Pathology Lab 1

• Describe the concepts of atrophy vs. aplasia

Atrophy = CELL IS SMALLER, nerve is cut so muscles get smaller
Aplasia =
• Describe the concepts of hypertrophy vs. hyperplasia
Plasia = number of cells in the tissue. (Hyperplasia = more cells, aplasia =
less)
• Hyperplasia = Adaptive response in cells capable of
replication
• Replicate more – like liver regrowth, wound healing
• If the cells cannot divide, then they will be hypertrophy instead
Trophy = Size of cells
• Hypertrophy – pregnant uterus
• Describe the concepts of reversible changes
1. Cellular swelling
2. Fatty change – accumulation in lipid vacuoles, in cells that do fat metabolism
3. Increased eosinophilic staining (pink), which is more pronounced closer to necrosis
4. Plasma membrane alterations – loosening of intercellular attachments
5. Mitochondrial changes
6. Bigger ER
7. Nuclear condensation
• Describe the concepts of irreversible changes
No more nucleus, not survivable
Apoptosis (not always pathologic – no explode open) and necrosis (pathologic)
• Describe the progression from granulation tissue to fibrosis (tissue repair)
Inflammaton  Granulation tissue  Fibrosis or regrowth of normal tissue
Granulation: Necrotic tissue is cleared and replaced with vascular fibrous tissue
Granulation tissue/fibrosis starts about 10 days after injury and develops until scar is formed
• Differentiate granulation tissue from granulomatous inflammation (e.g. granuloma)
Granulation tissue – normal response to any injury
• More capillaries and fibroblasts
Chronic inflammation: plasma cells, monocytes, lymphocytes, some macrophages/monocytes
• Granulomatous inflammation – looks like cheese – cheese necrosis
• Usually due to bacteria or other diseases
• Distinctive form of chronic inflammation
• Aggregates of activated macrophages (epithelial cells, scattered
lymphocytes
• Have many multinucleated giant cells (fusion of multiple activated
macrophages)
Granuloma = Multinucleated giant cell that forms through fusions of activated macrophages
• TH1 response?
• Short terminology difference between granulation tissue and granulomatous inflammation
Granulation tissue – more capillaries and fibroblasts
Granulomatous inflammation – type of chronic inflammation
• Aggregates of activated macrophages, giant cells, T cells, walling off of offending agents
• Describe subtypes of necrosis
• Brief introduction of metaplasia & dysplasia
Metaplasia = reversible change in which one differentiated cell type is replaced by another type – reprogramming

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 Four most common causes of cancer deaths
o 1. Lung cancer (incidence 1 in 13-16)
o 2. Breast cancer (1 in 8) and Prostate Cancer (1 in 7)
o 3. Colorectal cancer (1 in 20)
 Cancers are special
o Melanoma and renal cell cancer – immune responsive cancers, can use immunotherapy
o Malignancies in immunocomprised hosts (HIV, post-transplant)
o Testicular cancer – can treat even if it is metastasis
o Examples of GYN and Peds
 What to do
o Epidemiology
 Know about if it is common top 4 cancer, or not common, racial, MF difference, age
o Risk factors, screening, prevention: are there screening? Genetic, exposure, hereditary, precursos
 Example: polyp always there for colon cancer
o Histopathology: what does it look like under the microscope – know what cancer looks like vs normal
o Diagnostic – what molecular marker
o Staging: how to stage so you can choose for clinical trials or drugs
 Imaging: PET CT always good but not always the best
 Who gets surgery, who gets radiation, who needs both, where we wait (prostate)
o Know only the basic important pathways for certain cancers

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 Lecture 1: Response to Injury and Malignant Transformation

 Response to cell injury

o Hypertrophy, hyperplasia, atrophy, metaplasia = all attempts to compensate for stress/injury
 Describe the concepts of hypertrophy versus hyperplasia
o Hypertrophy – increase in cell size, so larger organ
 (pregnancy, lifting weights, fat storage (normal),
hypertrophic cardiomyopathy (not normal)
o Hyperplasia – increase in cell number
 Normal: hormonal (menstrual cycle), compensatory
hyperplasia (bone marrow if you bleed)
 Not normal: too much hormone signaling, abnormal wound
healing
 Uncontrolled can be cancerous
 Describe the concepts of atrophy versus aplasia
o Atrophy – shrink in size of cells/ or loss of cell (in size or number)
 Different than necrosis or apoptosis
 Can be lack of use, lack of hormonal stimulation,
aging, lack of good blood flow or nutrition
o Aplasia – Lack of formation (usually congenital so you
don’t make the organ, of infection  aplasic anemia)
 Describe the progression from granulation tissue to fibrosis
o Tissue injury  Acute inflammatory cells  chronic
inflammatory cells  more vasculature  Granulation
tissue  formation of fibrosis/scar
o Granulation tissue purpose: – bring elements from the
blood to heal the tissue: Inflammation, angiogenesis,
migration of fibroblasts
 Very loose tissue, can see capillaries
 Differentiate granulation tissue from granulomatous
inflammation (e.g. granuloma)
 Apoptosis : orderly programmed death, part of development to
separate your toes
 Describe subtypes of necrosis
o Necrosis: form of cell death, by severe acute injury, cells swell, plasma membrane burst, elicit inflammation
o Coagulative necrosis
 Cell die, but cell outline and basic tissue is still intact, looks very pink because lack of nuclei
 Due to ischemia, usually in heart, kidney, or liver
o Liquefactive Necrosis
 Abscess see this – neutrophils and nuclear/cell material that is broken down
o Gangrenous necrosis- vascular disease/diabetes – get poor perfusion of toes so need surgery
o Caseous Necrosis
 Has Granulomas!
 Granuloma: nodular collection of inflammatory cells: specifically with epitheloid histiocytes
o Sometimes has multinucleated giant cells
 Caused by Tb, foreign material, fungal, immunotherapy drugs, Autoimmune diseases
o Fat necrosis – local destruction of fat, usually because of ischemia or acute pancreatitis  lipase  digest
peripancreatic fat
o Fibrinoid necrosis
 Seen in polyarteritis nodosa
 Walls replaced by fibrin and inflammatory cells…
 Understand the concepts of metaplasia and dysplasia
o Metaplasia: reversible change in which one mature cell type is replaced by another mature cell type
 Adaptive process to deal with chronic injury
 Indicator of chronic injury, could be precursors to dysplasia and carcinoma
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  Example: If you have constant reflux, the squamous cells in esophagus change to columnar or
cuboidal cells
 Or for respiratory epithelium  squamous epithelium (this is precursor to squamous lung
cancer)
o Dysplasia
 Many tissue and organs have predictable pathway from
hyperplasia  dysplasia  Cancer
 This is useful because you can sometimes identify and treat
lesions before malignant
 Harder to tell in soft tissue
o Neoplasia: New abnormal cellular growth, includes cancer and its
precusors (dysplasia)
 Understand the progressive transformation of tissue from metaplasia to
dysplasia, carcinoma in situ, and eventually invasive carcinoma
o Smoking  injury to epithelial lining of respiratory tract  squamous metaplasia and hyperplasia 
squamous dysplasia  invasive squamous carcinoma
o Cervical dysplasia (detect dysplasia or precancer)  cervical cancer because of HPV virus
 Cancer causing mutations
o 1. Proto-oncogenes mutation
o 2. Tumor suppressor gene mutation
o 3. DNA mismatch repair gene mutation
o 4. Apoptosis regulating gene mutations

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 Lecture 2: Morphological Features of Cancer, Nomenclature, and Staging

 Understand the different types of neoplastic diseases and their nomenclature

(e.g. malignant melanocytes = melanoma, malignant epithelial cells =
carcinoma, malignant mesenchymal cells = sarcoma)
o Behavior classification: benign of malignant
 Benign – remain localized, can be surgically removed
 Malignant: neoplasms that invade
o Histogenetic classification: what cell did it originate from
 Define benign versus malignant (e.g. adenoma/adenocarcinoma;
leiomyoma/leiomyosarcoma; teratoma/teratocarcinoma)


 Describe basic methods to determine the tissue of origin of a malignancy (cytologic

characteristics, architecture, histochemical staining, molecular tools)
o Cytologic: get individual cells – pap smear and spread on slide
 Aspiration of tumor in thyroid, liver, pancreas, or fluid
 Pro: minimally invasive, do not need anesthetic
 Con: lose tissue architecture – often is screening before histolic
o Histolic – whole tissue, go to slide, tissue architecture is intact
 Example: breast biopsy, lymph node, cervical biopsy
 Pro: intact tissue, provide definitive diagnosis
 Con: more invasive, increased complication
 Recognize characteristic features of malignancy (cytologic features of malignant cells with nuclear/cytoplasmic
abnormalities, histologic features of malignancy with abnormal growth, architecture, invasion and metastasis)
 Benign vs malignant
o Benign tumors will look like normal counterpart and slow growing
 Local invasion – pushing growth, compress adjacent cells, often encapsulated, slow growing, can be
removed without recurring
o Malignant tumors can look similar, or totally different, grow rapidly
 Tumor can outgrow blood supply, so it can cause tumor necrosis
 Local invasions: malignant neoplasm invade and destroy
 After it invades, the body responds with DESMOPLASIA
o Inflammation and scar tissue, like a knife that cuts through tissue which gives many
cancers a hard texture, so you can see through US
 Types of local invasion:
o 1. Perineural: tumor invades around nerves and track them (prostate, pancreas)
o 2. Lymphatic: tumor within lymphatic spaces – go through lymph nodes (breast)
o 3. Vascular invasion: tumor in blood vessels; Liver and kidney carcinomas
 Metastases: most likely it is malignant: have characteristic pattern of spread
 Prostate  bone, Breast  bone and brain, Ovary  peritoneal cavity
o How to determine differentiation
 Look at size, variability, color of nucleus, nuclear/cytoplasmic ratio, etc
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  More of these things = malignant
 Understand the purpose of clinical and
pathological staging, describe the TNM system
o Low grade = well differentiated
o High grade = poorly differentiated
o Stage: description of extent and spread of cancer
 Stages are best markers for the survival rate
 Understand complications of cancer: why is cancer a leading cause of death?
(local complications, systemic/metabolic effects, effects of metastatic disease)
o Effects of tumor on patients
 Local effects: push on adjacent organs, cause ulceration or perforation, invade adjacent organs
 Metastases: local effects of metastasis: pushing on brain, replacing marrow space
 Paraneoeplastic syndrome: not by pushing
 Due to immunological response of factors secreted by tumo
 Can give you fevers, diarrhea (tumors that secret VIP), serotonin toxicity, etc
o Common types of cancer
 SUPER number 1. Melanoma
 1. Female breast
 2. Prostate
 3. Lung and bronchus
 4. Colon
o What do people die of
 Infection, respiratory, thrombosis/embolism, organ failure because of cancer invasion, cachexia
from hormones released, respiratory failure

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 Lecture 3: Cancer cell biology and Tumor microenvironment
 To understand that neoplastic transformation of a normal stem/progenitor cell into a cancer-initiating cell requires an
unlucky combination of genetic and epigenetic defects accumulating in th at one cell.
o Alterations needed
 Proliferation deregulated – they do not grow faster, they just keep growing
 Differentiation – changes the profile so they all look different
 Senescence blocked – (senescence is the loss of cell to grow – deals with telomeres)
 Apoptosis reduced
 Genome destabilized – drives metastasis and drug immunity
 Colorectal cancer as an example, understand how genomic
data from The Cancer Genome Atlas (TCGA) have
supported the conclusion that gain-of-function and loss-of-
function mutations in oncogenes and tumor suppressor
genes, respectively, drive neoplastic transformation to
deregulate proliferation, compromise differentiation, block
senescence, reduce apoptosis, and destabilize the genome.
o Familial Adenomatous polyposis – only has one
functional copy of APC (tumor suppressor gene)
o APC blocks WNT signaling (which is important for
proliferation)
 BMP also suppresses WNT and is important
for differentiation
 Without differentiation, cannot make the crypt intestinal thing for absorption (which I guess is bad)
o Two types of cancer: hypermutated or non-hyper-mutated
 Higher rate of mutations(See with SKY) vs abnormal chromosomes in quantity and quality (see in
genome sequencing)
 Review briefly the receptor tyrosine kinase (RTK)-RAS-RAF-MEK-ERK pathway that drives proliferation.
o Gain of function for Ras and Raf function in 85% of human cancers
 Review briefly the RTK-PI3K-(PIP3)-AKT pathway that drives metabolism to promote survival and is antagonized
by tumor suppressor PTEN.
o PIP3 promote cell metabolism and growth
o PTEN is tumor suppressor gene
 Review briefly the Myc-Cdk/Cyclin-E2F pathway that drives DNA replication and is antagonized by tumor
suppressor p16Ink4A and RB.
 Review briefly the MDM2-p53 pathway in which MDM2 (oncogene) inhibits p53 (tumor suppressor) that drives
growth arrest or apoptosis when cells are stressed.

 Proliferation deregulated – RB-E2F and p16lnk4a, Differentiation –

 Senescence blocked – PTEN, Apoptosis reduced: p53
 Genome destabilized –
 Review briefly the BCL2 gain-of-function expression that inhibits apoptosis. Using pancreatic cancer as an example,
understand that cancer is a progressive disease with continuous evolution and selection of more and more aggressive
clones of cancer cells.

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 Understanding that cancer cell favors anabolism over catabolism to sustain the deregulated proliferation. As an
example, cancer cells favor the conversion of glucose to nucleotides rather than to ATP through OXPHOS. This
anabolic phenotype is known as Aerobic Glycolysis or the Warburg Effect.
o Drive anabolism to make DNA
 Using breast cancer as an example, understand that cancer occurring in non-vital organs only causes mortality when it
spreads to vital organs.
o Breast  bone and brain
o Breast  enter capillary (local invasion) after
angiogenesis go into the liver and adhere to blood
vessel  escape from blood vessel to form
micrometastasis
 The epithelial cells lose some of their traits and
gain skills to move.. how cool? And become
more MESENCHYMAL!
o Estrogen receptor are in breast epithelial cells, and you
can screen for these in the brain to find metastasis
 Understanding that the interactions between cancer cells and
normal cells: including endothelial cells, fibroblasts, myofibroblasts and immune cells (in innate and adaptive
immunities) are important to the progression and the spread of cancer cells throughout the body.
o Cancer microenvironment
 Angiogenesis: endothelial cells to sprout new blood vessels
 Endothelial cells have villus so it can get more nutrients and water
o Intestine – replaced continuously by the crypt – stem cells
 This is the source of differentiated epithelial cells and intestinal carcinomas
 Tissue remodeling: stromal myocytes, fibroblasts, tissue macrophages to support growth
 Immune Evasions: immune cells, cytotoxic T cells are inactivated
 Invasion/Metastasis: all of the above
 Understanding the process of tumor angiogenesis.
o Single epithelial cell is sprouting through existing capillaries
o VGEF is secreted and the capillaries come to it
 Understanding the processes of local invasion and distant metastasis.
o The cancer cells move on collagen for local invasion
 Understanding that metastasis of epithelial cancer cells requires
o Activation of an epigenetic program known as EMT (epithelial mesenchymal transition) to stimulate
invasion and migration
o Then followed by MET (mesenchymal epithelial transition) to allow colonization in vital organs.
 Learning that implanted scaffolds can trap metastatic cancer cells.
o TRAP… because this woman loves research

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Lecture 4: Environmental Causes of Cancer and Cancer Prevention
 Origin of cancer
o Somatic mutation theory: INTIATORS
 Mutagens are acquired genetic and epigenital changes
 Need to dysrgulate growth and be immortal
o Also need promoters: MITOGENS, environment stuff, good
immune environment
 INFLAMMATION!!!! these are harder to specifically
identify
 Review chemical carcinogenesis, especially tobacco and occupational
exposures (e.g., asbestos, vinyl chloride, benzenes) and describe synergistic interactions between agents. Recognize
carcinogenic actions of UV/ionizing radiation and sources of exposure (especially medical exposures and some
historic examples
o Tobacco – leads to 1/5 deaths
 Major cause of premature death worldwide
 This is an initiator and a promoter (because it causes inflammation)
o Alcohol
o Ionizing radiation (leukemia, breasts, lung, thyroid)
 15% of ionizing radiation comes from medical radiation
 1/10 americans undergo CT scan/yr
o Viral cancers (HPV)
 Causes 18% of cancers globally
 HPV: 5% of cancers worldwide
 Primary prevention = vaccination and protection – give vaccination at age 11 and 12
 Secondary prevention: PAP, early detection (pap smears)
 Unclear if it works, but so far, seems like it is helping
o Asbesto: Mg silicates used in construction – leads to lung cancer risk – this is promoter
o Vinyl chloride – PVC pipes: chronic exposure is promoter as well
 Hepatocellular carcinoma
 3rd leading cause of cancer related death
 Risk factor: viral hepatitis, alcohol, vinyl chloride and aflatoxin
o This activates kupffer cells and stellate cells  necrosis  regeneration
(inflammation) fibrosis and cirrhoises (chronic inflammation yay death)
o ROS are secreted to be able to deal with inflammation, which causes mutations
o UV radiation
 Complete carcinogen = is promoter and intiator
 UVA- inflammation, UVB – DNA damage
 Melanin content determines UV sensivity, absorbs inflammation, and decreases DNA damage
 Discuss preventable causes of cancer: especially tobacco and alcohol, ionizing radiation (esp. exposure for medical
diagnostic), viruses, environmental toxins
o Carcinogens  Mutations and inflammation
o Prevention = decrease initiators and chronic inflammation
 High risk patients might need extra stuff
o Cancer prevention= decrease cancer related and overall mortality
by lowering CA incidence
 NO TOBACCO
 Health diet (more fruit, vegetable, less alcohol, processed
meats)
 Physical activity, no sun, get immunized, avoid risky
behavior
o Avoid carcinogens, lifestyle, diet, medical stuff, and do early
detection

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 Describe the influence of diet and exercise on incidence and recurrence of common cancers
o Lots of cancers is because of increased weight, estimated to cause 20% of cancer-related deaths
o Worldwide, 35% of adult is overweight, 3.6% of cancers worldwide attribute to body weight
o Bodyweight can increase estrogen and more IGF-1, which might increase cancer but many confounding
factors in study
 Direct: initiator and promoter
 Indirect: Associated conditions: DM and inactivity
o Diabetes increase risk of lots of cancer
o Diet = low carb diet  greater weight loss, better cholesterol profiles, but how you lose that weight affects
mortality
 Low carbs also decrease heart disease, whereas low-fat diet is bad
 Discuss the role of surgical prevention in high-risk patients (familial cancer syndromes, IBD)
o COLON AND BREAST
o If you have familial lynch syndrome – surgery can help
o Can get breasts cut off

Overall, decrease inflammation

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Lecture 5: Cancer Genetics

 2.1: Recall that cancer is a Genetic disease: the

principles of genetic instability and the step-wise
accumulation of somatic mutations.
o Small tumor: Needs signals to GROW and
never STOP, and never die
o Malignant tumor: get blood supply, grow
forever, and invade tissue
o Environment is important: need to escape
immune, remodel tissue, and Warburg effect
(cancer cell get more energy through
glycolysis, lactic acid, no mitochondrial
oxidative phosphorylation)
 2.2: Recognize endogenous (eg., Reactive oxygen
species) vs exogenous (eg.,Mutagens or Radiation)
sources of DNA damage & the significance of faulty
DNA repair.
o DNA Damage
 1. ROS species (mitochondria/oxygen
metabolism, chronic inflammation,
chemicals, ionizing radiation)
 2. UV radiation, direct damage (thymidine dimers, ss and ds breaks)
 3. Chemical carcinogens (mutagens)
 4. DNA replication/repair errors
 2.3: Understand the characteristics and functions of Oncogenes vs.Tumor Suppressor genes (TSGs): Oncogenes: Src,
‘RTKs’ (Her2), Ras, Raf, c-myc; Tumor Suppressor Genes: p53, Rb, NF1, BRCA1/2, APC, PTEN
o Tumor suppressors: STOP GROWING
 Block signaling from oncogene, arrest proliferation in mid-cell cycle, lead to apoptosis
 Point mutation, insert/delete, fusion with another gene (inactivate), more degradation
 Without these, even unamplified protooncogene  oncogene
 P53 is a tetramer, so one bad hit can screw it up
 Specific proteins
 TSC1 and TSC2 genes attenuate mTOR signaling
o Get tuberous sclerosis complex (also lots of benign
tumors)
 PTEN (tumor suppressor gene) decreases PI3K signaling
o Leads to Cowden syndrome (AD condition that has benign overgrowths called
hamartomas)
o

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 Oncogene: GROW MORE
 Drive hyperplasia but not SUFFICIENT to cause cancer (most likely NOT hereditary, just drives
tumor growth)
 Can be mutation within existing gene, foreign gene, chromosomal translocation
 Chromosomal translocation
o Promoter scape: oncogene is placed behind a different gene promoter
o Gene fusion event: gene is placed in frame with another gene so there is gain of
function from chimera (BCR-abl)
 Do not have to have activating mutation, could just have MORE of that (proto) Oncogene
 Her2 amplification in breast cancer
o MycN amplication in neuroblastoma
 You genetically progress towards cancer when cells proliferate (more changes to get mutations), and when genome is
instable
 Hyperplastic cells more likely to get new
mutations
 These can be mutations in a single bp (K-
Ras) or large segment of chrosome (BCR-abl)
 2.4: Understand key mechanisms that activate/upregulate
oncogenes: Dominant point mutations at key sites,
Amplification of oncogenes, Chromosomal rearrangement to
yield constitutively expressed or active genes.
 2.5: Understand mechanisms of tumor suppressor
inactivation: Point mutations and deletions occuring in
widespread locations, leading to loss of
heterozygosity/function. Often, need Two Hits to knockout
both alleles.
o Rasa and Raf is 85% of cancers!
 2.6: Understand the molecular basis of common hereditary cancer syndromes: Li Fraumeni Syndrome,
Retinoblastoma, Neurofibromatosis, BRCA-1/2, APC, Lynch syndrome.
o Lynch syndrome – mutation in Mismatch repair in DNA: in MSH2, so increased risk for cancer
 Sometimes have no polyps in colorectal cancer
o BRCA-1/2 – BRCA do dsDNA repair, increase risk for breast or ovarian cancer
o APC: colon cancer with polyps!
 APC protein is tumor suppressor gene, Ashkenazi Jews
o Li Fraumeni Syndrome – Loss of P53, or CHEK2 (which intiates p53)
 See primary neoplasms in children/young adults
o Retinoblastoma – los of RB gene that suppresses retinoblastoma
o Neurofibromatosis – NF1 gene (tumor suppressor gene), which attenutates Ras Signaling
 Spread of café au lait birthmarks and is really bad if p53 is also lost
 2.7: Understand common examples of viral carcinogenesis: understand the association between HBV/HCV and
hepatocellular cancer, HPV and cervical/penile/head&neck ca, EBV and Burkitts lymphoma/nasaophayngeal ca,
KSHV and Kaposis sarcoma/lymphoma
o Introduce Viral oncogene
o Disrupt tumor suppressors – virus wants proliferation machinery
o Integrate into critical genomic sites
o Promotion of ongoing DNA damage - foster ongoing inflammatory response, lots of ROS
 HPV: 16 and 18
o Produces oncoproteins (E6 – blocks p53, and E7 – interacts with Rb and cMyc), weakest of viruses are most
effective because they break more. It is the PRIMARY CAUSE OF TUMORS
 Human Polyoma Virus (MCV)  merkel cell carcinoma by blocking p53, rb, and others
 Epstein Bars Virus – Can cause Burkitt’s lymphoma by rearrangement the chromosome translocation
o In Asians, also causes nasopharyngeal carcinoma
 Kaposi’s sarcoma – only in immunosuppressed patients
 Hep C virus: and Hep B – chronic inflammation so ROS interact with liver cells

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Lecture 6: Cancer Genomics & Molecular Targets for Therapy

 Understand the principles of next-generation DNA sequencing, feasibility and cost of whole exome and whole
genome sequencing, bioinformatics requirements to interpret results
o Basically, for clinical tests, if you can genotype patients beforehand, then you can get higher success rates.
Precision medicine yay
o Get swab of cells, get DNA and sequencing with Sanger sequencing (primer and divide into 4 rxn, each with
different nucleotides)
o NGS – dissect, add linkers, bridge PCR, and amplifies varying fragments, then fluorescent tag them)
 Wash and take picture, then get a new primer and take picture, 30-50 bp each and then put together
 Cannot detect if there is increased gene expression because computer just puts them all together
 Therefore, have to do additional hybridization array
 Apply the concept of “driver” and “passenger” mutations, in the context of the many genes mutated in a typical
human cancer
o Driver: a known oncogene or tumor suppressor
 Variation observed is known to activate or compromise function
o Passenger: mutation that is present, but doesn’t drive the tumor biology
 Do not contribute to success of tumor, so not important, not given to you
o VUS (variant of unknown significance) – mutation in oncogene/tumor suppressor but has no known role in
altering protein function
 Understand “druggable” targets and review the major signaling pathways targeted for cancer therapy
o Oncogenes with point mutation, often enzymes such as tyrosine kinases **** IMPORTANT
o 1. Raf
o 2. Pi3k – mtor inhibition
o 3. EGFR
o Also can do Jak/Stat pathway, which is in
blood
o We do not have drugs that treat Ras yet,
can block Raf, or PI3K (which is super
toxic) so usually block mtor downstream
o Cannot drug transcription factors
 Appreciate the concept of cancer
heterogeneity and progression, and understand
the emergence of resistance to targeted
therapies
o Cancer is heterogenous so when you give
drugs, you need to give it so it affects all of them
 This is because although if you target the mutation that is in most genes, the other mutations can still
help proliferate in other ways because yay cancer is all different, relapses could be from other ones
 Discuss use of cancer genomics in clinical practice
o Can use chemical compounds, antibodies as drugs
o
 DNA repair
o PARP are proteins that bind to Single strand breaks and they attract other repair proteins
 BRCA negative patients cannot repair DNA
 PARP inhibitors prevents ATP polymerization so for tumor genes that already have messed up DNA
repair systems, taking out this last resource to help survive kills the tumor cells

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 Pathology Lab 2
 Understand the concepts of metaplasia and dysplasia
o Metaplasia
 Reversible change in which one adult differentiated cell type is replaced by another cell type
 This is adapting to the environment
 This is not pre-cancerous – this is a normal physical change
o Dysplasia: DISORDERED GROWTH
 Pre-neoplastic, only refers to epithelial! All look different!
 Disorderly, but non-invasive proliferation, loss in architectural orientation, increase in mitotic activity
 Carcinoma in situ
 Dysplasia is marked and it has affected ALL the epithelium but has not penetrated the
basement membrane
 Out of a set number of pre-neoplastic lesions, less than 20% likelihood to develop a cancer
 Therefore, we have no idea what dysplasia does or turn into..
 Cancer vs pre-cancerous: biggest difference is that cancer invades.
 Almost 90% of lesions within the cervix are related to HPV, higher CIN is more likely to turn into
cancer.
 CIN = cervical intraepithelial neoplasia
 SIL = squamous intraepithelial lesion
 This is still REVERSIBLE
o Neoplasia (new growth): this defines a TUMOR
 A cancer = growth of unregulated proliferation
 Invasive cancer = cells that replicate too much, but also migrate
 Understand the progressive transformation of tissue from metaplasia to dysplasia, carcinoma in situ, and eventually
invasive carcinoma
o Carinoma = IN THE EPITHELIAL CELLS (in GI, respiratory tract, urogenital tract)
 Or also from epithelial-lined ducts
 Cacinomas that have glandular configurations are adenocarcinoma
o Non-epithelial = lots of other names = SARCOMA
 Sarcomas from soft tissue (cartilage, bone, fascia, smooth/skeletal muscle, blood vessels,
lymph, covering of organs (mesothelium)
 Recognize characteristic morphological features of malignancy (cytologic features of malignant cells with nuclear and
cytosolic abnormalities, histologic features of malignancy with abnormal growth patterns, architecture, invasion and
metastasis)
o 1. Degree of differentiation and anaplasia
o 2. Rate of growth
o 3. Local invasion
o 4. Metastasis (distant spread)
o Nomenclature
 One parenchymal cell type
 Tumors of epithelial orgin
 Tumors of mesenchymal origin
 More than one neoplastic cell type = mixed tumor
 More than one neoplastic cell type from more than one germ layer = teratogenous
 Review examples of benign and malignant tumors of epithelial, mesenchymal, neuroendocrine, and stem cell origin.
Understand tumor nomenclature.
o Tumors are usually darker because they have more nuclei
o

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Lecture 7: Cancer Screening
 Discuss successful and problematic cancer screening programs (breast,
cervix, colon and lung cancer =”successful”; ovarian and prostate
cancer =”not successful”)
o Preventative benefits for A or B will be covered by the ACA
o Advantages
 Early detection in asymptomatic individual
 Early detection  early treatment  decrease mortality
o Considerations
 Lead time bias – no change in overall survival (but then
it looks like the survival is longer since the diagnosis is
made earlier)
 Length time bias – screening tends to reveal slow growing cacners which are less deadly
 Selection bias – patients may different than general population
 Over diagnosis: finding cancers that wouldn’t cause problem
o Diagnostics
 Screening = pt without clinical sign of disease, Diagnostic – patient with symptoms
 Prognostic = likely outcome (LDH, sed rate, WBC count, PSA velocity)
 Predictive = Respond to therapy (HER-2, PDL1)
 Tracking treatment response = reflect cancer burden (hCG)
o Different screenings
 Recommended: breast, cervical, colon, and lung
 Lung – lead to 20% reduction in lung cancer, 217 people screened for one life
o Low dose CT – risk for radiation (so you can induce other cancers)
 Overreading in the community – in non-pulmonary clinics, maybe more pokes
o Risk for lung cancer is 20x higher for smokers
o Gets a grading of B, because its costly, but it makes an impact
 Mammograms (B):
o Depends on familial risk, Screening is recommended every other year 50 – 74 years old
o BRAC1 mutation = 1 in 300
o BRCA2 mutation = 1 in 800
 90% of early onset cancer is caused by BRCA1 or 2 mutation
o Picking up indolent breast cancers
o Other mutations = (ATM, Li-fraumeni (TP53), CHEK2, Cowden syndrome (PTEN),
Hereditary diffuse gastric cancer (CDH1), Peutz-Jeghers syndrome (SKT11)
 Colorectal Screening (A)
o 50-75 years, colonscopy every 10 years
 If someone has Lynch cancer, must screen more (and endometrial cancer)
 Makes up 2-4% of colon cancer
 Not good at detecting
 Cervical Cancer
o HPV infections cause of nearly all cervical cancers
o High risk HPV infection will go away, but 10% it stays
o HPV test finds 16, 18 – but there are 12 other high risk genotypes
o Pap smear, do over 21 , HPV vaccine targets 16, 18 and 6, 11
o After 3 years, vaccines prevent 99% CIN2 and 3 by HPV 16 or 18
o Screen every 3 years PAP smear
 Do not screen: ovarian and prostate, overian CA125 screening is worse
 Prostate
o About 1 in 1000 screend will get cancer, and 1 in 3000 without metastasis
o Many men harm with screening: , do not do over 70
 False positive (high PSA, no cancer), biopsy have complications
 Over diagnosis: prostate grows very slowly and no symptoms
 Harm from treatment: surgery and radiation  incontinence and erectile
dysfunction
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 Understand the methods, limitations, and implications of genetic screening
o Risk stratifications: find specific mutations can make screening more
specific
o Allows for consideration for preventative strategies, including
prophylactic surgeries and chemoprevention
o Methods
 Ask about familial history (when did cancer start, what type,
pathology, testing?, polyps?
 Test first the person who has the cancer,
 Discuss the use of laboratory markers for cancer diagnosis and their limitations (screening versus diagnosis versus
prognosis versus aid in treatment selection versus tracking treatment responses) – examples: PSA, CEA, CA125
o BRAF – oncogene, somatic mutation
o If you find a positive test – confirm the hereditary cancer , and deal with the new guildines
o Negative test – maybe the testing methods will improve, so do further testing later on
o VUS –
o

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Lecture 8: Cancer Diagnosis: Sample procurement by IR and sample analysis by the pathologist

 1.Discuss indications for biopsy and methods of acquisition of material for tissue diagnosis
o Help with diagnosis: malignant vs benign
o Good for staging, and cellular, molecular and genetic characterization
o To get tissue
 Surgery: incisional/excisional biopsy, lymph node sampling
 Minimally invasive: endoscope (GI, pulm), percutaneous (IR) = MIIPS
 Use fine need aspiration, Core biopsy needle, brush biopsy (ureters – only if cells can come off),
alligator forceps: chomp chomp
 Fine needle: 20-25 G, free cells, clumps of tissue
 Core biopsy: cutting needle: tubes of tissue
 Coaxial needing = guiding needle which is portal so you can go in multiple times
o How to see:
 Ultrasound: real time imaging, best resolution, no radiation, but cannot see bone or air
 Good for lesions in liver, kidney, thyroid, superficial LN, pleural based masses, muscle
 CT: good for long lesions, deep lesions, targets bethind bone/air, or chunky people
 Intermittent visualization.. so not continuously
 Less commonly
 Fluorescopy (sclerotic bone lesion)
 MRI (limited equipment that wont kill them)
o Before you biopsy
 Make sure the results would be helpful, and lesion has to be visible, and safe to get through
 Give patient moderate sedation, hold anticoagulatns and antiplate medications and see INR
 Get permission
 Risk: bleeding, infection, damage to surrounding tissue, nondiagnostic sample, tumor seeding –
pulling the tumor back and it goes into other place
 Benefits: avoid surgery, more acute diagnosis and staging
o Plan: choose imaging modality
o Plan safe path, do not go through arteries, or bowel do not penetrate through pleura more than once for lung
biopsy, do not touch other organs
 Avoid nerves
o Go for the most active of the lesion: PET-avid, irregular, nodular, edge – use the smallest needle possible
 2.Understand when a percutaneous, image-guided biopsy of a mass by Interventional Radiology is indicated, feasible
and safe
o Depends on tumor type and location, can get diagnostic tissue 70-95% of the time, depending on where
o Complications
 Lung: pneumothorax, bleeding, air embolism
 Abdomen: bleeding, infection, damage to organ/adjucent, tumor seeding
 MSK: tumor seeding, bleeding, infection
o Technically feasible to biopsy a mass with image, if there is imaging and safe path
 3.Discuss the general procedure for image-guided needle biopsy of masses in the body, biopsy yields, and potential
complications
o 1. Preliminary imaging to identify target  Mark skin
o 2. Prep and drape
o 3. Time out
o 4 Check that you have all your needles and gauges
o 5. Number skin, use numbing needle
o 6. Place coaxial needle into edge of mass using US or CT
o 7. Take sample through coaxial needle by core biopsy and/or fine needle aspiration
o 8. Give sample to pathologist, if needed get more with/without adjusting coaxial needle
 Put it in formalin or RPMI (live cell)

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Lecture 8: Pathology How to make diagnosis

 Understand basic sample processing by pathology, and review

morphological criteria for malignancy in cytological and biopsy material
o Biopsy via surgery, percutaneous, or endoscopy
o Biopsy in formalin, give clinical indications, describe the
fragments, and get vibratome and IHC staining
o Cytologic specimens: can examine under microscope by pathology
o Old days vs now
 Old: H&E, Dx by morphology and cytology
 Now: lots of IMC, Molecular (PCR, FISH), sequencing
 Stains:
o Mucicarmine: mucin turns pink, so if the tumor has pink, it produces mucin, so it is
glandular  Adenocarcinoma
o Iron in tissue terns blue – see if there is way too much iron in the liver 
hematomacrosis
o IHC for finding tissue of orgin, and predictive markers and prognosis
o For breast: normal gland is two layers long ~ myoepithelial cells + epithelial cell  it is benign
 Her2 : prognosis and predictive
 Her2+ are more aggressive but we also have a drug: Herceptin
o Can also do Flow cytometry (RMPI) – can do up to 9 antibodies at once
 Very used for hemato-lymphoid cells
 Describe immunological tools (histochemical staining, flow cytometry) to classify tumors according to their cell of
origin – examples: cytokeratins, vimentins, CD45, neuroendocrine markers
o Flow cytometry good for lymphomas
o Karyotype
 Count chromosomes: can only detect large scale abnormalities
o FISH: more expensive – need to know what you are looking for
 Mantle cell lymphoma – can tell if you have a translocation
 HER-2 : look for amplifications
o PCR: Need to know targets
 Discuss conventional cytogenetics vs FISH vs PCR for the detection of specific genetic abnormalities and how this is
used in the classification of certain tumors
o EGFR mutations and ALK translocation in lung cancer, Her2 amplication in breast cancer

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