
change
preeclampsia, and infection Fibrosis • Absent
** - Gestational trophoblastic neoplasia Granulomas • Present (with multinucleated giant cells)
Feature Partial Mole Complete Mole
Pathology
Embryo-Fetus Often present Absent
Amnion, Fetal
Often present Absent
erythrocytes
Villous edema Focal Widespread
Trophoblastic
Slight to severe Marked
proliferation
Trophoblastic
Mild Marked
atypia
Complete mole → Partial mole → partial circumferential

complete trophoblastic proliferation A 25-year-old female is seen in the clinic due to doubling of
circumferential vision. Physical examination shows exophthalmos and
trophoblastic weak extraocular muscle movement. There is a painless
proliferation diffuse enlargement of the thyroid gland but there is no
lymphadenopathy. Which of the following laboratory
A 51-year-old female is seen in the ENT clinic due to a findings are expected in this patient?
painful neck mass, palpitations, weight loss and heat A. Increased thyrotropin-releasing hormone level
intolerance. Physical exam reveals a diffusely enlarged and B. Decreased thyroid-stimulating hormone level
tender thyroid gland. Biopsy reveals lymphocytes, C. Very high levels of thyroid peroxidase autoantibodies
macrophages, follicular cells and multinucleated giant D. Decreased free thyroxine level
cells. Which of the following is the likely diagnosis of the GRAVES DISEASES
patient’s condition? FEATURE GRAVES DISEASE
A. Lymphocytic thyroiditis • Hyperthyroidism
B. Graves Disease Triad • Ophthalmopathy → Exophthalmos
C. Hashimoto thyroiditis • Dermopathy
D. De Quervain thyroiditis
• Type II Hypersensitivity
THYROIDITIS
• Autoantibodies against TSH receptor
• Inflammatory diseases of the thyroid gland • TSI (Thyroid stimulating Ig): mimics TSH
• Common thyroiditides (See the following table for discussion of Pathology
actions (most common)
the first three) • TSH receptor blocking Ig (TSB): results in
o Hashimoto thyroiditis (Struma lymphomatosa) hypothyroidism
o Subacute lymphocytic (Painless) thyroiditis (Postpartum
• Thyroid gland: Diffuse hypertrophy and
thyroiditis)
hyperplasia
o Granulomatous (De Quervain thyroiditis) Morphology
o Pseudopapillary hyperplasia
o Scalloped colloid
o Interstitial lymphoid infiltrates (T cells > B PHEOCHROMOCYTOMA
cells) with germinal centers • Cytogenetic origin: chromaffin cells of medulla
• Ophthmalopathy: Deposition of GAGs, • Releases catecholamines
lymphocytic infiltration → Fibrosis (Orbit and • Morphology
EOMs) o Zellballen (nests of cells surrounded by sustentacular cells)
• Dermopathy (Pretibial myxedema): Dermal o Salt and pepper chromatin
thickening (due to deposition of GAGs and o Metastasis: Only reliable criterion for malignancy
lymphocytic infiltration) • Clinical manifestation: Hypertension (predominant)
• Triad: Diaphoresis, Headaches, Palpitations
A 50-year-old male was seen in the clinic due to a painless • Laboratory findings: ↑ Urinary excretion of free catecholamines
anterior neck mass associated with difficulty in and metabolites (vanillylmandelic acid (VMA) and
swallowing. Other symptoms present include diarrhea and metanephrines)
flushing. Laboratory tests show elevation in serum
calcitonin. Which of the following is the likely cell of origin
of this lesion?
A. Chief cells
B. Oxyphil cells
C. Follicular cells
D. Parafollicular C cells
MEDULLARY THYROID CARCINOMA
• Associated with MEN2
• Clinically present with paraneoplastic syndromes (VIP, ACTH)
and high levels of Calcitonin (but usually without hypocalcemia)
• Associated with unfavorable prognosis
• Morphology:
o Small, polygonal to spindle-shaped cells
o Acellular amyloid deposits
o Familial forms: Multicentric, bilateral, (+) parafollicular C cell
hyperplasia
o Sporadic (More common): (-) parafollicular C cell hyperplasia
A 46-year-old female has had bilateral diffuse pain in the

thighs and shoulders for the past 6 weeks causing difficulty
from rising from the chair and climbing steps. A faint
violaceous rash developed around the orbits and on the
skin of her knuckles. Physical revealed motor strength of
4/5 in all extremities. Lab tests should ANA positive and
presence of Anti-Jo-1 antibodies. Which of the following
A 35-year-old female was seen in the emergency room malignancies can cause this paraneoplastic condition?
because she collapsed. A ventricular fibrillation was A. Uterine carcinoma
detected and was then converted to a sinus rhythm. For the B. Thymic carcinoma
past 3 months, she experienced palpitations, tachycardia, C. Breast carcinoma
tremors, diaphoresis and headache. Recently, her D. Acute promyelocytic leukemia
symptoms became worse with her BP measuring at 155/90 PARANEOPLASTIC SYNDROMES
mmHg. Physical examination is unremarkable. Which of • Signs and symptoms not referable to the anatomic distribution
the following laboratory findings is likely present in this of the tumor
patient? • May involve ectopic hormone production by tumor cells
A. Increased serum free T4 • Importance:
B. Increased urinary homovanillic acid level o Initial manifestation of occult neoplasm
C. Increased urinary free catecholamines o May cause significant clinical problem
D. Decreased serum cortisol level o May mimic metastatic disease
DERMATOLOGIC DISORDERS
Immunologic;
Gastric carcinoma
Acanthosis secretion of
Lung carcinoma
nigricans epidermal growth
Uterine carcinoma
factor
Bronchogenic
Dermatomyositis carcinoma Immunologic
Breast carcinoma
INFLAMMATORY MYOPATHIES
DERMATOMYOSITIS POLYMYOSITIS
• Juvenile (most common
inflammatory
Age/ myopathy)
• Usually adult A 35-year-old woman has experienced malaise, fatigue,
associations • Adults: usually a
and joint pain for the past 5 months. On physical
paraneoplastic
syndrome examination, the joint involvement is symmetric, and most
of the affected joints are in the hands and feet. The right
• Myalgias + Proximal weakness → Distal second and third digits have a “swan neck” deformity, and
Weakness
weakness (Late) there is ulnar deviation of both hands. Which of the
• Heliotrope rash: following laboratory findings is most likely to be reported
Periorbital lilac in this patient?
discoloration A. Positive Borrelia burgdorferi serologic test
Skin changes • Gottron papules: • None B. Calcium pyrophosphate crystals in a joint aspirate
Dusky red patches over C. Serum positive for ACPA
knuckles, knees and D. Hyperuricemia
elbows RHEUMATOID ARTHRITIS
• Immunologic damage to • CD8+ T cell- FEATURE RHEUMATOID ARTHRITIS
small blood vessels mediated
Pathogenesis Primary
(Type I interferon damage to pathologic • Autoimmunity
response) muscle abnormality
Mononuclear • Perimysial
• Endomysial • Primary: Cartilage destruction is caused
infiltrate • Perivascular Role of
by CD4+ T cells and antibodies reactive
Pattern of • Random, inflammation
• Perifascicular with joint antigens
atrophy Patchy • Often begins with small joints of fingers;
DERMATOMYOSITIS Joints involved progression leads to multiple joints
involved
• Pannus: Mass of edematous synovium,
inflammatory cells, granulation tissues,
and fibrosis → invasion and destruction
of cartilage
Pathology
• Severe chronic inflammation
• Joint fusion (Ankylosis)
• Rheumatoid nodules: Necrotizing
Images from: https://dermnetnz.org/topics/adult-onset-dermatomyositis/ granulomas (Fibrinoid necrosis)
Serum • Various: Rheumatoid factor, Anti-
antibodies citrullinated peptide antibody
A biopsy of a right distal femoral mass from a 19-year-old
Extra-articular
male showed neoplastic cells with various shapes and sizes • Yes (Lungs, Heart, Other organs)
involvement
with large hyperchromatic nuclei in a background of
neoplastic bone arranged in a “lace-like” pattern. Which of Systemic
• Present (can precede joint involvement)
the following mutated genes will cause a 1000-fold symptoms
increase of this condition? • Swan neck deformity: PIP
A. INK4a Physical Hyperextension, DIP flexion
B. TP53 examination • Boutonniere deformity: PIP Flexion DIP
C. MDM2 Hyperextension
D. RB
OSTEOSARCOMA A 6-year-old boy was brought by his mother due to multiple
• Bimodal age incidence subcutaneous nodule along the right shoulder. Further
o Most occur in <20 years old (75%) physical examination shows multiple café-au-lait spots on
o Older adults (Secondary osteosarcomas) the skin as well. Biopsy of the subcutaneous nodule shows
§ Associated with predisposing conditions multiple nerve fascicles that are expanded by infiltrating
tumor cells resulting to a “bag-of-worms” appearance.
• Most common location: Metaphysis of long bones (Knee i.e.
Which of the following statements are true regarding this
distal femur, proximal tibia (50%))
lesion?
• Radiographic findings: Periosteal lifting (Codman triangle),
A. Verocay bodies are also present in this lesion.
infiltrative borders (Sunburst appearance), Lytic and blastic
B. This lesion can become large and can mimic the
lesions
appearance of Meissner corpuscles.
• Molecular pathogenesis (Nice-to-know) C. This lesion has a high risk of transforming to a
o Tumor suppressor gene inactivation: RB, TP53, CDKN2A
malignant lesion.
o Oncogene overexpression: MDM2, CDK4 (inhibits p53 and RB, D. This lesion is associated with neurofibromatosis type 2.
respectively)
NEUROFIBROMA
• Morphology
o Cytologically malignant cells • Heterogeneous cell composition
o Bone formation (usually lace-like pattern) (Diagnostic) o Neoplastic Schwann cells: S-100(+)
o Abundant cartilage: Chrondroblastic osteosarcoma o Perineurial-like cells
o Fibroblasts
o Mast cells
o Spindle cells: CD34 (+)
• Forms
o Superficial cutaneous neurofibroma: Multiple if NF-1
associated
o Diffuse neurofibroma and plexiform neurofibroma: NF-1
associated
• Mutation: NF1 (Ch17) inactivation → unbridled RAS activation
→ tumorigenesis
• Morphology
o Superficial cutaneous neurofibroma
§ Well-circumscribed, unencapsulated
§ Relatively lower cellularity than Schwannomas
§ Heterogeneous population of cells (see above) embedded in
a collagenous stroma with a “Shredded carrot” appearance
o Plexiform neurofibroma
§ “Bag of worms” appearance: Consequence of expansion and
thickening of multiple nerve fascicles by the tumor PROTOTYPES OF NEURODEGENERATIVE DISEASES
• Clinical significance: In NF1 patients, plexiform neurofibromas ANATOMIC LOCATION CLINICAL CONDITION
can transform into MPNSTs Cortex • Dementias
Basal Ganglia and Brainstem • Parkinsonism
Spinal cord and Cerebellum • Ataxia
Motor neurons • Muscle atrophy
A biopsy of nerve from a patient with Lou Gehrig Disease

will show which of the following histologic findings?
A. Bunina bodies
B. Lewy bodies
C. Pick bodies
D. Negri bodies
AMYOTROPHIC LATERAL SCLEROSIS
• Loss of upper motor neurons and lower motor neurons
o Consequence: Denervation of Skeletal muscles → weakness
and atrophy
• Pathogenesis: SOD1 (Ch21) mutation
• Morphology: Predominantly motor involvement
o Upper motor neurons: Cerebral cortex
§ Atrophic BA 4,6 (Precentral gyrus)
A 58-year-old male was seen in the neurologist clinic due o Lower motor neurons: Brainstem and Spinal cord
to increasing difficulty in initiating voluntary movements § Thinned anterior roots
and inability to perform activities of daily living for 1 year. § Loss of motor neurons and cranial nerve motor nuclei
Physical examination shows difficulty in initiating § Bunina bodies: PAS(+) cytoplasmic inclusions seen in
movement but can easily follow if someone is walking remaining neurons
ahead. Facies appear expressionless. When the patient
died, autopsy revealed pallor of the substantia nigra and AMYOTROPHIC LATERAL SCLEROSIS: MORPHOLOGY
locus ceruleus. Which of the following additional clinical
findings is compatible with these abnormalities?
A. Ataxia with ambulation
B. Symmetric weakness in the extremities
C. Choreiform movements
D. Tremors at rest
PARKINSON DISEASE
• Loss of Dopaminergic neurons in Substantia Nigra
• Dementia with Lewy Bodies: Parkinson + Dementia
• Triad: Tremor, Rigidity, Bradykinesia
• Morphology
o Pallor of substantia nigra and locus coeruleus
o Lewy body (α-synuclein): Cytoplasmic, eosinophilic,
inclusion with a dense core surrounded by a pale halo
o Dementia with Lewy Bodies: Lewy bodies in cortical and
brainstem neurons
PARKINSON DISEASE: MORPHOLOGY

• Characteristic gross findings: Pallor of the substantia nigra and
locus ceruleus
o Due to loss of pigmented catecholaminergic neurons
• LEWY BODIES → found in some of the remaining neurons →
single or multiple, cytoplasmic, round to elongated inclusions
with a dense core and pale halo
o Composed of fine filaments → α-synuclein
o Can also be found in the cholinergic neurons of the basal Slide from lecture of Dr. RGR Abesamis
nucleus of Meynert + other basal nuclei including the locus

• Anterior roots of the spinal cord are thin due to loss of LMN
ceruleus, and dorsal motor nucleus of the vagus
axons
• Severe cases: atrophy of the precentral motor gyrus
• Reduction in the number of anterior horn neurons in the spinal
cord + reactive gliosis
o Also seen in the hypoglossal, ambiguous and motor trigeminal
cranial nerve nuclei
• BUNINA BODIES → PAS-positive cytoplasmic inclusions seen in
remaining neurons
• Skeletal muscles innervated by degenerated LMN →
NEUROGENIC ATROPHY
A 5-year-old boy died after brain herniation and an

autopsy was conducted. Pertinent history included
complaints of headaches for the past week along with
ataxia. A brain biopsy was done revealing sheets of small
round blue cells with some arranged in rosettes. A mass is
most likely present in which of the following locations?
A. Basal ganglia
B. Cerebellum
C. Cranial Nerve VIII
D. Fourth Ventricle
MEDULLOBLASTOMA
• Malignant embryonal tumor of the cerebellum
• Predominantly afflicts children
• Morphology (Classic type)
o Small, round, blue cells with Homer-Wright pseudorosettes
(as in Neuroblastoma)
o Highly proliferative (Mitosis and Ki-67 index)
• Common complication: Dissemination to CSF
• Radiosensitive
• Molecular subtype is a prognostic factor i.e. WNT-activated
medulloblastomas: very favorable prognosis
Slide from lecture of Dr. RGR Abesamis
From lecture of Dr. Arie Perry
END OF PATHOLOGY PHASE 2
TOPNOTCH MEDICAL BOARD PREP PATHOLOGY PHASE 3 HANDOUT BY EUGENE G. ODOÑO I MD
An 8 month old infant is brought to the clinic. He was
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communication. No part of the handout, video or other review material may be reproduced, scanty lymph nodes and tonsils. Workup revealed
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Topnotch Medical Board Preparation Incorporated. Any violation and or infringement, B cell in circulation. What is the most likely
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A. isolated IgA deficiency
B. common variable immunodeficiency
DISCLOSURE C. Bruton’s disease
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REMINDERS
1. Phase 3 serves as the final coaching. It is expected that you have finished
at least the Phase 1 videos prior to watching the Phase 3 videos
2. The guided content of the video lectures are seen within the handout.
Answers to questions / blanks will be seen in the Phase 3 video.
This handout is only valid for the September 2021 PLE batch.
This will be rendered obsolete for the next batch
since we update our handouts regularly.
PATHOLOGY – PHASE 3
By Eugene G. Odoño I MD
The increase in size of the uterus during pregnancy
is an example of:
A. Pathologic Hypertrophy
2.
B. Pathologic Hyperplasia
C. Physiologic Hyperplasia
D. Physiologic Hypertrophy
PATHOLOGY CONCEPT: CELLULAR ADAPTATIONS

ADAPTATION DEFINITION STIMULUS MECHANISM EXAMPLES
• PHYSIOLOGIC
• áFunctional • Myometrial hypertrophy in gravid uterus
demand • áProtein (hormonal stimulation)
HYPERTROPHY áOrgan/cell SIZE
• Hormonal synthesis • Muscle of bodybuilders (functional demand)
stimulation • PATHOLOGIC
• LVH in hypertensive heart disease
• Growth factor-
driven • PHYSIOLOGIC
proliferation of • Pubertal breast changes (hormonal)
• Hormonal
HYPERPLASIA áNUMBER of cells mature cells or • Liver regeneration (compensatory)
• Compensatory
• áOutput of new • PATHOLOGIC
cells from tissue • Endometrial hyperplasia (hormonal)
stem cells
• âWorkload
• Denervation
• âProtein • PHYSIOLOGIC
• Ischemia
synthesis • Embryonic atrophy (notochord and
â in cell size AND • Malnutrition
ATROPHY • áProtein thyroglossal duct)
number • Loss of degradation • PATHOLOGIC
endocrine
• Autophagy • Senile atrophy of brain
stimulation
• Pressure
• Squamous (Columnar to squamous; most
Differentiated cell common): Vitamin A deficiency
• Reprogramming
METAPLASIA type replaced by • Stress • Columnar: Barrett esophagus
of stem cells
another cell type • Connective tissue: Myositis ossificans after
intramuscular hemorrhage
Which of the following is not a component of Which of the following is a characteristic of

Tetralogy of Fallot? necrosis?
A. Ventricular septal defect A. Apoptotic bodies
3. 4.
B. Overriding aorta B. Cell shrinkage
C. Right ventricular hypertrophy C. Inflammation
D. Suprapulmonic stenosis D. All of the above
TOPNOTCH MEDICAL BOARD PREP PATHOLOGY PHASE 3 HANDOUT BY EUGENE G. ODOÑO I MD Page 1 of 31
PATHOLOGY CONCEPT: NECROSIS AND APOPTOSIS GM2 gangliosidoses
Features Necrosis Apoptosis Tay-Sachs
Enlarged Hexosaminidase A GM2 ganglioside
Cell size Reduced (shrinkage) disease
(swelling)
Sandhoff GM2 ganglioside,
Pyknosis à Fragmentation into Hexosaminidase A and B
disease globoside
Nucleus Karyorrhexis à nucleosome-sized
Karyolysis fragments GM2
Ganglioside activator
gangliosidosis GM2 ganglioside
Intact; altered protein
Plasma variant AB
Disrupted structure, especially
membrane
orientation of lipids Sulfatidoses
Enzymatic Intact; maybe
Cellular Metachromatic
digestion; may released in apoptotic Arylsulfatase A Sulfatide
contents leukodystrophy
leak out of cell bodies
Adjacent Arylsulfatase A, B, C; Sulfatide, steroid
Frequent No Multiple
inflammation steroid sulfatase; sulfate, heparan
sulfatase
Physiologic or Invariably Often physiologic; iduronate sulfatase; sulfate, dermatan
deficiency
pathologic role pathologic may be pathologic heparan N-sulfatase sulfate
Krabbe disease Galactosylceramidase Galactocerebroside
What is the most common cause of mitral
regurgitation? Ceramide
Fabry disease α-Galactosidase A
A. Rupture of Papillary Muscle after Myocardial trihexoside
5. Infarction Gaucher
B. Rheumatic Heart Disease Glucocerebrosidase Glucocerebroside
disease
C. Mitral Annular Calcification
Niemann-Pick
D. Mitral Valve Prolapse
disease: types A Sphingomyelinase Sphingomyelin
VALVULAR HEART DISEASE: ETIOLOGY
and B
MITRAL STENOSIS AORTIC STENOSIS
Postinflammatory scarring Postinflammatory Mucopolysaccharidoses (MPSs)
(RHD) scarring (RHD) MPS I-H Dermatan sulfate,
Senile calcific aortic α-L-Iduronidase
(Hurler) heparan sulfate
stenosis
Calcification of MPS II (Hunter) Iduronate 2-sulphatase
congenitally deformed
valve Mucolipidoses (MLs)
MITRAL REGURGITATION AORTIC REGURGITATION Deficiency of
Abnormalities of Abnormalities of phosphorylating
Leaflets/Commissures Leaflets/Commissures enzymes essential for the
• Postinflammatory scarring • Postinflammatory scarring formation of mannose-6-
I-cell disease
• Infective endocarditis (RHD) phosphate recognition
(ML II) and Mucopolysaccharide,
• Mitral valve prolapse • Infective endocarditis marker; acid hydrolases
pseudo-Hurler glycolipid
• Drugs (e.g., fen-phen) • Marfan syndrome lacking the recognition
polydystrophy
marker cannot be
Abnormalities of Tensor Aortic Disease targeted to the
Apparatus • Degenerative aortic lysosomes, but are
• Rupture of papillary muscle dilation secreted extracellularly
• Papillary muscle dysfunction • Syphilitic aortitis Other diseases of complex carbohydrates
(fibrosis) • Ankylosing spondylitis
• Rupture of chordae • Rheumatoid arthritis Fucose-containing
tendineae • Marfan syndrome sphingolipids and
Fucosidosis α-Fucosidase
Abnormalities of LV Cavity glycoprotein
and/or Annulus fragments
• LV enlargement Mannose-containing
Mannosidosis α-Mannosidase
(myocarditis, dilated oligosaccharides
cardiomyopathy) Aspartyl-2-deoxy-2-
• Calcification of mitral ring Aspartyl- Aspartylglycosamine
acetamido-
glycosaminuria amide hydrolase
glycosylamine
Bone marrow biopsy from a 4/F reveals distended
phagocytic cells. These cells are enlarged, with an Other lysosomal storage diseases
eccentrically placed nuclei and a “crumpled tissue Wolman Cholesterol esters,
paper” cytoplasm. What is the enzyme defect? Acid lipase
6. disease triglycerides
A. Gaucher Disease
B. Galactosylceramidase
C. Hexosaminidase Alpha-fetoprotein can be used as a tumor marker
for which of the following?
D. Glucocerebrosidase
I. Seminoma
Major II. Yolk Sac Tumor
Disease Enzyme Deficiency Accumulating 7.
III. Hepatocellular carcinoma
Metabolites A. II only
Glycogenosis B. I and II
Type 2—Pompe α-1,4-Glucosidase C. II and III
Glycogen D. I, II, and III
disease (lysosomal glucosidase)
Sphingolipidoses
GM1 ganglioside,
GM1 GM1 ganglioside β-
galactose-containing
gangliosidosis galactosidase
oligosaccharides
Tumor Markers Tumor Types Which of the following describes Klinefelter
Hormones syndrome?
Trophoblastic tumors, A. Patient has one or more X chromosomes and
Human chorionic one or more Y chromosomes
nonseminomatous testicular
gonadotropin 9. B. The most consistent feature is male
tumors
hypogonadism
Calcitonin Medullary carcinoma of thyroid C. Patients are at a higher risk of developing Type
Catecholamine and Pheochromocytoma and related 1 Diabetes mellitus
metabolites tumors D. All of the above are correct
Oncofetal Antigens
Liver cell cancer, Which of the following is considered a stable tissue?
α-Fetoprotein nonseminomatous germ cell A. Epidermis
tumors of testis 10. B. Liver
C. Brain
Carcinoembryonic Carcinomas of the colon, pancreas,
D. Heart
antigen lung, stomach, and heart
PATHOLOGY CONCEPT: TISSUE REPAIR
Lineage-Specific Proteins
CLASSIFICATION OF TISSUES BY REGENERATIVE CAPACITY
Multiple myeloma and other TISSUE DESCRIPTION EXAMPLES
Immunoglobulins
gammopathies
Continuously lost and
Prostate-specific • Surface
replaced either by
antigen and prostate- epithelium
Prostate cancer Labile proliferation of residual
specific membrane • Hematopoietic
cells or maturation of
antigen stem cells
stem cells
Mucins and Other Glycoproteins • Liver
Cells are quiescent
CA-125 Ovarian cancer • Kidney
(in G0)
CA-19-9 Colon cancer, pancreatic cancer Limited capacity to • Pancreas
CA-15-3 Breast cancer Stable proliferate • Endothelium
Cell-Free DNA Markers (except liver) • Fibroblasts
EGFR mutants in Proliferate in response • Smooth muscle
Lung cancer
serum to injury and tissue loss cells
TP53, APC, RAS Terminally • Neurons
mutants in stool and Colon cancer Permanent differentiated and • Cardiac and
serum non-proliferative skeletal myocytes
TP53, RAS mutants in
Pancreatic cancer
stool and serum Which of the following scenarios will least likely
TP53, RAS mutants in cause a red infarction?
Lung cancer
sputum and serum A. Infarction of the lung caused by pulmonary
TP53 mutants in urine Bladder cancer embolism
11. B. Infarction of the kidney caused by systemic
A patient who died of lobar pneumonia underwent thromboembolism
autopsy. Under the microscope, the alveoli are filled C. Infarction of the myocardium during a heart
with fibrin, red cells, and neutrophils. What is the attack, with an attempt at reperfusion
stage of pneumonia? D. Infarction of the small intestine
8.
A. Congestion INFARCTION
B. Red Hepatization FEATURE RED INFARCT WHITE
C. Gray Hepatization INFARCT
D. Resolution
• Venous occlusion • Solid
LOBAR PNEUMONIA: MORPHOLOGY
• Loose, spongy tissues (lung) organs
Stage Gross Microscopic • Organs with dual blood • End-
supply (lung & bowel) arterial
vascular engorgement Setting
• Tissues previously congested circulation
heavy, intra-alveolar fluid with few • Reperfusion of a site of (heart,
Congestion boggy, neutrophils previous arterial occlusion spleen,
and red Often with the presence of and necrosis kidney)
numerous bacteria • Wedge-shaped with occluded vessel at apex
Gross
confluent exudation with and periphery of organ at base
Red Red, • Ischemic, coagulative necrosis
neutrophils, red cells, and fibrin
Hepatization solid o (EXCEPT in brain: liquefactive necrosis)
filling the alveolar spaces
Microscopic • Most are ultimately replaced by scar tissue
disintegration of red cells and o (EXCEPT in septic infarcts: abscess
Gray Gray,
the persistence of a formation)
Hepatization solid
fibrinosuppurative exudate
Which of the following describes congestion?
progressive enzymatic digestion
A. Active process
of exudate to produce granular,
12. B. Erythematous
semifluid debris that is
C. Caused by reduced outflow of blood
Resolution resorbed, ingested by
D. Results in accumulation of oxygenated blood
macrophages, expectorated, or
HYPEREMIA VS CONGESTION
organized by fibroblasts
growing into it
A father and his son were found unconscious inside o Failure to degrade substance
a locked car of a mall parking lot. The car was idling o Deposition of indigestible substance
with the airconditioning turned up and the windows • Accumulations
closed. There was no external evidence of foul play. o Lipids (triglycerides, cholesterol and
13. What is the most likely cause of death? cholesterol esters)
A. Murder o Proteins
B. Cyanide poisoning o Hyaline (eosinophilic material)
C. Carbon monoxide poisoning o Glycogen
D. Organophosphate poisoning o Pigments
§ Exogenous (anthracosis, tattoo)
Example of metastatic calcification: § Endogenous (lipofuscin, melanin, hemosiderin)
A. Senile calcific aortic stenosis
14. B. Psammoma bodies
C. Calciphylaxis
D. Saponification
CALCIFICATIONS
Parameter Dystrophic Metastatic
Type of
Necrotic Viable
tissue
Increased Which of the following tumors is malignant?
Causes: A. Rhabdomyoma
• PTH excess 18. B. Parathyroid Adenoma
Serum • Bone resorption C. Chondroma
Normal D. Hepatoma
calcium (secondary to primary
bone marrow tumors) TERMINOLOGY
• Vitamin D disorders Tissue
Benign Malignant
• Renal failure “Origin”
Basophilic, amorphous granular, clumped Epithelial Origin
Histology appearance; either intra- or extra-cellular; Squamous Squamous cell Squamous cell
heterotopic bone may be formed Epithelium papilloma carcinoma
Psammoma bodies Lung involvement Lining of
Adenoma Adenocarcinoma
Clinical (sand-like lamellated (respiratory compromise); Glands/Ducts
importance concretions); seen in nephrocalcinosis (renal Mesechymal Origin
papillary cancers dysfunction) Fat Lipoma Liposarcoma
Cartilage Chondroma Chondrosarcoma
Examination of a peripheral blood smear from a Bone Osteoma Osteosarcoma
25/M showed faggot cells with Auer rods. What is Blood Vessels Hemangioma Angiosarcoma
the diagnosis? Smooth
Leiomyoma Leiomyosarcoma
15. A. Acute monocytic leukemia Muscle
B. Acute lymphoblastic leukemia Striated
Rhabdomyoma Rhabdomyosarcoma
C. Acute promyelocytic leukemia Muscle
D. Acute myelocytic leukemia Hematopoietic
Leukemia
Cells
15/M had carbuncle on his left arm. He also noticed Mixed Tumors
an enlarged lymph node on his axilla. If the cause of Benign Mixed
the carbuncle is Staphylococcus aureus, the lymph Tumor Malignant Mixed
node would most likely show: (Pleomorphic Tumor
16.
A. Paracortical hyperplasia Adenoma)
B. Follicular hyperplasia Teratomas Mature Teratoma Immature Teratoma
C. Sinus histiocytosis
D. Reticular hyperplasia 30/F presented with vomiting, fever and chills. She
LYMPHADENITIS developed progressive hypotension and a
PATTERN MORPHOLOGY EXAMPLES coalescing purpuric rash that eventually covered
• á in number of • Rheumatoid almost all of the body. Blood culture showed
secondary lymphoid arthritis Neisseria meningitidis. She died within 24 hours
Follicular 19. after admission. Which of these would most likely be
follicles (germinal • Toxoplasmosis
hyperplasia found on autopsy?
centers) • Early HIV
infection A. Greenish meninges coated with exudate
Paracortical • Expansion of the T- • Acute viral B. Liquefactive necrosis of the brain
hyperplasia cell zones infections C. Bilateral Adrenal hemorrhages
• á in size and number • Nonspecific D. Pseudomembranes in the respiratory tract
of cells lining • Usually in
Sinus 22/F was found dead in her room, with a plate of
lymphatic sinusoids malignancies
histiocytosis peanuts by her side. Autopsy showed distended
•á intrasinusoidal
macrophages lungs, with the airways occluded by thick tenacious
mucous plugs with eosinophils and slender-pointed
Deposition of lipofuscin is located in which crystals. The airways also showed thickened airway
organelle? walls, subbasement membrane fibrosis, increased
A. Endoplasmic reticulum vascularity, increase in the size of the submucosal
17. 20.
B. Golgi complex glands and number of the goblet cells, and
C. Ribosome hypertrophy of the bronchial wall muscle. She most
D. Lysosome likely died of:
A. Anaphylaxis
PATHOLOGY CONCEPT: INTRACELLULAR ACCUMULATIONS
B. Bronchial obstruction
• Causes C. Pneumonia
o Inadequate removal of substance D. Status Asthmaticus
o Accumulation of abnormal endogenous substance
44/M consulted for muscle weakness. It started one fasciculations and occasional cramping. There were
year ago when he noticed that he was dropping no tremors, memory loss, or dementia. Diagnosis?
21. objects frequently and had difficulty performing A. Alzheimer disease
fine motor tasks. The disease progressed to B. Parkinson disease
generalized muscle weakness and wasting, with C. Huntington disease
D. Lou Gehrig’s disease
Disease Clinical Pattern Inclusions Genetic Causes
Rapidly progressive Kuru plaques and diffuse PrPsc
Prion diseases PrP
dementia deposits
Alzheimer disease (AD) Dementia Aβ (plaques) and tau (tangles) APP, PS-1, PS-2, trisomy 21
tau tau
Behavioral changes,
Frontotemporal lobar degeneration TDP-43, progranulin,
language TDP-43
(FTLD) C9orf72
disturbance
FUS FUS
α-synuclein (mutations or
Hypokinetic α-synuclein
amplification)
movement disorder
Parkinson disease (PD) tau LRRK2
with or without
dementia α-synuclein or none DJ-1, PINK1, parkin
Parkinsonism with
Progressive supranuclear palsy (PSP) abnormal eye tau tau
movements
Parkinsonism with
Corticobasal degeneration (CBD) asymmetric tau ---
movement disorder
Parkinsonism,
Multiple system atrophy (MSA) cerebellar ataxia, α-synuclein ---
autonomic failure
Hyperkinetic
Huntington disease (HD) Huntington (polyglutamine) Htt
movement disorder
Spinocerebellar ataxias (SCA-1, 2, 3, 6, 7, Various proteins (polyglutamine

Cerebellar ataxia Multiple loci
17 and DRPLA) containing)
Weakness with SOD1 SOD1

Amyotrophic lateral sclerosis (ALS) upper and lower TDP-43 TDP-43, C9orf72
motor neurons signs FUS FUS
Lower motor neuron
weakness, Androgen receptor
Spinal bulbar muscular atrophy (SBMA) Androgen receptor
diminished (polyglutamine containing)
androgen
While spelunking, a 25/M was bitten by a bat. He Biopsy of the kidney from a renal transplant patient
just ignored the bite. Two months later, he showed extensive interstitial mononuclear cell
developed malaise, headache, and fever, which infiltration and edema, with lymphocytes between
progressed to hyperesthesia with violent motor endothelium and vessel wall, and endothelitis. What
responses, “hydrophobia”, and convulsions. The 23. is the type of rejection?
patient then developed meningitic signs, flaccid A. Hyperacute
22.
paralysis, coma, and respiratory failure. Upon B. Acute Cellular
autopsy, the brain would show: C. Acute Humoral
A. Lewy Bodies D. Chronic
B. Neurofibrillary Tangles
C. Pick bodies
D. Negri bodies
Rejection Onset and mechanism Clinical findings Microscopic findings
• Minutes or hours after • Cyanotic, mottled, and • Neutrophils rapidly accumulate within
transplantation flaccid kidney; may arterioles, glomeruli, and peritubular capillaries
Hyperacute
• Antibody-mediated (pre-formed excrete few drops of • Thrombotic occlusion of the capillaries
anti-donor antibodies) bloody urine • Fibrinoid necrosis of arterial walls
• Tubulointerstitial (Type I): Tubulonterstitial
• Days; months or years after
lymphocytic inflitrate
Acute cellular cessation of immunosuppression
• Vascular (Type II): swollen endothelial cells with
• Cell-mediated • Clinical and
focal lymphocytic infiltration (endothelitis)
biochemical signs of
• Days; months or years after
renal failure
Acute antibody- cessation of immunosuppression • Inflammation of glomeruli and peritubular
mediated • Antibody-mediated (produced capillaries; focal thrombosis of small vessels
after transplantation)
• Vascular lesions:
• Intimal thickening with inflammation
• Rise in serum • Glomerulopathy, with duplication of the
• Months after transplantation creatinine over a basement membrane
Chronic
• Cell-mediated period of 4 to 6 • Peritubular capillaritis with multilayering of
months peritubular capillary BM
• Interstitial fibrosis and tubular atrophy with loss
of renal parenchyma
A resected parotid gland In hyperplastic arteriolosclerosis, what is the
tumor show cystic spaces mechanism of the “onion-skinning” of the blood
lined by a double layer of vessel?
neoplastic epithelial cells A. Intimal thickening due to deposition of lipid
resting on a dense lymphoid and extracellular matrix
stroma. The epithelial lining 28. B. Smooth muscle cells with thickening and
consists of a upper layer of reduplication of the basement membrane
palisading columnar cells C. Separation of the layers of tunica media due to
24.
with abundant granular dissection of blood
eosinophilic cytoplasm and a D. Deposition of laminated thrombi with lines of
lower layer of cuboidal- Zahn
polygonal cells.
A. Pleomorphic adenoma What are the steps in leukocyte recruitment in acute
B. Mucoepidermoid carcinoma inflammation?
C. Warthin tumor A. Rollingà diapedesis à margination à
D. Adenoid cystic carcinoma adhesion
B. Adhesion à rolling à margination à
29.
K.R., 17/M, fractured his left tibia while diapedesis
skateboarding. 2 days later, he had sudden onset C. Diapedesis à adhesion à rolling à
dyspnea, tachypnea, and tachycardia, accompanied margination
by delirium and coma. What would be the most D. Margination à rolling à adhesion à
likely autopsy finding? diapedesis
A. Gas bubbles within the cerebral and INFLAMMATION: RECRUITMENT OF LEUKOCYTES
25. pulmonary circulation • Influx of leukocytes into the tissue
B. Fetal squames within pulmonary capillaries o Mediated and controlled by adhesion molecules and
C. A saddle embolus lodged at the pulmonary chemokines
artery bifurcation o Phases
D. A thrombus attached to the left atrium § Margination
E. Fat globules and hematopoietic cells within § Rolling
the pulmonary circulation § Adhesion
§ Diapedesis/Transmigration
A 32/F singer was noted to be weak and severely § Migration towards the chemotactic stimulus
underweight. She continued her diet restrictions,
eating little, against her physician’s and therapist’s
advice, saying that she ‘looked too fat’. She also
started to illicitly take in levothyroxine to speed up
26.
her metabolism. What is the diagnosis?
A. Anorexia nervosa
B. Bulimia Nervosa
C. Kwashiorkor
D. Marasmus
ANOREXIA AND BULIMIA NERVOSA
ANOREXIA
FEATURE BULIMIA NERVOSA
NERVOSA
Self-induced Binge eating à
Definition starvation à vomiting (purging)
weight loss
Highest death rate More common than
Epidemiologic
of any psychiatric anorexia nervosa
significance
disorder
FINDINGS
Amenorrhea (â Rocker-bottom feet, cleft lip and palate, VSD:
Endocrine GnRH, FSH, LH) A. Down Syndrome
Hypothyroidism 30. B. Edward Syndrome
Gelatinous C. Patau Syndrome
--- D. DiGeorge Syndrome
transformation of
Bone and
marrow
marrow
â Bone density (â
Estrogen)
Pulmonary Aspiration
--- Esophageal and
GIT
gastric rupture
CVS â K+ à Cardiac arrhythmias
30/F complained of vulvovaginal discomfort, with

associated yellow frothy vaginal discharge. There
was dysuria and dyspareunia. Colposcopic
examination showed an erythematous vaginal
mucosa and a “strawberry cervix”. Microscopic
examination of the vaginal discharge showed pear-
27.
shaped flagellated organisms. What is the causative
organism?
A. Herpes simplex virus
B. Candida spp.
C. Trichomonas vaginalis
D. Gardnerella vaginalis
PATHOLOGY CONCEPT: SEVERE ACUTE MALNUTRITION
FEATURE MARASMUS KWASHIORKOR
• Weight ≤ 60% • Protein > caloric
Definition and of normal deprivation
cause • Caloric
deprivation
PROTEIN COMPONENT
Somatic protein • Affected • Relatively spared
compartment
• Minimally • Affected (â
Visceral protein depleted albumin)
compartment (normal
albumin)
FINDINGS
Growth failure • Present
• “Flaky paint” skin,
Skin --- loss of hair color
and hair loss
Edema --- • Present
Loss of fat and
• More marked • Present
muscle atrophy
Liver --- • Fatty liver
• Findings common in Kwashiorkor, and
are RARE in Marasmus
Small bowel • Mucosal atrophy and loss of villi and
microvilli (and intestinal enzymes)
• Most common: disaccharidase deficiency
• Hypoplastic marrow (â precursors)
• Anemia (variable morphology)
Hematologic
• Thymic and lymphoid atrophy (more
What is the pathophysiology of gastroesophageal marked in Kwashiorkor)
reflux disease (GERD?) • Cerebral atrophy
A. Increase in gastric acid production Brain • â Neurons
B. Lower esophageal valve incompetence • Impaired white matter myelinization
31.
C. Transient lower esophageal sphincter
relaxation 44/F patient complained of headache, progressive
D. Increased gastric pressure due to pyloric loss of hearing on both ears and vertigo. On workup,
obstruction CT scan showed bilateral masses at the
vestibulocochlear nerve. There were also two dural-
Which of these hemolytic anemias is characterized based masses over the cerebral convexity. Excision
by intrinsic, intravascular hemolysis? of the masses revealed that the vestibulocochlear
A. Hereditary spherocytosis 34. nerve masses are schwannomas, and the dural-
32. based masses are meningiomas. What is her most
B. G6PD deficiency
C. Paroxysmal nocturnal hemoglobinuria likely diagnosis?
D. Disseminated intravascular coagulation A. Tuberous sclerosis
HEMOLYTIC ANEMIAS B. Neurofibromatosis type 1
Type of C. Neurofibromatosis type 2
Disease Site of hemolysis D. Von Hippel-Lindau Syndrome
hemolysis
NEUROFIBROMATOSIS
Hereditary
Intrinsic Extravascular Neurofibromatosis Neurofibromatosis
spherocytosis (HS) Parameter
type 1 type 2
G6PD deficiency Intrinsic BOTH
Inheritance
Sickle cell anemia (SCA) Intrinsic Extravascular AD; NF1 (Ch17) AD; NF2 (Ch22)
and gene
Thalassemia Intrinsic Extravascular Incidence More common Less common
Paroxysmal nocturnal
Intrinsic Intravascular • Neurofibromas • Bilateral eight
hemoglobinuria (PNH)
• MPNSTs nerve
Immunohemolytic BOTH (depending • Optic nerve gliomas schwannomas
anemias Extrinsic
on type) • Other glial tumors • Multiple
Microangiopathic and hamartomatous meningiomas
hemolytic anemia Extrinsic Intravascular
lesions • Ependymomas
Macroangiopathic • Pheochromocytomas (commonly
Extrinsic Intravascular Components
hemolytic anemia • Pigmented iris intraspinal)
nodules (Lisch
Which of the following statements is/are true? nodules)
A. In marasmus, protein deprivation is more • Cutaneous
severe than caloric deprivation. hyperpigmented
B. In kwashiorkor, the visceral protein macules (Café au lait
33. spots)
compartment is spared.
C. In kwashiorkor, there is hepatic steatosis due
to inability to export lipids.
D. All of the above are true.
CNS FAMILIAL TUMOR SYNDROMES Frequent
Tuberous sclerosis Von-Hippel mononuclear and
Parameter diagnostic RS cells; Uncommon; M
complex Lindau disease
Inheritance/ Lymphocyte background greater than F;
AD/TSC1 (Ch9) AD/VHL (Ch3) rich infiltrate rich in T tends to be seen in
gene affected
• Subependymal • Hemangioblasto lymphocytes; RS cells older adults
giant-cell mas CD15+, CD30+; 40%
astrocytomas • Cysts involving EBV+
• Renal the pancreas, Uncommon; more
Reticular variant:
angiomyolipomas liver, and kidneys common in older
Frequent diagnostic
• Retinal glial • Renal cell males, HIV-infected
Components RS cells and variants
hamartomas carcinoma Lymphocyte individuals, and in
and a paucity of
• Pulmonary • Pheochromocyto depletion developing
background reactive
lymphangioleiomy ma countries; often
cells; RS cells CD15+,
omatosis • Cafe au lait spots presents with
CD30+; most EBV+
• Cardiac advanced disease
rhabdomyomas Frequent L&H
(popcorn cell)
Uncommon; young
variants in a
The following will produce a mononuclear infiltrate Nodular males with cervical
background of
except? lymphocyte or axillary
follicular dendritic
A. Treponema pallidum predominant lymphadenopathy;
35. cells and reactive B
B. Hepatitis B mediastinal
cells; RS cells CD20+,
C. Cytomegalovirus
CD15-, C30-; EBV-
D. Streptococcus pyogenes
OUTCOMES OF ACUTE INFLAMMATION
A 12/M ate a burger from a shady burger chain. The
next day, he developed blood-tinged diarrhea and
abdominal cramping, associated with fever and
vomiting. Three days later, on he developed
thrombocytopenia, microangiopathic hemolytic
anemia, and increasing serum creatinine and blood
urea nitrogen. Bleeding time is prolonged, but PT
37.
and PTT were normal. What is the pathophysiology
of the disease?
A. Decreased ADAMTS13 levels
B. Toxin-mediated endothelial damage
C. Excessive complement activation
D. Release of tissue factor and activation of the
coagulation cascade
THROMBOTIC MICROANGIOPATHIES
Thrombotic
Hemolytic-uremic
Parameter thrombocytopenic
syndrome (HUS)
purpura (TTP)
• Microangiopathic
What is the most common subtype of Hodgkin hemolytic anemia
Lymphoma? • Microangiopathic
• Thrombocytopenia
A. Nodular Sclerosis Hodgkin Lymphoma hemolytic anemia
Syndrome • Renal failure
36. B. Mixed Cellularity Hodgkin Lymphoma • Thrombocytopenia
• Fever
C. Lymphocyte-Rich Hodgkin Lymphoma • Renal failure
• Neurologic
D. Lymphocyte-Predominant Hodgkin manifestations
Lymphoma Decreased:
SUBTYPES OF HODGKIN LYMPHOMA accumulation vWF
Morphology and Typical Clinical ADAMTS13* multimers à
Subtype Normal
Immunophenotype Features level promote platelet
Frequent lacunar cells activation and
and occasional aggregation
diagnostic RS cells; Most common • Typical HUS: E. coli
background infiltrate subtype; usually O157:H7 (Shiga-
composed of T stage I or II disease; like toxin makes
lymphocytes, frequent endothelium
Nodular eosinophils, mediastinal Other types --- procoagulant)
sclerosis macrophages, and involvement; equal • Atypical HUS:
plasma cells; fibrous occurrence in males defects in excessive
bands dividing and females (F = complement
cellular areas into M), most patients activation
nodules. RS cells young adults
CD15+, CD30+; Which of the following can cause Cushing disease?
usually EBV- A. Pituitary macroadenoma
Frequent More than 50% 38. B. Adrenocortical adenoma
mononuclear and present as stage III C. Exogenous steroids
diagnostic RS cells; or IV disease; M D. All of the above
background infiltrate greater than F;
Mixed
rich in T lymphocytes, biphasic incidence, Which of the following is a cyanotic heart disease?
cellularity
eosinophils, peaking in young A. Atrial Septal Defect
macrophages, plasma adults and again in 39. B. Transposition of the Great Vessels
cells; RS cells CD15+, adults older than C. Coarctation of the Aorta
CD30+; 70% EBV+ 55 D. Patent Ductus Arteriosus
CONGENITAL HEART DISEASE
• Right-to-Left Shunts (“Cyanotic Heart Disease”)
o 5 Ts
o Truncus Arteriosus
o Transposition of the Great Vessels
o Tricuspid Atresia
o Tetralogy of Fallot
o Total Anomalous Pulmonary Venous Return
• Left-to-Right Shunts
o Atrial Septal Defect
o Patent Foramen Ovale
o Ventricular Septal Defect
o Patent Ductus Arteriosus
• Obstructive
o Coarctation of the Aorta
o Pulmonic Stenosis/Atresia
o Aortic Stenosis/Atresia
What percentage of alcoholics will develop

cirrhosis?
A. 10-15%
40.
B. 20-25%
C. 70-75%
D. 90-95% BLEEDING PARAMETERS: SUMMARY
DISEASE PC BT PT PTT
Ehler-Danlos syndrome N N N N
Immune thrombocytopenic purpura ↓ ↑ N N
Thrombotic thrombocytopenic purpura ↓ ↑ N N
Bernard-Soulier disease ↓ ↑ N N
Glanzmann thrombasthenia N ↑ N N
Von Willebrand disease N ↑ N ↑
Hemophilia N N N ↑
Vitamin K deficiency N N ↑ ↑
DIC ↓ ↑ ↑ ↑
Ferruginous bodies are

most likely seen in
These bleeding disorders are characterized by a which of these
normal prothrombin time except? conditions?
42.
A. Immune thrombocytopenic purpura
41. A. Coal worker’s pneumoconiosis
B. Glanzmann thrombasthenia
C. Hemophilia B. Silicosis
D. Disseminated intravascular coagulation C. Asbestosis
COAGULATION CASCADE D. Berylliosis
• Series of amplifying enzymatic reactions that lead to deposition
of an insoluble fibrin clot 31/F postpartum patient developed worsening
• Extrinsic pathway dyspnea, dizziness, orthopnea, dependent edema,
o assessed by prothrombin time and easy fatigability. Physical examination revealed
o Factors 7, 10, 5, 2, 1 systolic ejection murmur at the lower left sternal
• Intrinsic pathway edge. Echocardiography showed enlarged left
o assessed by the partial thromboplastin time 43. ventricle and decreased ejection fraction. What is
o Factors 12, 11, 9, 8, 10, 5, 2, 1 the most likely diagnosis?
A. Dilated cardiomyopathy
• Vitamin K-dependent coagulation factors: 10, 9, 7, 2
B. Hypertrophic cardiomyopathy
C. Restrictive cardiomyopathy
D. Hyperplastic cardiomyopathy
FEATURE DILATED (Most common) HYPERTROPHIC RESTRICTIVE
EF < 40% 50-80% 45-90%
Dysfunction Systolic (impaired contractility) Diastolic (impaired compliance)
• Genetic
• Genetic (Most
• Alcohol common
• Amyloidosis
• Peripartum cause)
• Radiation-
• Myocarditis • Friedrich
induced fibrosis
Causes • Hemochromatosis ataxia
• Endomyocardial
• Chronic anemia • Storage
fibrosis
• Doxorubicin diseases
• Idiopathic
• Sarcoidosis • Infants of
• Idiopathic diabetic
mothers
Ischemic, valvular, hypertensive, Hypertensive heart disease
Mimic Pericardial constriction
congenital heart disease Aortic stenosis
• Massive myocardial
hypertrophy, usually without
• Enlarged, heavy, flabby heart with • Fibrosis
ventricular dilation
dilation of all chambers, usually with • Amyloidosis: Amyloid deposition
o Asymmetrical septal
concomitant hypertrophy o Heart (interstitium, conduction
hypertrophy: IVS thicker
• Non-specific histologic findings tissue, valves, endocardium,
Morphology than ventricular free wall
• Arrhythmogenic cardiomyopathy • Myofiber disarray
pericardium)
(Autosomal dominant) o Intramural arteries and arterioles
• Fibrotic narrowing of small
o Severely attenuated RV wall with à compression à myocardial
intramural arteries
massive fatty infiltration and fibrosis ischemia
• Interstitial and replacement
fibrosis
The following are true about the pathophysiology of LEPROSY: CLINICAL FORMS
achalasia except: FEATURE TUBERCULOID LEPROMATOUS
A. There is incomplete lower esophageal Cell-mediated
sphincter relaxation Intact Depressed
immunity
44. B. There is increased lower esophageal sphincter Lepromin skin
tone Positive Negative
test
C. There is aperistalsis of esophagus Immune TH1
D. There is decreased lower esophageal TH2 > TH1
response TH17
contraction (+) not protective; may
cause erythema
The most common benign bone tumor shows: Antibodies (-)
nodosum, vasculitis,
A. A bony excrescence attached to the underlying and GN (Type III HSR)
bone by a stalk, covered by a thin cartilage cap Peripheral
B. Well-circumscribed nodules of cytologically nerve Asymmetric Symmetric
benign hyaline cartilage involvement
C. sheets of compact polyhedral cells that have Lipid-laden
45.
well-defined cytoplasmic borders, moderate Morphology Granulomatous macrophages (Lepra
amounts of pink cytoplasm, and cells) with globi (AFB)
hyperlobulated nuclei with longitudinal Rare
grooves AFB Many (multibacillary)
(paucibacillary)
D. Fibroblasts arranged in a storiform pattern;
with admixed macrophages
An 1 year old infant was normal at birth but patient
still observed to have poor head control, inability to
25/F found it difficult to breastfeed after her most sit with support, does not follow objects, (+)
recent pregnancy which was complicated by uterine hepatosplenomegaly, there was (+) cherry red spot
atony. She had little milk production, which led her on eye exam, the patient eventually succumbed to
to switch to bottle feeding. After a year, her menses pneumonia and complications, post mortem
still had not returned, and she developed weakness, 48. histology showed vacuolation, ballooning of
46. cold intolerance, and lethargy. She had also gained neurons and foaminess of the macrophage
weight. The most likely diagnosis is? cytoplasm, what is the most likely diagnosis?
A. Breastfeeding failure A. Tay-Sachs disease
B. Hypothyroidism B. Niemann-Pick disease
C. Iron-deficiency anemia C. Gaucher disease
D. Sheehan syndrome D. Von Gierke disease
47/F presents with muscle weakness, leading to foot Three weeks after his stag party, B.J. had a solitary,
drop and a clawhand deformity. There was also loss firm, nontender, raised red papule at the glans
of sensation, such as on the lateral aspect of the leg, penis, which eventually eroded into an ulcer with
the medial aspects of the palm, and on the nodular indurated borders. He was most likely infected with:
cutaneous lesions in the face, elbow, and knee. 49.
A. Haemophilus ducreyi
Biopsy of the lesions revealed accumulations of B. Klebsiella granulomatis
47.
lipid-laden macrophages, filled with masses of acid- C. Treponema pallidum
fast bacilli. Diagnosis? D. Neisseria gonorrhoeae
A. Xanthoma
B. Tuberculosis
C. Tuberculous leprosy
D. Lepromatous leprosy
STAGE LESIONS MORPHOLOGY Which of these is a true hermaphrodite?
• Plasma cell-rich A. Phenotypic male with both X and Y
infiltrate, chromosomes on karyotyping
macrophages, 50. B. Patient with congenital adrenal hyperplasia,
lymphos with ovaries and phenotypic male genitalia
• Chancre: Painless C. Patient with both ovarian and testicular tissue
• Proliferative
lesion in penis D. B and C
endarteritis à
(males), vulva, and
intimal fibrosis • Genetic sex – presence or absence of Y chromosome
Primary cervix (females) à
• Lymph nodes: non- • Gonadal sex – histologic characteristics of the gonads (ie. ovary
erosion à ulcer with
specific acute or or testis)
indurated borders
chronic • Ductal sex – whether there are derivatives of the wolffian or
(hard chancre)
lymphadenitis, müllerian ducts
plasma cell-rich • Phenotypic/genital sex – appearance of the external genitalia
infiltrates, or • True hermaphroditism – presence of both ovarian and
granulomas testicular tissue
• Pseudohermaphroditism – disagreement between phenotypic
• Mucocutaneous • Same as chancre,
and gonadal sex
Secondary lesions (oral cavity, but with less
palms, and soles) inflammation
1/F has an abdominal mass. Biopsy revealed a
• Aortitis: obliterative tumor composed of sheets of small round cells with
endarteritis of vasa scanty cytoplasm, dark nuclei, and indistinct cell
vasorum of borders. Homer-Wright rosettes are present. No
proximal aorta à tubule formation or immature mesenchyme
51.
• Aortitis medial scarring à present. Diagnosis?
• Neurosyphilis (in loss of elasticity A. Wilms Tumor
CNS module) • Gumma: central B. Neuroblastoma
Tertiary C. Immature teratoma
• Gumma (Skin, coagulation necrosis
subcutaneous tissue, surrounded by D. Hemangioma
bone, joints, liver) plump, palisading
macrophages and 57/M complains of a three-year history of painful
fibroblasts, plasma erections and a “crooked penis”. Physical
cell-rich infiltrate, examination showed a palpable mass-like
scant treponemes induration on the dorsolateral aspect of the penis.
On erection, the penis was angulated/deviated
52.
ORGAN MORPHOLOGY OF CONGENITAL SYPHILIS about 40° to the right. Diagnosis?
• Osteochondritis and periostitis A. Priapism
Bones • Tibia: Saber shins (excessive new bone growth) B. Penile fracture
• Nose: Saddle nose (destruction of vomer) C. Syphilis
• Fibrosis (hepar lobatum), mononuclear D. Peyronie’s disease
Liver
infiltrates, vascular changes
• Diffuse interstitial fibrosis Pellagra, a disease characterized by dementia,
dermatitis, and diarrhea, is caused by deficiency in:
Lung • Pale, airless lung (pneumonia alba) in stillborn
A. Thiamine
infants 53.
B. Niacin
• Triad of late manifestations
C. Riboflavin
• Interstitial keratitis D. Pyridoxine
Others
• Hutchinson teeth (screwdriver or peg-shaped) VITAMIN DEFICIENCY SYNDROMES
• Eight nerve deafness FAT-SOLUBLE
• Night blindness, xerophthalmia, blindness
• Squamous metaplasia
Vitamin A
• Vulnerability to infection, particularly
measles
• Rickets in children
Vitamin D
• Osteomalacia in adults
• Spinocerebellar degeneration, hemolytic
Vitamin E
anemia
Vitamin K • Bleeding diathesis
WATER-SOLUBLE
Vitamin B1 • Dry and wet beriberi, Wernicke and
(thiamine) Korsakoff syndrome
• Ariboflavinosis, cheilosis, stomatitis,
Vitamin B2
glossitis, dermatitis, corneal
(riboflavin)
vascularization
Niacin • Pellagra—Three Ds: Dementia,
(Vitamin B3) Dermatitis, Diarrhea
Vitamin B6 • Cheilosis, glossitis, dermatitis, peripheral
(pyridoxine) neuropathy
• Megaloblastic pernicious anemia and
Vitamin B12 degeneration of posterolateral spinal cord
tracts
Vitamin C • Scurvy
Folate • Megaloblastic anemia, neural tube defects
Pantothenic • No nonexperimental syndrome
acid recognized
Biotin • No clearly defined clinical syndrome
Durck’s granulomas is a brain lesion found in:
A. Meningeal tuberculosis
B. Cerebral sarcoidosis
53.
C. Tertiary syphilis
D. Cerebral malaria
Which of these is not a component of innate immunity?

A. Natural Killer Cells
54. B. Dendritic Cells
C. Complement
D. B cells
Which of these members of the complement system is an anaphylatoxin?

A. C1
55. B. C3a
C. C3b
D. C6
Which of these cytokines is responsible for the recruitment of neutrophils and monocytes in inflammation?
A. TNF-α
56. B. IL-1
C. IL-10
D. IL-17
Principal Principal Actions in Dandy-Walker Arnold-Chiari

Cytokine Parameter
Sources Inflammation malformation malformation
In Acute Inflammation • Enlarged
Stimulates expression of posterior fossa • Chiari II: small
Macrophages, endothelial adhesion (hypoplasia of posterior fossa
TNF mast cells, T molecules and secretion the cerebellar with misshapen
Defect
lymphocytes of other cytokines; vermis) cerebellar tonsils
systemic effects • Cystic dilatation • Chiari I: low-lying
Macrophages, of the fourth cerebellar tonsils
endothelial cells, Similar to TNF; greater ventricle
IL-1
some epithelial role in fever • Chiari II:
cells noncommunicatin
Macrophages, Systemic effects (acute g hydrocephalus
IL-6
other cells phase response) (due to associated
aqueductal
Clinical
Macrophages, • Hydrocephalus stenosis)
Recruitment of manifestations
endothelial cells, • Lumbar
leukocytes to sites of myelomeningocele
Chemokines T lymphocytes,
inflammation; migration • Chiari I: clinically
mast cells, other
of cells in normal tissues silent or
cell types
hydrocephalus
Recruitment of What is the morphology of the type of renal cell
IL-17 T lymphocytes neutrophils and carcinoma arising from the proximal convoluted
monocytes tubule?
In Chronic Inflammation A. Tumor composed of rounded to polygonal
Dendritic cells, Increased production of cells with abundant clear or granular
IL-12
macrophages IFN-γ cytoplasm
Activation of 59.
B. Cuboidal or low columnar cells lining papillae
T lymphocytes, macrophages (increased with foam cells within the papillary cores
IFN-γ
NK cells ability to kill microbes C. Solid sheets of pale eosinophilic cells with
and tumor cells) perinuclear halo
Recruitment of D. Irregular channels lined by highly atypical
IL-17 T lymphocytes neutrophils and epithelium in a hobnail pattern
monocytes
The following statements about the pathogenesis of
Which of these toxic heavy metals causes itai-itai COVID-19 is true except:
disease? A. The SARS-CoV-2 has a tropism for the lung
A. Arsenic because it binds the ACE2 protein on the
57.
B. Cadmium alveolar epithelial cells
C. Lead B. Patients who died of COVID-19 exhibit diffuse
D. Mercury 60.
alveolar damage
C. The pulmonary inflammatory infiltrates in
This is characterized by an enlarged posterior fossa, COVID-19 are mostly neutrophilic
absent or rudimentary cerebellar vermis that is D. The host immune response and locally
replaced by a large ependyma-lined cyst released cytokines produce acute lung injury
representing the enlarged fourth ventricle. and acute respiratory distress syndrome
58.
A. Arnold-Chiari malformation
B. Chiari type I malformation Over the past few years, a 57/M longtime smoker
C. Dandy-Walker malformation gradually developed dyspnea, with occasional
D. Joubert syndrome cough with scanty sputum. Physical examination
POSTERIOR FOSSA ANOMALIES showed a “barrel chest” deformity. Diagnosis?
Dandy-Walker Arnold-Chiari A. Asthma
Parameter 61.
malformation malformation B. Emphysema-predominant Chronic
Obstructive Pulmonary Disease
C. Bronchitis-predominant Chronic Obstructive
Pulmonary Disease
D. Lung carcinoma
Chest X-ray shows hyperinflated lungs and a small Follow-up CT scan showed an incidental finding of a
heart. Diagnosis? 4x3.5x3 cm mass at the bifurcation of the right
A. Asthma mainstem bronchus, with enlarged hilar lymph
B. Emphysema-predominant Chronic nodes. What is the most likely diagnosis?
62.
Obstructive Pulmonary Disease A. Asthma
63.
C. Bronchitis-predominant Chronic Obstructive B. Emphysema-predominant Chronic
Pulmonary Disease Obstructive Pulmonary Disease
D. Lung carcinoma C. Bronchitis-predominant Chronic Obstructive
CHRONIC OBSTRUCTIVE PULMONARY DISEASE Pulmonary Disease
FEATURE BRONCHITIS EMPHYSEMA D. Lung carcinoma
Age (years) 40-45 50-75
Dyspnea Mild; late Severe; early Biopsy of the mass showed round, oval, or spindle-
Early; copious Late; scanty shaped cells with scant cytoplasm, ill-defined cell
Cough borders, finely granular nuclear chromatin, and
sputum sputum
Infections Common Occasional absent or inconspicuous nucleoli. Nuclear molding
Respiratory and necrosis are present. Mitotic count is high.
Early, periodic End-stage 64. There is basophilic staining of vascular walls.
insufficiency
Diagnosis?
Uncommon, end-
Cor pulmonale Common A. Squamous cell carcinoma
stage
á B. Adenocarcinoma
Airway resistance N or slightly á
C. Small cell carcinoma
Elastic recoil Normal â
D. Metastatic carcinoma
Prominent
Hyperinflation
Chest radiograph vessels
Normal heart size With regards to the previous case, which
Large heart
paraneoplastic syndromes is not associated with the
Appearance Blue bloaters Pink puffers
tumor?
65. A. Lambert-Eaton syndrome
B. Cushing syndrome
C. Hypercalcemia due to PTHrP secretion
D. Syndrome of inappropriate ADH secretion
LUNG CARCINOMAS
FEATURE ADENO-CARCINOMA SQUAMOUS CELL SMALL CELL
Prevalence Most common (50%) 2nd most common (20%) 3rd most common (15%)
Site Peripheral Central/hilar Either
Association with Yes but low (Most common
Yes Almost always
tobacco smoke type in never smokers)
Paraneoplastic Hypercalcemia (PTH, PTHrP, SIADH (ADH)
Non-specific
syndromes PGE, Cytokines Cushing syndrome (ACTH)
Clinical classification NSCLC SCLC
• Glandular differentiation • Keratinization (squamous
chromatin and inconspicuous nucleoli
(with different patterns) pearls or cells with intensely
Morphology • Extensive necrosis
• Mucin production (Invasive eosinophilic cytoplasm)
• Azzopardi effect: Basophilic staining
mucinous adenocarcinomas) • Intercellular bridges
of vascular walls
24/F consulted for a breast mass. On physical Biopsy of the breast mass showed a well-defined
examination, the slow-growing subareolar mass lesion with proliferation of the interlobular and
was noted to be rubbery, nontender and movable. intralobular stroma with compression of the
No breast discharge is seen. What is the most likely epithelial components. No stromal overgrowth
66. diagnosis? 69. seen. Diagnosis?
A. Fibroadenoma A. Fibroadenoma
B. Invasive Ductal Carcinoma B. Invasive Ductal Carcinoma
C. Gynecomastia C. Gynecomastia
D. Acute mastitis D. Acute mastitis
24/F consulted for a breast mass. On physical Biopsy of the breast mass showed an infiltrative
examination, the slow-growing subareolar mass lesion with malformed glands composed of
was noted to be rubbery, nontender and movable. dysplastic cells exhibiting cytologic and nuclear
No breast discharge is seen. What is the most likely atypia. The myoepithelial layer is absent. Diagnosis?
70.
67. diagnosis? A. Fibroadenoma
A. Fibroadenoma B. Invasive Ductal Carcinoma
B. Invasive Ductal Carcinoma C. Gynecomastia
C. Gynecomastia D. Acute mastitis
D. Acute mastitis
55/F presented with anasarca associated with
24/M consulted for “lumpy breasts”. On physical petechial bleeding. 24-hour urine collection showed
examination, there are ill-defined, soft to rubbery, proteinuria of 4.47 g/day. She also had malar rash
tender masses in the breast. There is a nipple and oral ulcers. Diagnosis?
71.
discharge. What is the most likely diagnosis? A. Measles
68.
A. Fibroadenoma B. Systemic lupus erythematosus
B. Invasive Ductal Carcinoma C. Immune thrombocytopenic purpura
C. Gynecomastia D. Herpes simplex
D. Acute mastitis
With regards to the previous case, additional tests showed thrombocytopenia. Diagnosis?
A. Measles
72. B. Systemic lupus erythematosus
C. Immune thrombocytopenic purpura
D. Herpes simplex
SYSTEMIC LUPUS ERYTHEMATOSUS DIAGNOSTIC CRITERIA

Criterion Definition
Clinical Criteria
Acute cutaneous lupus Malar rash (fixed erythema, flat or raised, over the malar eminences), photosensitivity
Chronic cutaneous lupus Discoid rash: erythematous raised patches with adherent keratotic scaling and follicular plugging
Nonscarring alopecia Diffuse thinning or hair fragility in the absence of other causes
Oral or nasal ulcers Oral or nasopharyngeal ulceration, usually painless
Nonerosive synovitis involving two or more peripheral joints, characterized by tenderness, swelling, or
Joint disease
effusion
Serositis Pleuritis (pleuritic pain or rub or evidence of pleural effusion), pericarditis
Renal disorder Persistent proteinuria >0.5 g/24 hours, or red cell casts
Neurologic disorder Seizures, psychosis, myelitis, or neuropathy, in the absence of offending drugs or other known causes
Hemolytic anemia Hemolytic anemia
Leukopenia: <4.0 × 109 cells/L (4000 cells/mm3) total on two or more occasions, or
Leukopenia or lymphopenia
Lymphopenia: <1.5 × 109 cells/L (1500 cells/mm3) on two or more occasions
Thrombocytopenia: <100 × 109 cells/L (100 × 103 cells/mm3) in the absence of offending drugs and
Thrombocytopenia
other conditions
Immunologic Criteria
Antinuclear antibody (ANA) Abnormal titer of antinuclear antibody by immunofluorescence
Anti-dsDNA antibody Abnormal titer
Anti-Sm antibody Presence of antibody to Sm nuclear antigen
Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anti-
cardiolipin antibodies, (2) a positive test for lupus anticoagulant using a standard test, or (3) a false-
Antiphospholipid antibody
positive serologic test for syphilis known to be positive for at least 6 months and confirmed by negative
Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
Low complement Low C3, C4, or CH50
Direct Coombs test Assay for anti–red cell antibody, in the absence of clinically evident hemolytic anemia
Which test are you going to order to best support the Parameter Transudate Exudate
diagnosis? Plasma protein
Absent Present
A. Measles IgG and IgM leak
73.
B. ANA Protein content of
C. paracentesis Low High
fluid
D. Herpes simplex IgG and IgM Specific gravity < 1.012 > 1.012
AUTOANTIBODIES Fibrin Absent Present
Inflammatory cells Absent Present
Disease Autoantibody
Renal biopsy showed diffuse thickening of the
Anti-dsDNA capillary walls due to deposition of subepithelial
Systemic Anti-UI-RNP immune complexes. If this case was lupus, what is
Lupus Anti-Sm - specific for SLE the pattern of lupus nephritis?
Erythematosus Anti-Ro (SS-A)/anti-La (SS-B) 75.
A. Class II lupus nephritis
Anti-phospholipid (APAS) B. Class III lupus nephritis
Anti-DNA topoisomerase I C. Class IV lupus nephritis
Systemic
Anti-centromere D. Class V lupus nephritis
sclerosis
Anti-RNA polymerase LUPUS NEPHRITIS
Sjögren Anti-Ro (SS-A) CLASS Light Microscopy Immunofluorescence
Syndrome Anti-La (SS-B) Minimal
Anti-Jo1 (histidyl aminoacyl-tRNA mesangial Normal ICs in mesangium
synthetase) (Class I)
Autoimmune Mesangial cell
Anti-Mi2 Granular mesangial Ig
myositis Mesangial proliferation; often
Anti-MDA5 and complement w/o
Anti-TIF1γ proliferative with mesangial
involvement of
Anti-CCP (cyclic citrullinated peptides) – (Class II) matrix
Rheumatoid glomerular capillaries
specific for RA accumulation
Arthritis PMNs, necrosis,
Rheumatoid factor - not specific
crescents, and
Paracentesis of the ascites would most likely yield a hyaline thrombi
Focal
fluid that: Wire-loop
(Class III) Subendothelial IC
A. Has a high protein content appearance of
74. deposits
B. Has a specific gravity of <1.012 capillaries
C. Has high fibrin content <50% of glomeruli
D. Is purulent Diffuse Type III with ≥50%
PATHOLOGY CONCEPT: TRANSUDATE VS EXUDATE (Class IV) of glomeruli
Membranous Diffuse capillary Subepithelial IC
Parameter Transudate Exudate
(Class V) thickening deposits
Abnormalities in Increased vascular
Pathophysiology Advance
Starling forces permeability Sclerosis of >90%
sclerosing ---
Vascular glomeruli
Normal Increased (Class VI)
permeability
Type 1 Diabetes Type 2 Diabetes
Clinical
Onset: usually adult;
Onset: usually childhood and
increasing incidence in
adolescence
childhood and adolescence
Normal weight or weight loss Vast majority are obese
preceding diagnosis (80%)
Increased blood insulin
Progressive decrease in
(early); normal or moderate
insulin levels
decrease in insulin (late)
Circulating islet
autoantibodies (anti-insulin, No islet autoantibodies
anti-GAD, anti-ICA512)
Diabetic ketoacidosis in Nonketotic hyperosmolar
absence of insulin therapy coma more common
Genetics
Major linkage to MHC class II
No HLA linkage; linkage to
genes; also linked to
candidate diabetogenic and
polymorphisms in CTLA4 and
obesity-related genes (e.g.,
PTPN22, and insulin gene
TCF7L2, PPARG, FTO)
VNTRs
Pathogenesis
Dysfunction in T-cell selection
Insulin resistance in
and regulation leading to
peripheral tissues, failure of
breakdown in self-tolerance
compensation by β cells
to islet autoantigens
Pathology
Insulitis (inflammatory
No insulitis; amyloid
infiltrate of T cells and
55/M obese patient noticed that he was urinating deposition in islets
macrophages)
more frequently and is getting more thirsty often. Mild β-cell depletion
β-cell depletion, islet atrophy
He also noticed some weight loss, even if he is eating
even more. Diagnosis? Most common acute metabolic complication of his
76.
A. Benign Prostatic hyperplasia disease?
B. Hyperthyroidism A. Diabetic ketoacidosis
C. Type 1 Diabetes Mellitus 79.
B. Hyperketotic hyperosmolar syndrome
D. Type 2 Diabetes Mellitus C. Thyrotoxicosis
Workup showed fasting blood glucose of 207 mg/dL D. Hypoglycemia
and an HbA1c level of 7.8%. Diagnosis? Which of the following is a macrovascular
A. Benign Prostatic hyperplasia complication of his disease?
77.
B. Hyperthyroidism A. Nodular glomerulosclerosis
C. Type 1 Diabetes Mellitus 80.
B. Proliferative diabetic retinopathy
D. Type 2 Diabetes Mellitus C. Accelerated atherosclerosis
Which of the following is the pathophysiology of his D. All of the above
disease? 20/M medical student underwent PPD skin testing.
A. Immune complexes deposit as amyloid in the 48 hours later, the inoculation site showed a 13 mm
islets induration. This means that:
78.
B. Increase in thyroid hormone production by A. He has not been exposed to tubercle bacilli
the thyroid gland 81.
B. He had been exposed to tubercle bacilli
C. Type IV hypersensitivity reaction C. He has tuberculosis
D. Associated with insulin resistance D. He has tuberculosis and must be checked for
HIV status
With regards to the previous question, what type of
hypersensitivity reaction underlies the principle of
the test?
82. A. Cell-mediated
B. Immune-complex mediated
C. Antibody-mediated
D. Immediate
PATHOLOGY CONCEPT: HYPERSENSITIVITY REACTIONS

Production of IgE antibody → immediate Vascular dilation, edema, smooth
Immediate (type I) release of vasoactive amines and other muscle contraction, mucus Anaphylaxis; allergies; bronchial
hypersensitivity mediators from mast cells; later recruitment production, tissue injury, asthma (atopic forms)
of inflammatory cells inflammation
Production of IgG, IgM → binds to antigen on Phagocytosis and lysis of cells;
Antibody-mediated
target cell or tissue → phagocytosis or lysis of inflammation; in some diseases, Autoimmune hemolytic anemia;
(type II)
target cell by activated complement or Fc functional derangements without Goodpasture syndrome
hypersensitivity
receptors; recruitment of leukocytes cell or tissue injury
Deposition of antigen-antibody complexes →
Immune complex- complement activation → recruitment of
toxic molecules
Activated T lymphocytes → (1) release of Perivascular cellular infiltrates; Contact dermatitis; multiple
Cell-mediated (type
cytokines, inflammation and macrophage edema; granuloma formation; cell sclerosis; type I diabetes;
IV) hypersensitivity
activation; (2) T cell-mediated cytotoxicity destruction tuberculosis
Three years later, he developed easy fatigability, The mass and the symptoms persisted, and he
dyspnea, and weight loss. Chest X-ray showed underwent biopsy of the pulmonary mass. Which of
bilateral pleural effusion, a 7 cm mass at the left the following organisms/conditions may also cause
lower lobe and enlarged mediastinal lymph nodes a necrosis pattern most similar to that caused by
83. with calcification. What do you call this finding? 84. tuberculosis?
A. Ghon’s focus A. Sarcoidosis
B. Ghon’s complex B. Staphylococcus aureus
C. Ranke’s complex C. Histoplasma capsulatum
D. Simon’s focus D. Paragonimus westermani
Which of the following statement about findings in tuberculosis is true?

A. The Ghon’s complex can be seen in a previously exposed and sensitized person.
85. B. Reactivation (secondary) tuberculosis is usually seen in the subpleural area in the lower lobes.
C. Tuberculosis causes caseating granulation tissue surrounded by epithelioid and multinucleated giant cells.
D. Miliary tuberculosis is caused by hematogenous spread of M. tuberculosis.
Arkoudis NA, Pastroma A, Velonakis G, et al. Solitary round pulmonary lesions in the pediatric population: a pictorial
review. Acta Radiol Open. 2019;8(5):2058460119851998. Published 2019 May 31. doi:10.1177/2058460119851998
TUBERCULOSIS: CLINICAL DISEASE
GHON COMPLEX
RANKE COMPLEX
MILIARY TUBERCULOSIS
11/M has fever, cough, and a maculopapular rash With regards to the previous case, which viral
that started in the face and now extends throughout infection is implicated in the development of the
the body. Examination of the sputum shows tumor?
multinucleate giant cells with eosinophilic nuclear 89. A. Human immunodeficiency virus
86. and cytoplasmic inclusion bodies. Diagnosis? B. Hepatitis B virus
A. Varicella C. Human T-lymphocyte Virus 1
B. Rubella D. Epstein-Barr virus
C. Rubeola INFECTIONS AND ASSOCIATED CANCERS
D. Roseola
Infection Associated cancer Etiologic agent
What is the pathognomonic sign of this disease? • Squamous cell HPV 16, 18, 31,
HPV infection
A. Dewdrops on rose petal lesions carcinoma 33
87. B. three-day rash Clonorchis
C. Koplik spots Liver fluke sinensis
• Cholangiocarcinoma
D. Subacute sclerosing panencephalitis infection Opistorchis
viverrini
Resection of the ileum in a 10/M showed a diffuse • Gastric
infiltrate of intermediate-sized lymphoid cells with Peptic ulcer adenocarcinoma Helicobacter
round to oval nuclei, coarse chromatin, several disease • Gastric MALT pylori
nucleoli, and moderate cytoplasm. The tumor had a lymphoma
high mitotic index and numerous apoptotic cells, • Hepatocellular
Hepatitis HBV, HCV
88. which are phagocytosed by the macrophages, giving carcinoma
a characteristic “starry-sky pattern”. Diagnosis?
A. Hairy cell leukemia • Napsopharyngeal Ca
B. Follicular lymphoma • Some types of HL
Mononucleosis EBV
C. Multiple Myeloma • B-cell NHL
D. Burkitt Lymphoma • Burkitt lymphoma
Infection Associated cancer Etiologic agent DERMATOLOGIC

•
Gastric carcinomas
• Adult T-cell Acanthosis Immunologic;
--- HTLV-1 •
Lung carcinomas
leukemia nigricans secretion of EGF
•
Uterine carcinomas
• Primary CNS
HIV •
Bronchogenic
AIDS lymphoma Dermato-
HHV-8 (KSHV) carcinoma Immunologic
• Kaposi sarcoma myositis
• Lung carcinoma
Schistosoma
Chronic cystitis • Bladder SCCA OSSEOUS, ARTICULAR AND SOFT TISSUE CHANGES
haematobium
Hypertrophic
osteoarthro- • Bronchogenic
44/M presented with a 2 month history of a V-
pathy and carcinoma Unknown
shaped rash on the neckline, progressing to
clubbing of • Thymic neoplasms
generalized hyperpigmented rashes. Patient also
fingers
had facial erythema, photosensitivity, and lilac-
VASCULAR
colored discoloration of the eyelids. Muscle pain
developed one month after the onset of the rash. • Pancreatic
Venous
There was also progressive muscle weakness carcinoma Tumor products
thrombosis
starting in the proximal muscles, characterized by • Bronchogenic (mucins that
(Trousseau
90. inability to climb stairs, inability to stretch hands, carcinoma activate clotting)
syndrome)
dysphagia, and inability to turn his neck. There were • Other cancers
also dusky red patches over knuckles, knees, and Disseminated
• Acute promyelocytic Tumor products
elbows (Gottron papules). What is the most likely intravascular
leukemia that activate
diagnosis for this case? coagulation
• Prostatic carcinoma clotting
A. Systemic lupus erythematosus (DIC)
B. Dermatomyositis Non-bacterial
C. Rheumatoid arthritis thrombotic • Advanced cancers Hypercoagulability
D. Duchenne muscular dystrophy endocarditis
What is the definitive test for the diagnosis of this Red cell
• Thymic neoplasms Unknown
disease? aplasia
A. Antinuclear antibody OTHERS
91. Tumor antigens,
B. Anti-Mi2 antibody Nephrotic
C. Rheumatoid factor • Various cancers immune
syndrome
D. Muscle biopsy complexes
Patient was eventually found out to have an
associated malignancy. What is the most likely A 10/M has a mild upper respiratory tract infection
malignancy that the patient has? characterized by pharyngeal edema, epiglottic
92. A. Bronchogenic carcinoma swelling, and punctate abscesses in the tonsillar
B. Prostate carcinoma crypts. What is the predominant inflammatory
C. Colorectal carcinoma 93. response to the infection?
D. Gastric carcinoma A. Suppurative
B. Mononuclear-Granulomatous
SYNDROME CANCERS MECHANISM C. Cytopathic-Cytoproliferative
ENDOCRINOPATHIES D. Tissue Necrosis
• Small cell lung SPECTRUM OF INFLAMMATORY RESPONSES TO INFECTION
cancer Type Pathogenesis Example
Cushing ACTH or ACTH- • Increased vascular
• Pancreatic
syndrome like substances permeability Staphylococcal
carcinoma
• Neural tumors Suppurative • Leukocyte (neutrophil) infections
(Purulent) infiltration Tissue
• Small cell lung
• Chemoattractants abscesses
cancer Antidiuretic
SIADH • Formation of “pus”
• Intracranial hormone or ANP
• Mononuclear cell
neoplasms
(monocytes,
• Squamous cell macrophages, plasma
Hypercalcemia carcinomas cells, lymphocytes)
(Probably the • Breast carcinomas Mononuclear & Syphilis
PTHrP, TGF-α, infiltrates
most common • Renal cell Granulomatous Tuberculosis
TNF, IL-1 • Cell-mediated immune
paraneoplastic carcinomas response to antigens
syndrome) • Adult T-cell • Formation of
leukemia/lymphoma granulomata
• Ovarian carcinoma • Viral Transformation of
• Fibrosarcoma Insulin or insulin- Cells Cervical cancer
Hypoglycemia Cytopathic- • Necrosis or Chickenpox,
• Other mesenchymal like substance
sarcomas Cytoproliferative Proliferation (including shingles
multinucleation) HPV
• Renal cell carcinoma
• Linked to neoplasia
• Cerebellar
Polycythemia hemangioma Erythropoietin • Toxin or lysis-mediated
• Hepatocellular destruction
Clostridium
carcinoma Tissue Necrosis • Lack of Inflammatory
perfringens
• Phosphaturic cells
Osteomalacia FGF-23 • Rapidly progressive
mesenchymal tumor
MUSCLE • Repetitive injury à Chronic
Chronic
• Bronchogenic fibrosis hepatitis with
Inflammation/
Myasthenia carcinoma Immunologic • Loss of normal cirrhosis (Hep
Scarring
• Thymic neoplasms parenchyma B & C)
• Severe immune
No reaction MAI
compromise
Two weeks later, the patient developed fever, This patient then developed oliguria, “smoky” urine,
migratory polyarthritis, and a neurologic disorder periorbital edema, and hypertension. Examination
characterized by involuntary, rapid purposeless of the urine showed dysmorphic erythrocytes and
movement. The patient also had subcutaneous red cell casts. What is the pathophysiology?
95.
nodules and erythema marginatum. Physical A. Release of vasoactive amines
examination revealed tachycardia, irregular B. Antibodies bind to target tissue
94.
heartbeat, and a pericardial friction rub. What is the C. antigen-antibody complex deposition
type of hypersensitivity reaction? D. T-cell mediated cytotoxicity
A. Type I
B. Type II In relation to the case above, renal biopsy was done.
C. Type III What would be the finding under
D. Type IV immunofluorescence microscopy?
96. A. Granular deposits of IgG and C3
B. Linear IgG and C3 deposits
C. IgA deposits in the mesangium
D. None

Production of IgE antibody → immediate Vascular dilation, edema, smooth
Immediate (type I) release of vasoactive amines and other muscle contraction, mucus Anaphylaxis; allergies; bronchial
hypersensitivity mediators from mast cells; later recruitment production, tissue injury, asthma (atopic forms)
of inflammatory cells inflammation
Production of IgG, IgM → binds to antigen on Phagocytosis and lysis of cells;
Antibody-mediated
target cell or tissue → phagocytosis or lysis of inflammation; in some diseases, Autoimmune hemolytic anemia;
(type II)
target cell by activated complement or Fc functional derangements without Goodpasture syndrome
hypersensitivity
receptors; recruitment of leukocytes cell or tissue injury
Deposition of antigen-antibody complexes →
Immune complex- complement activation → recruitment of
toxic molecules
Activated T lymphocytes → (1) release of Perivascular cellular infiltrates; Contact dermatitis; multiple
Cell-mediated (type
cytokines, inflammation and macrophage edema; granuloma formation; cell sclerosis; type I diabetes;
IV) hypersensitivity
activation; (2) T cell-mediated cytotoxicity destruction tuberculosis
Most Frequent Glomerular Pathology

Disease Clinical Pathogenesis Fluorescence Electron
Presentation Light Microscopy
Microscopy Microscopy
Primarily
Granular IgG and C3 in subepithelial
Immune complex Diffuse endocapillary
Postinfectious GBM and mesangium; humps;
Nephritic syndrome mediated; circulating or proliferation; leukocytic
glomerulonephritis Granular IgA in some subendothelial
planted antigen infiltration
cases deposits in early
disease stages
Linear IgG and C3 in
No deposits in
anti-GBM antibody
anti-GBM and
mediated GN;
Anti-GBM antibody ANCA mediated
granular IgG, other
Crescentic (rapidly Nephritic mediated; immune Extracapillary GN; immune
Igs, and/or
progressive) syndrome; rapid complex mediated; proliferation with complexes at
complement in
glomerulonephritis progression ANCA mediated and crescents; necrosis various locations
immune complex
unknown in immune
mediated GN; or no
complex
deposits in ANCA
mediated GN
mediated GN
In situ immune complex

Membranous Nephrotic PLA2R antigen in most Diffuse capillary wall Granular IgG and C3; Subepithelial
nephropathy syndrome cases of primary thickening diffuse deposits
disease
Unknown; loss of Effacement of foot

Minimal change Nephrotic
glomerular polyanion; Normal; lipid in tubules Negative processes; no
disease syndrome
podocyte injury deposits
Nephrotic Unknown Effacement of foot

Focal segmental syndrome; non- Ablation nephropathy Focal and segmental Focal; IgM + C3 in processes;
glomerulosclerosis nephrotic Plasma factor (?); sclerosis and hyalinosis many cases epithelial
proteinuria podocyte injury denudation
Mesangial proliferative
Membrano-
or
proliferative Nephritic/nephrotic Subendothelial
Immune complex membranoproliferative IgG ++ C3; C1q ++ C4
glomerulonephritis syndrome deposits
patterns of proliferation;
(MPGN) type I
GBM thickening; splitting

Acquired or genetic
Dense-deposit Hematuria or
dysregulation of the
disease (MPGN Chronic renal membranoproliferative C3; no C1q or C4 Dense deposits
alternative complement
type II) failure patterns of proliferation;
pathway
Focal mesangial
Recurrent Mesangial and
proliferative IgA ± IgG, IgM, and C3
IgA nephropathy hematuria or Unknown paramesangial
glomerulonephritis; in mesangium
proteinuria dense deposits
mesangial widening
In relation to the case above, the patient eventually MYOCARDIAL INFARCTION: MORPHOLOGIC FEATURES
developed valvular lesions. The valve most TIME GROSS FEATURES LIGHT MICROSCOPE
commonly affected is: REVERSIBLE INJURY
97. A. Mitral valve 0-½
B. Aortic Valve None None
hour
C. Tricuspid valve IRREVERSIBLE INJURY
D. Pulmonic valve Usually none
½-4
None Variable waviness of fibers at
In relation to the case above, the valvular lesions hours
border
would be described as: Early coagulative necrosis
A. Small warty vegetations attached to the line of 4-12 Dark mottling
Edema
closure hours (occasional)
hemorrhage
B. Large, irregular, destructive masses that can Ongoing coagulative necrosis
98.
extend into the chordae Pyknosis of nuclei
C. Small bland vegetations attached to the line of 12-24 Myocyte hypereosinophilia
closure Dark mottling
hours Marginal contraction band
D. Small- to medium-sized vegetations on either necrosis
or both sides of the valve leaflets Early neutrophilic infiltrate
Coagulative necrosis, with
Mottling with
1-3 loss of nuclei and striations
yellow-tan infarct
days brisk interstitial infiltrate
center
of neutrophils
Beginning disintegration of
dead myofibers with dying
Hyperemic border
3-7 neutrophils
Central yellow-tan
days Early phagocytosis of dead
softening
cells by macrophages at
infarct border
Maximally yellow-
Well-developed phagocytosis
7-10 tan and soft, with
of dead cells
days depressed red-tan
Granulation tissue at margins
margins
Well-established granulation
10-14 Red-gray depressed
tissue with new blood vessels
days infarct borders
and collagen deposition
Gray-white scar,
55/M experienced crushing precordial chest pain, 2-8 progressive from Increased collage deposition,
associated with rapid, weak pulse and diaphoresis. weeks border toward the with depressed cellularity
ECG showed ST elevation. Cardiac markers were core of infarct
requested. What is the most sensitive and specific >2
99. cardiac marker you could request? Scarring complete Dense collagenous scar
mos
A. cTnI
B. CK MB
C. Myoglobin
D. LDH
TIME OF RETURN TO
MARKER PEAK
RISE NORMAL
Cardiac troponins 3-12 hours 24 hours 5-14 days
CK-MB 4-8 hours 24 hours 2-3 days
With regards to the previous case, the patient died

48 hours later. What is the expected finding under
the light microscope?
A. None
100. B. Coagulation necrosis and brisk interstitial
infiltrate of neutrophils
C. Phagocytosis of dead cells with formation of
granulation tissue
D. Increased collagen deposition
With regards to the previous case, what is the pattern of myocardial necrosis?
A. Subendocardial
101. B. Transmural
C. Endocardial
D. Multifocal microinfarction
MYOCARDIAL INFARCTION: PATHOGENESIS
A 57-year old male suddenly experienced right-

sided weakness and numbness, slurring of speech,
and loss of consciousness. The patient died two days
later from complications. On autopsy the brain
102. would reveal:
A. Coagulative necrosis
B. Liquefactive necrosis
C. Caseous Necrosis
D. Fat necrosis
Examination of the arteries of the Circle of Willis

showed atheromas. Which of the following
statements regarding atheromas are true?
A. Atheromas are raised medial lesions with a
soft grumous core of lipid covered by a fibrous
cap.
103.
B. Atheromas are composed of striated muscle
cells, macrophages, and T cells.
C. The most important causes of endothelial
injury and dysfunction are hemodynamic
disturbances and hypercholesterolemia.
D. All of the above.
ATHEROSCLEROSIS: PATHOGENESIS
Further examination showed thrombus formation in the left middle cerebral artery. What is the least likely
possible cause of the thrombus formation?
A. Plaque rupture
104.
B. Erosion of fibrous cap
C. Hemorrhage into the plaque
D. Critical stenosis
Which of the following vessels is least likely to be CHRONIC GASTRITIS

affected by atherosclerosis? H. PYLORI-
A. Popliteal artery FEATURE AUTOIMMUNE
105. ASSOCIATED
B. Coronary artery CLINICAL
C. Internal carotid artery
Acid
D. Brachial Artery á to slightly â â
production
A peripheral blood smear from a 47/F showed Gastrin N to á á to markedly á
macro-ovalocytes and nuclear hypersegmentation Antibodies to
in the neutrophils. Physical examination showed Antibodies to H. parietal cells
Serology
peripheral neuropathy and a loss of papillae in the pylori (Proton pump and
106. tongue. What is the most probable cause? IF)
A. Iron deficiency Atrophy, pernicious
B. Folate Deficiency Peptic ulcer, anemia,
C. B12 Deficiency Sequelae
adenoCA, MALToma adenocarcinoma,
D. Erythropoietin Deficiency carcinoid tumor
Low socioeconomic
In relation to the case above, a stomach biopsy was Autoimmune
status, poverty,
performed, along with other tests. The most likely Associations disease: thyroiditis,
residence in rural
finding is: DM, Graves
areas
107. A. Inflammation of the antrum MORPHOLOGY
B. Neutrophilic infiltrates Location Antrum Body
C. Decreased gastrin
Superficial, in lamina Deep, in gastric
D. Neuroendocrine hyperplasia Inflammation
propria glands
Inflammatory PMNs, subepithelial Lymphocytes,
infiltrate plasma cells Macrophages
H. PYLORI- It is important to test this patient because patients
FEATURE AUTOIMMUNE
ASSOCIATED with this syndrome almost always develops this
In H. pylori corpus- preventable tumor.
predominant 113. A. Papillary thyroid carcinoma
Chief cell loss atrophic gastritis: Diffuse and B. Pancreatic neuroendocrine tumor
(Atrophy) Patchy distribution extensive C. Medullary Thyroid Carcinoma
(Multifocal atrophic D. Parathyroid Carcinoma
gastritis) MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES
FEATURE MEN1 MEN2
Hyperplastic/inflam Neuroendocrine RET (MEN2A and MEN2B
Other lesions Mutation MEN1
matory polyps hyperplasia have distinct mutations)
• Pituitary: Most
CBC from a 52/F showed hemoglobin of 7.4 g/dL common:
with decreased RBC count, mean corpuscular Prolactinomas • Common lesions
volume and mean corpuscular hemoglobin. What is • Parathyroid: Most o Pheochromocytoma
the most likely diagnosis? common: Primary o Medullary thyroid
108. hyperparathyroidism carcinoma: MEN2B-
A. Polycythemia vera
o Adenoma or associated MTCs are
B. Pernicious anemia
Hyperplasia more aggressive than
C. Iron-deficiency anemia
Syndrome • Pancreas (PanNET) those associated with
D. Thalassemia MEN2A
o Most common:
Pancreatic • MEN2A: Parathyroid
Which test would you order to confirm the Polypeptide hyperplasia
diagnosis? o Most common • MEN2B: Neuromas,
A. JAK2 mutation analysis types that produce Ganglioneuromas,
109. B. Folate and B12 levels hypersecretory Marfanoid habitus
C. Ferritin, serum iron, total iron binding states: Insulinoma,
capacity Gastrinoma
D. Hemoglobin electrophoresis Important due to MTC
Genetic Importance not well-
(mortality prevented by
screening established
22/M consulted for “feelings of impending doom”. early thyroidectomy)
Physical examination showed a blood pressure of
170/110 and a heart rate of 120 bpm. During the The hepatitis profile of a patient shows the
consult, the patient experienced headache and following: HBsAg (+), Anti-HBs (-), Anti-HBc IgG (+),
palpitation. He was sweating profusely and his HBeAg (+). The patient has:
hands were trembling. Imaging showed a right 114. A. Active Hepatitis B
110. B. Chronic Hepatitis B Carrier
adrenal mass. Urinary vanillylmandelic acid was
elevated. Diagnosis? C. Chronic Active Hepatitis B
A. Adrenocortical adenoma D. Vaccination against Hepatitis B
B. Adrenocortical carcinoma SEROLOGY OF HEPATITIS B
C. Pheochromocytoma Anti- Anti-
D. Malingering Time Period HBsAg HBeAg
HBs HBc
Incubation
All of the following statements are true about the (+) Negative Negative (+)
Period
previous case, except:
Acute
A. 10% are extraadrenal (+) Negative (+) IgM (+)
111. Infection
B. 10% of sporadic cases are bilateral
C. 10% are benign Window
Negative Negative (+) IgM Negative
D. 10% not associated with hypertension Period
Complete
Negative (+) (+) IgG Negative
With regards to the previous case, patient was also Recovery
noted to be tall, with long fingers, toes, arms, and Chronic
(+) Negative (+) IgG Negative
legs, and hyperextensible joints. This patient needs Carrier
to be tested for mutations in what gene? Chronic Active (+) Negative (+) IgG (+)
112.
A. MEN1 Vaccinated Negative (+) Negative Negative
B. MEN2
C. RET Which of the following is true about Hepatitis B?
D. CDKN1B A. Transmitted via fecal-oral route
B. DNA virus
115.
C. Has the highest rate of progression to chronic
hepatitis
D. Defective virus
VIRAL HEPATITIDES
Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Circular defective
Type of virus ssRNA Partially dsDNA ssRNA ssRNA
ssRNA
Fecal-oral Parenteral;
Parenteral, sexual
Route of transmission (contaminated intranasal cocaine Parenteral Fecal-oral
contact, perinatal
food or water) use
Mean incubation period 2–6 weeks 2–26 weeks 4–26 weeks Same as HBV 4–5 weeks
10% (co-infection);
Frequency of chronic In immunocompromised
Never 5%–10% >80% 90%-100% for
liver disease hosts only
superinfection
HBsAg or HBcAg ELISA for HCV Serum IgM and IgG Serum IgM and IgG
Serum IgM
Diagnosis antibodies; PCR antibodies; PCR for antibodies; PCR for antibodies; PCR for HEV
antibodies
for HBV DNA HCV RNA HDV RNA RNA
The patient in the previous case eventually developed edema. There was proteinuria of 4g/day and dysmorphic
RBCs in the urine. What is the expected renal biopsy finding?
A. Proliferation of the mesangial cells and increased mesangial matrix with “duplication” of the basement membrane
116.
B. Uniform and diffuse effacement of the foot processes
C. Uniform and diffuse thickening of the glomerular capillary wall
D. Retraction and collapse of the glomerular tuft

Primarily
Granular IgG and C3 in subepithelial
Immune complex Diffuse endocapillary
Postinfectious GBM and mesangium; humps;
Nephritic syndrome mediated; circulating or proliferation; leukocytic
glomerulonephritis Granular IgA in some subendothelial
planted antigen infiltration
cases deposits in early
disease stages
Linear IgG and C3 in
No deposits in
anti-GBM antibody
anti-GBM and
mediated GN;
Anti-GBM antibody ANCA mediated
granular IgG, other
Crescentic (rapidly Nephritic mediated; immune Extracapillary GN; immune
Igs, and/or
progressive) syndrome; rapid complex mediated; proliferation with complexes at
complement in
glomerulonephritis progression ANCA mediated and crescents; necrosis various locations
immune complex
unknown in immune
mediated GN; or no
complex
deposits in ANCA
mediated GN
mediated GN
In situ immune complex
Membranous Nephrotic PLA2R antigen in most Diffuse capillary wall Granular IgG and C3; Subepithelial
nephropathy syndrome cases of primary thickening diffuse deposits
disease
Unknown; loss of Effacement of foot
Minimal change Nephrotic
glomerular polyanion; Normal; lipid in tubules Negative processes; no
disease syndrome
podocyte injury deposits
Nephrotic Unknown Effacement of foot
Focal segmental syndrome; non- Ablation nephropathy Focal and segmental Focal; IgM + C3 in processes;
glomerulosclerosis nephrotic Plasma factor (?); sclerosis and hyalinosis many cases epithelial
proteinuria podocyte injury denudation
Membrano-
or
proliferative Nephritic/nephrotic Subendothelial
Immune complex membranoproliferative IgG ++ C3; C1q ++ C4
glomerulonephritis syndrome deposits
patterns of proliferation;
(MPGN) type I
Acquired or genetic
Dense-deposit Hematuria or
dysregulation of the
disease (MPGN Chronic renal membranoproliferative C3; no C1q or C4 Dense deposits
alternative complement
type II) failure patterns of proliferation;
pathway
Focal mesangial
Recurrent Mesangial and
proliferative IgA ± IgG, IgM, and C3
IgA nephropathy hematuria or Unknown paramesangial
glomerulonephritis; in mesangium
proteinuria dense deposits
mesangial widening
In relation to the previous case, which of the LARGE-VESSEL VASCULITIDES

following is the expected finding in the liver biopsy? GIANT CELL TAKAYASU
A. Deposition of fibrous tissue FEATURE
117. ARTERITIS ARTERITIS
B. Ground-glass hepatocytes • Most common
C. Hepatocyte apoptosis form of vasculitis • Diagnosed in
D. All of the above Epidemiologic
among elderly patients <50 years
significance
adults in US and old
In relation to the previous case, the patient Europe
eventually developed a vasculitis of the renal • Temporal • Aortic arch and
arteries with no pulmonary involvement. What is • Ophthalmic branches
the expected finding? Vessel
• Vertebral • Great vessels
A. Segmental, transmural necrotizing affected
• Aorta (giant cell • Pulmonary,
inflammation with fibrinoid necrosis with aortitis) coronary, renal
118. temporal heterogeneity of lesions
• Headache
B. focal transmural necrotizing lesions with • Ocular
leukocytoclasia • Pain/tenderness
disturbances
along course of
C. necrotizing lesions with extravascular Prominent • Marked
necrotizing granulomas superficial
clinical weakening of the
temporal artery
D. necrotizing lesions with extravascular findings pulses in the upper
necrotizing granulomas and eosinophils • Diplopia or
extremities
complete vision
(pulseless disease)
loss
• Intimal thickening
• Medial granulomatous inflammation with
Morphology fragmentation of internal elastic lamina
• Lymphocytic infiltrates (CD4 > CD8)
• Multinucleated giant cells (in GCA)
MEDIUM-VESSEL VASCULITIDES
FEATURE POLYARTERITIS NODOSA KAWASAKI DISEASE
Epidemiologic • Important cause of MI in children (coronary artery
• Associated with Hepatitis B
significance aneurysms)
• Coronary arteries
Vessel affected • Renal and visceral vessels (never pulmonary)
• Small vessels
• Fever > 5 days
• Conjunctival injection
Prominent clinical • Symptoms referable to visceral ischemia and infarction
• Mucosal erythema
findings • Hypertension (renal vessels)
• Cervical lymphadenopathy
• Polymorphous exanthem
• Segmental, transmural necrotizing inflammation, often with superimposed aneurysms and/or thrombosis
• Fibrinoid necrosis
Morphology o PAN: prominent fibrinoid necrosis
o Kawasaki: less prominent fibrinoid necrosis
• Temporal heterogeneity of lesions
SMALL-VESSEL VASCULITIDES
• Also called allergic granulomatosis
• Seen in vasculitis associated
and angiitis • Previously called Wegener’s granulomatosis
Epidemiologic with Henoch-Schönlein
• Associated with asthma, allergic • Widespread GPA looks like PAN + Pulmonary
significance purpura (HSP) and connective
rhinitis, and eosinophilia (blood involvement
tissue disorders
and tissues)
ANCA • MPO-ANCA (p-ANCA) • PR3-ANCA (c-ANCA)
Vessel • More common: Kidney and • Small and medium-sized vessels (prominent
• Cutaneous, GIT, renal
affected Lung pulmonary involvement), may involve renal vessels
• Persistent pneumonitis with bilateral nodular and
Prominent • Palpable purpura, GI bleed, FSGS cavitary infiltrates (95%)
• Hemoptysis
clinical • Cardiomyopathy (toxicity from • Chronic sinusitis (90%)
• Hematuria and Proteinuria
findings myocardial eosinophilic infiltrates) • Mucosal ulcerations of the nasopharynx (75%)
• Renal disease (80%)
• PAN but temporally
• Acute necrotizing granulomas of respiratory tract
homogeneous lesions
• PAN + Extravascular necrotizing • Necrotizing or granulomatous vasculitis
Morphology • Fragmented PMNs in post-
granulomas and eosinophils • Focal, segmental necrotizing GN often crescentic
capillary venules
GN
(leukocytoclastic vasculitis)
5/F presented in the emergency room with If the patient is experiencing hypovolemic shock,
symptoms of dehydration. The mother indicated what is the main pathophysiology?
that the patient had been passing out “rice-water- A. Failure of the myocardial pump
121.
like” stools for three days, with accompanying B. Inadequate blood/plasma volume
vomiting and loss of appetite. The diarrhea C. Activation of cytokine cascades
119. persisted despite the patient having little food D. Loss of vascular tone
intake. What type of diarrhea is this? PATHOLOGY CONCEPT: SHOCK
A. Secretory Shock Setting Mechanism
B. Osmotic • Myocardial
C. Malabsorptive infarction Failure of myocardial
D. Exudative • Ventricular pump resulting from
DIARRHEA rupture intrinsic myocardial
Cardiogenic
• Increased in stool mass, frequency, or fluidity • Arrhythmia damage, extrinsic
• Four major categories • Cardiac tamponade compression, or
o Osmotic diarrhea – caused by excessive osmotic force • Pulmonary obstruction to outflow
exerted by unabsorbed luminal solutes; abates with fasting embolism
o Malabsorptive diarrhea – results from generalized failure of • Fluid loss (e.g.
nutrient absorption; associated with steatorrhea; abates with hemorrhage, Inadequate blood or
Hypovolemic
fasting vomiting, diarrhea, plasma volume
o Secretory diarrhea – characterized by isotonic stool; persists burns, or trauma)
during fasting Activation of cytokine
o Exudative diarrhea – characterized by purulent, often bloody cascades
stools; persists during fasting • Overwhelming
• Peripheral
Shock microbial
vasodilation and
What is the pathophysiology of the disease in the associated infections
pooling of blood
with systemic • Superantigens
previous question? • Endothelial
inflammation • Trauma
A. Toxin-mediated efflux of ions from the activation/injury
(Septic shock) • Burns
intestinal enterocytes • Leukocyte-induced
• Pancreatitis
120. B. Presence of unabsorbed solutes in the damage
intestinal lumen • DIC
C. Inability to digest and absorb food Loss of Vascular Tone
• Anesthetic accident
D. Toxin-mediated necrosis of the intestinal Neurogenic à systemic
• Spinal cord injury
enterocytes vasodilation
• IgE-mediated
Systemic Vasodilation
hypersensitivity
Anaphylactic and increased vascular
reaction à
permeability
histamine release
72/M had urinary frequency, dysuria, and having to 30/M presented with chronic cough of 1 month
strain while voiding. Digital rectal exam revealed a duration, associated with low-grade afternoon fever
prostatic nodule. Which of these tests are you going and weight loss. Sputum examination showed
to order to arrive at the diagnosis? trophozoites of Pneumocystis jiroveci. His CD4 count
122.
A. Transrectal ultrasound was 159 x 106/L. The following are true about of his
B. MRI underlying disease except?
C. Serum PSA A. The virus can also infect macrophages and
D. Prostate biopsy 130. dendritic cells.
B. Completion of the viral life cycle in latently
What is the normal serum PSA value for this patient? infected cells occurs only after cell activation
A. 2.5 ng/mL C. Central nervous system disease results from
123. B. 3.5 ng/mL infection and apoptosis of neurons
C. 4.5 ng/mL D. The level of RNA is a useful marker of disease
D. 6.5 ng/mL progression and is of clinical value in the
management of this disease
Patient’s serum PSA value is 64.5 ng/mL. Diagnosis? NATURAL COURSE
A. Acute prostatitis • Acute infection
124. B. Benign prostatic hyperplasia o Infection of CD4+ T cells à death of infected cells
C. Prostatic carcinoma o Dissemination to lymphoid tissues
D. None of the above o Viremia à acute retroviral syndrome
• Chronic infection: Clinical Latency
If the prostate biopsy showed glandular and • Continuous HIV replication in the lymph nodes and spleen
fibromuscular proliferation with the glandular
component composed of large to cystically dilated
glands, lined by two layers, an inner columnar and
an outer cuboidal or flattened epithelium. What is
125.
the diagnosis?
A. Acute prostatitis
B. Benign prostatic hyperplasia
C. Prostatic carcinoma
D. None of the above
If the prostate biopsy showed proliferation of small

crowded glands without branching and papillary
infolding, lined by a single uniform layer of cuboidal
or low columnar epithelium. The outer basal cell
126. layer is absent. What is the diagnosis?
A. Acute prostatitis
B. Benign prostatic hyperplasia
C. Prostatic carcinoma
D. None of the above
24/M consults with a one week history of watery

diarrhea, occasionally tinged with blood. The
diarrhea is associated with cramping abdominal
pain, weight loss, and anorexia. Stool examination
reveals trophozoites with ingested erythrocytes.
127.
What is the most likely etiologic agent?
A. Yersinia enterocolitica
B. Giardia lamblia
C. Entamoeba histolytica
D. Cryptosporidium parvum
With regards to the previous case, what is the most

commonly affected site?
A. Ascending colon
128.
B. Jejunum
C. Rectum
D. Stomach
Biopsy of the gastrointestinal tract would show:

A. Widespread erosion and pseudopolyps
B. Flask-shaped ulcers with a narrow neck and a
129. broad base
C. Normal histology
D. Lacteals and lymph nodes distended with
foamy macrophages
What is the least likely mechanism of

immunodeficiency in the previous case?
A. Loss of CD4+ T cells
B. Defective complement activation system
131.
C. Defective macrophage and dendritic cell
functions
D. Destruction of architecture of lymphoid
tissues
29/M consulted for intermittent attacks of bloody FEATURE
PRIMARY BILIARY PRIMARY SCLEROSING
diarrhea with abdominal pain and cramping, CIRRHOSIS CHOLANGITIS
temporarily relieved by defecation. There was no • Small to medium-
Bile ducts • Extrahepatic and large
associated fever. Endoscopy revealed affectation of sized
involved intrahepatic
the colon from the rectum to the ascending colon, intrahepatic
132. with broad-based ulcers and pseudopolyps. • Florid duct
Diagnosis? lesion:
A. Typhoid fever Lymphocytic
B. Irritable bowel syndrome and/or
C. Crohn’s disease granulomatous
bile duct • Acute and chronic
D. Ulcerative colitis
destruction inflammation à “onion-
• Cirrhosis with skin” fibrosis and stricture
Colonic biopsy showed crypt abscesses, gland Histologic elongated à luminal obliteration
distortion, and inflammatory infiltrates limited to pearls cirrhotic nodules • Lithiasis in proximal dilated
the mucosa. Diagnosis? (“garland- segments
133. A. Typhoid fever shaped”) • Biliary cirrhosis (because of
B. Irritable bowel syndrome • Nodular obstruction)
C. Crohn’s disease regenerative
D. Ulcerative colitis hyperplasia:
Regenerative
Crohn’s Ulcerative nodules without
FEATURE fibrosis
Disease Colitis
MACROSCOPIC • Radiologic imaging of
Bowel region Ileum + colon Colon only Diagnosis • Liver biopsy biliary tree (beading of
contrast medium)
Distribution Skip lesions Diffuse
• Increased risk for • Increased risk for
Stricture Yes Rare Sequelae
HCC cholangiocarcinoma
Wall appearance Thick Thin
MICROSCOPIC
The patient is at an increased risk of developing the
Inflammation Transmural Limited to mucosa
following except:
Pseudopolyps Moderate Marked
A. Colonic adenocarcinoma
Superficial, broad- 135. B. Hepatocellular carcinoma
Ulcers Deep, knife-like
based C. Cholangiocarcinoma
Lymphoid reaction Marked Moderate D. The patient is at risk of developing all of the
Fibrosis Marked Mild to none above
Serositis Marked Mild to none
Granulomas Yes (~35%) No
Fistulae/sinuses Yes No
END OF PATHOLOGY PHASE 3
CLINICAL
Yes (in colonic
Perianal fistula No
disease)
Fat/vitamin
malabsorption
Yes No BUZZWORDS
With colonic QUESTION ANSWER
Malignant potential Yes Clinical findings of infant with
involvement
Recurrence after seizures, muscle weakness,
Common No hypotonia, feeding problems,
surgery • Leigh syndrome
Toxic megacolon No Yes psychomotor development
arrest, extraocular palsies,
Blood workup for the patient in the previous case and lactic acidemia
revealed elevated alkaline phosphatase and • Multifocal lesions with
elevated bilirubins. Contrast imaging of the Histologic findings of Leigh spongiform appearance
hepatobiliary tree revealed “beading” of the syndrome of brain tissue and
134. contrast medium. Diagnosis? vascular proliferation
A. Typhoid fever • Mutations in
B. Irritable bowel syndrome Main pathology of Leigh mitochondrial DNA that
C. Crohn’s disease syndrome interfere with baby’s
D. Ulcerative colitis energy generation
Clinical findings of a child
• Rheumatic fever
PRIMARY BILIARY PRIMARY SCLEROSING with sudden onset fever with
FEATURE • Arthritis is the most
CIRRHOSIS CHOLANGITIS pain initially on both knees
common presentation
• Median age 50 later involving the ankles, and
Age • Median age 30 years • Sydenham’s chorea –
years occasional movements of
involuntary movements
upper and lower extremities.
Gender • 90% Female • 70% Male Had sore throat 2 weeks ago. of the limbs
• Sjögren Laboratory test that is most
syndrome (70%) helpful in establishing the • Anti-streptolysin O titer
Associated • Inflammatory Bowel
• Hashimoto diagnosis of RF
conditions Disease (70%)
Thyroiditis Pathogenesis of rheumatic • Antigen antibody
• Scleroderma fever reaction
Middle-aged man with
• 65% ANCA (+) recurrent epigastric pain
• 95% AMA (+) • ANA variable, AMA typically occurring 1-3 hours after
Serology
• 40-50% ANA(+) (-) meals and is worst at night. • Perforated peptic ulcer
• 6% ANA (+) Was rushed to the ER one
night due to severe pain on
• Strictures and beading of
the back and chest.
Radiology • Normal large bile ducts
• Pruning of smaller ducts
Common radiograph finding • Multiple vesicular
of perforated peptic ulcer lesions over the face and
• Pneumoperitoneum
showing subdiaphragmatic extremities
air • High grade fever
Bacteria associated with • Prodrome of respiratory
• Helicobacter pylori Clinical features of varicella
peptic ulcer disease infection
Clinical features of anemia, • “Dew drop on a rose
thrombocytopenia, and petal” rash
cytokine storm with systemic • Vesicles rupture leaving
• Hemophagocytic
activation of CD8+ and crusts but no scars
lymphohistiocytoma
macrophages which Newborn baby noticed to
phagocytose blood cell have no bowel movements • Imperforate anus
progenitors in the marrow despite a good appetite
Most common trigger of • Failure of cloacal
hemophagocytic • Epstein-Barr virus Pathology of imperforate anus
diaphragm to involute
lymphohistiocytoma Initial management of
Clinical course of • Hydration
• Rapid progression of newborns with imperforate
hemophagocytic • Avoidance of sepsis
multi-organ failure, anus
lymphohistiocytoma if left Patient who drank water from
shock, and death
untreated a nearby store developed
Most common site of • Cholera
• Bone rice-water stools over the
metastasis of prostate cancer next 2 days
• Prostatitis • Elaboration of an
• Infarction of nodular Pathogenesis of cholera enterotoxin which acts
Possible factors that would
hyperplasia on bowel mucosal cells
result to PSA elevation
• Diagnostic procedure What is the organism
done on prostate itself • Vibrio cholera
involved in cholera
• Get the rate of change in Newborn baby failed to pass
Use of PSA velocity to predict PSA which is usually 0.75 meconium at immediate
eventual abnormal values in ng/mL per year with at postnatal period presenting • Hirschsprung’s disease
men at risk for prostate least 3 PSA with abdominal distension
cancer measurements over a and bilious vomiting
period of 1.5-2 years. • Normal migration of
Proper documentation of the • Effective screening Pathogenesis of
neural crest from cecum
following leads to better • Early diagnosis Hirschsprung’s disease
to rectum is arrested
prognosis in cervical cancer • Curative therapy • Fluid and electrolyte
Another way to detect imbalance
cervical cancer aside from the • Colposcopy Complications of
• Perforation and
annual Pap Smear Hirschsprung’s disease if left
peritonitis
DNA virus that has the highest untreated
• Development of
oncogenic risk for cervical • HPV 16 enterocolitis
cancer Newborn baby who kept
• Increased gland size vomiting all the food he ate
compresses urethra, showing thin noncanalized • Esophageal atresia
leading to obstruction cord replacing a segment of
Characteristics of benign
• Most common cause of the esophagus on radiography
prostatic hyperplasia
lower urinary tract Esophageal atresia occurring
symptoms in males near the tracheal bifurcation
• Fistula
• PSA levels ≤ 4 ng/mL is associated with this
• It is hormonally condition
Pathophysiology of BPH
influenced by • Pneumonia
testosterone and Complications of esophageal
• Aspiration
dihydrotestosterone atresia
• Suffocation
• Hyperplasia of glandular Lab test to be requested for
Expected histologic findings
and stromal tissues with an old man with difficulty in
of BPH
papillary buds starting and stopping the
• Old men urine stream accompanied by
• Serum PSA level
• Incontinence, decrease in dysuria, frequency,
urine stream, terminal hematuria, and palpation of a
dribbling, abdominal nodule upon DRE in the outer
Clinical features of BPH straining when urinating peripheral area of the gland
• Need to urinate • Androgen regulated to
frequently cleave and liquefy
• Urge despite difficulty seminal coagulum
initiating voiding formed after ejaculation
Histopathologic findings at • Intraepithelial vesicles • Product of prostatic
Characteristics of PSA
the base of the vesicle in with intranuclear epithelium secreted in
varicella lesions inclusions the semen
• Lesions were scratched • Enlarging prostate in
Cause of presence of scar in aging men would have
while sleeping because of
varicella higher serum PSA
pruritus
Length of the course of illness • 2 weeks after respiratory Histologic finding • The outer basal cell layer
in varicella infection distinguishing cancer cells of found in benign lesion is
the prostate absent
Patient consulting with Mutation in the gene of this
gradual onset of coughs and lipoprotein results in a
• LDL
sore throat associated with receptor disease of familial
headache, chills, malaise, hypercholesterolemia
fever; wheezes and rales on Cell alteration that explains
• Mycoplasma
auscultation; peribronchial the decrease in the size of calf
pneumoniae • Atrophy
pneumonia with thickened muscles after 6 weeks of
bronchial markings, streaks of immobilization
interstitial infiltration, and Component of the ECM that is
areas of subsegmental lost in an elderly with x-ray
atelectasis on chest x-ray findings of eroded and joint
Laboratory test to diagnose • Culture of pulmonary space narrowing in the knee
• Hyaluronan
mycoplasma pneumonia specimen joint surfaces with loss of
Most significant cutaneous compressibility and
• Erythema multiforme lubrication of articular
pathology associated with
major
mycoplasma pneumonia cartilaginous surfaces
• Type 1 diabetes are • Progressive loss of upper
usually insulin motor neurons in the
Main pathology involved in
dependent cerebral cortex and
amyotrophic lateral sclerosis
Characteristic features of a • An autoimmune beta cell lower motor neurons in
(ALS)
type 1 diabetic patient distinctive process can the spinal cord and
develop brainstem
• 4-10% can occur after Leucocytic cells that may be
age 30 the main type of cell in • Eosinophils
Pathogenesis of Type 1 • Beta cell death at the allergic reactions
Diabetes pancreatic islet Type of histology in a young • Neurofibroma
This immune system female with multiple small • Pigmented nodules of the
component mediates the islet • T lymphocytes macules over the body and iris (Lisch nodules)
destruction extremities and firm, rubbery • Cutaneous
Most malignant and bumps under the skin with 3 hyperpigmented macules
aggressive form of lung • Small cell carcinoma iris hamartomas (café au lait spots)
cancer Clinical problem present with
Hormones predominantly obstruction of the lung • Asthma
produced by small cell • ACTH and ADH airways as the pathology
carcinoma • Significant negative
Pathology present in a patient
Apical lung cancers that intrathoracic pleural
with obstructive lung disease
invade the cervical pressure required for
• Pancoast tumor having pulsus paradoxus
sympathetic ganglia and ventilation
produce Horner syndrome Most characteristic lesions of
Wart-like new growth on the SLE result from immune
• Skin
hands and feet of patient with complex deposition in which
history of exposure to their of the least area
• Arsenic keratosis
town river where Marcopper Condition in which a blast cell
• Acute myeloid leukemia
Mining drainage would with an Auer rod is seen
usually pass Deficiency of this enzyme
Diagnostic tool to confirm the causes the liver cells to store • Glucose-6-phosphatase
• Excision biopsy
arsenic keratosis glycogen
Complication that may arise • Damaged caused by
• Develops into squamous
from the arsenic keratosis autoimmune diseases is
carcinoma
lesion progressive
Type of hypersensitivity • Chronic with relapses
reaction after developing General features of and remissions
difficulty of breathing with autoimmune diseases • Clinical and pathologic
marked inspiratory stridor manifestations are
• Type 1
from laryngeal edema with determined by nature of
mild urticaria and swelling underlying immune
within 5 minutes of bee sting response
on her hand Most common cause of
Type of cell that plays a part • Graves’ disease
endogenous hyperthyroidism
in Type 1 hypersensitivity • Lymphocyte Patient presenting with
reaction unilateral enophthalmos,
• Can be given miosis, anhidrosis, ptosis of
parenterally, easily the left eye and face with • Bronchogenic carcinoma
available emergency chest x-ray finding of left (Pancoast tumor)
drug upper lobe opacity and • Horner syndrome
Characteristics of epinephrine
• The reaction is triggered destruction of first rib
for treating Type 1
by mast cell bound IgE presenting with left upper
hypersensitivity reaction
releasing histamine chest pain
• Fastest acting agent to Test that is consistent with
• Presence of Heinz bodies
treat life threatening G6PD deficiency
conditions Sheath of connective tissue
• Perineurium
Risk factor for development of • Multiple exposure to surrounding fascicle of axons
esophageal adenocarcinoma radiation Female infant who often wet
Panmyelosis is a the top of her diaper showing
characteristic of which type of • Polycythemia vera a connection from the bladder • Persistent urachus
blood cancer to the umbilicus in imaging
study
Jeepney driver who Condition with distinctive
developed acute cough crescents formed by
productive of phlegm with • Bronchitis proliferation of parietal cells
• Rapidly progressive
pathology in his lower lung and migration of monocytes
glomerulonephritis
airways and macrophages in the
Presence of atherosclerotic urinary space in light
• Aneurysm formation
plaques make a person microscopy
• Atheroembolism
susceptible to the following Morphological atypical
• Vascular thrombosis
conditions keratinocytes described as
• Distal acinar emphysema enlarged cells with eccentric,
Underlying pathologic disease • Koilocytes
• Underlies many cases of pyknotic nuclei surrounded
which can cause mediastinal by a perinuclear halo found in
spontaneous
shift HPV infection
pneumothorax
Immune cells that rapidly Intracellular pathway that
recognize and destroy virally • NK cells mediates EGF binding to the
infected cells epidermal cell surface
Characteristic of most normal • They have one axon and receptors which is followed • Cyclin-dependent kinase
neurons multiple dendrites by transcription factor
Microscopic changes translocation and DNA
• Squamous (basal) cell transcription
occurring in distal esophagus
hyperplasia Pathology of a rapidly • Presence of circulating
with 5-year history of GERD
Etiologic factor in an elderly progressive anti-glomerular
factory worker presenting glomerulonephritis with basement membrane
with increasing dyspnea and concomitant diffuse antibodies
decreased breath sounds in pulmonary hemorrhage • Goodpasture syndrome
all fields of the left lung Cells in the CNS which are
• Asbestos responsible for recycling the
without cough and sputum • Astrocytes
production with pleural glutamate that is released at
biopsy findings of spindle and synapses
cuboidal cells invading Subcellular structure found in
adipose tissue macrophages responsible for
Capillaries with fenestrated the accumulation of the
endothelium that have gaps • Endocrine glands hemosiderin pigment in the • Lysosome
between the endothelial cells • Intestinal villi rust-colored sputum in a
but with continuous • Renal glomeruli patient with congestive heart
basement membrane failure
Likely cause of death with • Basal ganglial Male patient admitted for
autopsy finding of Charcot- intracerebral testicular pain presenting
Bouchard aneurysms hemorrhage with swollen and inflamed
• Drugs right testis and CT scan • Hydrocele
Factors contributing to the revealing abnormal
• Sex hormones
pathogenesis of SLE accumulation of fluid in the
• UV light exposure
cavity of the tunica vaginalis
Cause of early clinical
manifestations of congestive • Pulmonary congestion • Acts on mitochondria by
heart failure inducing oxidative stress
and generating reactive
• Obstruction of medium-
Pathology in rhonchi oxygen species (ROS)
sized airways
• Activating apoptosis,
• Lesions are due to
mutating mtDNA,
intimal thickening and Mechanism of cadmium
altering gene expression,
lipid accumulation toxicity
inhibiting respiratory
• Plaques vary in size but
chain complexes,
Characteristics of can coalesce to form
reducing ATP synthesis,
atherosclerotic plaques larger masses
and altering the inner
• Atheromatous plaques
mitochondrial
are white-yellow and permeability
encroach on the lumen of
Rare multisystem
the artery
autoimmune disease of
• Production of unknown etiology with
Hallmark of SLE
autoantibodies hallmarks of necrotizing
Pathology present in an • Loss of pigmented • Wegener’s
granulomatous inflammation
elderly female presenting neurons in her granulomatosis
of the upper/lower
with bradykinesia, cogwheel substantia nigra • Granulomatosis with
respiratory tract, necrotizing
rigidity, and resting tremor • Parkinson’s Disease polyangiitis (GPA)
glomerulonephritis, and
Elderly male complaining of autoimmune necrotizing
difficulty in urination with systemic vasculitis affecting
DRE findings of prostate predominantly small vessels
gland twice its normal size Idiopathic inflammatory
• Hyperplasia
wherein TURP is done and myopathy with characteristic
microscopy revealed nodules cutaneous findings of
of glands with intervening heliotrope and Gottron
stroma papules frequently affecting • Dermatomyositis
the skin and muscles but may
also affect the joints,
esophagus, lungs, and less
commonly heart
Most common bacterial cause • Group A beta-hemolytic
of tonsillopharyngitis streptococci (GABHS)
Virus responsible for Burkitt’s
• Epstein-Barr Virus
lymphoma
Cancer correlated to urinary
• Squamous cell carcinoma
schistosomiasis, Schistosoma
of the urinary bladder
haematobium
Percentage of alcoholics that
• 10-15%
will develop cirrhosis
Distance of incisor to LES • 32-50 (40) cm
Disease associated with
• Kimura disease
Warthin-Finkeldey cells
MRI typical appearance of • Cerebral arteriovenous
“bag of black worms” malformation
Percentage of individuals with
• 0.4-2.8% RF
streptococcal infection that
• 0.2-20% GN
will go to RF and GN

Pathology

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Pathology

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TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN DIGITAL HANDOUT BY DR.

Important Legal Information

annotation, it is understood that the concept is already

PATTERNS OF REVERSIBLE CELL INJURY TYPES OF CELL DEATH

disaggregation of granular and

MECHANISMS OF CELL INJURY

↓ Energy-dependent Damage to lipids,

NECROSIS NECROSIS APOPTOSIS

ATP DEPLETION • Two phases: • Two pathways of initiation phase:

synthesis, ↑ misfolded • ↑ misfolded proteins → unfolded APOPTOSIS: INITIATION PHASE

APOPTOSIS: EXECUTION PHASE

Initiation phase – Intrinsic • Caspase 9

OTHER MECHANISMS OF CELL INJURY

INTRACELLULAR ACCUMULATIONS INTRACELLULAR HYALINE EXTRACELLULAR HYALINE

• Cholesterol esters PIGMENTS

longer! If you decrease your caloric intake, there will be Defec7ve

These are enzymes in your body that are adapted to food

2. INFLAMMATION AND REPAIR GENERAL STEPS: 5Rs

Endothelial cell contraction happens upon exposure to inflammatory

REGULATION (CONTROL) OF THE RESPONSE

ARACHIDONIC ACID METABOLITES AND THEIR FUNCTION

SYSTEMIC EFFECTS OF INFLAMMATION

REPAIR BY CONNECTIVE TISSUE DEPOSITION

FACTORS THAT IMPEDE REPAIR

THROMBOSIS IN THE HEART (MURAL THROMBI)

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APAS)

• Turbulent injury can injure endothelium

4. GENETIC DISORDERS • Clinical manifestations:

• Familial hypercholesterolemia SULFATIDOSES

X-LINKED DOMINANT DISORDERS (XD)

• Activation of: C3b SYSTEMIC LUPUS ERYTHEMATOSUS

Class I lupus nephritis – least common pattern of LN. • Associated autoantibodies

PATTERNS OF KIDNEY REJECTION

IMMUNODEFICIENCY SYNDROMES WISKOTT-ALDRICH SYNDROME

• Recurrent bacterial and enteroviral infections

• Blocks in maturation pathways of B cells → AIDS-DEFINING ILLNESSES

INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS

TUMOR GRADING AND STAGING

IMMUNOHISTOCHEMISTRY o Determination of origin of metastatic tumors

SPECTRUM OF INFLAMMATORY RESPONSES TO INFECTION

OTHER GRAM-NEGATIVE SEXUALLY TRANSMITTED INFECTIONS (STIS)

• Produced by APCs, induces TH1 differentiation (occurs NATURAL HISTORY OF TUBERCULOSIS

Question: Are granulomas always present in tuberculosis?

EXTRAPULMONARY TUBERCULOSIS • Gastrointestinal tract

PARASITIC DISEASES TRYPANOSOMIASIS

TREMATODES ACUTE CHRONIC

8. ENVIRONMENTAL LEAD POISONING

Metallic mercury • Elemental mercury

o Organisms: P. aeruginosa (Most common), MRSA, Candida

IONIZING RADIATION ANOREXIA AND BULIMIA NERVOSA

OLIGOHYDRAMNIOS (POTTER) SEQUENCE

• Complications: NECROTIZING ENTEROCOLITIS

FETAL HYDROPS SUDDEN INFANT DEATH SYNDROME (SIDS)

NATURAL HISTORY OF ATHEROSCLEROSIS

ANEURYSMS AND DISSECTION

TYPES OF ANEURYSMS (A-D) AND DISSECTION (E) TYPES OF AORTIC DISSECTION

SMALL-VESSEL VASCULITIDES (ANCA VASCULITIDES)

THROMBOANGIITIS OBLITERANS (BUERGER DISEASE) PHLEBOTHROMBOSIS AND THROMBOPHLEBITIS

TUMORS INTERMEDIATE-GRADE (BORDERLINE TUMORS)

TYPES OF HEART FAILURE

CONGENITAL HEART DISEASE VENTRICULAR SEPTAL DEFECT

VSD Blood flow:

ATRIAL SEPTAL DEFECT