Chapter 3 (Lectures 6 & 7) – Neoplasia
Neoplasia
Basic Principles
1. Neoplasia
a. Characteristics = new tissue growth that is:
i. Unregulated
ii. Irreversible
iii. Monoclonal
1. Derived from a single mother cell
b. These features distinguish it from hyperplasia and repair
i. Hyperplasia  due to increase stress but it is regulated, reversible,
and polyclonal
2. Clonality
a. Historically = determined by glucose-6-phosphate dehydrogenase
(G6PD) enzyme isoforms
i. G6PD is X-linked
ii. Multiple isoforms  only one is inherited from each parent
1. Females have one active variant  one isoform is
inactivated by lionization in a random fashion
iii. Normal ratio of active forms in each cell = 1:1
1. Hyperplasia = isoform ratio maintained
a. Is polyclonal  aka derived from multiple cells
2. Neoplasia = only one isoform is present
a. Is monoclonal
iv. Key point: G6PD therefore can be used to determine if growth is
because of hyperplasia or neoplasia
1. Can also be determined by androgen receptor isoforms that
are also present on the X chromosome
3. B cell Clonality (same game as G6PD but this time for lymph nodes)
a. Determined by Ig light chain phenotype
i. Light chain forms = kappa or lambda
ii. Normal ratio of kappa to lambda = 3:1
1. Hyperplasia (due to infection) of B cells = ratio maintained
a. Aka the growth is polyclonal
2. Neoplasia proliferation (i.e. due to Lymphoma) of B cells =
ratio > 6:1 or inverses (i.e. 1:3)
a. Aka monoclonal proliferation
iii. Video notes:
1. Things that enlarge a lymph node:
a. Metastatic cancer
b. Reactive hyperplasia (i.e. infection)
c. Lymphoma
4. Neoplastic tumors
a. Are either Benign or Malignant (both of which are monoclonal)
i. Benign = remain localized within tissue  do not metastasize
ii. Malignant (cancer) = invade locally and have potential to
metastasize
b. Nomenclature
Lineage
Epithelium
Mesenchyme
a. Key point: metastasis doesn’t need to happen in
every single patient it just has the potential in every
patient
Benign
Adenoma (glands)
Papilloma (finger-like)
Lymphocyte
Lipoma
Osteoma
Chondroma
Angioma
(Does not exist)
Melanocyte
Nevus (mole)
Malignant
Adenocarcinoma (glands)
Papillary carcinoma (fingerlike)
Liposarcoma
Osteosarcoma
Chondrosarcoma
Angiosarcoma
Lymphoma
Leukemia
Melanoma
Notes:
 Mesenchyme = CT or Soft Tissue
o Fat, blood vessels, bone, cartilage
 When benign epithelial tumor produces glands  adenoma
 When benign epithelial tumor produces finger like papilla  papilloma
o Papillary finger like structures  growth of epithelial cells that overlie a CT
core with a blood vessel in the center
Epidemiology
1. Cancer = 2nd leading cause of death in children and adults
a. Leading causes of children deaths
i. Accident
ii. Cancer
iii. Congenital defects
b. Leading causes of adult deaths
i. Cardiovascular
ii. Cancer
iii. Chronic respiratory disease
2. Most common cancers by incidence in adults (excluding skin)
a. Breast/prostate
b. Lung
c. Colorectal
3. Most common cause of cancer mortality
a. Lung
b. Breast/prostate
c. Colorectal
Role of Screening
1. Cancer begins as a single mutated cell
2. Clinical symptoms  occurs approximately after 30 divisions
3. Each division  increases mutations
a. Cancers do not produce symptoms until late in disease
b. Late detection = poor prognosis
c. Early screening
i. Goals
1. Detect dysplasia before it becomes carcinoma
a. Dysplasia = has mutations but is reversible
b. Cancers = mutations and is irreversible
2. Detect carcinoma before clinical symptoms appear
ii. Efficacy of screening  requires a decrease in cancer-specific
mortality
4. Examples of Screening Methods
a. Pap smear  detects cervical dysplasia (CIN)
b. Mammography  detects in situ breast cancer (e.g. DCIS)
i. Detects calcified areas
ii. Detects smaller masses (e.g. 1 mm)
1. Mass need to be 2mm in order to be palpable
c. Prostate Specific Antigen (PSA) and Digital Rectal Exam  prostate cancer
i. Prostate cancer  most common in poster 1/3  doesn’t compress
urethra under late in the disease
1. Aka why we use DRE to feel this area
ii. BPH  involves center of the gland  compresses very early
d. Hemoccult test (for occult blood in stool) and Colonoscopy  detects colonic
adenoma and colonic carcinoma
i. Adenocarcinoma of the colon  vast majority develop from
adenomas (the A  C sequence)
ii. If catch adenoma  can’t develop into carcinoma
iii. If find carcinoma  hopefully catch before clinical symptoms
Carcinogenesis
Basic Principles
1. Cancer initiation = stem cell DNA damage
a. Escapes DNA repair mechanisms but is NOT lethal
b. Carcinogens = agents that damage DNA
i. Examples:
1. Chemicals
2. Oncogenic viruses
3. Radiation
2. Important Carcinogens and Associated Cancers
Carcinogenic Agent
Chemicals
Aflatoxins
Alkylating agents
Alcohol
Arsenic
Associated Cancer
Comments
Hepatocellular carcinoma
-From Aspergillus  can contaminate
stored rice and grains
-Side effect of chemotherapy
Leukemia/Lymphoma
Squamous cell carcinoma:
Oropharynx
Upper esophagus
Pancreatic carcinoma
Hepatocellular carcinoma
Lung cancer
-Arsenic = in cigarette smoke
Asbestos
Cigarette smoke
Nitrosamines
Naphthylamine
Vinyl chloride
Nickel, Chromium,
Beryllium, or Silica
Oncogenic Viruses
EBV
HHV-8
(Human Herpes Virus
subtype 8)
HBV & HCV
(Hepatitis virus)
HTLV-1
(Human T cell Leukemia
Virus)
High-risk HPV
(Subtypes: 16, 18, 31, 33)
Radiation
Ionizing
-Nuclear reactor
accidents
-Radiotherapy
Nonionizing
-UVB sunlight (most
common source)
Squamous cell carcinoma - Skin
Angiosarcoma – Liver
Carcinoma – Lung
Mesothelioma – Lung
(Mesothelium = cells of the pleura)
Carcinoma:
Oropharynx
Esophagus
Lung
Kidney
Bladder
Cervical and Pancreatic*
Carcinoma – Stomach
(Intestinal type)
Urothelial carcinoma - Bladder
Angiosarcoma – Liver
Carcinoma – Lung
Carcinoma – Nasopharyngeal
Burkitt Lymphoma
CNS lymphoma in AIDS
Kaposi sarcoma
Hepatocellular carcinoma
Adult T-cell leukemia/lymphoma
-Test for poisoning  fingernails
-Asbestos exposure  more likely to
develop lung cancer > mesothelioma
-Cigarette smoke = most common
carcinogen in the world
-e.g. Polycyclic hydrocarbons
-Urothelium  smoking  risk for
carcinoma due to being bathed in the
filtered carcinogens
*Just have to remember
-Found in smoked foods
-High rate of stomach carcinoma in
Japan
Derived from cigarette smoke
-Occupational exposure  used to make
PVC pipes
-Occupational exposure
-Nasopharyngeal = seen in Chinese
males and Africans (presents with neck
mass)
Kaposi – tumor of endothelial cells
Presentation = purple raised lesions on
skin
Patients = Eastern European males, AIDS,
transplant
“Think about it”
“Think about it  T cell virus  causes
leukemia and lymphoma”
Squamous cell carcinoma:
Uvula
Vagina
Anus
Cervix
Adenocarcinoma – Cervix
AML
CML
Papillary carcinoma - Thyroid
Generates hydroxyl (OH) free radicals
Basal cell carcinoma - Skin
Squamous cell carcinoma - Skin
Melanoma – Skin
Results from formation of pyrimidine
dimers in DNA (normally excised by
restriction endonuclease)
3. DNA mutations eventually disrupt key regulators  allows growth and spread
a. Examples:
i. Proto-oncogenes
ii. Tumor suppressor genes
iii. Regulators of apoptosis
Oncogenes
1. Proto-oncogenes
a. Essential for cell growth and differentiation (the accelerator)
b. Mutations  form oncogenes  lead to unregulated cellular growth
2. Oncogenes
a. Categories
i. Growth factors
1. PDGFB  astrocytoma
ii. Growth factor receptors
1. ERBB2 [HER2/neu]  breast cancer
iii. Signal transducers
1. Example = Ras
a. Ras-GDP = inactive
i. Form associated with GF receptors
b. Ras-GTP = active
c. Has intrinsic GTPase activity
i. Augmented by GTPase activating protein
(GAP)
d. Mutated Ras  inhibits GAP activity 
constitutively active Ras
iv. Nuclear regulators
v. Cell cycle regulators
1. Cyclins and cyclin-dependent kinases (CDKs)
a. Phosphorylate proteins that drive the cell cycle
i. Example = cyclinD/CDK4  P
retinoblastoma protein  promotes
progression through G1/S checkpoint
3. Important Oncogenes and Associated Tumors
Growth Factor
PDGFB
Growth Factor
Receptors
ERBB2
[HER2/neu]
RET
c-KIT
Signal Transducers
Function
Mechanism
Associated Tumor
Platelet-derived GF
Overexpression 
makes autocrine loop
Astrocytoma
Epidermal GF receptor
Amplification
Subset of breast carcinomas
Neural GF receptor
Point mutation
Stem cell GF receptor
Point mutation
MEN 2A
MEN 2B
Sporadic medullary carcinoma Thyroid
GI stromal tumor
RAS gene family
GTP-binding protein
Point mutation
ABL
Tyrosine kinase
T (9; 22) with BCR
(Philadelphia)
Carcinomas
Melanoma
Lymphoma
CML
ALL (some types)
Transcription factor
T (8; 14) involving Ig H
Burkitt lymphoma (B cells)
Transcription factor
Transcription factor
Amplification
Amplification
Neuroblastoma
Carcinoma – small cell Lung
Cyclin
T (11; 14) involving Ig H Mantle cell lymphoma
(“11 y/o not touch 14 y/o follicles’)
Amplification
Melanoma
Nuclear Regulators
C-MYC
N-MYC
L-MYC
Cell Cycle Regulators
CCND1 (cyclin 1)
CDK4
Cyclin-dependent
kinase
Notes:
 Myc is translocated to the Ig H location on chromosome 14, which is normally an
“ON” location. Once in this position, Myc will be expressed in the same “ON” fashion
that the Ig H would have been
o Histologic findings = starry sky appearance
 Tumor cells = sky (blue)
 Stars = Mf eating dying cells (white)
 G1  S phase = most highly regulated cell cycle step
 Mantle cells lymphoma
o Expansion of the mantle region in the lymph node
 Regions = Follicle  Mantle  Margin
o Cyclin D1 gene is on chromosome 11
Tumor suppressor genes
1. Regulate cell growth  decrease (suppress) risk of tumor formation (brakes)
2. Examples
a. p53
i. Regulates G1  S
ii. Mechanism (traffic cop  show me your DNA)
1. DNA damage  p53 slows cell cycle and upregulates DNA
repair enzymes
2. Too much damage  apoptosis
a. p53   BAX   Bcl2  cytochrome C leaks into
cytoplasm
iii. Knudson 2 hit hypothesis
1. Both copies of p53 gene must be knocked out for tumor
formation
a. Most of the time they both are sporadic
2. Loss is seen in > 50% of cancers
iv. Li-Fraumeni Syndrome
1. Germline mutation = 1st hit
2. Somatic mutation = 2nd hit
3. Characterized by the propensity to develop multiple types
of carcinomas and sarcomas
b. Retinoblastoma (Rb)
i. Holds the E2F transcription factor
ii. When Rb is P by cyclinD/CDK4  release of E2F allow for
progression though the G1/S checkpoint
iii. Rb mutation  constitutively free E2F  unregulated progression of
cell cycle  uncontrolled growth
iv. Knudson 2 hit hypothesis
1. Unilateral retinoblastoma (rare)
a. 2 somatic hits that are sporadic mutations
2. Familial retinoblastoma
a. Germline mutation = 1st hit
b. Somatic mutation = 2nd hit
c. Characterized by bilateral retinoblastoma and
osteosarcoma
Regulators of Apoptosis
1. Bcl2
a. Anti-apoptotic protein  stabilizes mitochondrial membrane  blocks
release of cytochrome C
b. Disruption  cytochrome C into cytosol   apoptosis
c. Follicular lymphoma
i. Cause = Overexpression of Bcl2 (“was found in B cell lymphoma”)
ii. Mechanism:
1. t (14;18) moves Bcl2 from chromosome 18  to the Ig
heavy chain locus on chromosome 14   Bcl2
a. “18 y/o would touch 14 y/o follicles”
2.  Mitochondrial stability   apoptosis
3. B cells that would normally undergo apoptosis during
somatic hypermutation in the lymph node germinal center
accumulate  leading to lymphoma
Other Features of Tumor Development
1. Telomerase
a. Normal = telomeres shorten with serial cell divisions, eventually resulting
in cellular senescence
b. Tumors = need telomeres for cell immortality
i. Telomerase is often upregulated in cancers  preserves telomeres
2. Angiogenesis
a. Needed for tumor survival and growth
i. Angiogenic factors  commonly produced by tumor cells
1. Examples:
a. VEGF
b. FGF
3. Avoiding immune surveillance
a. Normal
i. Mutations  produce abnormal proteins  present on MHC 1 
recognized by CD8  cell destroyed
b. Tumors
i. Downregulate MHC 1 expression  avoid surveillance
ii. Immunodeficiency (both primary and secondary)   risk of cancer
Tumor Progression
Tumor Invasion and Spread
1.  Mutations  eventually results in tumor invasion and spread
2. Mechanism
a. Downregulation of E-cadherins  results in the dissociation of attached
epithelial cells
b. Cells attach to laminin associated with the BM
c. Secrete collagenase  destroy basement membrane (collagen type 4)
d. Cells attach to fibronectin in ECM  spread locally
e. Entrance into vascular or lymphatic vessels  metastasis (distant spread)
Routes of Metastasis
1. Lymphatic
a. Characteristic of carcinomas
b. Initial spread = regional draining lymph nodes
2. Hematogenous spread
a. Characteristic of sarcomas and some carcinomas
i. Example of carcinomas that spread via blood “things w/ lots of
blood – Kidney, Liver, Thyroid, Placenta”
1. Renal cell carcinoma  via renal vein
2. Hepatocellular carcinoma via hepatic vein
3. Follicular carcinoma of the thyroid
4. Choriocarcinoma (placenta)
3. Seeding of body cavities
a. Characteristic of ovarian carcinoma
i. Often involves the peritoneum  omental caking
Clinical Characteristics
Clinical Features
1. Benign tumors
a. Slow growing
b. Well circumscribed
c. Distinct
d. Mobile to touch
2. Malignant tumors
a. Rapid growing
b. Poorly circumscribed (i.e. irregular shape)
c. Infiltrative
d. Fixed to surround tissues and local structures
3. Malignant vs. Benign
a. Need biopsy to diagnosis
i. Some benign tumors can grow in malignant-like fashion
ii. Some malignant tumor can grow in benign-like fashion
Histological Features
1. Benign tumors = well differentiated
a. Organized growth
b. Uniform nuclei
c. Low nuclear to cytoplasmic ratio (i.e. lots of cytoplasm)
d. Minimal mitotic activity
e. Lack of invasion  of basement membrane or local tissue
f. No metastatic potential
2. Malignant tumors = poorly differentiated (anaplastic)
a. Disorganized growth
b. Nuclear pleomorphism (many cell sizes and shapes) and hyperchromasia
c. High nuclear to cytoplasmic ratio
d. High mitotic activity with atypical mitosis
e. Invasion  through basement membrane or into local tissue
f. Metastatic potential = the hallmark of malignancy
3. Immunohistochemical Stains and Target Cell Types
Immunohistochemical stain
Intermediate Filaments
Keratin
Vimentin
Desmin
GFAP
Neurofilament
Others
PSA
ER
Thyroglobulin
Chromogranin
S-100
Tissue Type
Epithelium
Mesenchyme
Muscle
Neuroglia
Neurons
Prostatic epithelium
Breast epithelium
Thyroid follicular cells
Neuroendocrine cells
(e.g. small cell carcinoma of lung
and carcinoid tumors)
Melanoma
Schawnnoma
Langerhans cell histiocytosis
Serum Tumor Markers
1. Proteins released by tumors into serum  e.g. PSA
2. Useful for:
a. Screening
b. Monitoring:
i. Response to treatment
ii. Recurrence
3. Elevated levels require tissue biopsy for diagnosis of carcinoma
Grading of Cancer (grade with glass slide – i.e. microscope)
1. Microscopic assessment of differentiation
a. “How much a cancer resembles the native tissue in which it grows”
b. Takes into account
i. Architectural features
ii. Nuclear features
c. Grades
i. Low = well differentiated  aka resembles normal tissue  good
prognosis
ii. High = poorly differentiated (aka undifferentiated)  aka looks like
something else  poor prognosis
Staging of Cancer
1. Assessment of size and spread of cancer
2. Key prognostic factor  MORE important than grade
3. Determined after final surgical resection of the tumor
4. Utilizes TNM staging system:
a. T = Tumor
i. Size and/or depth of invasion
b. N = Nodes
i. Spread to regional lymph nodes
ii. Is the second most important prognostic factor
c. M = Metastasis
i. MOST important prognostic factor