Pathoma Lecture Notes

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Pathoma Lecture Notes

Chapter 1: Growth Adaptations, Cellular Injury, and Cell Death

1.1 Growth adaptations




- Increase in cell number

- Change in cell type due to reprogramming of stem cell

- Proliferation of precancerous cells

- Reversible

- Reversible

- Reversible

- Pathologic hyperplasia can progress to cancer

- Can progress to dysplasia and cancer

- Can progress to cancer

- BPH don't increase risk of cancer

- Apocrine metaplasia don't increase risk of breast cancer

- Etiology: - Etiology: - Etiology: • Physiologic (ex• Vit A deficiency • Long standing pregnancy) (keratomalacia, pathologic hyperplasia • Pathologic (ex - …) myositis ossificans) or metaplaisa • Cellular stress (barret's esophagus) Processes


Hyperplasia and Hypertrophy

• Usually, hyperplasia and hypertrophy occur together • Permanent cell undergro hypertrophy only – cardiac myocytes, skeletal cells, and nerves. • Pathologic hyperplasia (not physiologic ex- pregnancy) can progress to dysplasia and cancer. • Exception is benign prostatic hyperplasia (is pathologic but does not increase risk of cancer).


• can occur by decrease in cell number (apoptosis) or decrease in cell size. • Decrease in cell size occurs by – ubiquitin-proteosome degradation of cytoskeleton and autophagy of cellular components


• change in cell type. • Mostly affects surface epithelium. Ex – barret’s esophagus (change from squamous to columnar) • MOA: occurs by reporgramming of stem cells • Reversible • Can progress to dysplasia and cancer. Ex – Barret’s. Exception – Apocrine metaplasia doesn’t increase risk of breast cancer. Apocrine metaplasia seen when fibrocystic changes in breast occur. • Vitamin A deficiency can result in metaplasia. Ex – keratomalacia and myositis ossificans. • Mesenchymal tissue can undergo metaplasia (ex – bone, blood vessel, fat etc). ex – myositis ossificans – inflammation of skeletal muscle reads to metaplasia to bony tissue.

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Fig – myositis ossificans Dysplasia

• disordered cell growth; proliferation of precancerous cells. Ex - Cervical intraepithelial neoplasia • Arises from longstanding pathologic hyperplasia or metaplasia • Reversible • If dysplasia persists, it can progress to cancer.


• Failure of cell production during embryogenesis. Ex – unilateral renal agenesis (failure to make 1 kidney)


• decrease in cell production in embryogenesis. Results in relatively small organ. Ex – streak ovary in Turner syndrome.

Extras – Vitamin A is necessary for maturation of immune system. 15-17 translocation in pt genome causes acute promyelocytic leukemia. The translocation causes mutation in vitA receptor – retinoic acid receptor. Mutation of receptors cause immune cells to be trapped in blast stage. Treatment for Promyelocytic leukemia is all trans retinoic acid (drug) which can bind to mutated receptor. Cells can mature and be neutrophil.

• Vitamin A is necessary for maintainence of special epithelial tissue in body – ex – conjucitva of eye. Conjuctiva is a thin delicate membrane that covers eye. Deficiency of vit A can result in metaplasia of cells in conjucitva where cells thicken which is called keratomalacia.

• Fig – keratomalacia.

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1.2 Cellular injury

1. What is cellular injury? - If cellular stress overcomes cell's ability to adapt, then cell gets injured. 2. -

What does cellular injury depend on? Type of stress Severity Type of cell - neurons can withstand hypoxia only for 3-5mins. Skeletal muscle can withstand for a very long time.

3. -

What are causes of hypoxia(low O2 delivery to tissue)? ischemia, hypoxemia (PaO2 fatty liver disease (VHY)

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Fig - T represents fat in hepatocyte; a hepatocyte is shown in circle • Reperfusion injury - During reperfusion of ischemic organ, immune cells will attack the dead tissue in presence of oxygen which will generate free radicals. More injury ensues. Classic example is blood troponin continuing to rise after reperfusion of heart after MI.

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1.5 Amyloidosis

1. What is amyloid? • Misfolded proteins that accumulates in extracellular space and damages tissue. Amyloid can't be removed and damaged organs must be transplanted 2. What are characters of amyloid? • Misfolded proteins have B-sheet arrangement • Amyloid are congo red positive (appear apple-green under polarized light)

Fig - apple-green appearing amyloid under polarized light • Amyloid can be deposited systemically or locally 3. What are 2 types of systemic amyloidosis? • Primary amyloidosis - When Ig light chain deposits systemically (in form of AL amyloid), it's called primary amyloidosis. It's associated with plasma cell dyscrasias (disease) - when plasma cells make ton of light chain, they will deposit. • Secondary amyloidosis - when SAA protein deposits systemically (in from of AA amyloid), it's called 2ndary amyloidosis. SAA is acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean fever.

4. What is familial mediterranean fever (HY)? • It's genetic disease with dysfunction of neutrophils that causes systemic amyloidosis. It's usually seen in people of mediterranean origin. • Pt will have high SAA that deposits at AA amyloid • Pt may present with acute fever and serosal inflammation (serosal inflammation of heart might mimic MI, of gut may mimic appendicitis) 5. • • •

What are classic findings of systemic amyloidosis? Kidney is most commonly involved - nephrotic syndrome is seen Restrictive cardiomyopathy or arrhythmia Hepatosplenomegaly, malabsorption, large tongue

6. How do you diagnose amyloidosis? • Requires tissue biopsy (needs to be congo-red positive) - usually take from rectum or abdominal fat pads 7. Describe senile cardiac amyloidosis (a type of local amyloidosis). • Caused due to deposition of non-mutated serum transthyretin in heart. Transthyretin is 2nd most common protein in blood. Cellular injury Page 5.1

common protein in blood. • Usually asymptomatic and seen in 25% of people >80 year 8. • • •

Describe familial amyloid cardiomyopathy (a type of local amyloidosis). Caused due to deposition of mutated serum transthyretin in heart. Leads to restrictive cardiomyopathy Usually seen in african americans (5% carry mutation)

9. Describe how type 2 diabetes has local amyloidosis in it. • Due to insulin resistance, pancreas produces lots of insulin. A byproduct amylin is also produced that deposits in islets of pancreas and cause amyloidosis. 10. Describe how alzhimer's has local amyloidosis in it. • B-amyloid precursor protein (BAPP) on chromosome 21 makes AB amyloid plaques. (Most individuals with Down's syndrome have Alzheimer's by 40 year age) 11. Describe how dialysis can cause local amyloidosis in joints. • Beta2 microglobulin is a protein that structurally supports MHC-I on cell surface. In dialysis, B2microglobulin isn't filtered well from blood. It then builds up in joints and cause amyloidosis. 12. Describe how medullary thyroid cancer can cause local amyloidosis in thyroid. • In MTC, overproduction of calcitonin leads to formation of calcitonin amyloid plaques in thyroid. (In FNA of thyroid, seeing tumor cells in amyloid background makes MTC more probable)

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Chapter 2: Inflammation, Inflammatory Disorders, and Wound Healing

2.1 Acute Inflammation (Part 1)

1. What is inflammation? • Process by which inflammatory cells, plasma proteins and fluid exit blood vessel to enter interstitial space 2. Explain acute inflammation - Characterized by edema and neutrophil in tissue (presence of neutrophils define acute inflammation) - Arises in response to infection or necrosis (necrosis is always followed by acute inflammation (HY)) - Goal is to clear pathogen or necrotic debris - Part of innate immunity (very quick response) 3. How does TLR work? - Toll like receptors (TLR)- present on cells of innate immune system (macrophage, dendritic cells) and adaptive immune system. In innate system, TLR recognize PAMP (pathogen associated molecular patterns)and DAMP (damage associated molecular pattern). Ex - CD14 (aka TLR-4) is a TLR on macrophage that recognizes lipopolysaccharide (LPS) which is shared by gram negative bacteria. (HY) 3.1 What chemical is upregulated by TLR? - NF-KB- NF-KB is a molecular switch that turns on acute inflammation (master regulator for both innate and adaptive immunity). - Type 1 interferon (alpha and beta) - inhibit viral replication in cells Arachidonic acid metabolism 4. Explain production and metabolism of arachidonic acid (AA). - Phospholipase A2 releases AA from phospholipid cell. - AA can then be metabolized by cyclooxygenase or 5-lipooxygenase. 5. What are the products of cyclooxygenase pathway and what are their functions. - Cyclooxygenase pathway produces prostaglandins (PG) - PGI2, PGD2 and PGE2. They increase vascular permeability and vasodilation. PGE2 also mediates feeeever and pain. Note that vasodilation happens at arteriole level and vascular permeability at post capillary venule level. 6. What are the products of lipooxygenase pathway and what are their functions - 5-Lipooxygenase pathway produces leukotrienes (LT). LTB4 attracts and activates neutrophils. LTC4, LTD4 and LTE4 mediate smooth muscle contraction (vasoconstriction, bronchospasm, and increased vascular permeability (contraction of pericytes opens up space between endothelial cells)). 7. -

What are 4 important things that attract and activate neutrophils? LTB4 (leukotriene) C5A (complement protein) IL8 (mechanism by which macrophage call neutrophil) Bacterial products TNF and IL1 (based on Abbas book)

Mast cells 7. What are 3 ways that activate mast cells? - Mast cells are found throughout connective tissue of body and are activated by Inflammation Page 1.1

- Mast cells are found throughout connective tissue of body and are activated by ○ Tissue trauma ○ Complement proteins C3a and C5a ○ Cross linking of cell surface IgE by antigen (2 or more IgE on a mast cell binds same antigen) 8. What is acute response of mast cells activation? - Histamine is released which causes vasodilation and increased vascular permeability. - Release proteolytic enzymes that kill bacteria or inactivate toxins 9. What is delayed response (after 4-5 hrs) of mast cells activation? - Mast cells produces arachidonic acid metabolites, particularly leukotrienes. (HY) Complement 10. What are three pathways of complement activation? - Classic pathway - C1 protein binds to IgG or IgM which is bound to antigen (pneumonic - GM makes classic cars) - Alternative pathway - microbial products directly activate complement - Mannose binding lectin (MBL) pathway - MBL binds to mannose on microorganisms and activate complement 11. -

How is membrane attack complex (MAC) formed? C3 convertase converts C3 to C3a and C3b C5 convertase converts C5 to C5a and C5b C5b joins with C6 and C9 to make membrane attack complex (MAC) which pokes hole in cell and kill it.

12. -

What are some key functions of complement proteins? (HY) C3a and C5a activate mast cells (stimulate degranulation) C5a is chemotactic for neutrophil C3b is opsonin for phagocytosis. Opsonins tag cells/waste for phagocytosis. MAC pokes hole in cell and kill it

13. What is hageman factor (aka factor 12 in coagulation cascade)? What systems does it activate? - It's inactive proinflammatory protein produced in liver that's activated by exposure to subendothelial or tissue collagen, and during severe gram negative sepsis - Plays imp role in DIC (disseminated intravascular coagulation - pathologic activation of coagulation cascade) and severe gram negative sepsis (sepsis activates hageman factor which in turn results in DIC) (HY). - It activates complement system, coagulation and fibrinolytic system (this results in DIC), and kinin system 13.1. Explain kinin system. - Kinin system cleaves high molecular weight kinin to bradykinin. Bradykinin results in vasodilation, increased vascular permeability and pain). Note - bradykinin system has histamine + pain functions 14. What two molecules mediate pain? - Prostaglandin E2 (cause feeever and pain) - Bradykinin Cardinal signs of inflammation - rubor, calor 15. What causes rubor (redness) and calor (warmth)? - Vasodialation due to arteriole relaxation mediated by - histamine (primary), bradykinin and PG. 16. What causes tumor (swelling)? Inflammation Page 1.2

16. What causes tumor (swelling)? - Increased vascular permeability at post capillary venule mediated by - histamine, bradykinin, lukotrienes, PG, and tissue damage. 17. What causes dolor (pain)? - Bradykinin and PGE2. 18. What causes fever? (VHY) - Macrophage release IL-1 and TNF. They go to perivascular cells of hypothalamus and increase activity of COX. (inflammosome also makes IL1) - COX causes increase in PGE2 in hypothalamus which increases temp set point.

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2.1 Acute Inflammation (Part 2)

1. What are 3 phases of acute inflammation? ○ Fluid phase - edema, complement activation etc ○ Neutrophil phase - peaks about 24 hrs ○ Macorphage phase - peaks about 2-3 days (Note that acute inflammation is not defined by time. It can happen for days or weeks. It is defined by whether neutorphils are primary player. If pus is present, it's still acute.) 2. What are steps of neutorphil exit? What proteins are key in each step? - Margination - Usually, heavy particles in blood are in center of vessel lumen. When blood vessel dilates, heavy particles come to edge of vessel and this is margination. It's first step of neutrophil arrival. - Rolling - endothelial cells express proteins called selectins which act as speed bump so that neutrophils roll and slow down. - Adhesion - cellular adhesion molecules (CAM) on endothelium binds to integrins on neutrophil resulting in adhesion. (HY) - Transmigration and chemotaxis - transmigration happens across vessel wall of postcapillary venules, and chemotaxis is movement to infection site after transmigration. Neutrophils are attracted by bacterial products, IL8, C5a and LTB4 - Phagocytosis - enhanced by opsonins (IgG and C3b) 3. What induces P selectin and E selectin? - P selectin release is induced by histamine. They are released from Weibel-Palade bodies in endothelial cells (another stuff made by weibel-palade body is Von-willieband factor). - E selectin release is induced by TNF and IL-1. 4. What protein on neutrophils does selectins bind to? - Sialyl Lewis X. It results in rolling . 5. What upregulates cellular adhesion molecules (CAM) on endothelium? - IL1 and TNF 5.5. What are major innate immunity cytokines? - IL-1 and TNF 6. What upregulates integrins on neutrophils? - C5a and LTB4 (recall that C5a and LTB4 are 2 of the 4 things that attract and activate neutorphils - other 2 being bacterial product and IL8) 7. What is leukocyte adhesion deficiency? Where is the mutation? - It's autosomal recessive mutation of integrins at CD18 subunit. 8. What are sign/symptoms of leukocyte adhesion deficiency (LAD)? (HY) - Delayed seperation of umbilical cord (HY) - After childbirth, the umbilical cord shuts. Due to no blood through it, it undergoes necrosis. Active inflammation ensues. Neutrophils come and eat up umbilical cord. However, in LAD, neutrophils won't come much because adhesion process is bad. - Increased circulating neutrophils (HY) - normally, half of neutrophils are in circulation and remaining half are stuck to endothelium of lung. Due to loss of adhesion, circulating Inflammation Page 2.1

remaining half are stuck to endothelium of lung. Due to loss of adhesion, circulating neutrophils will increase. - Recurrent bacterial infection but lack pus formation (HY) - Pus is dead neutorphil in fluid. If neutrophils can't get into tissue, pus can't form. 9. Where do neutrophils exit blood vessel? - Post capillary venule. 10. How does phagocytosis occur? - Neutrophils engulf stuff and make phagosome. Phagosome merges with lysosome to make phagolysososme. (C3b and IgG are major opsonins) 11. What is Chediak-Higashi syndrome? - It's an autosomal recessive protein trafficking defect (microtubule railroad tracks in the cells are defective). 12. What are sign/symptoms of Chediak-Higashi syndrome? (HY) - It's symptoms are based on impaired microtubule railroad tracks ○ Immune fingings Neutropenia (impaired cell division so low neutrophils)  Giant granules in leukocytes (newly made granules from golgi won't travel well to other parts of cell and pile up)  Increased pyogenic infections (phagosome merging with lysosome is impaired, so immune cells are less efficient at killing pathogens). ○ Defective primary hemostasis (granules in platelets won't move well) ○ Albinism (a melanocyte supplies melanin to about 25 keratinocytes. As railroad transport is defective, it's melanin won't be transported to other keratinocytes) ○ Peripheral neuropathy - stuff from cell body of neuron won't be transported to axon endings well.

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2.1 Acute Inflammation (Part 3)

1. What are two mechanism of phagocytosis? Which is more efficient • Oxygen dependent and oxygen independent. • Oxygen dependent is more efficient 2. Explain O2 dependent mechanism of phagocytosis. (HY) • It occurs in phagolysosome • Oxygen is converted to superoxide (radical) by NADPH oxidase (rxn called oxidative burst). • Superoxide is coverted to hydrogen peroxide by superoxide dismutase. • Hyrodgen peroxide is converted to bleach (HOCl) by myloperoxide (MPO) • HOCl kills organism

3. What is mechanism of Chronic granulomatous disease (CGD)? • Due to defect in NADPH oxidase, O2 dependent phagocytosis is bad and patient has chronic granulomas. Disease is autosomal recessive or X-linked. • As pt can't phagocytose, more and more macrophage and neutrophils are called to site resulting in formation of granulomas. 4. What are 5 catalase positive organism that cause symptomatic CGD? (HY) ○ S Aureus ○ P cepacia (often tested) ○ S marcescens ○ Nocardia ○ Aspergillus 5. Why do only catalase positive organism cause CGD? • Most bacterias produce H2O2 which can be converted to bleach by myloperoxidase in body. Therefore, most bacteria can't cause CGD despite mutation in human NADPH oxidase. However, when bacteria have catalase, that destroys H2O2 and formation of bleach is reduced which results in CGD. Inflammation Page 3.1

in CGD. 6. What is nitroblue tetrazolium (NBT) test? • It's a screening test for CGD. In the test, solution turns blue if superoxide radical is present. It tests if NADPH oxidase is functional. 7. What is clinical significance and NBT test result for people with myloperoxide (MPO) deficiency? • Most MPO patients are asymptomatic but have increased risk for candida infection. • They have normal NBT test. 8. Explain oxygen independent phagocytosis. • It's less effective and occurs via enzyme in secondary granules (ex - lsyozome and major basic protein). 9. Describe the resolution phase of acute inflammation. • Within 24 hours of resolution of inflammatory stimulus, neutrophils die by apoptosis. It creates pus. Pus is dead neutrophils in fluid. 10. Describe macrophage phase of acute inflammation. • It peaks 2-3 days after inflammation begins. • When monocytes get into tissue, they are called macrophage. They come to tissue in same steps as neutrophils. 11. Contrast phagocytosis of macrophage with that of neutrophil. • Phagocytotic killing of macrophage is mainly oxygen independent - via the enzymes in secondary granules. Lysozyme is main enzyme. • Phagocytotic killing of neutrophil is mainly oxygen dependent. 12. What happens after fluid, neutrophil and macrophage phase of acute inflammation? (HY) • Macrophage are managers which come in to check after 2-3 days of acute inflammation if neutrophils did a good job at clearing the damage. • If good job is done, macrophage secrete IL-10 and TGF-B. They are anti-inflammatory and induce healing. • If job is done poorly, macrophage secrete IL-8. It calls additional neutrophils to the site. • If macrophage sense that the offending organism needs to walled off, they create abscess. Abscess is walled off area of inflammation. • If macrophage sense that neutrophils can't do the job well (ex- neutrophils don't work well in viral injury), they initiate chronic inflammation by presenting antigen in MHC-2.

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2.2 Chronic inflammation

1. What is chronic inflammation? • Inflammation is bringing out immune cells into the tissue. In chronic inflammation, mainly lymphocytes are brought out. In acute inflammation, mainly neutrophils are brought out. • It's delayed response (adaptive immunity) and more specific.

Fig - chronic inflammation. Note the absence of multilobed neutrophil. Cell on left is lymphocyte. Middle cell is plasma cell (nucleus pushed to side, slight perinuclear halo). Cell on right is macrophage (clock face nucleus).

2. What are stimuli of chronic inflammation? • Persistent infection (most common) • Infection with virus, mycobacteria, parasites, fungi • Autoimmune disease • Foreign material • Some cancers T cells 3. Explain development and maturation of T-cells. • They are made in bone marrow and go to thymus. • In thymus, they become specific to an antigen and develop into either to CD4 helper or CD8 cytotoxic cell. 4. How are CD4 and CD8 T-cells activated? What is their second message for activation? • T cells are activated when they recognize antigens presented on MHC molecules only while a second signal is present. • Helper CD4 T cells read antigen from MHC II. MHC II present extracellular antigen and are present on antigen present cell. • Cytotoxic CD8 T cells read antigen form MHC I. MHC I present intracellular or viral antigen and are present on all cells in body • For CD4 cells, B7 on antigen presenting cell is the second signal that binds to CD28 on CD4 cells. CD40 on B cells also act as second signal that bind to CD40L on CD4 cells. • For CD8 cells, IL2 from CD4 cells is second signal for activation. 5. What do activated CD4 cells do? • Activated CD4 helper cells secrete cytokines. They have two subtypes - TH1 and TH2. 6. Explain purpose and function of cytokines secreted by activated CD4 TH1 cells. • TH1 secrete IFN gamma that enhances phagocytic ability of macrophage • TH1 also secrete IL2 which is T cell growth factor and CD8 cells activator 7. Explain purpose and function of cytokines secreted by activated CD4 TH2 cells. • TH2 cause eosinophil rich inflammation and/or reduce inflammation by secreting IL4, IL5 and IL10. Inflammation Page 4.1

• TH2 cause eosinophil rich inflammation and/or reduce inflammation by secreting IL4, IL5 and IL10. • IL 4 cause class switching to IgG and IgE • IL5 attracts and activates eosionophil, helps in maturation of B cells to plasma cells and cause class switching to IgA • Il10 (antiinflammatory cytokine) inhibits TH1 phenotype. 8. How do CD8 T cells kill cells? • They secrete perforins that make holes in host cell and secrete granzymes that activate caspase and induce apoptosis. • They express Fas ligand which binds to Fas receptor on host cell that activates apoptosis. 8.1. How is a self-reactive T-cell killed? - If there's a self-reactive T-cell, it will bind to MHC-antigen but the second signal won't be present. It will result in apoptosis or anergy. B cells 9. How are B cells produced? • Immature B cells are produced in bone marrow. Naïve B cells express IgM and IgD. 10. How are 2 ways by which B cells activated? How does isotype switching occur? • Binding of antigen to IgM or IgD activates B cells. Then they become IgM or IgD secreting plasma cells. • B cells can phagocytose and present antigen to CD4 cells via MHC II. CD40 on B cell can bind to CD40L on helper T cell providing 2nd signal for activation. • TH2 Helper T cell will secrete IL4 and IL5. IL4 and IL5 help in isotype switching of B cells, somatic hypermutation (aka affinity maturation), and maturation to plasma cells. Granulomatous inflammation 11. What is granulomatous inflammation? • It’s a type of chronic inflammation. It's defined by presence of epitheloid histiocytes (macrophage with abundant pink cytoplasm and elongated nuclei) (HY). You may also see multinucleated macrophages. In healthy tissue, macrophage have clear (aka foamy) cytoplasm. • Granulomas are surrounded by rim of lymphocytes and giant cells. • Only a certain conditions give granuloma so they help to identify diseases. 12. What cause noncaseating granulomas? • Defining feature of noncaseating granuloma is lack of central necrosis. • Causes: ○ Reaction to foreign material - ex- leaking of breast implants ○ Sarcoidosis - hallmark of sarcoidosis is production of non-caseating granuloma in multiple organs (mainly lungs) ○ Beryllium exposure ○ Crohn disease - hallmark of Crohn is noncaseating granuloma. (hallmark of UC is crypt abscess) ○ Cat scratch disease - give star shaped granuloma in neck

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Fig - noncaseating granuloma. Not abundant lymphocytes in periphery that indicates chronic inflammation. Note multinucleated cell. Presence of nucleus in epitheloid histiocytes means they are alive - making this noncaseating granuloma. 13. What causes caseating granuloma? • Characteristic of TB and fungal infections. If you see caseating granuloma, do AFB stain to look for TB, and GMS silver stain to look for fungal infections.

Fig - caseating granuloma. Note the central necrosis 14. How are granulomas formed? (HY) • Macrophage present antigen to CD4 T cells via MHC II • After binding, macrophage also secrete IL-12 that induce CD4 cells to differentiate to Th1 subtype • Th1 cells secrete IFN gamma which converts macrophage to epitheloid histiocytes and giant cells. Granuloma is hence formed. • These steps occur in both caseating and non-caseating granuloma

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2.3 Primary immunodeficiency

1. What is DiGeorge syndrome (HY)? • Failure to develop 3rd and 4th pharyngeal pouch due to 22q11 mutation. 2. What are presentation of DiGeorge syndrome? • T cell deficiency- problems fighting viral and fungal infection (due to lack of thymus as thymus develops from 3 rd and 4th pouch) • Hypocalcemia (due to lack of parathyroid) • Abnormalities of heart, great vessels, and face 3. What is SCID (severe combined immune deficiency)? • Pt have defective cell-mediated and humoral immunity (both T and B). 4. Etiology of SCID? • Cytokine receptor defects (main cause) • Adenosine deaminase deficiency (second main cause)(HY) - enzyme necessary for deamination of adenosine and deoxyadenosine. In lack of enzyme, adenosine and deoxyadenosine accumulates in immune cells causing toxicity. • MHC class II deficiency - CD4 won't be able to be activated. It leads to defective function of CD8 and B cells. 5. Presentations of SCID? • Lack of T cells result in fungal and viral infections • Lack of B cells result in bacterial and protozoal infections • Increased opportunistic infection and be wary to give live vaccines. 6. Treatment of SCID? • Sterile isolation (bubble babies) • Stem cell transplant 8. What is X-linked agammaglobulinemia? What is the mutation? • Name suggests pt lacks gammaglobulin (antibodies) in blood. There's a complete lack. • Occurs because naïve B cells can't mature to plasma cells. • Mutation is Bruton tyrosine kinase. It's a signaling receptor that helps maturation of B cells. 9. What is presentation of X-linked agammaglobulinemia? • • • • • •

Recurrent bacterial, enterovirus, and Giardia infection (HY). Enterovirus affects mucosa of GI tract. IgA protects mucosal surface, and lack of IgA results in enterovirus infection. Bacterial infection occurs because lack of antibodies affect opsonization. Giardia occurs for same reasoning as enterovirus. Presents after 6 month of life – because mom's antibodies last for about 6 months Don't give them live polio vaccines

10. What is common variable immunodeficiency disease? • Pt has low antibodies due to defective B or T cell 11. Presentation? • Pt has increased risk of bacterial, enterovirus, giardia infection, often in late childhood. • They have increased risk of autoimmune disease and lymphoma. (HY) 12. What is IgA deficiency? • This is most common Ig deficiency. Pt have low serum and mucosal IgA which increases risk of mucosal infections – especially viral. Inflammation Page 5.1

especially viral. Note – pt with celiac disease usually have IgA deficiency. 13. What is Hyper-IgM syndrome? • Pt have too much IgM. 14. What is pathophysiology of Hyper-IgM syndrome? What is presentation? • Patient has mutation in CD40 or CD40 receptor. Due to this, B cells can't activate CD4. In lack of good CD4, cytokines necessary for Ig class switching is not produced. Pt will have low IgA, IgG, and IgE. • Presentation is recurrent pyogenic infections, especially at mucosal sites. IgG is a opsonin, low amount results in more formation of pus. 15. What is Wiskott-Aldrich syndrome (WAS)? What causes it? (just memorize) • Pt have thrombocytopenia, eczema, and recurrent infections. Pt have defective humoral and cellular immunity. • Happens due to mutation in WASP (Wiskott-Aldrich syndrome protein) gene and is x-linked. 16. What are the consequence of the following complement deficiencies? (just memorize) • Deficiency from C5-C9 - increased risk of Neisseria infection (HY) • C1 inhibitor deficiency - hereditary angioedema characterized by edema of skin (especially periorbital) and mucosal

Fig - heriditary angioedema.

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2.4 Autoimmune Disorders 1. What causes autoimmune disorders? - Overactive immune system or loss of self tolerance. 2. -

What is epidemiology of autoimmune disorders. Present in about 1% of US popn. Most affects women. Classically affects women of childbearing age. Most autoimmune diseases are associated with other autoimmune diseases.

3. What is etiology of autoimmune disorders? - Environment triggers disease in genetically susceptible individuals.

Systemic Lupus 4. What happens in Lupus? - Lupus is a systemic autoimmune disease in which autoantibodies can cause type II (cytotoxic antibody bind and kill cells) or type III hypersensitivity reaction (antigen-antibody complex form and deposit in tissue causing damage). 5. What are clinical features of lupus? - Malar 'butterfly rash' upon exposure to sunlight is classic sign - Diffuse proliferative glomerulonephritis commonly occurs; other nephritic/nephrotic symptoms can occur too. Renal damage is common cause of death - Pleuritis and pericarditis, myocarditis, endocarditis - Libman-Sacks endocarditis - vegetations on both side of valve - Antibodies against blood result in - anemia, thrombocytopenia or leukopenia. Infections due to loss of immune system also a common cause of death. - CNS psychosis due to inflammation of CNS - Fever and weight loss (fever is sign of inflammation) - Arthritis

Fig - malar butterfly rash in lupus pt. 6. Describe Libman-Sacks endocarditis. - Mostly, endocarditis happens only on one side of valve (up or down). If it happens on both side of valve, it's called Libman-Sacks endocarditis and is characteristic of lupus. 7. How do we diagnose lupus? - ANA (anti-nuclear antibody) very sensitive for lupus - used for screening - Anti-dsDNA very specific for lupus

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8. -

What are three common drug that cause lupus? How do we diagnose? How do we treat? Hydralizine, procainamide and isoniazid Antihistone antibodies are specific for drug induced lupus Removal of drug causes remission of disease

9. -

What is antiphospholipid syndrome associated with SLE? What lab tests does it affect? Antibodies are made against proteins bound to phospholipid. Anticardioliptin antibody give false positive syphilis test. Lupus anticoagulant antibodies give falsely elevated PTT lab study but makes pt hypercoagulable.

10. Why do you keep pt with antiphospholipid syndrome on lifelong anticoagulation? - Because lupus anticoagulant antibodies make pt hypercoagulable and increase risk of stroke, DVT, hepatic vein thrombosis, placental thrombosis (pregnancy loss). Sjogren syndrome 11. What is sjogren syndrome? - Type IV (lymphocyte mediated) autoimmune destruction of lacrimal and salivary glands with resulting fibrosis. 12. What are clinical presentation of Sjogren syndrome? - Dry eyes, dry mouth and recurrent dental carries (bacteria accumulates as teeth aren't washed) in older woman. - Parotids may be enlarged due to fibrosis. - "Can't chew cracker, dirt in my eyes" 13. How do you diagnose Sjogren syndrome? - Presence of ANA is sensitive - Presence of anti-ribonucleoprotein antibodies is specific - (Anti SSA and anti SSB antibodies Sjogren syndrome A and sjogren syndrome B) 14. What other conditions is Sjogren syndrome associated with? - Other autoimmune disorders - especially rheumatoid arthritis - High risk for B-cell lymphoma (HY) - unilateral enlargement of partoid gland late in disease is indicative of B-cell lymphoma. Scleroderma (thick skin) 15. What is scleroderma? - Autoimmune tissue damage with activation of fibroblast and deposition of collagen (fibrosis) that thickens the tissue (also makes it tight and less mobile).

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Fig- scleroderma hands 17. -

What is diffuse type scleroderma? What are clinical presentation? How do you diagnose? Patient has diffuse skin and early visceral organ involvement. Esophagus most commonly affected - see solid and liquid dysphagia Diagnosis made by ANA and anti-DNA topoisomerase I antibody (aka SCL-70 antibody). SCL stands for scleroderma.

17. What is localized type scleroderma? What are clinical presentation? How do you diagnose? - Patient has local skin and late visceral organ involvement. - Presentation (CREST)○ Calcinosis (calcification of skin), anti-centromere Ab ○ Raynaud phenomena ○ Esophageal dysmotility- see solid and liquid dysphagia ○ Sclerodactyly ○ Telangiectasis of skin - Diagnosis made by anti-centromere antibody Mixed connective tissue disease 18. What is mixed connective tissue disease? How is it diagnosed? - It is autoimmune tissue damage with mixed features of SLE, scleroderma and polymyositis (autoimmune damage of proximal muscles). Think of patient with bunch of autoimmune condition. - Diagnosis made by presence of antibodies against U1 ribonucleoprotein.

Inflammation Page 6.3

2.5 Wound Healing

1. What is regeneration? - It's replacement of damaged tissue with native tissue. 2. What is repair? - Repair is replacement of damaged tissue with fibrous scar. It occurs when tissue lacks regenerative capacity or regenerative stem cells are lost. 3. What are 3 different types of tissue based on regeneration capacity? - Labile tissue - they are continuously regenerating ○ Intestine - stem cell in mucosal crypt ○ Skin - stem cell in basal layer (most bottom layer of epidermis) ○ Bone marrow - hematopoietic stem cells (HSC). (HY - You can't identify HSC by microscope. Presence of CD34 molecule tells it's HSC) ○ Lungs - stem cell is type 2 pneumocytes

Fig - circles are the crypts of bowel

Fig - line showing basal layer of skin - Stable tissue - they don't continuously regenerate but have the ability to regenerate if needed. ○ Liver ○ Proximal tubule of kidney - pt on acute tubular necrosis are put on dialysis until their proximal tubules regenerate Permanent tissue - can't regenerate ○ Myocardium Skeletal muscle Inflammation Page 7.1

○ Skeletal muscle ○ Neurons 4. What is granulation tissue (different from granuloma which occurs in chronic inflammation)? What are 3 important cell types in it? - It's present in early phase of repair. It contains ○ Fibroblasts (deposit type 3 collagen) ○ Capillaries ○ Myofibroblast (contract wound)

Fig - granulation tissue showing blood vessels, collagen and fibroblast. Contrast it with granuloma in chronic inflammation file. 5. What happens when granulation tissue is replaced by scar? What cofactor is needed? - Collagenase removes type 3 collagen and replaces with type I collagen. It needs zinc as cofactor (HY). 6. -

Where are 4 types of collagen found? Type 1 - bone (bone) - very high tensile strength Type 2 - cartilage (cartwolage) Type 3 - granulation tissue, embryonic tissue - very pliable/moldable Type 4 - basement membrane

7. How do regeneration and repair happen? What are some key molecules? - They occur by paracrine signaling via growth factors. Some of them are ○ Fibroblast growth factor (FGF) - powerfully induces angiogenesis and skeletal development ○ VEGF - angiogenesis ○ PDGF - induces growth of endothelium, smooth muscle and fibroblast ○ TGF alpha - epithelial and fibroblast growth factor ○ TGF beta - inhibits inflammation, important fibroblast growth factor 8. Contrast wound healing by primary vs secondary intention. - In primary intention, wound edges are brought together and there's minimum scar formation - In secondary intention, edges are far away and granulation tissue fills the gap. Due to presence of myofibroblasts, wound shrinks quite a lot. 9. Explain formation and structure of collagen. - Collagen is formed as multiple alpha strands inside cells. Multiple alpha strands intertwine to make procollagen and come outside cell. - Structure of alpha strand is Gly-X-Y, where X and Y are proline and lycine. - In extracellular space, multiple procollagen are crosslinked via hydroxyl groups in proline and lycine to make collagen. Inflammation Page 7.2

lycine to make collagen. - Vitamin C is needed to hydroxylate proline and lysine. - Crosslinking is done by lysyl oxidase which has copper as cofactor 10. -

What are some common causes of delayed wound healing? (HY) Infection is most common cause Vitamin C deficiency - causes poor hydroxylation of lycine and proline. Copper deficiency - lysyl oxidase can't cross link procollagen well Zinc deficiency - type III collagen can't be converted to type I by collagenase Foreign body, ischemia, diabetes, malnutrition etc

11. What is wound dehecence? - Rupture of wound - commonly seen after abdominal surgery 12. What is hypertrophic scar - Scar tissue being big but localized to wound. Caused by excess type I collagen

Fig- hypertrophic scar 13. -

Describe keloid (HY)? Scar tissue way out of proportion to the wound. Caused by excess type III collagen More common in african american Classically affects earlobes, face, and upper extremities.

Inflammation Page 7.3

Chapter 3: Principles of Neoplasia

3.1 Neoplasia 1. Define the following Neoplasia

- Neoplasia is cell growth that is monoclonal (arise from single cell), unregulated, and irreversible. - Contrast to hyperplasia (ex – hyperplasia of uterus during childbirth) which is polyclonal and is regulated.

Desmoplasia - Process by which tumor becomes firm (it is because neoplastic cells induce fibroblasts within the stroma to form abundant collagen) Carcinoma in - (aka high-grade dysplasia) - when dysplastic changes involve entire site thickness of epithelium (earliest form of epithelial malignancy) 2. What are two ways to determining monoclonality? - G6PD or androgen receptor isoforms, - Ig light chain phenotype for lymphomas.

3. How is monoclanity determined from G6PD? - G6PD is a protein with multiple isoforms which is encoded in X-chromosome. Let’s say a female has isoforms A and B in her 2 x chromosomes. Due to random silencing of Xchromosomes, her A:B protein ratio in hyperplasia or normal condition will be 1:1. If the ratio is different from 1:1, it strongly suggests monoclonality. 4. How is monoclonality determined from Ig light chain phenotype? - The ratio of K to Lambda light chain is 3:1. If the ratio is different than this, it suggests monoclonality 6. What are differences between benign and malignant neoplasm? Benign neoplasia

Malignant neoplasia

Remain localized and do not Invade locally and have potential to metastasize (don't metastasize have to be already metastasized) Slow-growing

Rapid growing




Fixed to surrounding tissue

7. Name the lineage of following benign and malignant tumors: Cell lineage


Malignant (cancer)





Papillary carcinoma

Mesenchyme Lipoma









doesn't exist Lymphoma


Nevus (mole) Melanoma (not melanosarcoma)

Neoplasia Page 1.1

Adenoma = tumor that makes glands Papilloma = tumor that makes papillary finger like structures 8. What are leading cause of death in adults in children? (HY) Adults


1. Cardiovascular disease

1. Accidents

2. Cancer

2. Cancer

3. Cerebrovascular disease 3. Congenital defects 9. What are leading cancers by incidence and death toll in male and females? Cancer by incidence


1. Prostrate 2. Lung

Female 1. Breast Cancer by death tolls Male

1. Lung

Female 1. Lung

2. Lung

3. Colorectal 3. Colorectal

2. Prostrate 3. Colorectal 2. Breast

3. Colorectal

- Table excludes squamous cell and basal cell carcinoma of skin - very common and malignant but rarely metastasize. Detected early and easily treatable. - Lung cancer doesn't have easy screening test like others. It's usually detected late. 10. -

What are some properties of neoplasia? Approximately 30 divisions before earliest symptoms arise (2^30 cells) Subsequent divisions results in increased mutations Cancers that don't produce symptoms till late (ex-ovarian, pancreatic, lung cancer- because lots of space to expand) will have accumulated tons of mutations and hence poor prognosis

11. What area goals of cancer screening? - Catch dysplasia before it becomes carcinoma (dysplasia is reversible) - Detect carcinoma before clinical symptoms Tests


Pap smear

- Cervical intraepithelial neoplasia


- Breast cancer - Ductal carcinoma in-situ

PSA (prostrate specific antigen) and DRE (digital rectal exam)

- Prostrate cancer (usually grow on rectal side and doesn't produce urinary syndrome until late; BPH grows centrally and produce urinary syndrome)

Hemoccult test and colonoscopy

- Colorectal cancer - Detect blood in stool (hemoccult test)

Neoplasia Page 1.2

3.2 Carcinogenesis (Part 1) 1. What do carcinogens do? What are examples? - They damage DNA. Ex - chemicals, viruses, radiation. 2. What are cancer associations of the following chemicals? (HY) Chemicals




- Hepatocellular carcinoma (most common cancer in some African countries)

- Derived from Aspergillus flavus; - Usually contaminates stored grains

Alkylating agents

- Leukemia - Lymphoma

- Found in chemotherapy drugs


- Squamous cell carcinoma (SCC)of oropharynx and upper esophagus(another risk is tobacco) - Pancreatic carinoma (EtOH causes chronic pancreatiis that incrases risk of cancer) - Hepatocellular carcinoma


- SCC of skin (women used to apply Arsenic to be fair-skinned) - test Arsenic poisoning from fingernail and hair follicles - Lung cancer (Arsenic present in cigarettes) - Angiosarcoma of liver


- Lung cancer (far more likely) and mesothelioma


- SCC of oropharynx and esophagus - MOST COMMON CARCINOGENIC - Lung cancer WORLDWIDE - Kidney and bladder cancer (urithelial carcinoma cells that line urinary tubes; most IMP risk factor: - Polycyclic hydrocarbons cigerrate - toxins from smoking in urine irritate main carcinogen the cells)


- Stomach carcinoma (intestinal type) (other stomach carcinoma is diffuse type but nitrosamine not associated)

- Found in smoked food; responsible for high stomach cancer in Japan


- Urothelial carcinoma of bladder

- Derived from cigarette smoke (excreted by urine)

Vinyl chloride

- Angiosarcoma of liver

- Occupational exposure (used to make PVC pipes)

Nickel, chromium, beryllium, or silica

- Lung cancers

- Occupational exposure

- 1 Billion people smoke worldwide 3. What are ongogenic association of the following viruses? Virus

Cancer type


- Nasopharyngeal carcinoma (Classic pt - Chinese male, African person) Neoplasia Page 2.1


- Nasopharyngeal carcinoma (Classic pt - Chinese male, African person) metastasizes early; classic presentation is neck mass - Burkitt lymphoma (Classic pt - African kids) - CNS lymphoma in AIDS


- Kaposi sarcoma (tumor of endothelial cell) (Classic pt - 1. older Eastern european males - take tumor out; 2. AIDS pt - treat HIV; 3. transplant pt reduce immunosuppression)


- Hepatocellular carcinoma


- Adult T-cell lukemia/lymphoma

HPV (type 16, 18, 31, 33)

- SCC of anogenital area (vagina, vulva, cervix, anus) - Adenocarcinoma of cervix

4. What are cancer association of ionizing and non-ioninzing radiation? Radiation type

Cancer types


Ionizing (nuclear reactor, radiotherapy)

- AML - CML - Papillary thyroid carcinoma (Cherbonyl kids have lots of papillary cancer)

- Generation of hydroxyl free radical

Nonionizing (UBV from sun most common)

- Basal cell carcinoma of skin - SCC of skin - Melanoma of skin

- DNA damage (formation of too much pyrimidine dimers to be excised by restriction endonuclease)

- In xeroderma pigmentosum, restriction endonuclease is bad and pt has high risk of BCC, SCC and melanoma of skin 5. What is most common cause of ionizing radiation in USA? - Radon (formed by decay of uranium) - present in soil and accumulates in closed space (basement) ○ 2nd most common cause of lung cancer in USA

Neoplasia Page 2.2

3.2 Carcinogenesis (Part 2) 1. -

What are three systems to be disturbed in carcinogenesis? (HY) Proto-oncogene Tumor suppressor genes Regulator of apoptosis

Protooncogenes 2. What are protooncogenes and how can they cause cancer? - Proto-oncogenes are essential for regular cell growth and differentiation - Mutation produces oncogenes that leads to unregulated cell growth 3. -

What are examples of protooncogenes? Growth factors and their receptors Signal transducers Nuclear regulators (transcription factors) Cell cycle regulators (move cell division stuff around in cell)

- Normally, binding of growth factors to its receptor induces signal transduction. In nucleus, cell cycle regulators are activated that induce cycling of cells through G1 - S G2 - M stages of cell division 4. What cancer are the following protooncogenes associated with and what's their function and mechanism of causing cancer? Cancer

Function of protooncogene

MOA of cancer

- Astrocytoma

- Platelet derived growth factor

Overexpression, autocine loop

ERBB2 (HER2/neu)

- Subset of breast cancer

Epidermal growth factor receptor



- MEN2A, MEN2B - Sporadic MTC

Neural growth factor receptor

Point mutation


- Gastrointestinal stromal tumor

Stem cell growth factor receptor

Point mutation

RAS gene family - Carcinoma - Melanoma - Lymphoma - (Found in ~70% of all cancers)

GTP-binding protein

Point mutation


- CML - Some ALL

Tyrosine kinase

Translocation - t(9,22) with BCR

- Burkitt lymphoma

Transcription factor

T (8,14) involving IgH

Growth factor PDGFB Growth factor receptors

Signal Transducers

Nuclear regulators C-MYC

Neoplasia Page 3.1


- Burkitt lymphoma

Transcription factor

T (8,14) involving IgH (heavy chain)


- Neuroblastoma

Transcription factor



- Lung carcinoma (small cell)

Transcription factor


CCND1 (cyclin D1)

Mantle cell carcinoma


T(11, 14) involving IgH



Cyclin dependent kinase


Cell-cycle regulators

Neoplasia Page 3.2

3.2 Carcinogenesis (Part 3), 3.4 Clinical Characteristics

1. Differentiate benign and malignant neoplasia. Benign neoplasia

Malignant neoplasia

Remain localized and do not metastasize

Invade locally and have potential to metastasize (don't have to be already metastasized)

Slow-growing (years)

Rapid growing (weeks/months)

Distinct (well localized, ex - can isolate by breast exam)

Infiltrative (can't distinguish from surrounding breast tissue in physical exam)

Mobile (ex - you can grab a breast tumor and move it around)

Fixed to surrounding tissue

- Classification of benign vs malignant requires biopsy 2. What are histologic differences of benign and malignant tumor? Benign neoplasia (well-differentiated)

Malignant tumor (poor differentiation)

- Organized growth

- Disoganized growth (doesn't look like tissue it's growing in)

- Uniform nuclei

- Nuclear pleomorphism with hyperchromasia (very dark blue)

- Low nuclear to cytoplasm ratio (more cytoplasm)

- High nuclear to cytoplasm ratio (less cytoplasm, big nuclei)

- Minimum mitotic activity

- High mitotic activity

- Lack of invasion

- Invasion

- No metastatic potential

Fig: Follicular thyroid adenoma (left) - note organized cell growth with colloid in between cells, uniform nuclei with lots of cytoplasm, minimum mitotic activity. Anaplastic thryoid carcinoma (right) - disorganized growth (cells look nothing like thyroid), large nuclei:cytoplasm ratio, nuclear pleomorphism, mitotic figure (very dark nuclei cell). 3. What's the absolute distinguishing feature between benign and malignant tumors? Neoplasia Page 4.1

3. What's the absolute distinguishing feature between benign and malignant tumors? - Potential to metastasize (benign tumors never metastasize, malignant tumors can metastasize) 3.5 What are some ways of identifying cell types in tumor? - Immunohistochemistry - Serum tumor markers 4. What is intermediate filament? How is immunohistochemistry of intermediate filament helpful in grouping cancer? (HY) - Intermediate filament are a type of cytoskeletal protein; different intermediate filament are present in different cell types. - Immunohistochemistry of intermediate filament helps in identifying cell types in tumor. Cell type

Intermediate filament present



Mesenchyme (connective tissue) VImentin Muscle






5. What immunohistochemical molecules help identify cancer of following cell types? Cell type

Immunohistochemistry molecule


PSA (prostrate surface antigen)

Breast epithelium

ER (estrogen receptor)

Thyroid follicular cells


Neuroendocrine cells (small cell cancer of lung and carcinoid tumor)

Chromogranin (HY)



- Well differentiated neuroendocrine tumor = carcinoid tumor. Poorly differentiated neuroendocrine tumor = small cell cancer. 6. What are serum tumor markers and what's their utility? - They are proteins released by tumors. - Useful for ○ Screening (ex- high PSA) - still need biopsy for diagnosis ○ monitoring response to treatment (ex- PSA should drop after prostrate cancer surgery) ○ recurrence of tumor (ex - same pt returns 2 year later with bone pain; check for PSA to see if it's prostrate cancer again) 7. -

What does tumor grading of well differentiated and poorly differentiated mean? Well differentiated - tumor resembles parent tissue - good prognosis Poorly differentiated - tumor doesn't resemble parent tissue - poor prognosis Look at cellular architecture and nuclear morphology to classify differentiation

8. -

What's staging of cancer? What's its value? Staging of cancer is based on size and spread It's no. 1 prognostic factor (more important than grade) Determined after final resection of tumor

Neoplasia Page 4.2

9. What's TNM staging of cancer? - T = tumor size and depth (size important for solid organ tumor, and depth important for tubular organs like colon) - N = spread to regional lymph nodes (2nd most important prognostic factor) - M = metastasis (no. 1 prognostic factor)

Neoplasia Page 4.3

3.3 Tumor progression 1. What are the steps in invasion and spread of tumor? - Downregulation of e-kedherin (e-kedherin is an adhesion molecules that keeps epithelial cells attached to each other) - Tumor cells attach to laminin in basement membrane - Tumor cells produce collagenase that destroys collagen 4 in basement mebrane. This helps tumor pass through basement membrane - Tumor cells bind to fibronectin in extracellular membrane and spread locally. It can now pass to blood vessel or lymphatics. 2. How do metastatic cancer spread? - Lymphatic spread is characteristic of carcinomas and less common for sarcoma. - Hematogenous spread is characteristic of sarcoma and some carcinoma - usually follows venous drainage and seeds at first capillary bed encountered - Seeding of body cavities - most common is peritoneum (ex - by ovarian carcinoma (omental caking)) but may also occur in the pleural or pericardial cavities, the subarachnoid space, and the joint spaces

Fig: omental caking by ovarian carcinoma 3. -

What are carcinomas that spread hematogenously? Renal cell carcinoma - renal vein Hepatocellular carcinoma - hepatic vein Follicular thyroid carcinoma Choriocarcinoma (placental cancer - of trophoblast cells - function of placenta is to invade blood vessels)

Neoplasia Page 5.1

Chapter 4: Hemostasis and Related Disorders

CMAP summary

Hemostasis Page 1.1

4.1 Primary Hemostasis Primary hemostasis - make a platelet plug Secondary hemostasis - make fibrin mesh by coagulation cascade to stabilize platelet plug 1. -

What are steps of primary hemostasis? Vasoconstriction Platelet adhesion Platelet activation Platelet aggregation

2. What causes vasoconstriction? - Vasoconstriction - mediated neurally and chemically. When endothelium is disrupted, endothelial cells secrete endothelin for vasoconstriction. NO and prostacyclin production goes down (they vasodialate). - Endothelin - powerful vasoconstrictor - NO and prostacyclin (prostaglandin I2)- vasodialator 3. What happens in platelet adhesion? - Platelet adhesion - VWF (von willieband factor) is a glue that binds to exposed collagen in damaged tissue. It then binds to glycoprotein VIII, and then glycoprotein IB (integrin IB) on platelet. VWF mainly comes from endothelial cells storage unit - Weibel Palade body (HY), but are also found in alpha granules platelets. (another important factor in weibel palade body is Pselectin) 4. What happens in platelet activation (aka degranulation)? - Platelet changes shape after adhesion and is activated. It secretes○ thromboxane A2 (very powerful degranulator made by cyclooxygenase (COX)), ○ alpha granules (contain fibrinogen and VWF), ○ delta granules (contain SAC - serotonin for vasoconstriction, ADP which is necessary for expression of GP IIB/IIIA receptor by platelet and stimulates degranulation, and calcium that helps in secondary hemostasis) 5. What happens in platelet aggregation? - A single fibrinogen is linked to multiple platelets via their glycoprotein IIB/IIIA. This creates platelet plug. Platelet plug is weak and needs secondary hemostasis (coagulation cascade) for stabilization. 6. What are 2 classification of platelet disorders? Hemostasis Page 2.1

6. What are 2 classification of platelet disorders? - Qualitative disorders - bad platelet - Quantitative disorders - good platelet but too few in numbers (petechiae (spots in skin due to bleeding) seen in thrombocytopenia and not usually in qualitative disorder) 6. What are common features of pt with problem in primary hemostasis ? - Key sign is mucosal and skin bleeding; intracranial bleeding with severe thrombocytopenia (low platelet) (can kill you). - Mucosal bleeding - epistaxis (nose bleeding), hemoptysis (coughing blood), GI bleeding, hematuria, and menorrhagia (heavy menses) - Skin bleeding - petechiae (bleeding spots on skin), purpura (>3mm bleeding spots), ecchymoses (>1cm), easy bruising. 7. -

What are some useful lab studies for platelet? Platelet count (normal is 150k-400k per microliter of blood) Bleeding time - prick patient and see how long it takes to stop bleeding - normal is 2-7 minute Blood smear - look under microscope Bone marrow biopsy - look at megakaryocytes (they make platelets)

Quantitative disorders 8. What is idiopathic thrombocytopenic purpura (ITP)? - Most common cause of thrombocytopenia in kids and adults. Autoimmune production of IgG against platelet antigens (ex- GP IIB/IIIA) - Antibodies are made in spleen, and tagged platelets are phagocytosed by spleen macrophages. Low platelets cause purpura (bleeding spots in skin)

9. Describe acute form of ITP? - Seen in children weeks after viral infection or immunization. - Self-limited disorder - resolves within weeks of presentation 10. Describe chronic form of ITP? - Classically seen in child bearing age woman - May be primary (idiopathic) or secondary (strong association with lupus- remember antibodies against blood is a common feature in lupus) - IgG can cross placenta and cause short-lived thrombocytopenia in children 11. -

What do we see in labs in ITP? Platelet count 100. RBC precursor doesn't divide much and the RBC end up being big. - Causes: ○ Megaloblastic anemia (anemia with big cells) - disruption in production of DNA precursors results in quick cytoplasmic development relative to nuclear development:  Folate deficiency  Vit B12 deficiency  Orotic aciduria  Folate and Vit B12 needed for DNA precursor synthesis ○ Alcoholism ○ Liver disease, drugs (ex- 5-FU)

Megaloblastic anemia Vit B12 and Folate deficiency 2. Describe relationship between folate and Vit B12. - Folate comes to body as methylated tetrahydrofolate (M-THF). - THF is the active form. M-THF donates it's methyl group to Vit B12. Vit B12 then gives methyl group to homocysteine. Homocysteine now becomes methionine.

RBC disorders Page 6.1

3. What is presentation of macrocytic anemia due to folate or vit B12 deficiency? - Megaloblastic anemia (impaired division of RBC precursors) - Hypersegmented neutrophil with >5 lobes (normal is 3-5 lobes) (impaired division of granulocytic precursors) - Megaloblastic changes in rapidly dividing cells (ex - intestinal epithelial cells)

Fig: hypersegmented neutrophils with large RBC (aka macroovalocyte) on the left- classic finding in megaloblastic anemia 4. What is difference between megaloblastic anemia and macrocytic anemia that's not megaloblastic? - In macrocytic anemia that's not megaloblastic, hypersegmented neutrophils and megaloblastic changes (ex - large intestinal epithelial cells) won't be seen. Large RBC will be seen. 5. Compare dietary information of folate and vit B12. Folate

Vit B12


Dark green vegetable and food

Animal derived proteins





Develops in months as body stores are minimum

Takes years to develop due to large hepatic storage

Causes of deficiency

- Poor diet (alcoholics, old) - Pernicious anemia (autoimmune destruction - Increased demand (pregnancy, of parietal cells of stomach) - most common cancer, hemolytic anemia) - Using proton pump inhibitor - Folate antagonists - Pancreatic insufficiency (Vit B12 won't be free (methotrexate - inhibits DHFR) from R-binder) - Damage to terminal ileum (Chron's, Diphylloborthium latum) - Vegans (dietary deficiency rare otherwise)

6. Compare clinical and lab findings of folate and Vit B12 deficiency. RBC disorders Page 6.2

6. Compare clinical and lab findings of folate and Vit B12 deficiency. Folate deficiency

Vit B12 deficiency

- Macrocytic RBC and hypersegmented neutrophils

- Macrocytic RBC and hypersegmented neutrophils

- Glossitis (inflammation of - Glossitis tongue - due to less turnover of tongue cells) - Low serum folate

- Low serum vit B12

- Increased serum homocysteine - Increased serum homocysteine (increases risk for (increases risk for thrombosis) thrombosis) - Normal methylmalonic acid; no neuro symptoms

- Increased methylmalonic acid in myelin cells which impairs spinal cord myelinization resulting in subacute combined degeneration of spinal cord

7. What are two important reactions that Vit B12 participate in? - DNA precursor synthesis (with folate) - Conversion of methylmalonic acid to succinyl Co. A

8. Why do we see increased serum homocysteine in folate deficiency? - Normally, dietary folate (M-THF) gives it's methyl group to Vit B12 which in turn gives it to homocysteine. Homocysteine now becomes methionine. - The reaction won't happen in folate deficiency and we'll see increased serum homocysteine. 9. Why will methylmalonic acid be increased in Vit B12 deficiency? - Because Vit B12 is necessary to convert methylmalonic acid to succinyl Coenzyme A. 10. Describe absorbtion of Vit B12 in gut (HY) - R-binder protein from saliva binds to Vit B12. The complex will travel till small bowel. There's Vit B12 is set free by pancreatic proteases. - The free Vit B12 binds to intrinsic factor secreted by parietal cells of stomach. - This complex will go to ileum and get absorbed there. 11. -

What are 3 P's of parietal cell? Proton pump - they pump proton to stomach to make it acidic Pink in histology (chief cells appear blue) Pernicious anemia if they get damaged - makes IF

Orotic aciduria Defn

- Inability to convert orotic acid to uridine monophosphate (UMP) that leads to accumulation of orotic acid (defect in de-novo purine synthesis pathway) - AR inheritence

Presentati - Megaloblastic anemia in children refractive to folate and vit B12 on - Failure to thrive, developmental delay - Orotic acid in urine but no hyperammonemia Treatment - UMP to pass the mutated enzyme Nonmegaloblastic macrocytic anemia RBC disorders Page 6.3


- Macrocytic anemia where DNA synthesis is unimpaired - RBC macrocytosis without hypersegmented neutrophils

Causes - Alcoholism - Liver disease - Hypothyroidism - Reticulocytosis

RBC disorders Page 6.4

5.4 Normocytic anemia

1. What is normocytic anemia? What are two types based on etiology?  Normocytic anemia is decreased RBC mass with normal-sized RBC (MCV - 80-100 µm3)  Types: o Peripheral destruction of RBC (will have reticulocyte >3%)  Extravascular hemolysis (RBC destroyed by liver, spleen and lymph)  Intravascular hemolysis (RBC destroyed within blood vessel) o Underproduction of RBC (no increased reticulocytes) 2.   

What are reticulocytes? They are young RBC released from bone marrow to replace dead RBC Seen as large cells with bluish cytoplasm (due to RNA) on blood smear Normally, 1-2% of RBC die every day and are replaced by reticulocytes.

3. How can reticulocyte be falsely elevated in anemia? How is reticulocyte count corrected?  Reticulocytes are measured as percent of total RBC. In anemia, total RBC goes down. It will elevating the percent of reticulocytes.  It’s corrected by multiplying reticulocyte percent x hematocrit/45. Total RBC

Total Reticulocyte

% of reticulocyte

Normal pt 100 (given)

2 (given)


Anemic pt



50 (given)


Corrected reticulocyte

23 (given)

4 x 23/50 = 2%

In this example, if we only look at % of reticulocyte, it looks as if bone marrow is normal. But from corrected reticulocyte, we know that anemic pt’s bone marrow is not producing adequate reticulocytes. 4. How can reticulocyte count differentiate cause of anemia? If corrected reticulocyte >3%

If corrected reticulocyte 3%

3. What happens in intravascular hemolysis? What's the presentation? RBC disorders Page 7.1

3. What happens in intravascular hemolysis? What's the presentation? • RBC is destroyed in blood vessels. Unlike macrophage breaking down hemoglobin to bilirubin, hemoglobin simply leaks out to blood. • Hemoglobin is carried by haptoglobin. Haptoglobin is not present a lot. So, pt will quickly have hemoglobinemia and hemoglobinuria (hemoglobin water soluble) • Hemosiderinuria after few days (HY) - hemoglobin in urine is picked up by renal tubular cells. Iron is recycled back and stored as hemosiderin. Renal tubular cells slough off (just like skin cells) and hemosiderin will be seen in urine. • Presentation: Immediate

After few days

- Decreased serum haptoglobin - Hemosiderinuria - Hemoglobinemia - Hemoglobinuria

RBC disorders Page 7.2

5.5 Normocytic Anemia with Extravascular Hemolysis

Hereditary spherocytosis 1. What is hereditary spherocytosis? What are the mutations? - In the disease, tethering proteins that attach RBC cytoskeleton to RBC membrane are mutated. RBC membrane blebs and are lost over time. RBC becomes more spherical. - Most common mutations are in proteins - ankyrin, spectrin, or band 3. 2. -

What are clinical and lab findings? See spherocytes - RBC becomes round instead of disc shaped (loss of central pallor) High RDW (some cells have lost tons of membrane and some only a little bit) high mean corpuscular hemoglobin concentration (MCHC) - high concentration of hemoglobin as cells are getting small - Extravascular hemolysis findings ○ Anemia - spherocytes can't move through splenic sinusoids well and are eaten by splenic macrophages (this is main problem) - having spherocytes isn't bad ○ Splenomegaly (overworked spleen) ○ Jaundice with unconjugated bilirubin, high risk for bilirubin gallstones

Fig: spherocytes with high RDW (note variability in RBC sizes and loss of central pallor) 3. What is one feared complication? - Increased risk of aplastic crisis with parvovirus B19 infection of erythroid precursors 4. How is diagnosis of hereditary spherocytosis made? - Osmotic fragility test - cells bursts in hypotonic solution very easily because cell doesn't have much membrane to expand out 5. What's it's treatment? - Splenectomy (having spherocytes isn't problem, spleen eating them is problem) - Anemia resolves but spherocytes persist and Howell-Jolly bodies are seen 6. What's Howell-Jolly bodies? - Some RBC's are impefectly made with little nucleus or nuclear material left. It's job of spleen to take them out or kill the defective RBC. Howell-Jolly bodies are RBC with nuclear remnant. It indicates splenic dysfunction

RBC disorders Page 8.1

Fig: Howel Jolly bodies

Sickle cell disease 1. What causes sickle cell anemia? • It’s caused due to mutation in B chain of hemoglobin that changes glutamic acid (hydrophilic) to valine (hydrophobic). Think GingiVa - from Glutamic acid to Valine • Disease is due to homozygous recessive mutation. Haterozygotes are protected against plasmodium falciparum malaria Phenotype

Hemoglobin composition

Sickle cell disease (homozygous mutation)

90% HbS, 8% HbF, 2%HbA2, no HbA

Trait (one mutated and one normal B chain) 55% HbA, 43% HbS, 2% HbA2 • HbS – sickle cell hemoglobin (in α2β2 protein, both copies of β are mutated) 2. What is pathogenesis of sickle cell anemia? • HbS polymerizes when deoxygenated (reversible). The polymers accumulate into needle shaped structures and make RBC sickle cell. • Sickling and de-sickling damages membrane leading to both intravascular and extravascular hemolysis (spleen eats damaged RBC); sickled RBC cause vaso-occlusion; massive erythroid hyperplasia to replace RBC. • Sickling increases with hypoxemia, dehydration and acidosis. • HbF protects against sickling. Kids protected for first few months of life.

3. What's treatment of sickle cell disease? - Hydroxyurea - it increases level of HbF. It protects against sickling 4. What are presentations of sickle cell disease? • Extravascular hemolysis – RBCs being sickle shaped and non-sickle cell repeatedly damages membranes. Reticuloendothelial system removes these damaged RBC. ○ Anemia ○ Jaundice with unconjugated hyperbilirubinemia ○ Increased risk for bilirubin gallstones • Intravascular hemolysis – due to membrane damage ○ Decreased haptoglobin Hemoglobinemia, hemoglobinuria RBC disorders Page 8.2

○ Hemoglobinemia, hemoglobinuria ○ Hemosiderinuria after few days ○ Target cells - hemoglobin leaks out due to membrane damage and extra membrane produces target cells • Massive erythroid hyperplasia (to compensate hemolysis and anemia): ○ Hematopoiesis in skull and facial bones (crewcut on X-ray and chipmunk face) ○ Extramedullary hematopoiesis (in liver, giving hepatomegaly - pt don't have spleen so don't get splenomegaly) ○ Risk of aplastic crisis with parvo B19 infection

Fig: chipmunk face (left) and crewcut appearance (right) seen in massive erythroid hyperplasia • Extensive sickling leads to vaso-occlusion 5. • • •

What are some physical findings in sickle cell disease due to vaso-occlusion? All findings based on infraction Dactylitis – due to vasoocclusive infaracts in bones – common in infants Autosplenectomy – shrunken, fibrotic and calcified spleen ○ Increased risk of encapsulated organism infection (staph aureus, strep pneumo, haemophilus influenza) ○ Salmonella paratyphi osteomyelitis (encapsulated) - most common cause of osteomyelitis is staph aureus; in sickle cell, it's salmonella. ○ Howel-Jolly bodies on blood smear - nucleated RBC • Acute chest syndrome (vaso-occlusion of pulmonary microcirculation) ○ Often precipitated by pneumonia ○ Presents with chest pain, SOB, lung infiltrates • Pain crisis • Renal papillary necrosis – presents as gross hematuria and proteinuria

Fig: vaso-occlusive complications of sickle cell disease - from left to right - autosplenectomy - small calcified spleen; renal papillary necrosis; dactilytis; Howel-Jolly bodies 6. What’s the most common cause of death in sickle cell patients? Kids

Hemophilus influenza infection


Acute chest syndrome RBC disorders Page 8.3


Acute chest syndrome

7. What is sickle cell trait? • Haterozygote carriers of sickle cell mutation have sickle cell trait. They have one mutated and one normal beta chain. • HbS (both beta chain mutated) makes 20%, it's acute leukemia) abnormal maturation of cells and increased blasts because cells can't fully differentiateWBC disorders Page 4.3

○ abnormal maturation of cells and increased blasts because cells can't fully differentiatethat's why increased risk of AML ○ Most pt die from infection or bleeding (some progress to AML) ○ Cytopenia and hypercellular bone marrow (cells are stuck in bone marrow and not going out) - Ex - Pseudo-Pegler-Huet anomaly - neutrophils with bilobed nuclei typically seen after chemotherapy

Fig: Pseudo-Pegler-Huet anomaly

WBC disorders Page 4.4

6.3 Chronic Leukemia

1. -

What is chronic leukemia? What are it's types? Chronic leukemia is proliferation of MATURE circulating lymphocytes. It's usually seen in adults and have insidious onset. Types: Cancer name

Cell type high

Chronic lymphocytic Naïve B cells (CD5 leukemia (CLL) and CD20 +ve) naïve kids smudge their food


- Most common leukemia overall - See smudge cell (like someone smashed a cell in slide) - See generalized lymphadenopathy - Small lymphocytic lymphoma is a type of CLL that affects tissue

Complicati • Transformation to diffuse large B-cell lymphoma (richter ons transformation) - see enlarging lymph nodes or spleen • Hypogammaglobulinemia - INFECTION MOST COMMON CAUSE OF DEATH Associatio • Autoimmune hemolytic anemia n Picmonic:

CaLL - CLL Epid

- Most common leukemia in adults (old people in pic)

Presentati - Often asymptomatic - both elderly are happy and dancing on - Smudge cell - cell smudged on glass of grandpa Associatio - Autoimmune hemolytic anemia - both IgM and IgG - cold n and warm sea anemone Hairy cell leukemia (rare leukemia)

Mature B cells (TRAP - Lymphadenopathy usually absent +ve (tartarate - Marrow fibrosis (dry bone marrow tap) resistant acid WBC disorders Page 5.1

resistant acid phosphatase) and hairy cytoplasm) hairs trap; mature people are hairy


Hairy guy with Basketball - hairy cell leukemia Presentati - Splenomegaly (can be the only finding) - hairy cells on accumulate in spleen - spleen baloon - Lymphadenopathy usually absent Treatment - Excelent response to 2-CDA (cladribine) - cloud ribbons Adult T cell Mature CD4+ cells leukemia/lymphoma

- Associated with HTLV-1; common in Japan and caribbean - Skin rash, generalized lymphadenopathy, hepatosplenomegaly, - lytic (punched out) bone lesion with hypercalcemia

- Excellent treatment to chemotherapy Mycosis Fungoides (cutaneous T-cell lymphoma)

Mature CD4+ cells that infiltrate skin

- See sezary cells (cerebriform nuclei) in blood smear - CD4 accumulation in skin produces rash, plaques and nodules called pautrier microabscess

Fig - Sezary cells, pautrier microabscss - microcospic and gross

WBC disorders Page 5.2

6.4 Myeloproliferative Disorders

1. -

What is myeloproliferative disorders? What's its presentation? Myeloproliferative disorders is neoplastic proliferation of mature cells of myeloid lineage Disease presents in late adulthood (50-60 years) Presentation: ○ Hypercellular bone marrow with increased WBC ○ All cells in myeloid lineage are increased, classification is based on what cell is dominantly present

2. What are types of myeloproliferative disorders? What is characteristic mutation? Disorder

Dominant cell


Chronic myeloid leukemia (CML)

Granulocytes (neutrophil, eosinophil, basophil); increased basophil (HY)

t(9;22) aka philadelphia chromosome - present in 95% of pt

Polycythemia vera (PV)


JAK2 kinase mutation

Essential thrombocythemia (ET)


JAK2 kinase mutation



JAK2 kinase mutation (50% of cases)

Chronic myelogenous leukemia (CML) 1. What is the mutation that causes CML? What's treatment? - T(9;22) produces philadelphia chromosome. It creates fusion of BCR on ch 22 with ABL receptor tyrosine kinase protein. It leads to increased tyrosine kinase activitiy. - Treatment ○ Imatinab - blocks tyrosine kinase activity (HY) ○ Hydroxyurea - inhibits ribonucleotide reductase (DNA synthesis) - prevent cell dividion ○ IFN alpha - increased destruction of cells ○ Hydroxyurea and IFN alpha can be used in many disease where cell divides too much 2. What is presentation and complication? - Splenomegaly is common - Complication: ○ Transformation to AML (2/3rd of cases) ○ Transformation to ALL (1/3rd of cases) 3. How do you diagnose CML? - Peripheral blood smear shows leukocytosis - too much WBC - FISH can be used to see philadelphia chromosome (seen in 95% of cases); however gene translocation is seen in 100% of cases.

WBC disorders Page 6.1

4. How do you distinguish CML from lukemoid reaction (reactive neutrophilic leukocytosis)? CML

Lukemoid reaction

Negative leukocyte alkaline phosphatase (LAP) stain (LAP present in normal neutrophils but absent in malignant neutrophils)

Positive leukocyte alkaline phosphatase (LAP) stain


No increase in basophil

t(9;22) present

t(9;22) absent

5. Picmonic for CML

WBC disorders Page 6.2



Mutation - t(9;22) - ninja and double tutu - Makes philadelphia chromosome (philadelphia cream cheese) - BCR-ABL fusion protein created - VCR - Abraham lincoln Treatment - Imatinib - eye-mat Polycythemia vera (PV) 1. What is PV? - Increase in RBC, WBC and platelets but main presentation is based on too much RBC.

1. What are presentation of PV? - Presentation based on increased viscosity of blood: ○ Flushed face due to congestion (plethora) ○ Intense itching, especially after bathing (due to histamine release from increased mast cells due to heat) ○ Erythromelalgia - severe burning pain, and red-blue discoloration due to blood clots in vessels of extremities; melalgia = buring pain in limbs ○ Hepatosplenomegaly (splenomegaly because there's too much RBC so amount of bad RBC will be high and spleen has to eat them; hepatomegaly because liver makes RBC due to mutation in JAK2 kinase). ○ Gout - proerythroblasts (RBC witn nucleus) will leak out and be eaten by spleen. Metabolism of nucleus increases uric acid. ○ Venous thrombosis  No. 1 cause of budd-chiari syndrome  Dural sinus thrombosis  Retinal vein thrombosis

WBC disorders Page 6.3

Fig: polycythemia presentation - from left to right: dural sinus thrombosis, Erythromelalgia, facial plethora, itching, hepatosplenomegaly, gout 2. -

How do you treat PV? Phlebotomy (first line) Hydroxyurea - second line (inhibits ribonucleotide reductase - DNA synthesis) Interferon alpha - increased destruction of proerythroblasts (can induce gout)

3. What's prognosis of PV? - Death within a year without treatment 4. How do you distinguish PV from reactive polycythemia? PV

Reactive polycythemia

Normal SaO2, low erythropoietin (EPO)

- If due to lung disease or high altitude- Low SaO2, high EPO - If due to ectopic EPO production, SaO2 normal, high EPO

Essential thrombocythemia vs Myelofibrosis 1. Differentiate essential thrombocythemia vs myelofibrosis Essential thrombocythemia (ET)


Neoplastic proliferation of platelets megakaryocytes divide too much. Thrombocyte = platelet

Neoplastic proliferation of megakaryocytes (megakaryocyte = cell with big nucleus)

Associated with JAK2 kinase mutation

Associated with JAK2 kinase mutation

Presentation Presentation: - increased risk of thrombosis and/or - Increased risk of thrombosis and/or bleeding, bleeding (low platelet due to too infection much thrombosis) - Hepatosplenomegaly - they will produce blood cells as marrow is fibrosed (MOST COMMON - Splenomegaly - spleen has to eat too much platelets CAUSE OF SPLENOMEGALY IN PT >55 YEAR - Rarely progress to marrow fibrosis OLD) or acute lukemia - Marrow fibrosis (due to PDGF production from megakaryocytes) will impinge on bone and - Rare risk for hyperuricemia or gout WBC disorders Page 6.4

- Rare risk for hyperuricemia or gout (only platelets are increased which don't have nucleus)

megakaryocytes) will impinge on bone and cause bone pain - Splenomegaly due to extramedullary hematopoiesis (due to marrow fibrosis) - Leukoerythroblastic smear (tear drop RBC - RBC squeezing through fibrosed marrow, nucleated RBC, immature granulocytes)

• Enlarged megakaryocytes in bone marrow biopsy

Fig: leukoerythroblastic smear, marrow fibrosis - Diagnosis: • Diagnosis of exclusion • See platelets >450k for >2 months

- Diagnosis: • Tear drop RBC • Bone marrow tap will be dry; see fibrosis in biopsy

- Treatment: • Asprin for low risk pt to prevent clot • Hydroxyurea , interferon alpha to reduce megakaryocyte formation • Plateletpheresis - take excess platelet from circulation in emergency condition

- Treatment: • Stem cell transplant - replace fibrosis • Transfusion to give blood cells that’s missing

- Leukoerythroblastic anemia is anemia due to space occupying lesion in marrow

WBC disorders Page 6.5

6.5 Lymphadenopathy (LAD)

1. When do you see painful vs painless lymphadenopathy? - Lymphadenopathy is enlarged lymph nodes. - Painful: ○ Lymph nodes draining a region of acute infection (acute lymphadenitis) - Painless: ○ Chronic inflammation (chronic lymphadenitis) ○ Metastatic carcinoma ○ Lymphoma 2. What are indications depending on what part of lymph node is enlarged? - Follicular enlargement (B cell region): ○ Rheumatoid arthritis ○ Early stages of HIV - Paracortex enlargement (T cell region): ○ Viral infection (ex - EBV) - Sinus histiocytes enlargement: ○ Lymph nodes draining with cancer

WBC disorders Page 7.1

6.6 Lymphoma, 6.7 Hodgkin Lymphoma

1. What is lymphoma? - Neoplastic proliferaion of lymphoid cells that makes a mass; may arise in lymph node or extranodal tissue.

2. Distinguish Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Hodgkin lymphoma

Non-Hodgkin lymphoma




Malignant cells

Reed-Sternberg cells (owl eye cells) - B cells induce inflammation and fibrosis

Lymphoid cells - many subtypes - most are B cell than T cells

Mass composition

Inflammatory cells and fibrosis (reactive cells) Lymphoid cells


- Painless lymphadenopathy - B symptoms - Bimodal: classically seen in young adult and >55 yrs

- Painless lymphadenopathy - Classically seen in late adults


Contiguous (touching); rarely extranodal

Diffuse; often extranodal


Guides therapy Radiation mainstray treatment

Limited importance

Leukemic phase Doesn't occur Prognosis


Much better prognosis than non-Hodgkins

WBC disorders Page 8.1



HIV and autoimmune diseases

Hodgkin lymphoma (HL) 1. What are Reed-sternberg cells? - Large B cells (CD 15 and CD 30 +ve) with multilobed nuclei and prominent nucleoli that looks like Owl eye - They produce cytokines which attract inflammatory cells and cause fibrosis (can be seen in biopsy)

2. What are presentation of Hodgkin lymphoma? - Due to cytokine release: ○ B symptoms - fever, chills, wt loss, night cells ○ Presence of reactive inflammatory cells that make bulk of tumor ○ Fibrosis 3. What are different subtypes of Hodgkin lymhoma and what are their characters? Subtype


Nodular sclerosis

- Most common type of HL - Classic pt is young adult female - Presents as enlarged cervical or mediastinal lymph nodes - Biopsy: • Lymph node is divided by band of fibrosis • Reed sternberg cells are present in lake like spaces (lacunar cells)

Fig: band of fibrosis (left), lacunar cells (a variant of Reed sternberg cells - right)

Mixed cellularity

- Associated with abundant eosinophils (reed sternberg cells produce IL-5)

Lymphocyte rich

- Best prognosis of all types

Lymphocyte depleted - Most aggressive of all types - Usually seen in HIV pt or old pt Non-Hodgkin lymphoma 1. What are types of non-hodgkin lymphoma? - Non-hodgkin lymphoma is classified based on cell size, cell type (B or T), pattern of cell growth, cell surface markers, translocations. - Types: ○ Small B cells  Follicular lymphoma - enlarged and too many follicles  Mantle cell lymphoma - cancer of mantle (area around follicle)  Marginal zone lymphoma - cancer of marginal zone (area around mantle)  Small lymphocytic lymphoma (CLL that involve tissue) ○ Intermediate B cell lymphoma  Burkitt lymphoma ○ Large B cells  Diffuse large B-cell lymphoma 2. What are the causes of the different NH lymphoma? NH lymphoma Cause

Remarks WBC disorders Page 8.2

NH lymphoma Cause


Follicular lymphoma

t(14;18) - BCL2 on ch 18 moves to Ig heavy chain locus on ch14 (BCL2 inhibits apoptosis by blocking Bax and bac from making channel in mitrochondrial membrane so cytochrome C can leak out)

- Can progress to diffuse large B cell lymphoma (presents as enlarging lymph node)

Mantle cell lymphoma

t(11;14) - Cyclin D1 on ch 11 goes to Ig heavy chain locus on ch14

- Often present in late adulthood with painless lymphadenopathy

Marginal zone - Chronic inflammatory state - Hashimoto thyroiditis, Sjogren lymphoma syndrome, H pylori gastritis (causes MALToma - a type of marginal zone lymphoma) Small lymphocytic lymphoma

- Chronic lymphocytic leukemia (naïve B cells; smudge cell) affecting tissue

Burkitt lymphoma

- t(8;14) - c-myc on ch 8 goes to Ig heavy chain locus on ch14 (myc is a protein in RAS-MAPK pathway - cellular proliferation and increased cyclin D production) - Associated with BV infection - Biopsy finding

Fig: starry sky appearance (night sky made of dark lymphocytes; WBC disorders Page 8.3

- Marginal zone made of postgerminal B cells

- Often present in child or young adult as extranodal mass: • African form - in jaws • Sporadic form - in abdomen

Fig: starry sky appearance (night sky made of dark lymphocytes; bright stars made up of mitotic figures)- left; right - african form appearing on jaws

Diffuse large B-cell lymphoma

- Arise sporadically or transformation of low grade lymphoma (exfollicular lymphoma, chronic lymphocytic leukemia)

- Most common NHL - High grade (aggressive) - Present in late adulthood as extranodal mass or enlarging lymph nodes

3. How do you distinguish follicular lymphoma from reactive follicular hyperplasia? Follicular lymphoma

Reactive follicular hyperplasia

- Cells are monoclonal

- Cells are polyclonal

- Bcl2 expression in follicles (Bcl2 - anti-apoptotic - No Bcl2 expression in follicles protein) - Disruption of lymph node architecture

- Preservation of lymph node architecture

- Lack of tingible body marcophage in germinal center

- Presence of tingible body marcophage (they eat bad B cells produced during somatic hypermutation)

Fig: bad lymph node architecture (follicles present not only in cortex) Fig: left (follulicular lymphoma lacking tingible body macohpage); right (follicular hyperplasia with tingible body macrophage) 4. What's treatment of follicular lymphoma? - Rituximab (anti-CD20 antibody) or low dose chemotherapy

WBC disorders Page 8.4

6.8 Plasma Cell Disorders (dyscrasias)

Multiple myeloma 1. What is multiple myeloma? What is molecular mechanism? - MM is malignant proliferation of plasma cells in bone marrow. It's most common primary malignancy of bone. - Serum IL-6 (aka RANK-L) may be increased that induces plasma cell growth and Ig production. 2. What are clinical features of MM? Bone pain with hypercalcemia

- Plasma cell produce IL-6 (RANK-L) that binds to RANK on osteoclasts (bone breaks down) - creates punched out lesions mainly on skull and vertebra

Elevated serum protein (M - Classically due too much IgG (55% of cases) or IgA (25%) spike present in serum production protein electrophoresis SPEP)

Increased risk of infection

- Even though too much Ig produced, lack of Ig specificity

Rouleaux formation on blood smear (rouleau = cylindrical packet of coins)

- Increased serum protein decreases charge between RBC and RBC makes stacks


• Plasma cells crowd out bone marrow so little RBC synthesis

WBC disorders Page 9.1

Primary AL amyloidosis

- Due to too much Ig light chain (they deposit in tissue)

Proteinurea and renal failure

- Free light chain protein excreted in urine as Bence Jones protein - Light chain deposition in kidney can cause renal failure

Fig: Bence Jones crystal (see in Waldenstrom macroglobulinemia too) • Mnemonic CRAB ○ HyperCalcemia ○ Renal involvement / Roulex formatin ○ Anemia / Amylodosis ○ Lytic Bone lesions Monoclonal Gammopathy of undetermined significance (MGUS) 1. What is MGUS? What's its significance? - Increased serum protein with M spike on serum protein electrophoresis but no other feature of MM (- no CRAB - no lytic bone lesion, no hypercalcemia, no rouleaux, no Bence Jones proteinura etc) - Significance: ○ Common in elderly (5% of >70 year old people) ○ 1% of pt with MGUS progress to multiple myeloma each year Waldenstrom Macroglobulinemia 1. What is Waldenstrom macroglobulinemia? What are clinical features? What is treatment? - B cell lymphoma with monoclonal IgM production (M for Macroblobulinemia) - Clinical features: ○ M spike present - due to hyper IgM ○ Presentation based on hyperviscosicity of blood due to IgM pentamer (no CRAB findings present) ▪ Retinal hemorrhage and stroke ▪ Bleeding - high blood viscosity leads to defective platelet aggregation ▪ Raynaud phenomena

WBC disorders Page 9.2

○ Generalized lymphadenopathy - Treatment: ○ Plasmapheresis to remove IgM from serum

WBC disorders Page 9.3

6.9 Langerhans Cell Histiocytosis

1. What is langerhans cell histiocytosis? What is histology finding? - It is neoplastic proliferation of Langerhans cells (dendritic cells in skin and mucus membrane derived from monocytes). Histiocyte = tissue macrophage - Histology finding: ○ Characteristic Birbeck (tennis racket) granules on electron microscopy ○ Cells are CD1a and S100 +ve by imunohistochemistry

Fig: Birbeck granules characteristic of Langerhans cell histiocytosis 2. Describe clinical features of different types of langerhans cell histiocytosis. Disease

Clinical presentations

Letterer-Swie disease (acute disseminated langerhans cell histiocytosis)

Malignant proliferation of Langerhans cells

- Rapidly fatal due to multiple organ involvement - Classic pt is 3 year old - Presentation: • Skull rash, Lytic skull defect • Diabetes insipidus • Exopthalmos

WBC disorders Page 10.1

• Exopthalmos

- Classic features: ○ If you see person's name, it's malignant and you see rash ○ if disease has 2 person's name, pt is 100) and CRP too

6. How do you diagnose temporal arteritis? What's a caution point? • Do a vessel biopsy - see inflamed vessel wall with giant cells and intimal fibrosis • Granulomatous vasculitis Vascutis, HTN Page 1.1

• Granulomatous vasculitis • Vessel is affected segmentally. Therefore, take a long segment out for biopsy. Negative biopsy doesn't rule out disease.

Fig - temporal arteritis biopsy. M is the media, I is the intima, F is the area of fibrosis between media and intima that has narrowed the lumen, circle above M shows giant multinucleated cells, circle left of F shows inflammation. 7. What is treatment of temporal arteritis (HY)? • Corticosteroid. Treat soon because of high risk of blindness due to involvement of ophthalmic artery. 8. Contrast symptoms of temporal arteritis with Takayasu arteritis (aka pulseless disease) - a type of large vessel arteritis? • Takayasu arteritis is same as temporal arteritis with a couple of exceptions○ Affects mainly adults 5 days ○ Shrieking irritability - extremely irritable kid ○ Conjuctivitis sparring area right next to iris ○ Erythematous rash of palms and soles and any mucocutaenous membrane (ex - strawberry tongue) ○ Enlarged cervical lymph nodes 14. What artery is preferentially involved in Kawasaki disease? (HY) • Coronary artery Vascutis, HTN Page 1.3

• Coronary artery • Complication ○ thrombosis with MI (3 year old kid with MI) - due to endothelial damage and exposure of collagen and tissue factor ○ aneurysm with rupture ((imagine a kid driving kawasaki bike with his hands and legs, his HR goes up - so the disease affects heart mainly) 13. What is treatment of Kawasaki disease? • Asprin to prevent thrombosis (antiplatelet drug - prevents formation of thromboxane A2) • IVIG (intravenous immunoglobulins) • Disease is self-limited 14. Why don't you give asprin to kids with viral disease? • Because they can get Rye syndrome - encephalopathy and massive liver necrosis. 15. What is Buerger disease (medium vessel vasculitis)? How do you treat it? • It's necrotizing vasculitis involving digits. Presents with ulceration, gangrene, and autoamputation of fingers and toes. • Disease associated with Raynaud phenomenon - pale to blue to red color change in digits due to exposure to cold. Pale and blue color are due to vasospasm; red is due to return of circulation. • Disease is associated with smoking - treatment is smoking cessation (HY) Small vessel vasculitis (wegner granulomatosis, microscopic polyangitis, chug-strauss, and Henoch Schonlein) • The first 3 of these disease can lead to RPGN. • Henoch Schonlein has IgA deposition and can lead to IgA nephropathy Wegner Granulomatosis

Microscopic polyangiitis

Necrotizing vasculitis

Necrotizing vasculitis

Necrotizing granuloma present

Granulomas absent

C-ANCA positive

P-ANCA positive

Affects nasopharynx, lungs, and kidney

Affects lungs and kidney and other organs

Treatment - cyclophosphamide, corticosteroids. Relapse common

Treatment - cyclophosphamide, corticosteroid. Relapse common


Henoch-Schonlein purpura

Necrotizing vasculitis

Most common vasculitis in children

Necrotizing Granulomas present

Palpable purpura in buttocks pathognomic

P-ANCA positive

Vasculitis due to IgA immune deposition. Can lead to IgA nephropathy

See asthma and eosinophila - pt misdiagnosed with allergies often

Disease usually follows upper respiratory tract infection

Affects multiple organs including lung and GI involvement can cause GI pain bleeding heart Treat by steroids if necessary. Disease self limited.

16. What is Wegner Granulomatosis (a type of small vessel vasculitis)? • Necrotizing granulomatous vasculitis involving nasopharynx, lungs, and kidneys. (think weCner's diseaseVascutis, HTN Page 1.4

• Necrotizing granulomatous vasculitis involving nasopharynx, lungs, and kidneys. (think weCner's diseaseand imagine a 'C' in a human body passing through nasopharynx, lungs and kidneys). 17. What is presentation of Wegner Granulomatosis? • Usually affect middle-aged males • Sinusitis or nasopharyngeal ulceration • Hemoptysis with bilateral nodular lung infiltrates • Hematuria due to RPGN (HY) • Serum C-ANCA level correlate with disease activity 18. How do you diagnose Wegner Granulomatosis? How do you treat it? • Pt are C-ANCA (cytoplasmic - anti neutrophil cytoplasmic antibodies) positive. • Biopsy shows large necrotizing granuloma with adjacent necrotizing vasculitis. • Treatment is Cyclophosphamide and corticosteroids. Relapse is common.

Fig - large necrotizing granuloma seen in Wegner granulomatosis. Granulomas are absent in microscopic polyangiitis. 19. What is microscopic polyangiitis (type of small vessel vasculitis)? Contrast this disease with Wegner granulomatosis (WG). • Necrotizing vasculitis involving multiple organs (hence the name polyangiitis), especially lung and kidney (similar to WG). • It's very similar to WG but nasopharyngeal involvement and granulomas are absent. • Serum P-ANCA (perinuclear - anti neutrophil cytoplasmic antibodis) correlate with disease activity instead of C-ANCA. • Treatment is same as WG - corticosteroids and cyclophosphamide. Relapses are common. 20. What are C-ANCA and P-ANCA? • In C-ANCA, anticytoplasmic antibodies mainly target cytoplasm away from nucleus. In P-ANCA, anticytoplasmic antibodies mainly target cytoplasm in perinuclear area (hence the name - perinuclear). 21. What is Churg-Strauss syndrome ( a type of small vessel vasculitis)? • Necrotizing granulomatous vasculitis with eosinophils. • Involves multiple organs, especially lungs and heart. • Asthma and peripheral eosinophila. • P-ANCA correlate with disease activity.

Vascutis, HTN Page 1.5

22. Differentiate Churg-Strauss and microscopic polyangiitis. Churg-Strauss

Microscopic Polyangiitis

• Necrotizing granulomas with eosinophils present • No granulomas • Peripheral eosinophila and asthma present

• No eosinophila or asthma

• Involves heart and lung

• Involve lung and kidney

• P-ANCA correlate with disease activity

• P-ANCA correlate with disease activity

23. What is Henoch-Schonlein purpura (type of small vessel vasculitis)? • Vasculitis due to IgA immune complex deposition • Most common vasculitis in children 24 What is presentation of Henoch-Schonlein purpura? • Classic presentation is palpable purpura on buttocks and legs. Usually, purpura aren't palpable. It's palpable in this case due to vasculitis • GI involvement - GI pain and bleeding • IgA nephropathy leads to hematuria (HY) • Usually occurs following an upper respiratory tract infection - the infection generates IgA as IgA protects mucosal site. Too much IgA cause deposition and disease. 25. How do you treat Henoch-Schonlein purpura? • Disease is self-limited. Treat with steroids if severe. Disease may recur.

Vascutis, HTN Page 1.6


1. What are two types of hypertension? • Pulmonary htn • systemic HTN (systolic or diastolic BP >140/90) - 25% of US popn are hypertensive 2. What are primary and secondary hypertension? • Primary HTN is when we don't know the etiology. It represents 95% cases of HTN. 3. What are risk factors for primary HTN? • Age • Race - high risk for African Americans, low risk for asians • Obesity • Stress • High salt diet • Lack of physical activity 4. How does high sodium cause HTN? • Systolic BP is a function of stroke volume • Diastolic BP is a function of total peripheral resistance • Sodium increases blood volume and peripheral resistance so increases both systolic and diastolic BP. 5. Describe renal artery stenosis as cause of secondary HTN. (HY) • Low blood flow to justaglomerular apparatus causes release of renin. Renin converts angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by ACE in lung endothelium. Angiotension II increases BP by two ways ○ Powerful vasoconstrictor - increases diastolic BP ○ Stimulate adrenal medulla to secrete aldosterone - it increases sodium reabsorption and potassium excretion from DCT. Water follows sodium and body will have more water increases systolic BP. 6. What is clinical presentation of renal artery stenosis (RAS)? • Atrophy of the stenosed kidney • Increased blood renin 7. What are important causes of RAS? • Artherosclerois (classically seen in old males) • Fibromuscular dysplasia (classically seen in young females) - developmental defect of blood vessel wall that results in irregular thickening of large and medium sized arteries, specially the renal arteries. 8. Distinguish benign and malignant HTN. Benign


Mild or moderate increase in BP

Severe increase in BP (200/120 mm Hg)

Clinically silent

May arise from preexisting benign HTN or de novo

Vessels and organs are damaged over time

Pt presents with acute end organ damage - acute renal failure, headache, papilledema MEDICAL EMERGENCY - pt can have fibrinoid necrosis of blood Vascutis, HTN Page 2.1

MEDICAL EMERGENCY - pt can have fibrinoid necrosis of blood vessel wall

Vascutis, HTN Page 2.2


1. What is arteriosclerosis? What are it's 3 patterns? - Arteriosclerosis is hardening of arterial wall. - Patterns○ Atherosclerosis - thickening of intima due to plaque(occurs in medium and large sized vessels) ○ Arteriolosclerosis - thickening of small vessels. Wall thickens due to protein deposition (hyaline arteriolosclerosis) or hyperplasia of smooth muscle (hyperplastic arteriolosclerosis) ○ Monckeberg medial sclerosis - calcification of media. Not very clinically significant

Artherosclerosis 2. Describe histology of artherosclerosis. - Artherosclerosis is an intimal plaque that obstructs blood flow. It contains necrotic lipid core with a fibromuscular wall. The lipid core can undergo dystropic calcification.

Fig - artherosclerosis. M is the media, I is the intima, the circle represents the necrotic lipid core with cholesterol crystals. The necrotic core is surrounded by a fibromuscular wall. 3. What are 4 most common sites for artherosclerosis? - Note artherosclerosis occurs in large and medium sized vessels Abdominal aorta Vascutis, HTN Page 3.1

○ ○ ○ ○

Abdominal aorta Coronary arteries Popliteal artery Internal carotid artery

4. What are key risk factors for artherosclerosis? (HY)





Hypercholesteremia (LDL increases risk and HDL reduces)

Gender (male and postmenopausal females at high risk. Estrogen has protective effect on pre-menopausal females)


Genetics (positive family history)

Diabetes 5. What is pathogenesis of artherosclerosis? - Intima is damaged --> lipids gets between intima and media -->lipid is oxidized and then phagocytozed by macrophage --> this makes fatty streak. Fatty streak is seen as early as teenagers. - Inflammation, healing and increased deposition of lipid occurs. A fibromuscular cap occurs due to inflammation and healing. 6. a)

What are some complication of artherosclerosis? It's complications account for >50% of disease in western world Artherosclerosis is asymptomatic until occlusion is >70% (HY) Stenosis of medium sized vessels (vessels that feed organs) ○ Peripheral vascular disease (popliteal A) ○ Angina (coronary A) ○ Ischemia bowel disease (mesenteric A) b) Plaque rupture with thrombosis ○ MI (coronary A) ○ Stroke (MCA) c) Plaque rupture with embolization ○ Results in artherosclerotic emboli (hallmark is cholesterol cleft in emboli)

Fig - presence of cholesterol cleft in embolus is hallmark of artherosclerotic embolus. d) Aneurysm due to weak wall - MOA - usually media and adventitia receives nutrient by diffusion from lumen. As artherosclerotic plaque increases, it creates diffusion barrier resulting in atrophy Vascutis, HTN Page 3.2

from lumen. As artherosclerotic plaque increases, it creates diffusion barrier resulting in atrophy of media and adventitia. Arteriolosclerosis 7. What is arteriolosclerosis? - Narrowing of small arterioles. - Causes - deposition of hyaline or hyperplastic media. 8. What is hyaline arteriolosclerosis? - Proteins leaking into vessel wall causes vascular thickening - Seen as pink hyaline on microscopy

Fig - pink hyaline in vessel wall characterstic of hyaline arteriolosclerosis 9. What are 2 causes of hyaline arteriolosclerosis? (VHY) - Benign HTN - high pressure forces protein into the vessel wall - Diabetes - non-enzymatic glycosilation of basement membrane makes vessel wall leaky and protein leaks in. This is how diabetes can cause nephrotic syndrome (diabetic nephropathy). 10. What is key consequence of hyaline arteriolosclerosis? (HY) - Reduced vessel diameter leads to end organ ischemia - Classically produces glomerular scarring (arteriolonephrosclerosis) which progress to chronic renal failure (that's how diabetic pt with long standing HTN die

Vascutis, HTN Page 3.3

Fig - glomerular scarring seen in arteriolonephrosclerosis 11. What is hyperplastic arteriolosclerosis? - Vessel wall thickens due to hyperplasia of smooth muscle - 'Onion-skin' like appearance

Fig - onion skin like appearance of blood vessel in hyperplastic arteriolosclerosis 12. What causes hyperplastic arteriosloclerosis? - Malignant HTN - this leads to acute renal failure (ARF) and fibrinoid necrosis of vessel 13. What are consequences of hyperplastic arteriosclerosis? - Reduced vessel diameter leads to end organ ischemia - Malignant HTN may lead to fibrinoid necrosis of vessel wall (another cause of fibrinoid necrosis is vasculitis) - Classically causes ARF with 'flea-bitten' appearance - flea-bitten necrosis is due to pin point hemorrhages (HY) Vascutis, HTN Page 3.4

Fig - flea bitten kidney classic of hyperplastic arteriolosclerosis due to pin point hemorrhage leads to ARF. Contrast glomerular scarring in chronic renal failure due to arterionephrosclerosis Monckeberg medial calcific sclerosis 14. Describe Monckeberg medial sclerosis. - Calcification of media - Does not obstruct lumen, therefore not clinically significant - Seen as incidental finding in X-ray or mammography

Fig- Enclosure shows monckeberg medial sclerosis. Note how it's limited to media and doesn't have much effect on lumen diameter.

Vascutis, HTN Page 3.5

Fig - mammography showing Monckelberg medial calcification of blood vessel

Vascutis, HTN Page 3.6

Aortic Dissection and Aneurysm

1. What is aortic dissection? - Blood leaks into the media through a break in intima and it rips the media in half

Fig - aortic dissection 2. What are two things required for aortic dissection? a. A ton of stress - therefore it mainly happens in proximal 10 cm of aorta b. Pre-existing weakness of media - caused by HTN or inherited defect of connective tissue 3. How does HTN weaken media and lead to aortic dissection? - HTN leads to hyaline arteriolosclerosis of vaso vasorum (blood vessel that supplies media and adventitia of aorta). Media weakens due to low supply of blood. 4. What is the most common cause of aortic dissection? - HTN 5. What are some connective tissue disorders that can lead to dissection? - Marfan syndrome - mutation in fibrillin-1 protein. Fibrillin is the base on which elastic fibers are laid down. Media has lots of elastic fibers - Ehlers-Danlos syndrome - mutation in collagen or proteins that interact with collagen. 6. What is clinical picture of aortic dissection? - Presents with tearing chest pain that radiates to the back - Most common cause of death is cardiac tamponade. Other causes include aorta bursting open and obstruction of arteries that branch off aorta. Aneurysms 7. What are two classic location of aneurysm? - Thoracic aneurysm - Abdominal aneurysm 8. What is a classic cause of thoracic aneurysm? - Tertiary syphilis- syphilis is end arteritis disease. It affects vaso vasorum and poor blood supply weakens aortic wall. Weak vessel wall leads to aneurysm - Tree bark appearance of aorta is classic finding - as vaso vasorum is affected, poor blood supply leads to fibrosis and scarring

Vascutis, HTN Page 4.1

Fig - normal aorta (left); tree bark like aorta in tertiary syphilis (right) 9. -

What are complications of thoracic aneurysm? Aortic insufficiency (HY) - as aorta dilates, the valves are pulled apart and can't close well Compression of mediastinal structures Thrombosis in wall of aneurysm due to disruption in laminar blood flow. It can embolize.

10. What is the most common site of abdominal aortic aneurysm (AAA)? Why is this the most common site? - Below the renal arteries and above aortic bifurcation - Vasa vasorum stops at the level of renal artery bifurcation. Therefore, artherosclerosis of aorta below this level leads to high level of media atrophy due to poor diffusion of nutrient and gases. The weak aortic wall leads to aneurysm. (note - most common location of artherosclerosis in human is abdominal aorta).

Fig: normal abdominal aorta (left); AAA (right) - note calcification of vessel wall and thrombosis 11. What is presentation of AAA? - >60 year old smoker male with HTN - Pulsatile abdominal mass that grows with time 12. What is complication of AAA? - Rupture, especially when >5cm in diameter - Presents with triad of hypotension, pulsatile abdominal mass and flank pain.

Vascutis, HTN Page 4.2

Chapter 8: Cardiac Pathology

8.1 Ischemic Heart Disease


Infarction - tissue necrosis due to lack of oxygen Ischemia - inadequate blood supply to an organ Hypoxemia - (PaO2 < 60mm Hg) Early MI - 50% thickness of airway.

5. With what is chronic bronchitis highly associated? - Smoking

6. What are the clinical features of chronic bronchitis? -

productive cough due to excessive mucous production, cyanosis ('blue bloaters') - mucus plugs trap CO2; increased risk of infection (anytime you plug a tube, it increases risk of infection behind the block) Reid index Increases to >50 from 25 mm Hg (normal is 10 mm Hg) is pulmonary hypertension 2. What are causes of pulmonary HTN? - Causes can be divided to primary and secondary. Primary pulmonary HTN

Secondary pulmonary HTN

- Etiology unknown (some familial forms related to BMPR2 mutation (HY) - see proliferation of vascular smooth muscle)

- Hypoxemia (COPD, interstital lung disease) - Increased volume in pulm circuit (congenital heart disease) - Recurrent pulmonary embolism (HY)

- Classically seen in young adult females 3. What are clinical characters of pulmonary hypertension? - Characterized by atherosclerosis of pulmonary trunk (HTN leads to artherosclerosis) and smooth muscle hypertrophy of pulmonary arteries, intimal fibrosis - See plexiform lesions with severe long standing disease - Right ventricular hypertrophy with cor pulmonale - Exertional dyspnea and right sided heart failure - if you see a young woman with exertional dyspnea, think pulmonary hypertension

Fig: plexiform changes - tuft of capillaries that arise as a complication of HTN

Pulmonary Page 5.1

9.7 Respiratory Distress Syndrome (RDS)

Acute respiratory distress syndrome 1. What is ARDS? - Respiratory distress due to damage to alveolar-capillary interface (diffuse alveolar damage). Protein rich fluid leaks into air sac. Protein rich fluid and epithelial cells are reorganized to make hyaline membrane. - Membrane blocks air exchange; membranes are sticky and promote alveoli collapse.

Fig: hyaline membrane seen on alveoli represents ARDS (right); diffuse whiteout seen in Xray in ARDS (left) 2. What are causes of ARDS? - Mechanism is activation of neutrophils that induces protease and free radical damage of type I and II pneumocytes. - It's occurs secondary to (100's of causes) ○ Sepsis ○ Infection ○ Shock ○ Trauma ○ Aspiration ○ Pancreatitis ○ DIC ○ Hypersensitivity reactions ○ Drugs 3. -

What's presentation of ARDS? Hypoxemia and cyanosis (due to thickened diffusion barrier and collapse of air sacs) White out on chest x-ray Hyaline membrane in alveoli on biopsy

4. How do you treat ARDS? What makes recovery complicated? - Ventilation with positive end-expiratory pressure (PEEP) - every time patient breathes out, the lung collapses a little more due to hyaline membrane. Positive pressure at end of respiration prevents this. - Treat underlying cause - Recovery may be complicated due to interstitial fibrosis. Type II pneumocytes (stem cells) are damaged and new cells can't be generated. (HY)

Pulmonary Page 6.1

Neonatal respiratory distress syndrome 1. What is neonatal respiratory distress syndrome? - Respiratory distress in newborn due to inadequate surfactant production. Alveoli collapse and hyaline membranes are seen. 2. How is enough surfactant production determined in fetus? - Surfactant (phosphatidylcholine aka lecithin) is produced by type 2 pneumocytes from 28 weeks; enough levels are not reached until 34 weeks (childbirth occurs in 40th week) - Amniotic fluid ratio of lechitin to sphingomyelin >2 indicates enough surfactant production 3. What are some causes of neonatal respiratory distress syndrome? - Premature birth - Caesarian section delivery - child lacks stress induced steroids; steroids increase surfactant production and release from pneumocytes - Maternal diabetes - insulin decreases surfactant production (high blood sugar from mom causes high insulin production in baby) 4. -

What is presentation of neonatal respiratory distress syndrome? Hypoxemia and cyanosis Ground glass appearance on X-ray Increased use of respiratory muscle; use of accessory muscle, grunting

5. What are it's complication? - High risk of patent ductus arteriosus and necrotizing enterocolitis (decreased - Supplemental oxygen used for treatment increases risk of free radical injury ○ retinal injury leads to blindness (O2 treatment for ARDS imp cause of blindness in neonates) ○ lung damage leads to bronchopulmonary dysplasia

Pulmonary Page 6.2

9.8 Lung Cancer

1. What are key risk factors for lung cancer? - Cigarette smoking (85% of lung cancer) ○ Risk directly linked to duration and amount of smoking (pack years) - Radon (2nd most common cause) - most common ionizing radiation exposure in USA ○ Colorless, odorless gas ○ Decay product of uranium ○ Found in soil, accumulates in closed space (basement) - Asbestos 2. -

What is carcinogenicity of cigarette smoking? Contains > 60 carcinogens Polycyclic aromatic hydrocarbons and arsenic are particularly carcinogenic Cancer risk directly increases with duration and amount of smoking (pack years)

2. -

What is presentation of lung cancer? Average age at presentation is 60. Most common cause of cancer death in USA Nonspecific presentation ○ Cough, wt loss, hemoptysis, post obstructive pneumonia

3. -

How do you diagnose lung cancer? Diagnosis requires biopsy Imaging reveals solitary nodule (coin-lesion) - growing lesion concerning Coin lesions also seen in (HY): ○ Granulomas - TB, fungus (ex - histoplasma in midwest) ○ Bronchial hamartoma - benign tumor of lung tissue + cartilage; often calcified in imaging ○ Harmartoma - disorganized mass that grows at same rate as surrounding tissue; made of same cells that makes the tissue

4. Describe the TNM staging of lung cancer. - T - tumor size i. Pleural involvement classically seen in adenocarcinoma (adenocarcinoma is peripheral) ii. Obstruction of SVC (superior vena cava syndrome) - distended head and neck veins with edema and blue discoloration of arms and face iii. Involvement of recurrent laryngeal nerve (hoarseness) or phrenic nerve (diaphragmatic paralysis) iv. Horner's - compression of sympathetic chain (ptosis, anhydrosis - in skin, miosis) - especially if tumor is at apex of lung (pancoast tumor) - N○ Spread to hilar and mediastinal lymph nodes - M○ Unique site of distant metastasis is adrenals (HY) ○ Others - brain, bone, liver 5. What's prognosis of lung cancer? - Poor (no effective screening method) - 5 year survival rate is 15% 6. What are two categories of lung cancer? Small cell carcinoma (15% of all lung carcinoma)

Non-small cell carcinoma (85% of all lung carcinoma)

Pulmonary Page 7.1

- Adenocarcinoma (40%) - glands or mucus production - Squamous cell carcinoma (30%) - keratin pearls or intercellular bridges - Large cell carcinoma (10%) - none of above features seen - Carcinoid tumor (5%) - Usually no amenable to surgery (treat with chemotherapy and radiation)

- Treat upfront with surgery (doesn't respond well to chemotherapy)

7. What are different types of lung cancer?


Cancer type



Small Cell carcinoma

- Treat with chemotherapy


Non-small cell carcinoma

Subtype Squamous cell carcinoma

Adenocarcinoma Broncheoalveolar carcinoma (Adenocarcinoma in situ) Large cell carcinoma (Bronchial) carcinoid tumor 3




- related to asbestos

- Common origin of metastasis - breast, colon

8. Classify the different types of lung cancer. Neuroendocrine (NE) tumor

Adenocarcinoma Related to smoking - small, large, squamous, adeno

Paraneoplastic syndrome

Undifferentiat Excellent ed and poor prognosis prognosis

- Small cell carcinoma (poorly differentiated NE cells)

- Adenocarcinom - Squamous cell carcinoma a (most common in male smokers

- Squamous cell carcinoma (PTHrp)

- Small cell carcinoma

- (Bronchial) - Bronchioalveola - Small cell carcinoma (male carcinoid tumor r carcinoma smokers) (well (adenocarcinom differentiated a in situ) NE cells)

- Bronchoal veolar carcinoma

- Small cell - Large cell carcinoma carcinoma (ADH, ACTH, Ab for Ca channel)

- Adenocarcinoma (most - Large cell common in female smokers carcinoma (Band non-smokers) HCG) broncheoalveolar carcinoma not associated with smoking - Large cell carcinoma 9. Describe the following types of cancer.





Small cell - Poorly differentiated small cell - Male smokers Central carcinoma and very aggressive (99% of small cell carcinoma pt are - Arise from neuroendocrine cells (Kulchitsky cells) smokers) - Chromogranin +ve (less +ve Pulmonary Page 7.2

Remarks - Associated with 5A and 1B - Produces ACTH - Produces ADH - Produces Ab for EatonLambert syndrome

- Chromogranin +ve (less +ve than carcinoid tumor)

Lambert syndrome (presynaptic Ca channel Ab) (paraneoplastic syndromes) - Anti-neuronal antibody syndrome (limbic encephalitis, cerebellar degeneration, opsoclonus, GI dysmotility, poly radiculopathy) - Amplification of myc oncogene - LOVES TO GO TO BRAIN - give prophylactic cranial irraditation - MOST AGGRESSIVE TYPE OF LUNG CANCER

Adenocar - Glands or mucin cinoma

- Most common tumor in nonsmokers and female smokers


- Most common tumor in male smokers


Fig: glandular structure in adenocarcinoma Squamous - Keratin pearls or intercellular cell bridges (by definition) carcinoma

- May produce PTHrp (paraneoplastic syndrome) - Hilar mass from bronchus - Associated with double C • HyperCalcemia- due to PTHrp • Cavitation

Figintracellular bridge

Fig: keratin pearl Large cell - Poorly differentiated and highly - Smoking carcinoma anaplastic cells (no keratin pearls, intercellular bridges, glands or mucin)

Central or peripheral

(Bronchial - Well differentiated ) neuroendocrine cells; Carcinoid chromogranin positive tumor

Central or - MOST COMMON PRIMARY peripheral LUNG CANCER IN CHILDREN (when central, - Low grade malignancy; rarely, can cause carcinoid makes polyp like mass in syndrome - caused due to bronchus) release of vasoactive substance (mainly serotonin) flushing, diarrhea, restrictive cardiomyopathy due to

- Not related to smoking

Pulmonary Page 7.3

- Poor prognosis - Poor response to chemotherapy; remove surgically - Paraneoplastic - may secrete B-HCG

Carcinoid tumor

(when central, makes polyp like mass in bronchus)

Low grade malignancy; rarely, can cause carcinoid syndrome - caused due to release of vasoactive substance (mainly serotonin) flushing, diarrhea, restrictive cardiomyopathy due to endocardial fibrosis

Fig: chromogranin positivity Bronchiol - Columnar cells that grow along - Not related to oalveolar preexisting bronchioles and smoking carcinoma alveoli; arise from clara cells (adenocar cinoma in situ)


- Excellent prognosis - Pneumonia like consolidation on imaging

Canon-ball nodules on imaging

- More common than primary tumors

Fig: normal alveoli top right; columnar cells on rest Metastasi - Most common source are s breast and colon carcinoma

Mesotheli - See psammoma bodies in oma biopsy (concentric calcifications - other HY cancer - papillary thyroid, meningioma, papillary serous ovarian)

- Highly associated with asbestos exposure (lung cancer more common in asbestos exposure)

- Malignant tumor of mesothelial cells (mesothelium is a membrane of simple squamous cells that lines body cavities: pleura , peritoneum, mediastinum and pericardium) - Tumor encases the lung

- Small cell carcinoma is poorly differentiated neuroendocrine tumor; carcinoid tumor is well differentiated neuroendocrine tumor. - Neuroendocrine cells have neurosecretory granules; chromogranin stains positive for neurosecretory granule. Pulmonary Page 7.4

- Neuroendocrine cells have neurosecretory granules; chromogranin stains positive for neurosecretory granule.

Pulmonary Page 7.5

9.9 Pleura

1. Describe anatomy of pleura? - It's lined by mesothelial cells - It produces pleural fluid 2. What are differences between spontaneous and tension pneumothorax? Spontaneous pneumothorax

Tension pneumothorax

- Often due to rupture of emphysematous bleb

- Often due to penetrating chest wall injury

- Often seen in young adults - Xray - trachea deviates to side of - X-ray - trachea pushed to opposite side of injury; medical collapse emergency; put chest tube

Fig: spontaneous pneumothorax (no tracheal shift) 3. Describe mesothelioma (malignant neoplasm of mesothelial cells). - Presentation: ○ Recurrent pleural effusion (mesothelial cells make pleural fluid) ○ Tumor encases the lung - Risk factor: Asbestos (lung cancer far more likely) Pulmonary Page 8.1

○ Asbestos (lung cancer far more likely)

Fig: mesothelioma (tumor encasing the lung)

Pulmonary Page 8.2

Chapter 10: Gastrointestinal Pathology

10.1 Oral Cavity

1. Describe the following oral cavity pathologies Presentation


Cleft palate - Cleft lip and palate usually occur and lip together -

Due to failure of facial prominence to fuse one superior, two from sides and two from inferior - in early pregnancy

Apthous ulcer

- Painful superficial ulceration of oral - Arise in relation to stress but resolves mucosa - gray base (granuloma) with spontaneously surrounding erythema

Behcet syndrome

- Recurrent apthous ulcer, genital ulcer and uveitis

- Can be seen in viral infection - Unknown etiology

Oral herpes - Dew drops in petal appearing painful - HSV 1 - usually occur in childhood ulcer - Virus remains dormant in trigeminal ganglia; stress and sunlight can activate virus and cause ulcers again 2. Describe the squamous cell carcinoma of oral cavity.


- Malignant neoplasm of squamous epithelia of oral cavity

Risk factor

- EtOH and tobacco

Common site

- Floor of mouth

Precursor lesions

- Leukoplakia • White plaque that can't be removed (unlike candida) - represents dysplasia - Erythroplakia (red plaque) • Vascularized leukoplakia and highly suggestive of squamous cell dysplasia

3. Differentiate leukoplakia from hairy leukoplakia - Both can't be scraped off. - Hairy leukoplakia is caused by EBV, usually seen in immunocompromized patients on side of tongue and is NOT precancerous - Leukoplakia is cancerous.

Fig: erythroplakia (right), leukoplakia (middle), hairy leukoplakia (left - not precancerous)

GI Page 1.1

10.2 Salivary Gland

1. Describe the following pathologies of the salivary gland. Presentation Mumps


- Bilateral inflammation Mumps virus of salivary glands - Orchitis - Pancreatitis - Aseptic meningitis

Sialaden - Mostly unilateral tis inflammation of salivary gland



- Increased amylase (can be from pancreas too)

Sterility, especially in teenagers

- Mostly due to obstructive stone leading to staph Aureus infection

2. Describe the following cancers of salivary gland (SG) Cancer




Pleomorphic adenoma

Most common tumor of SG

Mostly in parotids

Stromal (cartilage) and - Mobile painless circumscribed epithelial cells mass in angle jaw biphasic tumor - High recurrence; irregular margins and extension across capsule makes resection hard - Rarely becomes carcinoma - if it does, it will involve CN 7

Warthin tumor

2nd most common tumor of SG

Mostly in parotids

Cystic tumor with germinal center and lots of lymphocytes

Mucoepiderm Most common Mostly in oid carcinoma malignant tumor parotids of SG

Mucinous and squamous cell

GI Page 2.1


- Involves CN 7

10.3 Esophagus

1. Talk about features of following pathologies. Pathology



Tracheoesop Most common variant has proximal esophageal atresia with hageal fistula distal esophagus arising from trachea

- Vomiting, - polyhydroamnio s, - aspiration, - abdominal distension

Esophageal web

Protrusion of esophageal mucosa, most often in upper esophagus

- Dysphagia for poorly chewed food

Plummer venson syndrome

○ Severe iron deficiency anemia ○ Esophageal web ○ Beefy red tongue due to atrophic glossitis (inadequate cell turnover) ○ Usually seen in post-menopausal woman

Zenker diverticulum

- (false diverticulum) - only mucosa protrudes in upper esophagus at junction of esophagus and pharynx

- Halitosis (rotting food in diverticulum) - Dysphagia - Obstruction


- Longitudinal laceration of mucosa at gastroesophageal

- Painful

GI Page 3.1

Mallory Weiss syndrome

- Longitudinal laceration of mucosa at gastroesophageal junction - Cause - vomiting - usually alcoholism of bulimia - Risk for Boerhaave syndrome

Boerhaave syndrome

- Esophageal rupture leading to air in mediastinum and subcutaneous emphysema (crepitis)

- Painful hematemesis

Esophageal varices Definition

- Dilated submucosal veins in lower esophagus due to portal hypertension


- Esogpageal vein is connected to portal vein via left gastric vein

Epidemiology - Most common cause of death in cirrosis pt Presentation - Asymptomatic or present as painless hematemesis Achalasia Definition

- Disordered esophageal motility with inability to relax lower esophageal sphincter (LES) due to damage of ganglion cells in myenteric plexus


- Chagas disease (HY) - Idiopathic

Clinical features

- Dysphagia of solid and liquid food - Putrid breath (rotting) - High LES pressure on esophageal manometry - Bird beak sign on X-ray

GI Page 3.2

Complicatio - Increased risk for squamous cell carcinoma n Gastroesophageal reflux disease (GERD) Definition

- Reflux of stomach acid due to reduced LES tone

Risk factor

- Hiatal hernia - EtOH, tobacco - Obesity, fat rick diet - Caffeine

Clinical features - Heartburn (mimics cardiac chest pain) - Asthma (adult-onset) and cough - Damage to enamel of teeth Complication

- Barret esophagus (in 10% of pt with GERD) and strictures

Barret's esohagus Definition

- Metaplasia in lower esophageal mucosa from stratified squamous epithelium to columnar epithelium with goblet cells

Complicatio - May progress to adenocarcinoma n Histology

Fig: squamous epithelia on left, columnar epithelia with goblet cells (right) - barret's esophagus Esophageal carcinoma Adenocarcinoma

Squamous cell carcinoma

Epidemiolo - Most common esophageal cancer in western gy world (classically seen in lower 1/3rd of esophagus)

- Most common esophageal cancer worldwide

Risk factor

- EtOH and tobacco (most common cause) - Achalasia - Esophageal web (ex- PlummerVinson synd)

- Barret esophagus

GI Page 3.3

Vinson synd) - Esophageal injury (ex - lye ingestion) - Very hot tea Prognosis

- Poor (both type presents late)


- Progressive dysphagia of solid and liquid food - Weight loss, pain - Hematemesis - SCC may have hoarse voice (recurrent laryngeal nerve involvement) and cough (tracheal involvement) (HY)

Lymph node involvement

If cancer in upper 1/3rd of esophagus

Cervical nodes

Middle 1/3rd

Mediastinal or tracheobronchial nodes

Lower 1/3rd

Celiac and gastric nodes

GI Page 3.4

10.4 Stomach Sections of stomach

Gastroschisis and Omphalocele (schisis = break; omphalo = navel; cele = swelling) Gastroschisis

- Absence of anterior abdominal wall and exposure of abdominal contents outside


- Persistent herniation of bowel into umbilical cord - Due to failure of herniated intestines to return to body cavity, contents are covered by peritoneum and amnion of umbilical cord

Fig: omphalocele (middle), gastroschisis (right) Pyloric stenosis Definition

- Congenital hypertrophy of pyloric smooth muscle

Epidemology - M>F - Presents after 2 weeks of birth Presentation - Visible peristalsis and projectile non-bilious (non-green) vomiting after eating - Olive like mass on abdomen

Fig: visible peristalsis after eating in a kid with pyloric stenosis Treatment

- Myotomy (cut open pyloric sphincter

Acute and chronic gastritis GI Page 4.1

Acute and chronic gastritis Acute gastritis

Chronic gastritis

Definition - Acidic damage to stomach mucosa Defense against acid

- Chronic inflammation of stomach mucosa that leads to intestinal metaplasia

- Mucin produced by foveolar cells - Bicarb secretion - Normal blood supply (provides nutrition and picks up acid

Fig: intestinal metaplasia seen in chronic gastritis Etiologies - Severe burn (aka Curling ulcer) - due to loss of blood supply due to hypovolemia - Increased intracranial pressure (aka Cushing ulcer) - causes increased stimulation of vagus nerve and increased acid production - NSAIDs - decrease PGE2 (PEG2 decreases acid production, stimulate mucus, bicarb production and increases blood flow) - Chemotherapy - Shock - Heavy alcohol consumption

- Chronic autoimmune gastritis - Chronic H. Pylori gastritis

Differentiate chronic autoimmune gastritis and chronic H pylori gastritis.

Chronic autoimmune gastritis Defn

Chornic H pylori gastritis

- T cell mediated damage to gastric parietal cells (type 4 - H pylori produces urease to create basic environment; and hypersensitivity) protease damages mucosal defense - acidic damage to stomach


- Most common cause of gastritis (90%) - Antrum is most common site

Cli. Feat.

- Atrophy of mucosa and intestinal metaplasia (stomach - Intestinal metaplasia - high risk of intestinal type biopsy looks like intestine) - high risk of stomach adenocarcinoma of stomach adenocarcinoma - Epigastric abdominal pain - Achlorhydria (low acid) with increased gastrin levels - Increased risk of ulceration and antral G cell hyperplasia - Megaloblastic anemia (pernicious anemia) due to lack of IF


- see Ab against parietal cells and/or intrinsic factor (IF)



- +ve urea breath test - Stool antigen seen - Triple therapy (PPI + marcolide (clarithromycin) + amoxicillin - Intestinal metaplasia, gastritis and ulcer goes away after treatment

Increased risk of gastric adenocarcinoma (intestinal type) GI Page 4.2

Increased risk of adenocarcinoma (intestinal type) and MALToma



Peptic ulcer disease Definition - Solitary mucosal ulcer involving proximal duodenum (90% of cases) or distal stomach (10%) Differenc es

Duodenal ulcer

Gastric ulcer


- 95% due to H. pylori - Rarely due to Zolinger Ellision (ZE) syndrome

- 75% due to H. pylori - NSAID use - Bile reflux


- Epigastric pain that improves with meal

- Epigastric ulcer that worsens with meal


- Mostly in anterior duodenum.

- Mostly in lesser curvature of antrum


- If ulcer in posterior duodenum, rupture may lead to bleeding from gastroduodenal artery or pancreatitis

- Risk of bleeding from left gastric artery


- Ulcer with hypertrophy of Brunner glands

Risk of carcinoma

- Duodenal ulcers almost never malignant (duodenal carcinoma - May be caused by gastric extremely rare) carcinoma (intestinal subtype)

How do you differentiate if gastric ulcer is due to gastric carcinoma or not? Benign gastric peptic ulcer

Malignant gastric peptic ulcers (intestinal type)

- Usually small (2 cm Villous histology

Familial adenomatous polyposis (FAP) Presentation - Presence of 100 or 1000's of adenomatous colonic polyps - Will progress to cancer by 40 year (remove colon prophylactically) Mutation

- Autosomal dominant - APC mutation (chromosome 5)

1. Describe the following syndromes associated with FAP. Gardner syndrome

- FAP + fibromatosis + osteoma - Fibromatosis - usually presents as desmoplasia in retroperitoneum and destroy local tissue (non-neoplastic proliferation of fibroblasts) - Osteoma - benign tumor of bone; usually presents in skull

Turcot syndrome

FAP + CNS tumor (medulloblastoma and glial tumor) - you put turban on head

Juvenile polyp, juvenile polyposis and Peutz-Jeghers syndrome 1. Differentiate between the above three.

Juvenile polyp

Juvenile polyposis

GI Page 8.2

Peutz-Jeghers syndrome (aka heriditary intestinal

(aka heriditary intestinal polyposis) Sporadic, in children 80% of cases) - Presentation ○ Charcod's triad (biliary colic (RQU pain), fever, jaundice) ○ Reynaud's pentard (Charcod's triad + hypotension + altered mental status) - indicates sepsis as opposed to cholangitis only 12. Describe gallstone ileus. - Due to cholecystitis and fistula formation between gall bladder and small bowel, stone might enter small bowel and obstruct it. 13. -

Describe gallbladder carcinoma, it's risk factor, presentation and prognosis. It's adenocarcinoma of glandular epithelium of gallbladder wall Gallstones are major risk factors, esp with procelain gallbladder Presentation ○ Cholecystitis in old woman (cholecystitis is a disease of 40-50 year olds) - Poor prognosis.

Fig - gallbladder adenocarcinoma Liver and pancreas Page 2.3

Fig - gallbladder adenocarcinoma Choledocolithiasis 14. Describe clinical features of choledocolithiasis. - Stones within the biliary tree - 90-95% of pt with choledocolithiasis have cholelithiasis. But only 15% of pt with cholelithiasis have choledocolithiasis. - Lab finding ○ Contrast to cholelithiasis, we see sign of biliary tree blockage  Increased alk phosphatase  Increased bilirubin

Liver and pancreas Page 2.4

11.3 Liver: Jaundice 1. Explain the pathway of Bilirubin metabolism.

Note: conjugated bilirubin and direct bilirubin are same thing; non -conjugated and indirect are same.

UGT is Uridine glucuronyl transferase 2. What is significance of bile? - Bile is the only way of cholesterol excretion - Bile is the main way of copper and iron excretion. 3. What is presentation of jaundice? - First sign in scleral icterus (yellow sclera). Later see yellow skin - Occurs due to serum bilirubin >2.5mg/dl 4. Describe the following diseases of hyperbilirubinemia.


Lab values


Clinical features

Extravascular hemolysis (aka ineffective hemolysis)

High UCB

Too much UCB overwhelm liver

- Dark urine (increased urobilinogen) - High risk for pigmented bilirubin gallstones

Physiologic jaundice of newborn

High UCB

Newborn has transiently low UGT

- UCB is fat soluble and can deposit in basal ganglia (kernicterus) leading to neuro defect and death - Treatment - phototherapy - makes UCB water soluble and can be excreted by kidney (HY)

Gilbert syndrome

High UCB

Mildly low UGT activity (autosomal

- Jaundice during stress (ex - infection);

Liver and pancreas Page 3.1

Gilbert syndrome

High UCB

Mildly low UGT activity (autosomal recessive)

- Jaundice during stress (ex - infection); otherwise clinically silent

Crigler-Najjar syndrome

High UCB

Absent UGT

- Kernicterus, usually fatal

Dubin-Johnson syndrome

High CB

Low bilirubin canalicular transport protein (autosomal recessive)

- Dark liver (HY) (otherwise clinically silent)

Rotor syndrome

High CB

Low bilirubin canalicular transport protein (autosomal recessive)

- Lacks liver discoloration; otherwise same as Dubin-Johnson

Biliary tract obstruction (obstructive jaundice)

High CB High alk phosphatas e Low urine urobilin

Seen with gallstones, pancreatic carcinoma, cholangiocarcinoma, parasites, liver fluke

- Dark urine and pale stool - Pruritus due to increased plasma bile acids - Hypercholesterolemia with Xanthoma (bile is major way of cholesterol excretion) - Steatorrhea with malabsorption of fat soluble vitamin

Viral hepatitis

High CB and Inflammation disrupts inflammation UCB and small bile ductules

- Dark urine (due to CB) - Normal or low urine urobilinogen (CB is leaking out to blood and not going to duodenum)

Notes - Unconjugated bilirubin can't be excreted by urine as it's fat soluble. It floats in blood until it finds exit. - Conjugated bilirubin is water soluble, can leak out to blood and will go to urine and make it dark

Liver and pancreas Page 3.2

11.3 Liver: Hepatitis

1. What are true liver function tests (LFT)? - True liver function test tests for synthetic ability of liver ○ PT (INR) - most sensitive LFT ○ Albumin ○ Bilirubin 2. What are other LFT? - Aminotransferases ○ Aspartate aminotransferase (AST) - found in mitochondria. (also increases in muscle injury and MI) ○ Alanine aminotransferase (ALT) - found in cytosol (better test for hepatocyte injury than AST) - Alkaline phosphatase - most sensitive test for cholestasis (also present in bone) 3. -

Some notes on LFTIf aminotransferase>alk phos --> hepatocyte injury If alk phos > aminotransferase --> cholestatic injury If AST>ALT by >2:1 and if both are AST, usually viral or NAFLD

4. What does ALT>1000 IU/ml indicate? - It indicates severe acute hepatitis and has limited etiologies○ Shock liver (hepatic ischemia) ○ Drug induced liver injury ○ Acute viral injury 5. What does PT measure? - Prothrombin time (PT) measures time to convert prothrombin to thrombin. Therefore, it measures activity of liver derived factors 2, 7, 9 and 10. If pt's PT is low despite enough vit K intake, it's synthetic dysfunction. 6. What does the following findings indicate? Findings


Murphy's sign (inspiratory arrest during palpation of RUQ) Cholecystisis Charcot's triad (RUQ pain, fever, jaundice)




5. • • •

What are most common cause of ESLD? Hep C NASH EtOH

6. • • • •

What are signs of ESLD? Increased estrogen (gynecomastia, testicular atrophy) - liver converts estrogen to androgens Ascites, jaundice Hepatic encephalopathy- asterexis, clonus Palmar erythema, spider angiomata

Liver and pancreas Page 4.1

Viral hepatitis 1. What are some causes of viral hepatitis? - Hepatitis virus A-E (most hep C leads to chronic hepatitis; Hep A,E mainly acute only) • Acute hepatitis can progress to chronic cases • Other causes include CMV and EBV 2. Describe presentation of viral hepatitis. - Presentation○ Jaundice (mixed CB and UCB) with dark urine (due to CB) ○ Fever, malaise and nausea ○ Elevated liver enzyme (ALT>AST) ○ Symptoms last < 6 months (if >6 months, it's called chronic hepatitis) 3. Describe histology and pathophysiology of acute viral hepatitis. - Histology○ Viral damage occurs both in between hepatocytes and in portal tracts. - Pathophysiology○ For Hep virus, it's not the virus that causes the damage; it's the CD8 cells that kill hepatocytes. 4. What is a common complication and histology of chronic hepatitis? - Complication - Cirrhosis - Histology - Inflammation predominantly involves portal tract; not much damage to liver parenchyma.

Fig - L is liver parenchyma, P is portal tract. Note inflammation is mainly in portal tract only. 5. Describe Hep virus A and E. Transmission

Hep A

Hep E

- Feco-oral - Common in travelers

- Feco-oral - Commonly acquired from uncooked seafood or contaminated water

Acute/chronic - Mainly acute - Mainly acute only only Active infection marker

- See Hep E

- Presence of IgM marks active infection; presence of IgG marks prior infection that's resolved or immunization (immunization for Hep A only) Liver and pancreas Page 4.2


for Hep A only) - Hep E in pregnant woman associated with fulminant hepatitis (liver failure with massive liver necrosis) (HY)

6. How are Hep B and C virus transmitted? - Parenterally (unprotected sex, childbirth, IV drug, blood transfusion) 7. Describe serologic information about Hep B virus. (HY) - HBsAG (hep B surface antigen) ○ It is the key and first marker of infection. If it's present disease is present (either active or chronic). ○ It's the first serologic marker to rise. - HBeAG and HBV DNA ○ Envelope antigen indicates infectivity of virus. ○ If it's present, pt is highly infectious (can transmit virus) - HBcAB (hep B core antibody) ○ IgM Indicator of battle between body and hepatitis virus in acute and window stage.  Major Ab used to defeat the virus ○ IgG If present in absence of HbsAG, it indicates resolved disease  If present together with HBsAG for >6 months, it indicates chronic hepatitis - HBsAB (hep B surface antibody) ○ IgG  If it's present, then person has won the battle against virus (either it has resolved, or patient is immunized against it)  If it's present, then HBsAG will be absent.

8. Which Hep viruses have immunization? - A, B 9. Describe features of Hep C. - About 50% of acute cases progress to chronic case with cirrhosis - Both B and C are leading cause of liver cancer

Liver and pancreas Page 4.3

10. Describe serology of Hep C. - Presence of HCV-RNA confirms infection; persistance of HCV-RNA indicates chronic disease 11. -

Describe Hep D. It can't infect by itself and depends on HBV for infection. Coinfection - if HBV and HDV infect at same time Superinfection - if HBV infects pt with preexisting HDV (more severe than coinfection)

Liver and pancreas Page 4.4

11.3 Liver: Cirrhosis and Tumors 1. Describe cirrhosis. - It's end stage liver damage characterized by bridging fibrosis (fibrosis between portal tracts) and regenerative nodules of hepatocytes

Fig - note the regenerative nodules with fibrosis in between - characterstic of cirrhosis. (normal liver surface is smooth) 2. What mediates fibrosis? - Stellate cells (that lie below endothelial cells) secrete TGF-beta which mediates the fibrosis. 3. -

What is presentation of cirrhosis? Portal HTN Decreased detoxification Decreased protein synthesis

4. What are presentation of portal HTN? ○ Ascites  if SAAG (serum ascites albumin gradient - difference between serum albumin and ascites albumin) > 1.1 g/dl, 97% accurate for diagnosing ascites due to portal HTN.  If SAAG ALT (AST is located in mitochondria and alcohol is mitochondrial toxin) (HY)  May result in death - Cirrhosis ○ Present with signs and symptoms of regular cirrhosis 8. -

Describe non-alcohol fatty liver disease (NAFLD). Can progress from fatty changes to hepatitis to cirrhosis Diagnosis of exclusion; ALT>AST Associated with obesity

Hemochromatosis and Wilson's disease Hemochromatosis

Wilson's disease

Due to high Fe in body

Due to high Cu in body Liver and pancreas Page 5.2

High risk of cirrhosis and hepatocellular carcinoma

High risk of cirrhosis and hepatocellular carcinoma

Seen in old people

Seen in young people

Mutation in gene that regulates enterocyte Mutation in ability to excrete Cu into bile and ability to Fe metabolism load Cu in ceruloplasmin 9. Describe hemochromatosis. - Excess iron deposition (hemosiderosis) leads to tissue damage (hemochromatosis) - Damage due to generation of free radical by Fenten reaction (HY). 10. Describe the MOA of primary hemochromatosis. - Almost all Fe from diet is absorbed and stored by enterocytes. They regulate how much Iron to supply to body. - There's no real way to get rid of Iron (bile and bleeding excretes little bit) - In hemochromatotis, the regulatory mechanism of enterocytes is lost and all Fe is absorbed. - Mutation in HFE gene (most commonly c282y) leading to disregulation of enterocytes leads to 1 0 hemochromatosis. 11. What are some secondary causes of hemochromatosis? - Receiving blood transfusion 12. -

What is presentation of hemochromatotis? Seen mainly in late adulthood because it takes time for Fe to accumulate. Classic presentation is bronze skin, cirrhosis and 20 DM (aka bronze diabetes). Other presentations○ Increased ferretin, high serum iron ○ Low TIBC (total iron binding capacity) - whenever ferretin is high, TIBC will be low ○ Cardiac arrhythmia, gonadal dysfunction - due to Fe deposition

13. What is liver biopsy finding of hemochromatosis? - Brown pigments in hepatocytes (looks similar to lipofuscin - normal sign of old cells) - Prussian blue stain will turn Fe blue, but won't mark lipofuscin

Fig - brown pigments in hepatocytes (maybe hemochromatosis or lipofuscin)

Fig - prussian blue stain showing Fe deposition in hepatocytes

14. How do you treat hemochromatosis? What's its prognosis? Liver and pancreas Page 5.3

14. How do you treat hemochromatosis? What's its prognosis? - Blood donation - Increased risk of hepatocellular carcinoma (due to progression to cirrhosis) Wilson disease 15. What is wilson disease? - Autosomal recessive defect (ATP7B gene) that damages hepatocyte Cu transport and decreased ability to bind Cu to ceruloplasmin (bile main way to excrete Cu; ceruloplasmin Cu carrier in blood) leads to increased Cu in body. - Free radical production leads to damage. 16. What's presentation of Wilson's disese? Labs? - Presents in childhood (contrast to hemochromatosis that presents in adulthood) ○ Cirrhosis ○ Neuro - behavior changes, dementia, chorea, parkinsonism ○ Kayser Fleisher rings in cornea - due to Cu deposition ○ Increased risk of hepatocellular carcinoma - Treatment - chelating agent - Labs ○ High urine copper ○ Decreased serum ceruloplasmin ○ Increased Cu in liver biopsy Primary biliary cirrhosis and Primary sclerosing cholangitis Primary biliary cirrhosis

Primary sclerosing cholangitis (PSC)

- Autoimmune granulamotous destruction of intrahepatic bile ducts

- Inflammation and fibrosis of intrahepatic and extrahepatic bile ducts

- Associated with other autoimmune disease (classic pt women in child bearing age)

- Histology shows periductal fibrosis with 'onion skinning' - String and pearl appearance of bile ducts (due to interspersed fibrosis (string) and inflammation (pearl)

- Anti-mitochondrial antibody present. (HY)

- p-ANCA positive and associated with UC (UC is also p-ANCA positive) and cholangiocarcinoma.

- Pt present with obstructive jaundice; cirrhosis late complication; can cause hepatocellular carcinoma

- Pt present with obstructive jaundice; cirrhosis late complication; can cause hepatocellular carcinoma

Fig - preiductal fibrosis with onion skinning seen in PSC

Liver and pancreas Page 5.4

Fig - string and pearl appearance of biliary tree in PSC Reye syndrome 17. What is reye syndrome? - Fulminant (severe and sudden onset) liver failure with encephalopathy in children with viral syndrome that take asprin - Related to mitochondrial damage of hepatocytes - Kawasaki disease (vasculitis) affects mainly coronary artery and presents like viral illness in kids. But asprin is good to use in that case (HY) 18. -

What's presentation of reye syndrome? Hypoglycemia Elevated liver enzyme Nausea, vomiting May progress to coma and death

Hepatic cancer 19. Describe hepatic adenoma. - Benign tumor of hepatocytes - Associated with oral contraceptive use; tumor goes down with cessation of drug (HY) - Risk of rupture because tumor is right below liver capsule - lead to hemorrhage, especially during pregnancy 20. What are risk factors for hepatocellular carcinoma? - Chronic hepatitis (usually caused by hep B and C) - Anything that leads to cirrhosis - hemochromatosis, wilson's, NAFLD, EtOH FLD, alpha-1 antitrypsin deficiency - Aflatoxins derived from Aspergillus (HY) - countries that store grains can have Aspergillus grow on them and they have high incidence of hepatocellular carcinoma ○ Aflatoxin causes mutation in P53 mutation 21. What's relationship between hepatocellular carcinoma and Budd-chiari syndrome? - Hepatocellular carcinoma loves to invade hepatic vein and cause Budd-chiari - Presents with painful hepatomegaly and ascites (SAAG 2 Definition

- Presence of multiple ovarian follicular cysts

Epidemiology - Affects 5% of women of reproductive age Pathophysiol - Main finding is LH:FSH>2 ogy • High LH stimulates theca cells to produce lots of androgen (gives hirsuitism) • Androgen converted to estrone in adipose tissue. It gives -ve feedback to FSH secretion; Granulosa cells and eventually the follicle degenerates making cyst Presentation - Presentation based on LH:FSH>2 • Hirsuitism (Due to excess androgens) • Infertility (due to degenerated follicles) • HIGH RISK OF ENDOMETRIAL CARCINOMA (due to high estrone) • Insulin resistance and type 2 diabetes (10-15 years later) - Classic pt is obese young woman wih infertility, oligomenorrhea, and hirsutism.

Female GU Page 1.1

13.6 Ovarian Tumors

1. What are the types of ovarian tumors? - Ovary has 3 cell types: surface epithelium, germ cells and sex cord-stroma. Each cell type can give tumor Tumor type Tumor subtype


Surface epithelium

- Common (have cyst): • Serous tumor (filled with water) - BRCA1 mutation associated with serous carcinoma • Mucinous tumor (filled with mucin) - Less common (occur from metaplasia): • Endrometriod tumor • Brenner tumor

- Most common ovarian tumor (70% of cases) - Worst prognosis of all female genital tract cancer (often detected late) - presents as vague abdominal discomfort or sign of bladder compression (urinary frequency)

Germ cells

- Tumor subtype based on tissue made by germ cells

- Second most common ovarian tumor (15% of cases) - All are malignant except cystic teratoma


- Dysgerminoma (most common malignant germ cell tumor)

Placental - Choriocarcinoma tissue

Sex cord stroma

Fetal tissue

- Embryonal carcinoma - Cystic teratoma (most common germ cell tumor)

Yolk sac

- Endodermal sinus (yolk sac) tumor (most common germ cell tumor in kids) - Schiller-Duval bodies

- Granulosa-theca tumor

Granulosa and theca cells

- Sertoli-Leydig cell tumor

Sertoli and leydig cells

- Fibroma


Surface epithelial tumors 1. How are serous and mucinous tumor classified into benign, borderline, and malignant? Benign (aka cystadenoma)


- Has single cyst with simple, flat lining

- In between feature between benign - Has complex cyst with thick, shaggy lining ad malignant - Better prognosis than malignant but has malignant potential

- Mostly seen in premenopausal women (30-40 years) Female GU Page 2.1

Malignant (aka cystadenoCARCINOMA)

- Mostly seen in postmenopausal women (60-70 yrs)

(30-40 years)

(60-70 yrs)

2. What ovarian cancer is BRCA1 mutation associated with? - Serous carcinoma (serous cystadenocarcinoma) - Pt can get prophylactic salpingo-oophrorectomy along with bilateral mastectomy as prophylasxix. 3. Differentiate between endometroid tumor and brenner tumor.

Endometroid tumor

Brennor tumor

Tumor made of endometrial like gland (may arise from endometriosis)

Tumor made up of bladder like epithelium

Mostly malignant

Mostly benign

15% endometroid carcinoma associated with independent endometrial carcinoma (endometriod type)

Benign; bladder epithelium; brennor

4. Describe the following features of surface epithelial tumors of female reproductive tract. Distant metastasis Peritoneum (via direct contact) - see omental caking Serum marker

CA-125 - monitor treatment response and screening for recurrence

Germ cell tumors 1. Describe the following germ cell tumors Dysgerminoma


Embryonal carcinoma

- Malignant tumor with cells that resemble oocytes (large cells, clear cytoplasm, central nuclei) - fried egg apperance

Malignant tumor composed of cytotrophoblasts and syncytiotrophoblasts

- Malignant tumor - Tumor made up of fetal composed of tissue derived from >2 large primitive embronic layers (ex-skin, cells hair, cartilage, thyroid etc)

Malignant tumor that mimics yolk sac


Malignant (trophoblasts are very invasive

Malignant (aggressive)

- Mostly benign but if immature tissue (neural or somatic malignancy) present, indicates malignant potential


- Most common germ cell tumor

- Most common germ cell tumor in kids

Fig: hair and teeth seen in cystic teratoma

Fig: Schiller-Duval bodies (glomerulus like structure) classically seen on biopsy.

- Most common malignant germ cell tumor - Seminoma is male counterpart (histologically indistinguishable)

Fig: fried egg appearance on biopsy

Fig: Tumor is small, hemorrhagic and spreads hemotageneously early

Cystic teratoma

- Good prognosis; responds to - Poor response to radiotherapy chemotherapy - Serum LDL maybe elevated

- High Beta-HCG characterstic (made by syncytiotrophoblasts) may lead to thecal cysts in ovary

Female GU Page 2.2

- Hyperthyroidism in case of Struma ovarii (teratoma mainly composed of thyroid tissue)

Endodermal sinus (yolk sac) tumor

Sex cord-stromal tumors 1. What are sex cord stromal tumors? - Tumors resemble sex cord stromal tissue of ovary 2. Differentiate between three types of sex cord stromal tumors.

Granulosa-theca cell tumor

Sertoli-Leydig cell tumor

Tumor of granulosa and theca cells

Composed of Sertoli cells that make Tumor of fibroblast tubules and Leydig cells between tubules

Malignant, but minimum risk of metastasis Presentation based on excess estrogen production - Prior to puberty - precocious puberty - Reproductive age - menorrhagia and metrorrhagia - Postmenopause - endometrial hyperplasia with postmenopausal uterine bleeding


Benign tumor Cells may produce androgens: - Associated with pleural effusions and - See hirsuitism and virilization (more ascites (meigs syndrome) - syndrome masculine) resovles with removal of tumor

Fig: characterstic intracytoplasmic Reinke crystals of Sertoli-Leydig cell tumor Metastasis 1. Describe the two common tumor metastasis to ovary. Source


Krukenberg tumor

Gastric carcinoma (diffuse type)

- Mucinous tumor - Mostly bilateral (if unilateral, think primary mucinous carcinoma of ovary)

Pseudomyxoma peritonei (myxoma = tumor of connective tissue with mucus and gelatinous material)

Mucinous tumor of appendix

- Huge amount of mucus in peritoneum "jelly belly"

Female GU Page 2.3

Pseudomyxoma peritonei (myxoma = tumor of connective tissue with mucus and gelatinous material)

Mucinous tumor of appendix

Female GU Page 2.4

13.7 Gestational Pathology Ectopic pregnancy Definition

- Implantation of fertilized ovum at site other than uterine wall - Most common site is fallopian tube


- Key risk is scarring (secondary to pelvic inflammatory disease or endometriosis)

Presentation - Lower quadrant abdominal pain a few weeks after a missed period Prognosis

- Surgical emergency; bleeding and fallopian tube rupture can occur

Spontaneous abortion Definition

- Abortion 95% of cases) gy - Mostly seen in 15-40 year olds Risk factor - Cryporchidism - Klienfelter syndrome Division



Most common testicular tumor 55% of germ cell tumors

45% of germ cell tumors

Highly responsive to radiotherapy

Variable response to treatment

Metastasize late

Metastasize early

Excellent prognosis

Poor prognosis Include teratoma, embryonal carcinoma, endodermal sinus tumor, choriocarcinoma and mixed germ cell tumor

2. Differentiate the following testicular tumors. Seminoma


Embryonal carcinoma

Most common testicular tumor Malignant

Endodermal sinus (yolk sac)


Most common testicular tumor in children Malignant (in Malignant females, it's mostly benign)


Malignant; spreads early

- Large cells with clear - Mature fetal cytoplasm and tissue from >2 central nuclei embryonic layers - Forms homogenous mass with no hemorrhage or necrois

- Immature cells that may produce glands - Forms hemorrhagic mass with necrosis

- Schiller-Duval - Tumor of bodies on histology cyncytiotrophoblasts (glomerulus like) and cytotrophoblasts (placenta like tissue but absent vilil)

- B-HCG rarely increased

- AFP or B-HCG incresed

- AFP increased

- AFP or B-HCG increased

- B-HCG increased (syncytiotrophoblasts produce it) - Alpha subunit of HCG similar to FSH, LH and TSH; may see hyperthyroidism and gynecomastia

Male GU Page 3.2

14.4 Prostate

1. Describe histology of prostate gland. - Consists of gland and stroma (connective tissue) which is maintained by androgens (stromal cells make DHT by 5 alpha reductase from testosterone) - Glands are 2 cell layer thick ○ Inner luminal cells ○ Outer basal cells

Fig: G is for glands; S for stroma 2. Describe acute vs chronic prostatitis. Acute prostatitis

Chronic prostatitis

- Acute inflammation of prostate (mostly due to bacteria)

- Chronic inflammation of prostate

- Causes: • Chlamydia and gonorrhoeae in young adult • E coli and pseudomonas in old adults - Presentation: • Dysuria with fever and chills • On DRE, prostate is tender and boggy

- Presentation: • Dysuria with pelvic or lower back pain

- Prostatic secretion: • WBC high • +ve bacterial culture

- Prostatic secretion: • WBC high • -ve bacterial culture

Benign prostate hyperplasia Cause

- Age related change (present in most men >60 years) - No increased risk of cancer Male GU Page 4.1

- No increased risk of cancer Pathophys

- Related to increased dihydrotestosterone (DHT) • DHT made from testosterone by 5alpha-reductase in stromal cells • DHT acts on androgen receptors on stromal and epithelial cells resulting in hyperplastic nodules

Clinical features

- Presentation based on pinching of urethra • Problems starting and stopping urine stream; dribbling • Impaired bladder emptying - high risk of infection and hydronephrosis • Nocturia; polyuria • Hypertrophy of bladder wall muscle - increased risk for bladder diverticula • Microscopic hematuria maybe present


- Slightly increased prostate specific antigen (PSA) - made by prostatic glands and it liquefies semen (still 10 ng/ml highly worrisome for any age • Also see decreased free PSA as cancer makes PSA that’s bound.


Biopsy: • See small invasive glands with prominent nucleoli • Ducts maybe only one layer thick instead of having basal and laminal layer

Male GU Page 4.2

Fig: notice nucleus with prominent nucleoli Grading

- Based on tumor architecture alone (not on nuclear atypia) - Multiple region of tumor have different architecture - Gleason scoring: • Take two distinct areas and grade each (1-5). Total score = 10 • High grade = worse prognosis


- Lumbar spine or pelvis common site - See osteoblastic metastasis • Presents as lower back pain • Increased serum alk phosphatase, PSA and prostatic acid phosphatase (PAP)


- Prostatectomy for localized - Hormone suppression for advanced disease (goal to reduce testosterone and DHT) • GnRH analog (ex - leuprolide) - reduces LH and FSH production • Flutamide - competitive inhibitor of androgen receptor

Male GU Page 4.3

Chapter 15: Endocrine Pathology

15.1-15.2 Anterior and Posterior Pituitary Gland

Hormones by hypothalamus

Hormones made by ant. pituitary

1. Thyrotropin releasing hormone (TRH)

1. Thyrotropin (aka thyroid stimulating hormone)

2. Gonadotropin releasing hormone (GNRH) 2. Gonadotropin (FSH and LH) 3. Corticotropin releasing hormone (ACRH) 3. Adrenocorticotropin (ACTH) 4. Growth hormone releasing hormone

4. Growth hormone

5. Somatostatin

5. Prolactin (lactotropin) - most common pituitary adenoma

6. Prolactin inhibiting hormone (dopamine) Hormones in post. Pituitary (made in hypothalamus) 1. ADH (aka vasopressin) 2. Oxytocin - uterine contraction during pregnancy Anterior pituitary 1. What type of tumor is pituitary adenoma? - Benign tumor of anterior pituitary cells. - Can be functional (hormone producing) or non-functional (silent) 2. -

What are clinical presentation of non-functional tumor of pituitary? Bitemporal heminopsia (due to mass effect) Hypopituitarism (due to mass effect) Headache

3. -

What are most common functional tumor of ant. Pituitary? Prolactionma (most common pituitary adenoma) - 50% of adenomas Growth hormone (somatostatin) cell adenoma - 10-15% of adenomas ACTH cell adenoma - 10% of adenoma TSH cell, LH producing, and FSH producing adenomas are rare

4. What are clinical presentation of prolactinoma? How do you treat? - In females - galactorrhea and amenorrhea (prolactin inhibits GNRH synthesis and release) - In males - decreased libido and headache. Males don't get galactorrhea because they don't have sufficient breast tissue. - Treat - give prolactin inhibiting hormone (aka dopamine), dopamine agonists (bromocriptine or cabergoline) or surgery 5. What is functional unit of breast? - Terminal duct-lobular unit. Lobular unit has glands that make milk. Males only have terminal duct but not lobular unit so can't make milk. Females develop lobular unit after puberty.

Endocrine Page 1.1

Fig - rough sketch of terminal duct (TD) and lobular unit (LU)

6. What is clinical presentation of Growth hormone adenoma? - In kids - gigantism - In adults - acromegaly ○ Enlarged bones of hand, feet, jaws, large tongue. ○ Growth of visceral organs (cardiac failure is most common cause of death in these patients) - Secondary diabetes mellitus present (because GH inhibits glucose intake by cells; GH induces gluconeogenesis by liver) 7. -

How do you diagnose growth hormone adenoma? How do you treat? Elevated GH and IGF-1 (insulin like growth factor) - IGF is made by liver in response to GH Lack of GH suppression in response to oral glucose (why) Treatment○ Octreotide (somatostatin analog) ○ GH receptor antagonist ○ Surgery

Hypopituitary 8. When do we see hypopituitarism? - When >75% of pituitary parenchyma is lost 9. What are some causes of hypopituitarism? - Pituitary adenoma (common cause in adults ) - mass effect or apoplexy (bleeding in adenoma) reduces hormone production - Carniopharyngioma (common cause in kids) - same reason as above - Sheehan syndrome (HY) - during pregnancy, there's high need of hormones so pituitary doubles in size but its blood supply doesn't. Blood loss during parturition can trigger pituitary infraction. ○ Presents as poor lactation, loss of pubic hair (HY) and fatigue. - Empty sella syndrome - herniation of arachnoid or pia into pituitary can damage pituitary. ○ Can occur congenitally too

Posterior pituitary 10. What are clinical presentation and causes of central diabetic insipidus? What is diagnosis and treatment? - Presentation (based on loss of free water) ○ Polyuria and polydipsia ○ Hypernatremia and high serum osmolality ○ Low urine osmolality and specific gravity - Causes - damage (tumor, trauma, infection or inflammation) to hypothalamus or pituitary Endocrine Page 1.2

- Causes - damage (tumor, trauma, infection or inflammation) to hypothalamus or pituitary - Diagnosis - urine osmolality doesn't increase in response to water deprivation - Treatment - Desmopressin (ADH analog) 11. What are clinical presentation and causes of nephrogenic diabetic insipidus? - Presentation - same as central DI but no response to desmopressin - Causes - mutation or drugs (demeclocycline - old antibiotic, not used often now; and lithium) 12. What are clinical presentation and causes of syndrome of inappropriate ADH (SIADH)? - Presentation ○ Hyponatremia and low serum osmolality ○ Mental status change and seizure. - due to nerve swelling - Causes - ectopic production (ex - small cell carcinoma of lung) ○ CNS trauma ○ Pulmonary infection ○ Drugs (cyclophosphamide) - Treatment - free water restriction, demeclocycline

Endocrine Page 1.3

15.3-15.7 Thyroid 1. Differentiate T3 and T4 T4 (thyroxine)

T3 (triiodothyronine)

Both are made from tyrosine 10 times more potent than T4 Most of it made from T4 Thyroid secretes T4>>T3 T1/2 = 7 days

T1/2 = 7 days T4--> T3 conversion reduced in severe illness

2. -

How are thyroid hormones transported in blood? Tyrosine binding protein (carries 70%) Albumin (carries 20%) Transthyretin (pre-albumin) (carries 10%) Free T4 is 0.04% and free T3 is 0.03%

3. How are T3 and T4 made in thyroid gland? What is the key enzyme? - Key enzyme is thyroid peroxidase - Thyroglobulin are long chain of tyrosine that's stored as colloid in thyroid gland. T3/T4 are made from it. - Steps ○ Iodine is oxidized to oxidized iodine by thyroid peroxidase (oxidation step) ○ Oxidized iodine reacts with tyrosine to make monoiodotyrosine ○ Oxidized iodine reacts with monoiodotyrosine to make diiodotyrosine ○ The last two steps are called organification ○ Monoiodotyrosine + diiodotyrosine = triiodothyronine ○ Diiodotyrosine + diiodotyrosine = thyroxine ○ The last two steps are called coupling 4. What are functions of thyroid hormones? a. Increase or decrease gene transcription by binding to nuclear receptor b. Imp in development (Cretinism is mental retardation and dwarfism caused due to impairment of brain and skeletal development due to hypothyroidism) c. Increase BMR, O2 consumption and free radical formation d. Exacerbate diabetes mellitus (increase glycogenolysis and increase hepatic gluconeogeneis) (hyperthyroid = DM) e. Increase LDL receptors (hyperthyroidism = low serum LDL) f. Increase ionotropy (contractility), chronotropy (HR), g. Increase sensitivity to catecholamine for B1 receptors(hyperthyroidism = hyperactive SANS) h. Pulm - maintains hypoxic and hypocapnic drive (hypothyroid = hypoventilation and respiratory arrest) i. GI - increase gastric motility (hypothyroid= constipation, hyperthyroid = diarrhea) j. Skeletal - increase bone reasborption and decrease bone formation (hyperthyroid = osteopenia) k. Neuromuscular - (hyperthyroid = increased reflex, anxiety, hyperactivity; hypothyroid = decreased reflexes, fatigue and sluggish) 5. What causes thyroglossal duct cyst? (HY) - Thyglossal duct is a path for descent of thyroid from tongue to its location in neck. The cyst dies Endocrine Page 2.1

- Thyglossal duct is a path for descent of thyroid from tongue to its location in neck. The cyst dies out normally; if it persists, it may cause cystic dilation and seen as anterior neck mass. 6. What causes lingual thyroid? - If thyroid tissue persists at base of tongue, it's present as a mass. Hyperthyroidism (thyrotoxicosis) 7. What are presentation of hyperthyroidism? a. Increased basal metabolic rate (due to increased synthesis of Na/K pump) (HY) i. wt loss despite increase hunger ii. Tremor, anxiety, insomnia, and heightened emotions iii. Heat intolerence and sweating b. Increased SANS (due to increased expression and activity of B1 s) i. Cardiac - tachycardia, arrhythmia (esp in elderley) c. Hyperglycemia (increased gluconeogenesis and glycogenolysis) (HY) d. Hypocholesteremia and low serum LDL (increased LDL receptors) (HY) e. Diarrhea and malabsorption (increased GI motility) f. Osteopenia and hyercalcemia (increased bone reabsorption) g. Decreased muscle mass and weakness h. Oligomenorrhea 8. What is epidemiology of Grave's disease? What is it? - Most common cause of hyperthyroidism - Classically occurs in women of childbearing age (this group has high incidence of autoimmune disease) - Grave's is autoantibody IgG generation that stimulates TSH receptor leading to hyperthyroidism (type II hypersensitivity) 9. What are clinical presentation of grave's disease? - Diffuse goiter - TSH hormone is a trophic hormone that leads to hyperplasia and hypertrophy - Tibial myxedema and exopthalmus

10. What causes exopthalmos and pretibial myxedema (characterstic finding) in grave's? ○ Fibroblast behind eye and in tibia has TSH receptors. Excitation leads to glycosaminoglycan (chondroitin sulfate and hyaluronic acid) buildup, inflammation, fibrosis, and edema. ○ Myxedema feels like dough. And myx refers that edema is not caused by water. 11. What is histology of Grave's? - Histology shows irregular follicle and scalloped colloid and chronic inflammation

Endocrine Page 2.2

Fig - Thyroid in grave's. Notice irregular follicles. Also, the white space between colloid and thyroid tissue is called scalloped and is classic occurrence in Grave's. 12. What is treatment of Grave's? - B-blockers - Antithyroid durgs (methimazole, propylthiouracil, thyoamide) - concentrate in thyroid and block thyroid peroxidase; also prevent T4 --> T3 conversion in peripheral tissue - I-131 - thyroid takes it and gets destroyed (permanent hypothyroidism major complication) - Total thyredctomy 12.5. What are lab findings in Grave's? - Increased total and free T4 - Decreased serum TSH - Hypocholesteremia (HY) - Hyperglycemia (HY) 13. Differentiate thyroid storm vs myxedema coma Thyroid storm (hyperthyroid emergency)

Myxedema coma (hypothyroid emergency)

Presentation - fever (>400C), sweating, tachycardia/afib, delirium, nausea, vomiting

Presentation- mental status change from confusion to coma

Cause - increased catecholamines action and massive T3/T4 excess. Most common trigger - acute stress such as surgery, childbirth, MI.

Hypoglycemia, hypothermia, hypothermia, hypoventilism

Treatment - B-blockers, propylthiouracil, and steroids - give Iodine salt (wolff-chaikoff block - increased iodine in blood leads to decreased iodine uptake by thyroid and decreased production of thyroid hormones)

High incidents of death

Treatment- high dose of levothyroxine Cause- infection, stroke, in patients with hypothyroidism Endocrine Page 2.3

14. -

What causes multinodular goiter? Is it toxic? Multiple nodules and enlarged thyroid Caused due to relative iodine deficiency Usually nontoxic (rarely, some regions can be toxic, i.e., produce T3/T4)

Fig - multinodular goiter Hypothyroidism 15. What is cretinism? What are it's findings? - It's developmental delay caused due to hypothyroidism. - Classic findings ○ Mental retardation and dwarfism due to poor brain and skeletal development ○ Enlarged tongue (due to myxedema) ○ Umbilical hernia 16. -

What are causes of cretinism? Maternal hypothyroidism during early pregnancy Thyroid agenesis (pt don't develop thyroid) Dyshormonogenic goiter (pt can't make thyroid hormones - ex - pt with mutation in thyroid peroxidase gene) - Iodine deficiency

17. What's classic findings in myxedema (hypothyroidism in old kids and adults)? a. Myxedema - classically in tongue (large tongue) and larynx (gives deep voice) (HY) - due to increased TSH b. Decreased BMR and decreased SANS i. Wt. gain despite normal activity ii. Cold intolerane and decreased sweating iii. Bradycardia c. Hypoventilation and respiratory arrest - thyroid maintains respiratory drive d. Slow mental activity e. Muscle weakness f. Hypoglycemia, hypercholesteremia g. Oligomenorrhea (seen in both hyper and hypothyroidism) h. Constipation

18. -

What are causes of hypothyroidism? Hashimoto's (most common cause) Iodine deficiency Drugs (lithium) Endocrine Page 2.4

- Drugs (lithium) Thyroiditis 19. What is presentation of hashimoto's thyroiditis? What chemical is is associated with? What are lab results? - It's an autoimmune attack to thyroid peroxidase and thyroglobulins - Associated with HLA-DR5 (HY) - Initially see increase T3/T4 (and low TSH) due to gland destruction. Later on, we see decreased T3/T4 (and high TSH) due to gland destruction. - Suspect other autoimmune disease - type 1 DM, pernicious anaemia, rheumatic disease. - Lab results - anti TPO, anti-thyroglobulin, anti-microsomal antibodies, high TSH, low T3/T4 20. What is histologic appearance of Hashimoto's thyroditis? (HY) - Chronic inflammation (see lymphocytes) with germinal cells. - Presence of Hurthle cells (eosinophilic metaplasia of cells that line follicles).

Fig - Hashimoto's thyroiditis. CI is chronic inflammation. GC is germinal center. Little circles on left are herthel cells. 21. What disease do pt. with Hashimoto's have increased risk of? How? What's presentation? - B cell lymphoma. - How - Germinal center makes post germinal center B cells. It makes marginal zone which results in marginal zone lymphoma. - Presentation is pt with long standing hypothyroidism that presents with enlarged thyroid. 22. What is SUBACUTE GRANULOMATOUS (DE QUERVAIN) THYROIDITIS? What's its presentation? What's its prognosis? - It's granulomatous thyroiditis that follows viral infection (subacute means it occurs after acute process). - Presentation - Hypothyroidism is transient, and pt has tender thyroid (if a young female has tender thyroid, think subacute granulomatous thyroiditis). - Prognosis - It's self-limited and don't progress to hypothyroidism. 23. What is Reidel Fibrosing thyroiditis? What is presentation? - Chronic inflammation of thyroid with extensive fibrosis - Presentation ○ hard as wood thyroid that's non tender ○ Fibrosis may extend to local structures - ex - airway Clinically mimics anaplastic carcinoma but pt are younger and usually female(in anaplastic, Endocrine Page 2.5

○ Clinically mimics anaplastic carcinoma but pt are younger and usually female(in anaplastic, pt are older) Thyroid cancer 24. What are basics of thyroid cancer? - Most nodules are distinct and solitary - Most nodules are likely to be benign than malignant 25. What causes positive and negative in radioiodine uptake study? - Positive is when thyroid takes radioiodine injected in blood - Graves, nodular goiter - Negative - adenoma and carcinoma (do biopsy by FNA) 26. -

Describe follicular adenoma (adenomas are benign; adenocarcinoma are cancerous). Follicle proliferate in a benign way and are surrounded by a fibrous capsule Called follicular because tumor also makes thyroid follicle. Tumor mostly non-functional (don't secrete hormone)

Fig - follicular adenoma. Red line is the capsule that divides adenoma (bottom half) from normal thyroid (top half) 27. What are 4 types of thyroid carcinomas (malignant stuff)? a. Papillary carcinoma b. Follicular carcinoma c. Medullary carcinoma d. Anaplastic carcinoma 28. -

What is epidemiology, risk factor, prognosis and histologic feature of papillary carcinoma? Most common thyroid carcinoma (80% of thyroid carcinoma) Major risk - exposure to ionizing radiation in childhood Prognosis - excellent even though often spreads to cervical nodes Histology - Papillae of cells seen (so called papillary carcinoma - Diagnosis is made by nuclear features  Coffee bean nucleus (presence of nuclear groove)  Orphan eye annie nucleus (nucleus has white stuff resembling white of eye)  Psammomma bodies (concentric calcification of papillaes).

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Fig - Papillary carcinoma. red circles indicate orphan eye annie nucleus. Turquoise circle shows coffee bean nucleus.

Fig - Psammoma bodies in papillary carcinoma shown in black circle. 29. What is histologic feature of follicular carcinoma? Can you diagnose by FNA? - Similar to follicular adenoma (has fibrous capsule) but cells invade through capsule (hallmark) - FNA can't distinguish between follicular adenoma and follicular carcinoma because capsular invasion can't be assessed by FNA. - Even though most carcinomas spread via lymph nodes, follicular carcinoma spreads hematogenously (by blood).

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Fig - follicular carcinoma. Red line shows the capsule and the break in it. 30. -

What are 4 carcinomas that spread by blood instead of lymph? (HY) Renal cell carcinoma Follicular carcinoma of thyroid Hepatocellular carcinoma Corneal carcinoma

31. Describe medullary thyroid carcinoma (MTC). How is it diagnosis? - Malignant proliferation of parafollicular C cells that produce calcitonin - Diagnosis ○ Malignant cells in amyloid stroma - indicates MTC. (Calcitonin deposits in tumor as amyloid (cause localized amyloidosis), and +ve calcitonin immunostain) ○ Pt has high level of calcitonin which can lead to hypocalcemia

Fig - MTC biopsy. All the pink stuff seen is calcitonin amyloid. 32. Describe familial cases of MTC (HY). What's significance of RET oncogene (HY)? - Often associated with MEN 2A or 2B phenotype. (MEN = muliple endocrine neoplasia) - MEN 2A - often see MTC, pheochromocytoma and parathyroid adenomas Endocrine Page 2.8

33. -

MEN 2A - often see MTC, pheochromocytoma and parathyroid adenomas Men 2B - often see MTC, pheochromocytoma and ganglioneuroma of oral mucosa Familial cases of MTC is classically associated with mutation in RET oncogene If a person has RET oncogene, do a prophylactic thyroidectomy Describe anaplastic carcinoma. How do you diagnose? Has the worst prognosis of all thyroid carcinomas It is undifferentiated and classically seen in old people Tumor has +ve keratin stain Often invades local structures leading to dysphagia or respiratory compromise. Clinically similar to Reidel fibrosing thyroidiyis but cancer is often seen in old people and thyroidiyis in young females.

Fig - highly malignant cells in anaplastic carcinoma that don't resemble anything seen in thyroid usually

Endocrine Page 2.9

15.8 Parathyroid 1. -

What is vitamin D? How do we get it? Two most imp vitamin D are vit D3 (cholecalciferol) and vit D2 (ergocalciferol) Cholecalciferol (D3) is made from 7-dehydrocholesterol by UV in skin Ergocalciferol (D2) is taken from food. Both of those are activated by liver in unregulated way, and kidney in regulated way

2. How does kidney activate vitamin D? - Vit D itself is a prohormone. Kidney uses alpha 1 hydroxylase to make 1,25 OH D (active vitamin D). 3. What are functions of PTH hormone? - Chief cells make PTH that increase free serum calcium - PTH acts on 3 main tissue ○ Stimulate kidney to increase vit D activation ○ Increase Ca absorption from kidney and phosphate excretion (phosphate excretion key because it increases free Ca in blood) ○ Increase Ca and PO4 absorption from gut - this action is via Vit D ○ Increase osteoclast activity (PTH activates osteoblast which secretes M-CSF (macrophage colony stimulating factor) which increase osteoclast differentiation and activation) (HY) 4. -

What regulates blood PTH hormone? PTH release is highly sensitive to serum ca. Vitamin D also reduces PTH release Increase Ca ---> Gq and Gi activation. Gq increase calcium release in parathyroid cells ---> Decreases PTH synthesis. Gi decreases cAMP which reduces PTH synthesis - Low Ca ---> Gs activation. Gs increases cAMP which increases PTH synthesis

5. -

What are functions of Vit D? Main function is to maintain bone mineralization Increase Ca and PO4 reabsorption in kidney Increase Ca and PO4 absorption in gut Decrease PTH secretion

6. What are function of calcitonin and phosphatonin? - Tone down serum Ca and PO4 - Phosphatonins are important because intestinal absorption of phosphate is unregulated Primary hyperparathyroidism 7. Explain primary hyperparathyroidism. - Excess PTH; most common cause is PT adenoma (80%) - Other causes - PTH hyperplasia, PTH carcinoma 8. Describe presentation of PT adenoma (i.e., symptoms of hypercalcemia). - Benign; mostly asymptomatic - If symptomatic ○ Nephrolithiasis - kidney stone (classic is calcium oxalate) ○ Nephrocalcinosis - example of metastatic calcification - Ca deposits in tubules ○ CNS disturbance - depression, seizure Constipation, peptic ulcer, acute pancreatitis (HY) - think Ca as an enzyme activator that Endocrine Page 3.1

○ Constipation, peptic ulcer, acute pancreatitis (HY) - think Ca as an enzyme activator that activates pancreatic enzymes. ○ Osteitis fibrosa cystica - massive reabsorption of bone leading to fibrosis and cyst formation - Treatment - surgery 9. -

What are lab findings in primary hyperparathyroidism? Increase serum PTH High serum Ca Low serum phosphate (PTH increase phosphate excretion) High urine cAMP (HY) ○ PTH works in kidney via Gs to increase cAMP. Some cAMP gets to urine. - High serum alkaline phosphatase (HY) ○ Alkaline phosphatase generates alkaline environment in bone so that new bone can be laid down. Alk Phos is a sign of osteoblast activity. Remember that PTH first activates osteoblast which in turn activates osteoclast. Osteoblast activation leads to high alk phos.

Secondary hyperparathyroidism 10. What are some causes for 20 hyperparathyroidism? - Most common is chronic renal failure (HY) ○ Decreased phosphate excretion --> reduced free calcium in blood as most of it is bound to phosphate ---> increased PTH production and increased bone reabsorption 11. What are lab findings in 20 hyperparathyroidism? - Increased PTH - Decreased serum Ca (remember that the whole process is driven by high PO4. It binds to free serum Ca and reduces it) - Increased serum PO4 - Increased alkaline phosphatase (increased PTH leads to increase alk phos) Hypoparathyroidism 12. What are causes of hypoparythoroidism? - Autoimmune - DiGeorge syndrome (failure of develop 3rd and 4th pharyngeal pouch. Parathyroids develop from 3rd and 4th pharyngeal pouch). 13. -

What are its presentation - due to low Ca? Numbness and tingling (specially perioral) Muscle spasm (ex - when you put BP cuff on them or touch their face) Low serum Ca and PTH

Pseudohypoparathyroidism 14. What causes pseudohypoparathyroidism? - Caused due to end organ resistance of PTH - Hypocalcemia with increased PTH level (also see this is secondary hyperparathyroidism; but 20 hyperparathyroidism has increased serum phosphate levels too) - Autosomal dominant form (mutation of Gs) associated with short stature and short 4th and 5th digit

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15.9 Endocrine Pancreas Insulin - major anabolic hormone. Upregulates GLUT4 receptors in muscle and fat. Increased glucose leads to glycogen synthesis, fat synthesis, protein synthesis Glucagon - major catabolic hormone. Causes gluconeogenesis from AA, lipolysis and glycogenolysis. 1. -

Describe the anatomy of endocrine pancreas. Composed of cluster of cells called islet of Langerhans Single islet has many types of cells; each type producing one type of horome Insulin is made by B cells; lie in center of islet Glucagon is made by alpha cells.

Type 1 DM 2. Explain Type 1 DM - Autoimmune destruction of B cells by T lymphocytes (type 4 hypersensitivity) - see inflammation of islets - Autoantibodies against insulin - can be seen years before disease - Associated with HLA DR3 and DR4 3. What's presentation of type 1 DM? - Classically seen in children - Presentation (of insulin deficiency) ○ High blood glucose ○ Weight loss despite polyphagia (high hunger), low muscle mass - due to unopposed catabolic action of glucagon ○ Polyuria, polydipsia, glycosuria - Treatment - lifelong insulin 4. Explain mechanism of DKA (feared complication of type 1 DM) - Excess serum ketoacids; often triggered by stress (ex-infection) - Epinephrine increases glucagon that exacerbates lipolysis. Free fatty acids generated go to liver and get converted to ketones. 5. -

What is presentation of DKA? Hyperglycemia (>300 mg/dl) - due to unopposed glucagon actoin Anion gap metabolic acidosis (from ketoacids) Hyperkalemia (HY) ○ insulin stimulates Na/K pump. Also, acidosis is compensated by exchanging H+ from serum to K in cells. Much of the serum K will be lost in urine. So person has loss of total K from body; but has hyperkalemia - Kussmaul respiratin (to compensate for acidosis), dehydration (from diuresis), mental status change, fruity breath

6. -

How do you treat DKA? Give fluids - to treat dehydration Insulin Give potassium - because when you give insulin, K will go inside the cells; also serum K goes down as acidosis is treated

Type 2 DM 7. Explain type 2 DM. Endocrine Page 4.1

7. -

Explain type 2 DM. End organ insulin resistance Risk factor - obesity; Obesity reduces insulin receptors (HY) Higher genetic predesposition compared to type 1 DM

8. Describe presentation of type 2 DM. - Initially, see high insulin. Later on B cells get exhausted so see low insulin - Histology shows amyloid deposition in islets

Fig - amyloid deposition in Islets in type 2 DM. Amyloid is made of amylin - a protein produced with insulin. 9. What is presentation and diagnosis of type 2 DM? - Polyuria, polydipsia, hyperglycemia, often clinically silent - Diagnosis ○ Random glucose (>200 mg/dl) ○ Fasting glucose (>126 mg/dl) ○ Glucose tolerance test (>200/dl two hours after glucose load) 10. -

How do you treat type 2 DM? Weight loss and exercise first line Drugs Insulin

11. -

Describe hyperosmolar non-ketotic coma. MOA - High glucose levels (>500 mg/dl) leads to life threatening diuresis Don't see ketoacidosis because some insulin is present which prevents lipolysis and fat breakdown Hypotension Coma (due to osmolar effect in brain)

12. What are two major complications of diabetes? Give examples of diseases.(HY) - Non enzymatic glycosilation (NEG) of vascular basement membrane ○ NEG of large and medium vessels lead to artherosclerosis - ex - peripheral vascular disease leading to amputation ○ NEG of small vessel leads to hyaline arteriolosclerosis - ex - diabetic nephropathy (nephrotic syndrome) ○ NEG of hemoglobin leads to HbA1c - long term marker of glycemic control - Osmotic damage Endocrine Page 4.2

- Osmotic damage ○ Some cells in body can take sugars without insulin  Schwann cells - aldose reductase reduces glucose to sorbitol in Schwann cells. Sorbitol leads to osmotic damage. Leads to peripheral neuropathy.  Pericytes of retinal blood vessel - sorbitol cause osmotic damage and pericytes die. Leads to anurysm of retinal blood vessel. Rupture leads to blindness.  Lens - sorbitol build up leads to cataract.

13. What are some pancreatic endocrine tumor? - MEN 1 ○ Parathyroid hyperplasia and pituitary adenoma, pancreatic endocrine tumor - Insulinoma ○ Tumor makes insulin ○ Presentation Mental status change due to severe hypoglycemia that is relieved by glucose  Lab - Low glucose, high insulin, high C peptide (C peptide is made along with insulin) - Gastrinoma ○ Gastrin induces parietal cells in stomach to make acid ○ Presentation  Treatment resistant peptic ulcers (aka Zollinger Ellison syndrome)  Ulcers can extend to jejunum - Somatostatinoma ○ Somatostatin reduces acid production and contraction of gall bladder ○ Presentation  Achlorhydria (low acid production in stomach)  Cholelithiasis and steatorrhea (due to reduced bile release) - VIPoma ○ Vasoactive intensinal peptide greatly stimulates secretion of water and electrolytes in intestine, reduces gastric acid production. ○ Presentation  Watery diarrhea  Hypokalemia  Achlorhydria 14. What are two proteins that are made together with insulin? - Amylin - in type 2 DM, we see amyloid buildup due to amylin buildup - C peptide - can be tested in blood to see if pt is overadminstering insulin

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15.10-15.11 Adrenal Cortex and Adrenal Medulla Crotex - hormones are made from cholesterol (cortex is yellow due to cholesterol) Medulla- hormones made from tyrosine 1. What are three layers of adrenal? Zona glomerulosa Mineralocorticoid (Aldosterone) Zona fasciculata

Glucocorticoid (Cortisol)

Zona reticularis

Sex steroids

Pneumonic GFR for the zones. 2. Describe metabolism of cortisol.  Transport o 75% transported by transcortin (aka corticosteroid binding globulin) (made by liver) o 15% bound to albumin o 10% in free form  Receptor - nuclear receptor. Present in all body cell  Can bind strongly to mineralocorticoid receptor as mineralocorticoid itself. 3. How do you get hypokalemia from too much licorice ingestion?  Cortisol is inactivated to cortisone in kidney tubules by 11-B-hydroxysteroid dehydrogenase type 2 (reverse reaction by type 1 dehydrogenase). Licorice inactivates the type 2 enzyme, leading to active cortisol in kidney tubules.  As cortisol has high mineralocorticoid action, it leads to potassium excretion in kidney tubules leading to hypokalemia. 4. What are functions of glucocorticoids (called glucocorticoid because it increases glucose in blood)?  Increased glucose output by liver and decrease glucose intake by muscle, adipose (to increase glucose supply to brain and heart)  Decreased insulin sensitivity  Decreased immune activity via o Decreased arachidonic acid production (due to inhibition of phospholipase A2) o Low IL-2 production (IL2 important for proliferation of T cells) o Low histamine production  Increased alpha one receptor production and sensitivity to catecholamines (lack of cortisol causes extreme vasodialation, extreme hypotension and death)  Negative feedback to ACTH 5. How does adrenal insufficiency cause hypotension? - ↓glucocorticoid (GC)  too much vasodialation - ↓mineralocorticoid (MC) hypovolemia (too much Na and water wastage from kidney ) 6. What are clinical features of Cushing’s syndrome (too much GC)? - Muscle weakness (AA in muscles are used for gluconeogenesis) with thin extremities - Moon faces, buffalo hump, truncal obesity (high glucose in blood leads to insulin release; insulin is an anabolic hormone and leads to fat storage) - Abdominal striae (cortisol impairs collagen synthesis; blood vessels in stomach ruptures leading to striae formation) - HTN (increased sensitivity and production of alpha 1 receptor) Endocrine Page 5.1

- HTN (increased sensitivity and production of alpha 1 receptor) - Osteoporosis - Immune suppression 7. What are causes of cushings? Cause

Adrenal gland size

Exogenous cortisol (most common)

Both atrophied

Primary adrenal adenoma, hyperplasia, carcinoma (aka cushing's disease - 2nd most common)

One secreting cortisol big, other atrophied

ACTH secreting pituitary adenoma

Both large

Paraneoplastic ACTH secretion (ex - small cell carcinoma of lung)

Both large

8. How do you distinguish between cushing's due to ACTH made by pituitary vs pituitary made somewhere esse (paraneoplastic)? - Do a dexamethasone suppression test. ACTH produced by pituitary will go down but not the paraneoplastic one. 9. -

What is presentation of hyperadlosteronism? Hypernatremia, HTN Hypokalemia, metabolic alkalosis Aldosterone causes principal cell of kidney to take Na and excrete K.

10. Describe features of primary hyperaldosteronism. - Most commonly due to adrenal adenoma. Less common - hyperplasia and carcinoma - High aldosterone and low renin 11. Describe features of secondary hyperaldosteronism - Causes- fibromuscular dysplasia (classically seen in young woman where renal artery is stenosed), atherosclerosis of renal artery ○ As kidney sees low blood flow, RAAS is activated leading to high aldo - See high renin and high aldo 11. Describe cause of congenital adrenal hyperplasia (occurs in both androgen) - Most commonly seen due to deficiency of 21- hydroxylase (required to make cortisol and aldo) - Deficiency of cortisol leads to excess production of ACTH leading to hyperplasia of adrenals (remember ACTH is a trophic hormone) - Other causes - 11 hydroxylase and 17 hydroxylase deficiency (leads to low cortisol) 12. What is presentation of congenital adrenal hyperplasia? - Excess sex steroids (hormone production shunted towards sex hormone production due to deficient 21hydroxylase) o Clitoral enlargement o Precocious (early) puberty in males - Life threatening hypotension (cortisol deficiency) - Hyponatremia, hypovolemia; hyperkalemia, acidosis (aldo deficiency) 13. How does 11 hydroxylase deficiency present in contrast to 21 hydroxylase deficiency? - In 11 hydroxylase deficiency, we don't see effects of hypomineralocorticoid; but see effect of hypocortisol and excess sex hormone - Reason - Both 21 and 11 hydroxylase are required for cortisol production. 21 hydroxylase can produce weak mineralocorticoid, and 11 hydroxylase is needed to make strong mineralocorticoid.

Endocrine Page 5.2

Adrenal insufficiency 14. What is presentation of Waterhouse-Friderichsen syndrome (acute adrenal insufficiency)? - Commonly seen in kid with Niserria meningitis infection that causes DIC and then bilateral necrosis of adrenal glands - See massive hypotension

Fig - sac of blood adrenals classically seen in waterhouse friderichsen syndrome 15. -

What are causes of chronic adrenal insufficiency? Autoimmune (most common cause in developed world) TB (most common cause in developing world) Metastatic carcinoma to adrenals (lung cancer loves to go to adrenal)

16. -

What are presentation of chronic adrenal insufficiency? Hypotension (low cortisol) Hyponatremia, hypovolemia; hyperkalemia, acidosis (aldo insufficiency) Weakness Hyperpigmentation (HY) - ACTH is made from POMC. POMC also induces melanin synthesis. High ACTH means high POMC which leads to high melanin synthesis - classically seen in oral mucosa and skin. - only see in 10 adrenal insufficiency. - Vomiting and diarrhea (low cortisol)

17. -

Describe pheochromocytoma (tumor of adrenal medulla) Medulla is made of neural crest derived chromaffin cells (HY) Pheo is tumor of chromaffin cell Classic finding - brown tumor (because chromaffin cells are brown)

Fig - pheochromocytoma. Yellow parts seen in left and right are adrenal cortex. 18. What are presentation of pheochromocytoma? - Episodic HTN, headache, palpitation - Orthostatic hypotension may be seen - because alpha receptors are sensitized to high levels of Endocrine Page 5.3

- Orthostatic hypotension may be seen - because alpha receptors are sensitized to high levels of catecholamines - Diagnosis o increased serum metanephrines o Increased urine metanephrines and VMA o Epi and NE are metabolized to metanephrine and normetanephrine respectively. MAO converts both of them to VMA. - Treatment - surgery (HY - give phenoxybenzamine (irreversible alpha 1 blocker) before surgery because mechanical stress of adrenal can leak out epi and NE giving pt HTN and too much bleeding). 19. -

What are rule of 10's involving pheo? 10% bilateral 10% familial 10% malignant 10% located outside adrenal (HY - a common site is urinary bladder - classic presentation is a patient who experiences headaches and palpitation while urinating).

20. What are associations of pheo? - MEN 2A (MTC, pheo and parathyroid adenoma) and - 2B (MTC, pheo and mucosuloganglio neuroma esp in oral mucosa). MTC can kill pt so people with MEN go prophylactic thyroidectomy. Ret oncogene linked to MTC. - VHL disease (autosomal dominant mutation of von hippel lindau tumor suppressor gene - increased risk of hemangioblastoma of cerebellum, renal cell carcinoma, pheo) - NF type 1 21. Why don't you give beta blocker in pheo to control HR? - B2 is a vasodialator. B1 increases HR. If B blocker is given, we have uncontrolled alpha action (very severe vasoconstriction).

Endocrine Page 5.4

Chapter 16: Breast Pathology

16.1 Introduction

1. Describe the anatomy and histology of breast. - Anatomy: ○ Breast can develop anywhere along the milk line (a straight line from vulva to axilla) ○ In females, lobules and ducts are present in highest density in upper lateral part of breast ○ In males, lobules and ducts are present in highest density in subaerolar area ○ Estrogen and progesterone cause hyperplasia of breast lobules - Histology: ○ Terminal duct and lobular unit is the functional unit of breast. Lobules make milk and ducts drain them ○ Lobules and ducts are lined by two cell layers:  Luminal cell layer: columnar epithelial cell that makes milk in lobules  Myoepithelial cell layer: Outer layer; contracts to expell milk outside 2. What is galactorrhea? What are its causes? - Galactorrhea is milk production outside pregnancy - Causes: ○ Nipple stimulation ○ Prolactinoma ○ NOT A SIGN OF CANCER

Breast Page 1.1

16.2 Inflammatory Conditions

1. Describe the following inflammatory conditions of the breast. Cause



Acute mastitis

- Staph Aureus infection - Associated with breast feeding (fissures develop in nipple and bacteria enter)

- Erythematous breast - Purulet nipple discharge - May have abscess

- Continue drainage - Dicloxacill in

Periductal mastitis

- Usually seen in smokers. Smoking causes relative Vit a decifiency. Vit A deficiency causes squamous metaplasia of periductal cells. Cells produce keratin and block the duct resulting inflammation

- Subareolar mass with - nipple retraction - due to inflammation and fibrosis

Mammary - Chronic inflammation that causes dilation duct ectasia (ectasia) of subareolar duct (dialation)

- Periareolar mass with green-brown nipple discharge - Plasma cells on biopsy

Fat necrosis - Usually related to trauma

- Mass on physical exam or abnormal calcification on mammography (due to saponification) - Calcification and giant cells on biopsy

Breast Page 2.1

16.3 Benign Tumors and Fibrocystic Changes

1. Describe the following benign tumor and fibrocystic changes in the breast. Epidemiology Fibrocystic change


Most common change in premenopausal - Presents as vague irregularity women (hormone mediated) - seen in 30-60% (lumpy breast) in upper outer of women quardant - Cyst look blue-dome on gross exam

Fig: fibrocystic change presents as fibrosis of stromal cells and cystically dilated ducts

Intraductal papilloma

Classically seen in premenopausal women

- Bloody or serous nipple discharge - Usually present in one of the main lactiferous duct below areola and may cause nipple retraction

Fig: intraductal papilloma (mass has both epithelial and myoepithelial layers) Fibroadenoma - Most common benign neoplasm of breast (classically seen in premenopausal woman) hormone sensitive - mass grows during Breast Page 3.1

- Well circumscribed mobile marble like mass - move freely (contrast to infiltrative ductal

hormone sensitive - mass grows during pregnancy and maybe painful in menstruation cycle - Growth of fibrous part squeezes the lumen of duct

(contrast to infiltrative ductal carcinoma that's immobile) - Benign - 1.5-2x increased risk of cancer (FA)

Fig: Fibroadenoma (growth of both lobular and stromal cells)

Fig: gross speciman shows well demarked, capsulated tumor Phyllodes tumor (phyllodes = leaflike)

Classically seen in postmenopausal woman

- Fibroadenoma like tumor but much larger with overgrowth of fibrous part - Leaf like projection on biopsy (tumor of stromal cell - cells between lobules) - Maybe malignant in some cases - Most common in 5th decade

Fig: fingerlike projection of Phyllodes tumor (stromal tumor) - Only phyllodes tumor is mainly seen in postmenopausal woman and maybe malignant. All others are seen mainly in premenopausal woman and not usually malignant

Breast Page 3.2

2. What are the different types of fibrocystic changes and their associated breast cancer risk? Breast cancer risk


Fibrous, cysts and apocrine metaplasia

No increased risk

Ductal hyperplasia and sclerosing adenosis

2x increased risk in both breasts

Sclerosing = hard (fibrous); adenosis = too many glands; calcification maybe seen

Atypical hyperplasia

5x increased risk in both breasts

Hyperplasia maybe lobular or ductal

3. How do you distinguish intraductal papilloma from papillary carcinoma of breast? Intraductal papilloma

Papillary carcinoma

Both present as bloody nipple discharge More common in premenopausal women

As it's cancer, its more common in postmenopausal women

Papillary growth has both epithelial and myoepithelial cells

Papillary growth has epithelial cells but lacks myoepithelial cells

Breast Page 3.3

16.4 Breast Cancer

1. What are the risk factors for breast cancer? - Risk factors are associated with estrogen exposure ○ Female gender (female:male = 100:1 for breast cancer incidence) ○ Age - cancer usually seen in postmenopausal woman with exception of hereditary breast cancer ○ Early menarche/late menopause (increases estrogen exposure) ○ Obesity (fat cells converts testosterone to estrogen) ○ Atypical hyperplasia ○ First degree relative with breast cancer ○ Race - AA at more risk ○ BRACA +ve (BRACA 1 = risk of ovarian cancer and triple neg breast cancer; BRACA 2 = breast cancer in males) 2. What are the characters of the following types of breast cancer?

Ductal carcinoma in situ


Mass? Remarks?

- Cell proliferate in duct without invading basement membrane - Histologic subtypes present: • Comedo type: high grade cells with necrosis in duct with calcification

- No mass

Fig: DCIS mammography Fig: DCIS - note cellular proliferation, necrosis and centrally located calcification Invasive ductal carcinoma

- MOST COMMON INVASIVE CARCINOMA OF BREAST - >80% of cases - Invasive cancer that produces duct like structure in desmoplastic stroma - Subtypes: • Tubular carcinoma: ○ has well differentiated ducts without myoepithelial layer in desmoplastic stroma ○ Good prognosis • Mucinous carcinoma: ○ ducts in abundant extracellular mucin ○ Good prognosis • Medullary carcinoma: ○ high grade ductal cells associated with lymphocytes and plasma cells ○ Increased incidence of BRCA1 carriers ○ Good prognosis • Inflammatory carcinoma ○ carcinoma in dermal lymphatics ○ Poor prognosis (tumor already in lymph) ○ Presents as inflamed, swollen breast due to blockage of lymphatics - orange peel appearance; can be mistaken for acute mastitis

Breast Page 4.1

- Rock hard immobile mass - grossly see classic 'stellate' appearance - Most common of all breast cancer - Inflammatory has worst prognosis; others have relatively good; Invasive lobular has better prognosis than invasive ductal.

Fig: 'stellate' invasive ductal carcinoma

Fig: Peau d'orange (orange peel) appearance of inflammatory carcinoma Fig: Tubular carcinoma (left); mucinous carcinoma (right)

Fig: medullary carcinoma (left); inflammatory carcinoma (right) Lobular carcinoma in situ

- Cells proliferate in lobules without invading basement membrane - Often multifocal and bilateral - Characterized by dyscohesive cells lacking E-cadherin adhesion protein - Treatment: • Tamoxifen (to reduce risk of carcinoma) • Follow up closely because it can progress to invasive carcinoma

Invasive lobular - Cells characteristically grows in single file (aka Indian file) and may show carcinoma signet ring morphology - cells don't make duct because they lack Ecadherin - Usually bilateral

- No mass, no calcification - usually discovered incidentally - Often bilateral

- Often bilateral and multiple lesions in same location - Better prognosis than invasive ductal carcinoma - Associated with lobular carcinoma in situ in 90% of cases - Has diffuse invasive pattern of spread so difficult to detect by physical or radiologic exam

Fig: Small runs of invasive lobular carcinoma (arrows) with two adjacent foci of LCIS. 3. What are the prognostic factors for breast cancer? - TNM staging ○ Metastasis is most important prognostic factor but pt present early so not very useful ○ Spread of tumor to axillary lymph nodes (N) is most useful prognostic factor - Sentinel lymph node biopsy used to assess axillary lymph nodes 4. What is sentinel lymph node biopsy? - Many years before, doctors use to take out all lymph nodes in axilla to check for spread of breast cancer. In many patients, there was no Breast Page 4.2

- Many years before, doctors use to take out all lymph nodes in axilla to check for spread of breast cancer. In many patients, there was no spread and they had to suffer upper extremity edema due to lack of lymph nodes - Then doctors started to inject dye in tumor and check which lymph nodes in axilla the dye moved to. If the lymph nodes with dyes didn't had metastasis, the doctors didn't take out all the lymph nodes. If the nodes had metastasis, they would then proceed to take out all lymph nodes. This process is called sentinel lymph node biopsy. 5. What are the predictive values of breast cancer treatment? - Imprtant predictive values of treatment are presence of absence of overexpression of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu receptor. (HER2/neu are receptors in RAS/MAPK pathway).

Overexpression of ER, PR (nuclear receptor)

Good response to antiestrogenic agents (extamoxifen)

Overexpression of Her2/neu receptor (cell surface receptor)

Good response to trastuzumab (anti HER2 receptor Ab)

Triple negative receptor (none of above overexpressed) - usually seen in African American women

Poor pharmacological prognosis

6. What is Paget's disease of nipple? - Extension of ductal carcinoma in situ to lactiferous ducts and skin of nipple producing rash. Paget cells are present.

Fig: Paget disease of nipple Hereditary breast cancer Epidemiology

10% of breast cancer cases


- Seen in premenopausal cancer - Presence of multiple tumor - Having multiple first degree relative with breast cancer


- BRCA1- breast (medullary carcinoma - type of invasive ductal carcinoma) and ovarian carcinoma (serous carcinoma) - BRCA2 - breast carcinoma in males

Value of prophylatic bilateral mastectomy

- Decreases risk of carcinoma but not to zero

Male breast cancer Epidemiology

- 1% of all breast cancers

Common type

- Invasive ductal carcinoma


- Subareolar mall in older males (most breast tissue in males is in subareolar area - in females, it's in upper outer quadrant of breast) - May have nipple discharge

Genetic associations

- Klinefelter syndrome (XXY) - BRCA2 mutations

Breast Page 4.3

Chapter 17: Central Nervous System Pathology

17.1 Developmental Anomalies

Neural tube defects Defn

- Incomplete closure of neural tube due to folate deficiency prior to conception. Two types Anencephaly

Spina bifida

- Absence of skull and brain

- Failure of posterior vertebral arch to close

- Results in polyhydramnios as fetal swallowing of amniotic fluid is impaired

- Types: a. Spina bifida occulta (asymptomatic)- Vertebra is not fused because the plates of spinal arch can't fuse because neural tube didn't close properly - Asymptomatic; dimple of patch of hair overlying vertebral defect

b. Spina bifida - cystic protrusion of underlying tissue 1. Meningocele - meninges protrude 2. Meningomyelocele - meninges and spinal cord protrude

Detecti - Can be detected by elevated alpha-fetoprotein (AFP) in amniotic fluid and maternal blood. - AFP most abundant protein in young fetus blood (albumin of fetus) - made by fetal liver and yolk sac. on - AFP elevated in other cases too - hepatocellular carcinoma, liver metastasis, yolk sac tumor, germ cell tumor. Anatom - Neural plate invaginates early in gestation to make neural tube - Walls of neural tube - makes CNS y - Hollow lumen of neural tube - makes ventricles and spinal cord canal - Neural crest - makes peripheral nervous system

Neurology Page 1.1

Cerebral duct stenosis


- Stenosis of cerebral aqueduct (of sylvius) - connects 3rd and 4th ventricles; leads to hydrocephalous - CSF is made by choroid plexus lining the ventricles



- CSF leaks from 4th ventricle to subarachnoid space via foramen of Magendie (middle) and foramen of Luschka (lateral) Dandy walker malformation Defn

- Congenital failure of cerebellar vermis to develop so that 4th ventricle is massively dialated and cerebellum is absent; often accompanied by hydrocephalous - Presents as hydrocephalous, increased ICP and motor problem. - Associated with other abnormalities of CNS and malformation of heart, limbs etc.

Neurology Page 1.2

Arnold-Chiari malformation


- Congenital downward displacement of cerebellar vermis and tonsils through foramen of magnum, leading to obstructive hydrocephalous - Often associated with meningomyelocele - cerebellum is pulled downward

Neurology Page 1.3

17.2 Spinal Cord Lesions

Seringomyelia Defn

- Cystic degeneration of spinal cord usually on C8-T1 that affects the spinothalamic (anteriolateral) pathway and later on affects anterior horn (motor neurons) and lateral horn (SANS) - Typically spares dorsal column pathway (fine touch and position)

Presentati - Sensory loss of pain and temperature in upper extremities and 'cape like' on distribution (anterior white commissure of spinothalamic tract) - Muscle atrophy and weakness (anterior horn damage) - Horner's (lateral horn - hypothalamospinal tract damage) Poliomyelitis Defn

- Anterior horn neurons damage due to poliovirus infection

Presentation - Presentation based on lower motor neuron sign • Flaccid paralysis with muscle atrophy • Babinski -ve • Impaired reflexes Werding-Hoffman disease Defn

- AR inherited degeneration of anterior motor horn - Presents as floppy baby and death within a few years after birth

Neurology Page 5.1

Amotrophic lateral sclerosis (ALS) Defn

- Degeneration of both upper and lower motor neuron of corticospinal tract


- Most cases are sporadic - Some familial cases due to mutation in zinc-copper superoxide dismutase mutation (SOD1) - causes free radical injury in neurons

Presentati - Lower motor neuron signs: on • Flaccid paralysis and muscle atrophy • Fasciculations • Negative Babinski - Upper motor neuron signs: • Spastic paralysis with hyperreflexia • Increased muscle tone • +ve Babinski - Sensory system intact (distinguish from syringomyelia) - Atrophy and weakness of hand early sign Fredreich ataxia Defn

- Degenerative disorder of cerebellum and spinal cord due to unstable trinucleotide repeat (GAA) in frataxin gene (autosomal recessive)

Pathophys - Frataxin gene imp for mitochondrial iron regulation; loss results in iron buildup with free radical damage Presentati - Loss of multiple spinal tracts: on • Loss of vibration and proprioception • Muscle weakness in lower extremities • Loss of deep tendon reflex - Presents in early childhood; pt are wheelchair bound in few years

Associatio - hypertrophic cardiomyopathy n

Neurology Page 5.2

17.3 Meningitis Defn Cause

- Inflammation of leptomeninges (arachnoid and pia) Neonates

- Group B strep (no 1), E. coli, Listeria, H flu (non-vaccinated infants)

Teens and adults

- N. meningitis, Strep pneumo

Immunecompromise - Fungi (cryptococcus d Viral

- Most common is coxsackie (feco-oral transmission; kids)

Presentation - Classic triad of headache, fever and nuchal rigidity - Photophobia and vomiting - Altered mental status may be present Diagnosis

- Lumbar puncture • SC ends at L2; put needle between L4 and L5 - level of iliac crest; cauda equina continues to S2

CSF findings

Cells Bacteria Neutrophils

Glucose Protein Low



Lymphocytes Normal ?


Lymphocytes Low


Complicatio - Commonly seen in bacterial meningitis • Hydrocephalus, hearing loss and seizures - due to fibrosis ns • Death - due to herniation and cerebral edema

Neurology Page 6.1

17.4 Cerebrovascular Disease

Stroke Epdm

- No. 3 cause of death in USA - Neurons are susceptible to ischemia and undergo necrosis within 3-5 mins


Global cerebral ischemia Etiologi - Low perfusion (ex- atherosclerosis) es - Acute decrease in blood flow (ex - cardiogenic shock) - Chronic hypoxia (ex- anemia) - Repeated episodes of hypoglycemia (ex- insulinoma) Present - Presentation based on duration and magnitude of insult ation

Ischemic stroke (focal cerebral ischemia) Defn Subtype s

- Regional ischemia that causes focal neurological defects lasting >24 hours - If symptoms last 40 year olds)


- Unknown, maybe viral

Clinic features

- Skull is commonly affected • Hearing and vision loss - impengement of cranial nerves • Lion like face and increased hat size - Bone pain - due to micro fractures - Biopsy - mosaic pattern of lamellar bone

Treatment - Bisphosphonate - induce apoptosis of osteoclasts - Calcitonin - inhibit osteoclast function (to tone down blood calcium) Musculoskeletal Page 1.4

- Calcitonin - inhibit osteoclast function (to tone down blood calcium) Complicati - Risk of osteosarcoma during osteoblast overactivity phase on - High output cardiac failure due to formation of AV shunt in bone Osteomyelitis Defn

- Infection of marrow and bone


- Transient bacteremia - seen in kids - affects metaphysis - Open wound bacteremia - seen in adults - affects epiphysis


Most common cause (90%)

- Staph aurues

Sexually active young adult

- Neisseria gonorrhoeae

Sickle cell disease

- Salmonella

Diabetics and IV drug users

- Pseudomonas

Dog or cat bite/scratch

- Pasteurella

Vertebral osteomyelitis (Pott disease) - Mycobacterium TB Present.

- Bone pain with systemic sign of infection (fever, leukocytosis) - X-ray - shows lytic focus (abscess) - aka sequestrum, with surrounding sclerosis - aka involucrum

Diagnosis - Blood culture Treatmen - Antibiotics t

Avascular necrosis (aseptic necrosis) Defn

- Ischemic necrosis of bone and bone marrow


- Fracture (most common) - ex: avascular necrosis of femoral head - Steroids - Sickle cell anemia - vasoocclusive crisis n bone of hands and feet (presents as dactylitis) - Caisson disease (decompression sickness) - gas bubbles form in blood with depressurization

Complicatio - Osteoarthritis and fracture n

Musculoskeletal Page 1.5

18.2 Bone Tumors

Benign tumors Osteoma

- benign tumor most commonly seen on face - Associated with garderner's synrome (osteoma + FAP (familial adenomatous polyposis) + retroperitoneal fibrosis)

Chondroma - Divided as enchondroma (seen on medulla, mainly on small bones of hand and feet) or juxtacortical chondroma (seen on bone surface)

Fig: enchondroma (left); juxtacortical chondroma (right) Osteoid osteoma

- Benign tumor of osteoblast with osteoid core (radiolucent) most commonly seen on diaphysis - Size 2cm Musculoskeletal Page 2.1

• Size >2cm • Pain not relieved by asprin Osteochond - Most common benign tumor of bone roma - Tumor of bone with overlying cartilage cap; arises from lateral part of metaphysis and bone is contineous with marrow space - Overlying cartilage can rarely transform to chondrosarcoma

Giant cell tumor

- Biopsy shows multinucleated giant cells and sromal cells - Soap bubble lesions seen most commonly in epiphysis of long bones - mostly distal femur or proximal tibia - Locally aggressive and may recur

Malignant tumors Osteosarco ma


- Malignant tumor of osteoblast that has two peak incidence - most common in teenagers, then in elderly

Risk factors

- Familial retinoblastoma - Paget disease (during the osteolbastic hyperactivity phase) - Radiation exposure

Presentati - Occurs mostly in metaphysis of long bones (distal femur or proximal tibia mainly) on - Imaging shows destructive mass with 'sunbrust' appearance due to periosteal reaction and lifting of periosteum by adjacent tumor(codman triangle)

Musculoskeletal Page 2.2

Fig: sunburst appearance (left) and codman triangle (right) Biopsy

- Pleomorphic cells that produce osteoid

Chondrosa - Malignant tumor of cartilage seen in medulla that can grow out through cortex to make sessile rcoma paracortical mass - Seen mostly in central skeleton or pelvis


Ewing sarcoma


- Malignant tumor of poorly differentiated neuroectodermal cells seen most commonly in diaphysis of males breast>kidney>thyroid>lung - Usually causes osteolytic (punched out) lesion except prostate that cause oseoblastic (sclerotic) leison

Musculoskeletal Page 2.4

18.3 Joint DJD



+ve Rheumatic factor

Negative rheumatic factor

Affects both DIP and PIP (heubordin-bouchard nodes)

Affects mainly PIP symmetrically Affects mainly DIP (sausage fingers)- for psoriatic only

Pain worsens during day

Pain gets better during day Associated with HLA-DR4

Associated with HLA-B27

Degenerative joint disease Defn

- progressive degeneration of articular cartilage - aka non-inflammatory arthritis (no redness or swelling in joints). Synovial fluid accumulates but lymphocyte infiltrate are not seen. Lymphocyte infiltrate are hallmark in inflammatory arthritis - gout and RA.

Risk factors

- Obesity - Age - Trauma

Clinical features

○ Commonly affects hip, lower lumbar, DIP and PIP joints ○ Symptoms worsen during day (HY)

Pathologic features

○ Eburnation (bone rub) of subchondral bone ○ Pieces of bone might fall off in joint space (aka joint mice) ○ Enlarged DIP and PIP joints (heubordin-bouchard nodes) due to osteophyte formation (bone spurs) (HY)

Fig: from left to right - characterstic fibrillation of articular cartilage; 1=bone eburnation, 2 =subchondral cyst, 3 = normal articular cartilate; joint mice; osteophytes

Fig - osteophytes leading to heubordin-bouchard notes on the left x-ray. Right is normal hand xray

Rheumatoid arthritis Defn

- chronic systemic autoimmune joint disease that causes symmetrical polyarthritis and mainly Musculoskeletal Page 3.1


- chronic systemic autoimmune joint disease that causes symmetrical polyarthritis and mainly affects PIP and MCP joints - Classically seen in middle age woman


- Associated with HLA-DR4

Pathogene ○ Synovitis leading to formation of pannus (granulation tissue) sis ▪ Contraction of pannus by myofibroblast can lead to • ankylosis, • joint distortion, • damage of cartilage, • osteopenia (wearing away of bone due to inflammatory processes) Presentati - morning stiffness that improves with day on - Symmetric PIP involvement - DIP spared (HY) - both DIP and PIP involved in DJD. - Fever, malaise, myalgia, wt loss (systemic autoimmune signs) - Others: - Rheumatoid nodules - Vasculitis - Baker cyst (swollen bursa behind knee) - Pleural effusion, LAD, interstitial lung disease Labs (HY)

- Positive rheumatoid factor (IgM against Fc of IgG) - Presence of neutrophils and protein in synovial fluid.

Complicaio - Anaemia ns ○ chronic inflammatory state produces hepsydin (acute phase protein). Hepsydin blocks ability to use iron that's stored in macrophage. Results in anemia - Secondary amyloidosis (liver makes acute phase protein SAA that gets converted to AA amyloid deposition) Seronegative Spondyloarthropathy 7. What are clinical features of spondyloarthropathy? Explain its types. - Negative rheumatoid factor (aka seronegative) - Affects axial skeleton - Associated with HLA-B27 - Types ○ Ankylosing spondyloarthritis  Seen in young adult males  Presents with sacroiliitis and ankylosis of spine (bamboospine)  Uveitis - eye inflammation  Aortitis (weak aorta can lead to aortic regurgitation) ○ Reiter syndrome (reactive arthritis)  Can't see (conjuctivitis)  Can't pee (urethritis - pains with urination)  Can't climb tree (arthritis)  Usually seen in young males a week after GI or C trachomatis infection. ○ Psoriatic arthritis  Affects 10% of psoriatic patients  Affects axial and peripheral joints  Affects DIP of hands and feet (leads to sausage finger and toes) (HY) ○ Infectious arthritis  Most commonly seen with Neisseria gonorrhea (young adults)  Staph aureus (old people or kids).  Pt usually have only one joint affected - only the knee Musculoskeletal Page 3.2

 Pt usually have only one joint affected - only the knee  Pt have systemic signs like fever, increased WBC and elevated ESR  Can be easily treated with antibiotics Gout 8. What causes gout? - Caused due to deposition of MSU (mono sodium urate) crystals in joint. - Crystals arise due to hyperuricemia (uric acid is nucleotide breakdown product) ○ Occurs either by too much uric acid in blood ○ Or not enough filtration by kidney (more common cause) 9. What are some etiologies of hyperuricemia? Overproduction

Underexcretion (more common)

Psoriasis (increased skin turnover) Renal insufficiency Strenous exercise

Competition for excretion by - Drugs (thiazides, salicylate) - EtOH - Lactic acid - Ketosis - Glycogen storage disease

10. What is presentation of acute gout? - Most commonly seen as highly inflammatory monoarticular arthritis in great toe (podegra) - Acute inflammation (crystals activate macrophage) 9. What are secondary causes of gout? - Lukemia and Myeloproliferative Disorder - lots of cell turnover - Lesch-Nyhan syndrome ○ breakdown product of purine (xanthine and hypoxanthine) can be recycled. Patients who lack hypoxanthine guanine phosphoribosyl transferase (HGPRT) (enzyme that recycles these breakdown products) have high uric acid in blood. Uric acid is end product of purine breakdown. - Renal insufficiency 11. Why do alcohol and meat exacerbate acute gout? - EtOH compete with uric acid excretion in kidney. - Meat has lots of DNA/RNA and the purine metabolism increases uric acid. 12. What is presentation of chronic gout? - Tophi - UA crystals in soft tissue and joints - Renal failure ○ UA deposition in tubules ○ See white chalky deposits in kidney tubules with pink fibrosis - Lab○ Hyperuricemia ○ Needle shaped crystals without birefringence with plane light in synovial fluid 13. What is pseudogout? - It resembles gout but it's deposition of calcium pyrophosphate (not MSU) - Knee is to pseudogout (some involvement of wrist) as big toe is to gout. - Synovial fluid has weak positive birefringence under polarized light 14. What constitutes a positive birefringence? - Crystals that are horizontal are yellow (low crystals are yellow) Musculoskeletal Page 3.3

15. What lubricating substance is secreted by synovium? - Synovial fluid (rich in hyaluronic acid)

Musculoskeletal Page 3.4

18.4-18.5 Muscle and Neuromuscular Junction

Dearmatomyositis vs polymysosits Dermatomyositis



- Inflammation of skin and skeletal muscle

- Inflammation of skeletal muscle only


- Unknown; some associated with carcinoma

Presentati - Bilateral proximal muscle weakness; distal on muscles can be affected late - Rash on upper eyelids (heliotrope rash); malar rash - Red papules on elbows, knuckles and knees (Gottron papules)


- Increased creatine kinase - +ve ANA and anti-Jo-1 Ab


- Perimysial inflammation (CD4+) with perifascicular atrophy on biopsy

- Other than skin involvement, mimics dermatomyositis (bilateral proximal muscle weakness

- Endomysial inflammation (CD8+) with necrotic muscle fibers


X-linked muscular dystrophy Defn

- Degenerative disease with muscle wasting due to bad dystrophin protein and replacement of muscle by fat

Pathophy - Dystrophin protein is important in anchoring muscle cytoskeleton to extracellular matrix s - Most mutations are sporadic; large gene size predisposes to high mutation rate - DMD largest human gene Types

Duchenne muscular dystrophy

Becker muscular dystrophy

- Caused due to Deletion of dystrophin gene

- Caused due to mutation of dystrophin gene

Musculoskeletal Page 4.1

dystrophin gene - Presents as proximal muscle weakness at 1 year age; distal muscles involved later • Calf pseudohypertrophy characteristic finding (filled with fat) - Death due to cardiac or respiratory failure; myocardium commonly involved

- Clinically milder disease

- Elevated serum creatine kinase

Neuromuscular junction Myasthenia gravis vs Lambert-Eaton syndrome Myasthenia gravis

Lambert-Eaton syndrome


- Ab against postsynaptic Ach receptor at NM junction

- Ab against presynaptic Ca channel at NM junction

Pt popn

- Commonly seen in women - 15% of cases associated with thymic hyperplasia or thymoma

- Seen as paraneoplastic syndrome; commonly in small cell carcinoma of lung

Presentati - Muscle weakness that worsens with use and - Muscle weakness that improves with use and on improves with rest worsens with rest - Early eye involvement - ptosis and diplopia (MOST MUSCULAR DISEASE SPARE EYES) Treatment - Thymectomy improves symptoms - Use anti-cholinesterase agents to increase Ach in synapse

Musculoskeletal Page 4.2

- Resection of cancer resolves disease - Anti-cholinesterase don't help

18.6 Soft Tissue Tumor


- Benign tumor of adipose tissue - Most common benign soft tissue tumor in adult


- Malignant tumor of adipose tissue - Most common malignant soft tissue tumor in adults - Lipoblast is characteristic cell - immature fat cell with multiple fat vacuole that create scalloped appearance of nucleus

Fig: Top left - arrow points to scalloped nucleus in liposacoma; bottom left scalloped definition; right - normal adipose tissue biopsy Rhabdomyoma - Benign tumor of skeletal muscle - Cardiac rhabdomyoma is associated with tuberous sclerosis Rhabdomyosarc - Malignant tumor of skeletal muscle - Most common soft tissue tumor in children oma - Rhabdomyoblast is characterstic cell - desmin positive - Most common site is eyes, head and neck; vagina is classic site in young girls

Musculoskeletal Page 5.1

Chapter 19: Skin Pathology

19.1 Inflammatory Dermatoses 1. Describe the histology of epidermis. Layer


Stratum basalis

Stem cell layer

Statum spinosum

Appears spinous due to desmosomes between keratinocytes

Stratum granulosum See granules in keratinocytes Stratum corneum

See keratin and anucleate cells

INFLAMMATORY DERMATOSES Atopic dermatitis and contact dermatitis 1. Differentiate atopic dermatitis and contact dermatitis.

Atopic dermatitis

Contact dermatitis

Pruritic, erythematous, oozing rash with vesicles and edema

Same presentation

Skin pathology Page 1.1

and edema - Type I hypersensitivity reaction; associated with asthma and allergic rhinitis - Usually start in face in infancy; seen mostly on flexor surface afterwards

Type IV hypersensitivity. Some causes: - Poison ivy, nickel jewelry - Irritant chemical (ex- detergent) - Drugs (ex- penicillin) Treatment: topical glucocorticoid and remove offending agent

Acne vulgaris Presentation - Comedones (whitehead and blackheads), pustules, and nodules - Very common in adolescents Cause

- Chronic inflammation of hair follicle and associated sebaceous gland

Pathophysiol - Propionibacterium acnes - infection produces lipases that break sebum to ogy proinflammatory fatty acids which results in pustules or nodule - Hormone mediated - androgens increase sebum and excess keratin production. They block follicles and produce comedones Treatment

- Benzoyl peroxide (antimicrobial) - Vit A derivatives (reduce keratin production) - ex- isotretinoin

Psoriasis Presentation

- Well-circumscribed salmon-colored plaques with silvery scale, usually on extensor surface and scales - Pitting of nails

Pathophysiolo - Excess keratinocyte proliferation gy Etiology

- Autoimmune: associated with HLA - C - Environmental trigger may be present: ex - trauma


- Acanthosis- epidermal hyperplasia - Parakeratosis - retention of nuclei in stratum corneum - Munro microabscess - neutrophil collection in stratum corneum - Auspitz sign - thinning of epidermis above elongated dermal paiillae - results in bleeding when scale is picked off


- Corticosteroids - UV-A light with psoralen - Immune modulating therapy

Lichen planus

Presentation - Pruritic, purple papules with reticular white lines on surface (wickham striae) - Commonly seen on wrists, elbow, and oral mucosa Histology

- Inflammation of dermal-epidermal junction with a saw tooth appearance


- Unknown - Associated with Hep C infection

Skin pathology Page 1.2

19.2 Blistering Dermatoses Pemphigus vulgaris

Bullous pemphigoid

• IgG mediated attack to desmosomes

• IgG mediated attack to hemidesmosome

• Cell separate somewhere in stratum spinosum - vesicles rupture easily

• Cells separate in dermal-epidermal junction vesicles don't rupture easily

• Fish net immunofluorecence

• Linear immunofluorescence

• Histology - tombsonte cells, acantholysis (suprabasal vesicle), Nikolky sign

• Histology -

• Oral mucosa involved

Oral mucosa spared

Pemphigus vulgaris (pemphigus = watery blister) Cause

IgG mediated attack to desmosomes (desmoglein) (type II hypersensitivity) between keratinocytes


- Skin and oral mucosa bullae

Acantholysis Seperation of stratum spinosum keratinocytes (connected by desmosome) results in suprabasal bullae Tombstone cells

Basal cells are still attached to dermus and appear as tombstones

Nikolky sign

Bullae are thin walled and rupture easily making shallow erosions with dried crust

- Potentially fatal Immunofluorec Fish net immunofluorescence pattern- IgG surrounding keratinocytes ence

Bullous Pemphigod (pemphigoid = similar to pemphigus) Cause

- IgG mediated attack to hemidesmosomes (BP180) between basal cell and basement membrane


- Blisters on skin, usually in elderly (bullae don't rupture easily - contrast to pemphigus vulgaris) - Oral mucosa is spared - Clinically milder than pemphigus vulgaris

Immunofluoresce Linear pattern nce

Skin pathology Page 2.1

Immunofluoresce nce

Dermatitis herpetiformis Cause

- IgA deposition at tip of dermal papillae

Presentation - Grouped pruritic papule, vesicles and bullae


Strong association with celiac disease


Gluten free diet

Erythema Multiforme, Stevens-Johnson syndrome, and Toxic epidermal necrolysis Erythema multiforme

Presentatio - Hypersensitivity reaction with targetoid rash (target with n multiple rings) and bullae - Targetoid rash is due to central epidermal necrosis surrounded by erythema


Stevens-Johnson syndrome (SJS)

Toxic epidermal necrolysis

- HSV (most common) - Mycoplasma - Drugs (penicillin and sulfonamides) - Autoimmune (SLE) - Malignancy

• Erythema multiforme,bullae,necrosis,sloughing of skin with fever and mucous membrane involvement • Typically 2 mucous membrane involved - lips, eyes • Mostly associated with adverse drug reaction Presentati - SJS that occupies >30% of body surface with diffuse on sloughing of skin resembling large burn - Separation of cells at dermal-epidermal junction (scalded Skin pathology Page 2.2

- Separation of cells at dermal-epidermal junction (scalded skin syndrome separates at stratum granulosum)


- Most commonly due to adverse drug reaction

Skin pathology Page 2.3

19.3 Epithelial Tumors Seborrheic keratosis Presentation

- Benign squamous proliferation; common in elderly - Keratin filled cysts (horn cysts) - on extremities or face, coin like stuck on appearance


Keratin pseudocyst on histology

Leser-Trelat sign

- Sudden onset multiple seborrheic keratoses - Suggests underlying carcinoma of GI tract

Acanthosis nigricans Presentation - Epidermal hyperplasia with symmetric darkening of skin (velvet like skin) - Often presents in axilla, neck, groin


- Hyperinsulinemia - diabetes, obesity, Cushing - Visceral carcinoma - ex - gastric carcinoma

Basal cell carcinoma vs squamous cell carcinoma Skin pathology Page 3.1

Basal cell carcinoma vs squamous cell carcinoma Basal cell carcinoma

Squamous cell carcinoma

Definiti Malignant proliferation of basal cell (stem cell) on of epidermis

Malignant proliferation of supra-basal cell of epidermis - that’s why presentation is crusty

Epidemi ology

Most common HUMAN CANCER; locally invasive but rarely metastasize • 75% of non-melanoma skin cancer - Seen from 50s-70s

2nd most common skin cancer


Risk factors related to UVB exposure: - Albinism - Xeroderma pigmentosum (nucleotide excision repair damage) - Prolonged sun exposure

- Risk factor related to UVB exposure - Others: • Immunosupressive therapy • Arsenic exposure • Chronic inflammation (burn scar or draining sinus tract)

Progres sion

- Has stepwise progression like colon cancer. - Actinic keratosis - precursor lesion of SCC and presents as hyperkeratotic scaly plaque (0.07% of AK progress to SCC per year) - In Xeroderma pigmentosum, you see tons of actinic keratosis at very early age

Present - Pearly and shiny ation - Dialated (telangiectatic) vessel - Classic location is upper lip

- Crusty, nodular mass - Classic location is lower lip

Histolog - Nodules of basal cell with peripheral palisading • Keratin pearls y

Skin pathology Page 3.2

Histolog y

Treatm - Excision ent - Metastasis is uncommon

- Excision - Metastasis is uncommon

- Keratoacanthoma - well differentiated SCC that develops rapidly and regress spontaneously; presents as cup shaped tumor filled with keratin debris

Skin pathology Page 3.3

19.4 Disorders of Pigmentation and Melanocytes Melanocytes basic Melanocyte location

Basal layer

Embryogenic development From neural crest cells Melanin production

- Make melanin from tyrosine in melanosomes - Pass melanosomes to keratinocytes

Vitiligo, albinism, freckle (ephelis), and mesalma Vitiligo



- Localized loss of skin pigmentation

- Due to autoimmune damage of melanocytes

Mesalma - Mass like hyperpigmentation of cheeks

- Congenital enzyme defect (tyrosinase) of melanin production pathway - May involve eyes only or eye and skin

- Due to increased number - Associated with of melanosomes pregnancy and oral (melanocytes number contraceptives stay the same

- Increased risk for SCC, basal cell carcinoma, and melanoma (sun damage) Nevus Definition

- Benign neoplasm of melanocytes

Presentatio - Flat macule or raised papule n - Symmetric with sharp borders, evenly distributed Types

- Junctional nevus - melanocyte at dermal-epidermal junction; most common in kids - Compound (intradermal) nevus - melanocyte extension into dermis; most common in adults


- Most common acquired nevi appear in early childhood; evaluate lesions after 20 years age - Nevi changes is normal. Ex - hormones, pregnancy - Dysplasia is precursor to melanoma

Melanoma Definition

- Malignant neoplasm of melanocytes - often fatal

Epidemiology - Significant risk of metastasis (contrast to basal cell carcinoma and SCC of skin) Skin pathology Page 4.1

Epidemiology - Significant risk of metastasis (contrast to basal cell carcinoma and SCC of skin) Risk

- UVB induced DNA damaged - Dysplastic nevus syndrome (autosomal dominant disorder characterized by formation of dysplastic nevi that may progress to melanoma) • >50 nevi; usually appear around puberty and continue to develop beyond 40 - De novo melanoma is more common than dysplasia from nevus

Fig: dysplastic nevus syndrome Presentation - S-100 tumor marker - Mole with ABCDE• A = asymmetry • B = borders are irregular • C = color is non-uniform • D = diameter>6mm • E = evolution over time

Growth types - Radial - horizontal growth across epidermis; low risk for metastasis - Vertical - growth to deep dermis • Depth of extension (Breslow thickness) most important prognostic factor for metastasis Genetics

• Often associated with BRAF V600E kinase mutation (55% of cases) (HY)


• Vemurafenib (BRAF kinase inhibitor) for BRAF +ve tumors • Surgical excision

Variant of Skin pathology Page 4.2

Variant of melanoma

Superficial spreading

- Most common subtype - Dominant early radiant growth - Good prognosis

Lentigo maligna melanoma

- Lentiginous proliferation (radial growth) - Good prognosis


- Early vertical growth - Poor prognosis

Acral lentiginous

- Arises on palm or soles, often in dark skin individuals - Acral = affecting limbs

Skin pathology Page 4.3

19.5 Infectious Disorders Impetigo and cellulitis Impetigo


Presentati - Erythematous macules that progress to - Red, tender, swollen rash with fever on pustules; rupture of pustules causes honey crusted skin


- Superficial bacterial infection: Staph aureus, Strep pyogenes

- Deeper dermal and subcutaneous infection S aureus or S pyogenes

Epidemiol - Commonly affects children ogy - Risk for necrotizing fascitis due to infection with anaerobic 'flesh eating' bacteria (surgical emergency) Staphylococcal scalded skin syndrome Presentation

- Sloughing of skin with red rash and fever


- Exfoliative A and B toxin results in epidermolysis of stratum granulosum

Difference from toxic epidermal necrolysis

- Skin separation in TEN occurs at dermal-epidermal junction; separation in scalded skin junction occurs in stratum granulosum

Molluscum contagiosum Presentation - Firm, pink, umbilicated papules

Skin pathology Page 5.1



- Poxvirus infection


- Affected cells show molluscum bodies (cytoplasmic inclusion)

Classic pt

- Kids - Sexually active adults - Immunecompromised individuals

Skin pathology Page 5.2

Dermatologic morphology

Skin pathology Page 6.1