Rochelle Joyce Arado

Post-Graduate Intern
Nomenclature
• Neoplasia: “new growth”→ neoplasm
• “a neoplasm is an abnormal mass of tissue, the growth of which
exceeds and is uncoordinated with that of the normal tissues and
persists in the same excessive manner after cessation of stimuli
which evoked the change”
• Disorder of cell growth triggered by a series of acquired mutations
affecting a single cell and its progeny

• Oncology: study of tumors or neoplasms

• Basic Components:

1) Neoplastic cells- tumor parenchyma

-classification of tumors and biologic behavior
2) Reactive stroma- connective tissue, blood vessels, cells of the
adaptive and innate immune system
- growth and spread
 Benign Tumors
• Benign- gross and microscopic appearances are relatively innocent
• Will remain localized, will not spread, amenable to local surgical
removal
• Suffix –oma + name of cell type from which the tumor originates
• Adenoma- benign epithelial neoplasms derived from glands
• Papillomas- fingerlike or warty projections
• Cystadenomas- large cystic masses
• Papillary cystadenomas- papillary patterns that protrude into
cystic spaces
• Polyp- neoplasms (benign or malignant) macroscopically visible
projection above a mucosal surface
Malignant Tumors
• Malignant- “cancers,” crab: adhere to any part that they seize on in an
obstinate manner
• Invade and destroy adjacent structures and spread to distant sites
to cause death
• Sarcomas- malignant tumors arising in solid mesenchymal tissues
• Leukemias/lymphomas- arising from blood-forming cells
• Carcinomas- from any of the three germ layers
• Squamous cell- stratified squamous epithelium
• Adenocarcinoma- grows in glandular pattern
 Mixed Tumors
• divergent differentiation of a single neoplastic clone
• Such as tumors of salivary gland
• arise from a single clone capable of capable of producing both epithelial
and myoepithelial cells: Pleomorphic adenoma
• Teratoma- arising from more than one germ layer
• Totipotential germ cells
• Sites: ovaries, testes, midline embryonic rests

• Hamartomas- disorganized benign masses composed of

cells indigenous to the involved site
• Choristoma- heterotopic rest of cells; organized cells but
found in ectopic places
Characteristics of Benign and Malignant Neoplasm
• Differentiation and Anaplasia
• Differentiation- extent to which neoplastic
parenchymal cells resemble the
corresponding normal parenchymal cells:
morphologically and functionally

• Anaplasia- lack of differentiation

• “to form backward”
• Hallmark of malignancy
Morphologic changes

1. Pleomorphism- variation in size and shape

2. Abnormal nuclear morphology- nuclear to
cytoplasmic ratio 1:1 (N 1:4 or 1:6),
variable and irregular nuclear shape,
coarsely clumped chromatin and
distributed along the nuclear membrane
(hyperchromatic), abnormally large
nucleoli
3. Mitoses- indicative of rapid cell growth;
malignancy: atypical, bizarre mitotic
figures
4. Loss of polarity- anarchic and disorganized
5. Others- ischemic necrosis
• Metaplasia- replacement of one type of cell to another type
• Tissue damage, repair, regeneration
• Dysplasia- “disordered growth”

• “dysplasia may be a precursor to malignant transformation, it

does not always progress to cancer”
• Carcinoma in situ- marked dysplasia, involves the full thickness of the
epithelium, does not breech the basement membrane
• Invasive- breeches the basement membrane
• Local Invasion
• Growth accompanied by progressive infiltration, invasion, and destruction of
surrounding tissue
• Benign- lack the capacity to infiltrate, invade, or metastasize
• grow and expand slowly
• Capsule- rim of compressed fibrous tissue
• Malignant- well-defined tissue plane is lacking
• Pseudoencapsulated- slow growing malignant tumors
• Rows of cells penetrating the margin and infiltrating the adjacent structures (crablike)
• Metastasis
• Spread of tumor to sites that are physically discontinuous with the primary
tumor
• Equivocally marks a tumor as malignant
• Correlates with lack of differentiation, aggressive local invasion, rapid growth, and
large size
• Pathways:
1) Direct seeding- penetration into natural “open field”; most often: peritoneal cavity
2) Lymphatic spread- most common pathway for the initial dissemination of carcinomas
-follows the natural routes of lymphatic drainage
-sentinel lymph node: first node in a regional lymphatic basin that receives lymph flow from
the primary tumor
3) Hematogenous spread- Typical with sarcomas but seen with carcinomas
-venous invasion: follows the venous flow and rests at the first capillary bed
Epidemiology
• Environmental Factors
• Infectious agents
• Smoking
• Alcohol consumption
• Diet
• Obesity
• Reproductive history
• Environmental carcinogens
• Age
• Most occur in the later years of life (>55 years).
• Main cause of death
• women aged 40 to 79
• men aged 60 to 79

• Accounts for slightly more than 10% of all deaths in children

younger than age 15
• Common neoplasms of infancy and childhood- small round blue
cell tumors
• neuroblastoma, Wilms tumor, retinoblastoma, acute leukemias,
and rhabdomyosarcomas
• Acquired predisposing factors
• Chronic inflammations
• Precursor lesions
• Immunodeficiency states
• Chronic Inflammation
• Compensatory
proliferation of cells that
serves to repair the
damage
• Increase the pool of tissue
stem cells- particularly
susceptible to
transformation
• Activated immune cells
produce reactive oxygen
species (directly genotoxic)
and inflammatory
mediators (promote
bystander cell survival)
• Precursor Lesions
• Localized morpho­logic changes that are associated with a high risk of
cancer. Virtually all precursor lesions arise in epithelial surfaces.
• Many arise in the setting of chronic inflammation and can be recognized
by the presence of metaplasia
• Barrett esophagus- gastric and colonic metaplasia of the esophageal
mucosa in the setting of gastric reflux
• Squamous metaplasia of the bronchial mucosa- in response to smoking
• Squamous metaplasia of the
bladder mucosa- in response to
schistosomiasis infection
• Colonic metaplasia of the
stomach- in the setting of
pernicious anemia and chronic
atrophic gastritis
• Endometrial hyperplasia-
caused by sustained estrogenic
stimulation of the endometrium
• Leukoplakia- thickening of
squamous epithelium that may
occur in the oral cavity or on
the penis or vulva and give rise
to squamous carcinoma
• Immunodeficiency States
• immunodeficient, and particularly those who have deficits in T-
cell immunity, are at increased risk for cancers, especially those
caused by oncogenic viruses
Molecular Basis of Cancer
Genetic and Epigenetic alterations
• Carcinogenesis
• Nonlethal genetic damage
• Tumor: clonal expansion of a single precursor cell
• Target normal regulatory genes in cancer causing mutations
• Proto-oncogenes- “gain of function”
• Tumor suppressor genes- “loss of function;” haploinsufficiency
• Genes that regulate apoptosis- enhanced cell survival
• Genes involved in DNA repair- “mutator phenotype” →
genomic instability
• Impaired ability of the cell to recognize and repair
nonletheal genetic damage; acquires mutations at an
accelerated rate
• Accumulation of complementary mutations in a stepwise fashion over time
• “cancer hallmarks”
• Driver mutations- mutations that contribute to the development of the malignant
phenotype
• Initiating mutation- first driver mutation
• Cancer stem cells
• Loss of function mutations in genes that maintain genomic integrity: common early
step to malignancy
• Increases passenger mutations: mutations with no phenotypic consequence
• Tumor progression- pernicious tendency of tumors to become more
aggressive over time
• Darwinian selection “survival of the fittest”

• Epigenetic alterations
• DNA methylation
• Histone modification
 Cancer
Hallmarks
1) Self-sufficiency in growth signals: Oncogenes
• proto-oncogenes- promote cell growth→ oncogenes (mutated form)
• Oncoproteins: proteins that have the ability to promote cell
growth in the absence of normal growth-promoting signals
• Signaling Pathways that regulate cell behavior
• Receptor Tyrosine Kinase- most commonly mutated oncogenic
pathway in human neoplasms
• G protein-coupled receptor pathway
• JAK/STAT pathway
• WNT pathway
• Notch Pathway
• Headgehog pathway
• TGFB/SMAD pathway
• NF-KB pathway
• RAS Mutations.
• Point mutations of RAS family genes constitute the most common
type of abnormality involv­ing proto­oncogenes in human tumors.
• Stimulation of receptor tyrosine kinases by growth factors leads to
exchange of GDP for GTP and subsequent conformational changes
that generate active RAS
• which in turn stimulates both the MAPK and PI3K/AKT arms of the receptor
tyrosine kinase signaling pathway
• Activation of RAS is transient because RAS has an intrinsic GTPase
activity that is accelerated by GTPase-activating proteins (GAPs)
• GAPs prevent uncontrolled RAS activity.
• Oncogenic BRAF and PI3K Mutations.
• Like activating RAS mutations, activating mutations in BRAF stimulate
each of these downstream kinases and ultimately activate
transcription factors.
• Like BRAF, it activates a cascade of serine/threonine kinases, including
AKT, which is a key signaling node.
• mTOR, a sensor of cellular nutrient status, is activated by AKT and in
turn stimulates protein and lipid synthesis. BAD is a pro-apoptotic
protein that inactivated by AKT, an effect that enhances cell survival.
• Like RAS, PI3K is negatively regulated by an important “braking” factor
called PTEN.
• Transcription factor
• MYC is most commonly involved in human tumors
• Increased expression of MYC, a master transcription factor that
regulates genes needed for rapid cell growth by deregulation through
chromosomal translocations (Burkitt lymphoma, other hematologic
malignancies); gene amplication (neuroblastoma); increased activity of
upstream signaling pathways (many cancers)
• Progression of cells through the cell cycle is orchestrated by cyclin-
dependent kinases (CDKs), which are activated by binding to cyclins, so
called because of the cyclic nature of their production and degradation.
• The CDK-cyclin complexes phosphorylate crucial target proteins that
drive cells forward through the cell cycle.
• Expression of CDK inhibitors is downregulated by mitogenic signaling
pathways, thus promoting the progression of the cell cycle.
• There are two main cell cycle checkpoints one at the G1 /S transition
and the other at the G2 /M transition, each of which is tightly
regulated by a balance of growth pro­moting and growth
suppressing factors, as well as by sensors of DNA damage
• Gain­of ­function mutations in D cyclin genes and CDK4, oncogenes
that promote G1/S progression.
• Loss ­of ­function mutations in tumor suppressor genes that inhibit
G1/S progression.
2) Insensitivity to growth inhibition: Tumor suppressor genes
• Apply breaks to cell proliferation
• Leads to failure of growth inhibition
• “Two-hit” hypothesis
 RB: Governor of Proliferation

• First tumor suppressor gene discovered

• Key negative regula­tor of the G1 /S cell cycle transition
• RB function may be compromised in two different ways:
• Loss-of-function mutations involving both RB alleles
• A shift from the active hypophosphorylated state to
the inactive hyperphosphorylated state by gain-of-
function mutations that upregulate CDK/cyclin D
activity or by loss-of-function mutations that
abrogate the activity of CDK inhibitors
• Loss of normal cell cycle control is central to malignant transformation and
that at least one of four key regulators of the cell cycle (p16/INK4a, cyclin D,
CDK4, RB) is dysregulated in the vast majority of human cancers.

• The transforming proteins of several oncogenic animal and human DNA

viruses also act, in part, by neutralizing the growth­inhibitory activities of RB

• Antiproliferative effect of RB is abrogated in cancers by:

• Loss-of-function mutations affecting RB
• Gene amplifications of CDK4 and cyclin D genes
• Loss of cyclin-dependent kinase inhibitors (p16/INK4a)
• Viral oncoproteins that bind and inhibit RB (E7 protein of HPV)
TP53: Guardian of the Genome

• Regulates cell cycle progression, DNA repair, cellular senescence, and

apoptosis
• most frequently mutated gene in human cancers
• Li-Fraumeni syndrome
• encodes the protein p53
• nonstressed, healthy cells: held at bay through MDM2
• stressed cells: released from MDM2
• DNA damage and hypoxia
• “Oncogenic” stress
• Transient p53­induced cell cycle
arrest.
• p53 ­induced senescence
• p53­induced apoptosis
 APC: Gatekeeper of Colonic Neoplasia
• Adenomatous polyposis coli (APC):
member of the class of tumor
suppressors that function by
downregulating growth­promoting
signaling pathways
• A component of the WNT signaling
pathway
• A major function of the APC protein is
to hold β-catenin activity in check
E-cadherin

• A cell adhesion molecule

• role in contact-mediated growth inhibition of epithelial cells
• Germline loss-of-function mutations in the E-cadherin gene (CDH1):
autosomal dominant familial gastric carcinoma
CDKN2A

• complex locus that encodes two tumor suppressive proteins:

• p16/INK4a: augments RB function
• ARF: stabilizes p53

• Germline loss-of-function mutations: autosomal dominant familial

melanoma
• Biallelic loss-of-function seen in diverse cancers, including leukemias,
melanomas, and carcinomas
TGF-β pathway

• potent inhibitor of cellular proliferation in normal tissues

• Frequent loss-of-function mutations involving TGF-β receptors (colon,

stomach, endometrium) or downstream signal transducers (SMADs,
pancreas) in diverse carcinomas
• Complex role in carcinogenesis
PTEN
• Encodes a lipid phosphatase that is an important negative regulator of
PI3K/AKT signaling

• Germline loss-of-function mutations:

• Cowden syndrome- autosomal dominant disorder associated with a high
risk of breast and endometrial carcinoma
• Biallelic loss-of-function common in diverse cancers

NF1
• encodes neurofibromin 1: GTPase that acts as a negative regulator of RAS
• Germline loss-of-function mutations:
• neurofibromatosis type 1- autosomal dominant disorder associated with a
high risk of neurofibromas and malignant peripheral nerve sheath tumors
NF2
• encodes neurofibromin 2 (merlin): cytoskeletal protein involved in contact
inhibition
• Germline loss-of-function mutations:
• neurofibromatosis type 2-autosomal dominant disorder associated with
a high risk of bilateral schwannomas

WT1:
• encodes a transcription factor that is required for normal development of
genitourinary tissues
• Germline loss-of-function mutations:
• Wilms tumor- a pediatric kidney cancer
PTCH1
• encodes membrane receptor that is a negative regulator of the Hedgehog
signaling pathway
• Germline loss-of-function mutations:
• Gorlin syndrome- autosomal dominant disorder associated with a high
risk of basal cell carcinoma and medulloblastoma
• Acquired biallelic loss-of-function mutations of PTCH1 are seen frequently
in sporadic basal cell carcinomas and medulloblastoma

VHL
• encodes a component of a ubiquitin ligase that is responsible for
degradation of hypoxia-induced factors (HIFs)
• Germline loss-of-function mutations: von Hippel-Lindau syndrome
• Acquired biallelic loss-of mutations are common in sporadic renal cell
carcinoma
3) Altered Cellular Metabolism: The Warburg Effect
• distinctive form of cellular metabolism- high levels of glucose uptake
and increased conversion of glucose to lactose (fermentation) via the
glycolytic pathway
• provides rapidly dividing tumor cells with metabolic intermediates
• synthesis of cellular components

• Aerobic glycolysis provides rapidly dividing tumor cells

with metabolic intermediates that are needed for the
synthesis of cellular components, whereas
mitochondrial oxidative phosphor­ylation does not.
4) Evasion of Programmed Cell Death:
Apoptosis

• Apoptosis- protective response

to several pathologic conditions
that might contribute to
malignancy if the cells remained
viable
• 2 distinct programs that activate
apoptosis
• Extrinsic Pathway: signaling
through the death receptor
CD95/Fas
• Intrinsic Pathway: DNA
damage; most frequently
disabled in cancer
5) Limitless Replicative Potential (Immortality)
• evasion of senescence: RB-dependent G1 /S cell cycle checkpoint is
disrupted
• acquired genetic and epigenetic aberrations
• evasion of mitotic crisis: expression of telomeres (cells can restore
their telomeres and survive)
• capacity for self-renewal: cancer stem cells (symmetric and
asymmetric division)
6) Sustained Angiogenesis
• Neoplasms cannot enlarge beyond 1 to 2 mm in diameter
• induce angiogenesis
• dual effect on tumor growth:
• Perfusion- nutrients and oxygen
• endothelial cells- stimulate growth of adjacent tumor cells;
contributes to metastasis
• secreting growth factors
• controlled by a balance between angiogenesis promoters and inhibitors;
in angiogenic tumors this balance is skewed in favor of promoters
7) Ability to invade and metastasize
• Invasion and metastasis are the results of complex inter­actions
between cancer cells and normal stroma and are the major causes
of cancer-­related morbidity and mortal­ity.

• The metastatic cascade is divided into two phases:

• invasion of the extracellular matrix (ECM)
• vascular dissemination, homing of tumor cells, and colonization
• Invasion of the ECM initiates the metastatic cascade and is an active
process that can be resolved into several steps:
1) “Loosening up” of tumor cell–tumor cell interactions
2) Degradation of ECM
3) Attachment to novel ECM components
4) Migration and invasion of tumor cells
• Vascular dissemination, homing of tumor cells, and colonization
• Once in the circulation, tumor cells are vulnerable to destruction
• tend to aggregate in clumps (platelet-tumor aggregates)
• Arrest and extravasation of tumor emboli at distant sites
• The site at which circulating tumor cells leave the capillaries to
form secondary deposits is related to the:
• anatomic location and vascular drainage of the primary tumor
8) Ability to evade the host immune response
• Immune surveillance
• Implies that a normal function of the immune system is to
constantly “scan” the body for emerging malignant cells and
destroy them

• Cancer immunoediting
• Ability of the immune system to shape and mold the
immunogenic properties of tumor cells in a fashion that
ultimately leads to the darwinian selection of subclones that
are best able to avoid immune elimination
• Tumor Antigens:
• Products of mutated genes
• Overexpressed or aberrantly expressed cellular pro­teins
• Tumor antigens produced by oncogenic viruses (HPV, EBV – most
potent)
• Oncofetal antigens
• Altered cell surface glycolipids and glycoproteins
• Cell type–specific differentiation antigens
• Antitumor Effector Mechanisms:
• Cytotoxic T lymphocytes: virus-associated
neoplasms
• Natural killer cells: capable of destroying tumor
cells without prior sensitization; first line of
defense against tumor cells
• Macrophages kill tumors by mechanisms similar
to those used to kill microbes (production of ROS)

• Immune Surveillance and Escape

• Selective outgrowth of antigen­negative variants
(immunoediting)
• Loss or reduced expression of MHC molecules (↓
HLA class I molecules)
• Activation of immunoregulatory pathways
• Secretion of immunosuppressive factors by
cancer cells (TGF-B, galectins, IL-10, Prostaglandin
E2)
• Induction of regulatory T cells (Tregs)
9) Genomic Instability
• Genetic aberrations
• increase mutation rates
• very common in cancers and expedite the acquisition of driver
mutations that are required for transformation and sub­sequent
tumor progression
• HNPCC syndrome: defects in the mismatch repair system
• Show microsatellite instability, characterized by changes in
length of short repeats throughout the genome
• Xeroderma pigmentosum: defect in the nucleotide excision repair
pathway
• at increased risk for the development of cancers of the skin
exposed to UV light, because of inability to repair pyrimidine
dimers
10) Cancer-Enabling Inflammation
• Proposed cancer-enabling effects of inflammatory cells and resident
stromal cells include the following:
• Release of factors that promote proliferation: growth factors,
proteases
• Removal of growth suppressors: proteases degrade adhesion
molecules that mediate cell-cell and cell-ECM interactions
• Enhanced resistance to cell death: tumor associated macrophages
• Inducing angiogenesis: VEGF
• Activating invasion and metastasis: Proteases (invasion), TNF & EGF
(motility), TGF-B (promote epithelial-mesenchymal transitions)
• Evading immune destruction: soluble factors released by macrophages
and other stromal cells
Carcinogenic agents
and their cellular
interactions
 Carcinogenic Agents
• Direct- acting carcinogens: require no
metabolic conversion to become
carcinogenic.
• Indirect- acting carcinogen: chemicals
that require metabolic conversion to
become active carcinogens; the
carcinogenic product of metabolism is
called an ultimate carcinogen.
• Steps Involved in Chemical
Carcinogenesis:
1. Initiation (exposure
2. Permanent DNA damage (muta­tions)
caused by initiation
3. Promoters can induce tumors to arise
from initiated cells
Radiation Carcinogenesis
• Ultraviolet Rays
• Exposure to UV rays derived from the sun, particularly in fair­skinned
individuals, is associated with an in­creased incidence of squamous cell
carcinoma, basal cell carcinoma, and melanoma of the skin
• UV portion of the solar spectrum can be divided into three
wavelength ranges:
• UVA (320-400 nm)
• UVB (280-320 nm) - responsible for the induction of cutaneous
cancers
• UVC (200-280 nm)
• The carcinogenicity of UVB light is due to formation of pyrimidine
dimers in DNA.
• Radiation Carcinogenesis
• Ionizing Radiation
• Electromagnetic (x-rays, γ rays) and particulate (α
particles, β particles, protons, neutrons) radiations are all
carcinogenic.
• Exposure to radiation during imaging procedures such as
CT scans is linked to a very small, but measurable,
increase in cancer risk in children.
• Microbial Carcinogenesis

• HTLV- 1: adult T-cell leukemia/lymphoma

• HPV: benign warts, cervical cancer, oropharyngeal cancer
• EBV: Burkitt lymphomas, B-cell lymphomas in patients w/ T-cell
immunosuppression
• HBV, HCV: hepatocellular carcinomas
• Helicobacter pylori: gastric adenocarcinoma and MALT lymphoma
Clinical Aspects
of Neoplasia
Clinical Oncology
• Local and Hormonal Effects
• Location is a critical determinant of the clinical effects of both
benign and malignant tumors.
• Tumors may impinge upon vital tissues and impair their
functions, cause death of involved tissues, and provide a nidus
for infection
• Benign and malignant neoplasms arising in endocrine glands can
cause clinical problems by producing hormones (more typical of
benign tumors – differentiation)
• Cancer Cachexia
• Progressive loss of body fat and lean body mass accompanied by
profound weakness, anorexia, and anemia. It is associated with:
• Equal loss of both fat and lean muscle
• Elevated basal metabolic rate
• Evidence of systemic inflammation

• TNF- α (cachectin): leading suspect that may contribute to cachexia

• Proteolysis inducing factor: implicated in the muscle mass loss
Paraneoplastic Syndromes

• Some cancer­bearing individuals develop signs and symptoms that

cannot readily be explained by the ana­tomic distribution of the tumor
or by the elaboration of hormones indigenous to the tissue from
which the tumor arose
• Important to recognize for several reasons:
• Earliest manifestation of an occult neoplasm.
• May cause significant clinical problems and may even be lethal.
• Mimic metastatic disease and therefore confound treatment.
Grading and Staging of Tumors
• Grading
• Grade: based on the degree of differentiation of the tumor cells and
the number of mitoses or architectural features
• determined by cytologic appearance

• Staging
• Stage: extent of spread of a cancer within the patient
• based on the size of the primary lesion, its extent of spread to
regional lymph nodes, and the presence or absence of metastases
• determined by surgical exploration or imaging
• American Joint Committee on Cancer Staging: TNM Staging

• T for primary tumor

• T1 to T4 based on increasing size
• T0 is used to indicate an in situ lesion.
• N for regional lymph node involvement
• N1 to N3 would denote involvement of an increasing number
and range of nodes
• N0 would mean no nodal involvement,
• M for metastases
• M1 or sometimes M2 indicates the presence of metastases
• M0 signifies no distant metastases
 Laboratory Diagnosis of Cancer
• Histology and Cytologic methods
• Laboratory evaluation of a lesion can be only as good as the
specimen made available for examination.
• Adequate, representative, and properly preserved
• Several methods:
• Excision or biopsy: frozen section
• Needle aspiration: involves aspirating cells and attendant fluid
with a small-bore needle, followed by cytologic examination of
the stained smear
• Cytologic smears: widely used to screen for carcinoma of the
cervix; other forms of suspected malignancy in which tumor
cells are easily accessible or shed
• Immunohistochemistry
• Categorization of undifferentiated malignant tumors
• Determination of site of origin of metastatic tumors
• Detection of molecules that have prognostic or therapeutic
significance

• Flow Cytometry
• Circulating Tumor Cells
• Molecular and Cytogenetic Diagnostics
• Tumor Markers
• Biochemical assays for tumor-associated enzymes, hormones,
and other tumor markers in the blood cannot be used for
definitive diagnosis of cancer
• Contribute to the detection of cancer and in some instances are
useful in determining the effectiveness of therapy or the
appearance of a recurrence.