Neoplasia & Oncologic Pathology

Neoplasia & Oncologic Pathology
Marc Imhotep Cray, M.D.

Marc Imhotep Cray, M.D. 2
Basic Concepts in Oncology
Nomenclature and Definitions
Epidemiology of Cancer
Classification of Cancer
Cell Biology of Cancer

Neoplasia Nomenclature
3
 Neoplasia means “new growth” and indicates presence of cells or
tissues showing evidence of abnormally controlled or disordered
growth
 Neoplasms comprise cells that show differentiation along one or
more pathways of development
Benign vs Malignant
 Benign neoplasms expand locally but do not invade adjacent
tissues or spread to distant sites, while
 Malignant neoplasms (cancers) invade adjacent tissues and
spread to distant sites

4
Neoplasia Nomenclature (2)
Preneoplastic and neoplastic cellular changes
 Neoplasia Uncontrolled, clonal proliferation of cells
 Can be benign or malignant
 Dysplasia Disordered, non-neoplastic cell growth
 Used only with epithelial cells
 Mild dysplasia is usually reversible
 Severe dysplasia usually progresses to carcinoma in situ
 Differentiation degree to which a malignant tumor resembles its tissue of
origin
 Well-differentiated tumors closely resemble their tissue of origin
 Poorly differentiated look almost nothing like their tissue of origin
 Anaplasia Complete lack of differentiation of cells in a malignant neoplasm

5
 Genetic and environmental factors influence development of
neoplasia
 Most germline (i.e. inherited and present in all cells) genetic
influences on neoplasm development are polygenic in nature,
while;
 A minority of neoplasms occur in association with a clearly
defined inherited defect in a single gene (monogenic)
 Neoplasms vary in their relative incidence betw. populations and
different geographical areas as a result of differences in gene
pools and environmental contributors to disease development

6
 Neoplasm development is characterized by
accumulation of genetic defects within neoplastic cells
 In some neoplasms, this sequence is well characterized
 In others specific genetic mutations are found sufficiently
commonly that their detection may be used to confirm the
diagnosis of tissue type or to help to determine likely
biological behavior of neoplasm (i.e. how aggressively
neoplasm is likely to grow)

7
 Benign tumors may compress adjacent tissue but do not
invade it
 Malignant tumors grow locally, infiltrate adjacent tissue
and metastasize via lymphatic channels and blood vessels
to distant sites
 Benign tumors can cause death by compressing vital
structures (e.g. within brainstem) but otherwise generally
possess a much better prognosis than malignant tumors

8
 Malignant tumors commonly cause extensive local tissue
damage but tumor metastasis to distant sites is often
key process that causes death in advanced malignancy
 Benign and malignant tumors may also produce chemicals
such as hormones and, therefore, be associated with
clinical symptoms of hormone excess
 Called a “paraneoplastic syndrome”

Paraneoplastic syndromes
Syndrome Mechanism Example
Cushing Syndrome ACTH-like substance
Lung small cell anaplastic (oat cell)
carcinoma
Hypercalcemia
Parathormone-like
substance
Lung (squamous cell) carcinoma
Hyponatremia
Inappropriate ADH
secretion
Lung small cell anaplastic (oat cell)
carcinoma
Polycythemia
Erythropoietin-like
substance
Renal cell carcinoma
Trousseau
Syndrome
Hypercoagulable state Various carcinomas
Hypoglycemia Insulin-like substance Various carcinomas and sarcomas
Carcinoid
Syndrome
5-hydroxy-indoleacetic
acid (5-HIAA)
Metastatic malignant carcinoid
tumors
Neoplasia and Oncologic Pathology SDL Tutorial .pdf

10
Clinical and pathological features of neoplasms can indicate
whether they are benign or malignant in nature
Histopathological examination of malignant neoplasms is
important to determine how aggressively neoplasm is likely to
grow and metastasize
Features such as
 tumor type
 grade (histological assessment of aggressiveness)
 size and
 presence of lymph node metastases
are most commonly assessed features used to predict biological
behavior of malignant neoplasms

11
 Most cancers (>90%) arise from "epithelial" tissues, such
as inside lining of colon, breast, lung or prostate
 These are referred to as carcinomas and usually affect
older people
 Contrastly, sarcomas are tumors that arise from
"mesenchymal" tissues such as bone, muscle,
connective tissue, cartilage and fat

12
 Certain neoplasms occur primarily in childhood  e.g.
neuroblastoma and nephroblastoma
 Elderly individuals develop wear-and-tear diseases 
 osteoarthritis
 atherosclerosis-associated conditions e.g. ischemic
heart disease [IHD]) and
 Elderly individuals are at increased risk of many neoplasms

13
 Neoplasm development is commonly associated with genetic
abnormalities within neoplastic tissue however, proportion of
neoplasms that occur as a result of a single inherited germline
genetic abnormality (i.e. a mutation present within all of cells
making up an individual) is relatively low
 Examples include inherited predispositions to breast cancer and
colorectal cancer
o Although relatively uncommon, these inherited syndromes are
important since affected individuals may develop cancer at a young age
and sometimes develop multiple cancers
o Identification of affected families may allow cancer prevention
programs and/or detection of cancers at an early stage

More Definitions of Neoplasia
14
 Neoplasia is new, uncontrolled growth of cells that is not under
physiologic control
 A "tumor" or "mass lesion" is simply a "growth" or "enlargement"
which may not be neoplastic (such as a granuloma)
 The term "cancer" implies malignancy, but neoplasms can be
subclassified as either benign or malignant
 There is no single mechanism by which a neoplasm arises
• Many different mechanisms give rise to neoplasms what makes
diagnosis and treatment so challenging

“Cancer "or “Malignancy"
15
 The word "cancer "or "malignancy" strikes fear in a
patient hearing it for first time
• likely nothing else will be heard or remembered soon after that
• Provide empathy, "I know that this can be very difficult to hear"
• At a follow-up session, more details regarding a treatment plan
can be discussed
 Some urgency is required, as survival for average cancer, such as a
breast cancer, decreases by 1% per month of delayed diagnosis
and treatment
Introduction to Cancer Animations_Mechanisms of Medicine

Epidemiology of Cancer
10 Leading causes of death in United States
16
Number of deaths for leading causes of death in 2017
1. Heart disease: 647,457
2. Cancer: 599,108
3. Accidents (unintentional injuries): 169,936
4. Chronic lower respiratory diseases: 160,201
5. Stroke (cerebrovascular diseases): 146,383
6. Alzheimer’s disease: 121,404
7. Diabetes: 83,564
8. Influenza and pneumonia: 55,672
9. Nephritis, nephrotic syndrome, and nephrosis: 50,633
10. Intentional self-harm (suicide): 47,173
Source: CDC National Vital Statistics Reports, Vol. 68, No. 6, June 24, 2019

Cancer Incidence and Leading Causes of
Cancer Death in Men and Women in U.S.
17
Cancers w highest incidence in
men:
 Prostate cancer
 Lung cancer
 Colorectal cancer
Leading causes of cancer deaths in
men:
 Lung cancer
 Prostate cancer
Cancers w highest incidence in
women:
 Breast cancer
 Lung cancer
Leading causes of cancer deaths in
women:
 Lung cancer
 Breast cancer
Learn more: Cancer Facts and Figures, 2020_American Cancer Society.pdf
Important Note: Incidence of lung cancer and colorectal cancer both exceed incidence of
prostate and breast cancer when data for men and women are combined.

Percent distribution of the 10 leading causes
of death, by sex: United States, 2017.
18

Classification of Cancer
Grade and Stage of a Neoplasm
19
Grade:
 Grade of a neoplasm is determined pathologically
 Refers to cellular characteristics of neoplasm, especially degree of
differentiation of cells involved
 Grading of a neoplasm requires tissue usually from a biopsy
 Grades are reported by roman numerals I to III or I to IV, w higher
numbers representing more poorly differentiating cellular patterns

Grading of Malignant Neoplasms
Grade Definition
I Well differentiated
II Moderately differentiated
III Poorly differentiated
IV Nearly anaplastic

Grade and Stage of a Neoplasm cont’ed.
21
Stage:
 Stage of a cancer is determined clinically but often takes into
account information provided by pathologist (the grade)
 Stage is most frequently reported using tumor-node-metastasis
(TNM) system:
• T: Tumor size. T refers to local growth measured by size of primary tumor
• N: Nodes. N refers to involvement of regional lymph nodes and is an
indication of extent of tumor spread
• M: Metastases. M refers to the presence or absence of distant metastases
o Presence of metastases confers a high stage
 Staging is most helpful in determining prognosis Higher stages
indicate a poorer prognosis

22
Staging of Malignant Neoplasms
Stage Definition
Tis In situ, non-invasive (confined to epithelium)
T1 Small, minimally invasive within primary organ
site
T2 Larger, more invasive within the primary organ
site
T3 Larger and/or invasive beyond margins of
primary organ site
T4 Very large and/or very invasive, spread to
adjacent organs
N0 No lymph node involvement
N1 Nearby lymph node involvement
N2 Regional lymph node involvement
N3 More distant lymph node involvement
M0 No distant metastases
M1 Distant metastases present
In the diagram below utilizing a lung
carcinoma as an example, the
principles of staging are illustrated:

Comprehension Check Up
23
5. A 48-year-old woman goes to her physician for a routine physical examination.
A 4 cm diameter non-tender mass is palpated in her right breast. The mass
appears fixed to the chest wall. Another 2 cm non-tender mass is palpable in the
left axilla. A chest radiograph reveals multiple 0.5 to 2 cm nodules in both lungs.
Which of the following classifications best indicates the stage of her disease?
A. T1 N1 M0
B. T1 N0 M1
C. T2 N1 M0
D. T3 N0 M0
E. T4 N1 M1

E. She has a large invasive (high T) primary tumor mass with axillary
node (N > 0) and lung metastases (M1).
24
https://www.slideshare.net/shaifalyrustagi/the-anatomy-of-pectoral-region

Classification of Cancer cont’ed.
25
Based upon origin:
 Malignant neoplasms arising from tissue embryologically derived from
ectoderm or endoderm are usually carcinomas
 Examples include:
• Squamous cell carcinoma of cervix
• Adenocarcinoma of stomach
• Hepatocellular carcinoma
• Renal cell carcinoma
 Malignancies arising from mesoderm (connective tissues) are usually sarcomas
Examples include:
• Leiomyosarcoma
• Chondrosarcoma
• Osteosarcoma
• Liposarcoma

26
 Neoplasms with more than one cell type but arising from only one germ layer
are called "mixed tumors“
• Best example is benign mixed tumor (also called pleomorphic adenoma) of
salivary gland
 Neoplasms with more than one cell type and arising from more than one
germ layer are called teratomas
• Common in ovary
 Neoplasms ending in "-blastoma" resemble primitive embryonic tissues,
which are often pediatric neoplasms
Examples include:
• Retinoblastoma
• Neuroblastoma
• Hepatoblastoma
• Medulloblastoma

27
 Not all malignant neoplasms have benign counterparts:
• Hematopoietic and lymphoid cells (as in bone marrow and
lymph node) give rise to leukemias and lymphomas
o They have no benign counterpart
 Gliomas (astrocytomas, oligodengrogliomas, glioblastoma,
etc) arise from glial cells in CNS
 They have no benign counterpart

Carcinomas
28
 Carcinomas arise from epithelial surfaces
 in gastrointestinal tract, in respiratory tract,
 in urogenital tract,
 in biliary tract,
 in skin and
 in organs w epithelial-lined ducts (breast, pancreas, salivary gland, liver, etc)
 Endocrine glands, including testis and ovary, may also give rise to
carcinomas
 In general, carcinomas are composed of polygonal-shaped cells
• Carcinomas that form glandular configurations are called
adenocarcinomas
• Carcinomas that form solid nests of cells with distinct borders,
intercellular bridges, and pink keratinized cytoplasm (Cytokeratins=A
tumor marker) are called squamous cell carcinomas

Sarcomas
29
 Sarcomas arise from soft tissues
• connective tissues such as cartilage, bone, or fascia,
• smooth or skeletal muscle,
• blood vessels,
• lymph vessels,
• coverings of organs such as mesothelium
 In general, sarcomas are composed of very pleomorphic spindle-
shaped cells
 Sarcomas are generally big and bad

Environmental causes:
 Chemicals: including those that are man-made (such as aniline dyes
and bladder cancer), drugs (cigarette smoke, and lung cancer), and
natural compounds (aflatoxins and liver cancer) which are
carcinogenic
• Controversy: Glyphosate and Non-Hodgkin Lymphoma
o Research evidence: Chiu BC, Dave BJ, Blair A, Gapstur SM, Zahm SH, Weisenburger DD.
Agricultural pesticide use and risk of t(14;18)-defined subtypes of non-Hodgkin
lymphoma. Blood. 2006;108(4):1363-1369. doi:10.1182/blood-2005-12-008755
Causes of Neoplasia
30
Origin for many neoplasms is obscure however, some factor are
known to causes a cell to be transformed to a neoplastic cell

Causes of Neoplasia cont’ed.
31
 Oncogenic viruses: such as human papillomavirus (HPV)
implicated in most squamous cell carcinomas of cervix and
anogenital squamous papillomas, Epstein-Barr virus (EBV)
implicated in African Burkitt's lymphoma, hepatitis B virus (HBV)
implicated in development of hepatocellular carcinomas and
Herpesvirus 8 causes Kaposi sarcoma
Of Note:
The human T-lymphotropic virus, human T-cell lymphotropic virus, or
human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a
group of human retroviruses known to cause a type of cancer called adult
T-cell leukemia/lymphoma (=HTLV type 1)

32
 Radiation: Including;
• Ultraviolet (UV) light that induces pyrimidine dimers in DNA
and promotes skin cancers (Goodsell, DS. The Molecular Perspective:
Ultraviolet Light and Pyrimidine Dimers. The Oncologist 2001;6:298-299)
o Most skin cancers are a result of exposure to the UV rays in sunlight
o Both basal cell and squamous cell cancers (most common types of skin
cancer) are found on sun-exposed parts of body their occurrence is
related to lifetime sun exposure
o The signature mutation caused by UV light is a CC to TT mutation,
caused when a CC dimer is mispaired with two adenine bases during
replication b/c of these mutations, connection betw. UV damage to
DNA and cancer is quite clear
NB: Xeroderma pigmentosum. An autosomal recessive disease in which increased sensitivity to
sunlight is accompanied by a high incidence of skin cancers, including basal cell carcinoma,
squamous cell carcinoma, and malignant melanoma

33
• Ionizing radiation (such as gamma radiation/ x-rays) induces
mutations in DNA promotes malignancies such as leukemia,
thyroid, lung, colon, & breast CA
National Research Council (US) Committee on the Biological Effects of Ionizing Radiation (BEIR
V). Health Effects of Exposure to Low Levels of Ionizing Radiation: Beir V. Washington (DC):
National Academies Press (US); 1990. 2, Genetic Effects of Radiation.

Causes of Neoplasia: Chemical carcinogenesis
34
 Chemical carcinogenesis
• There are two steps: initiation and promotion
• An initiating carcinogenic agent irreversibly damages cell DNA
(it is mutagenic) to start the process
Examples of carcinogenic initiators include:
o alkylating agents like cyclophosphamide
o polycyclic aromatic hydrocarbons like epoxides found in
smoked foods
o aromatic amines or azo dyes used in food coloring
o aflatoxins in moldy peanuts
o nitrosamines in pickled foods
See: Carcinogens. IN: First AID for the USMLE Step 1 2020, Pg. 225.

Causes of Neoplasia (2)Chemical carcinogenesis
35
 A promoting agent (may be same as carcinogen) then acts
(reversibly) to cause proliferation of a neoplastic cell clone, but there
is a "dose-threshold" conc. of promoter below which neoplasia
will not occur
Examples of promoters include: hormones such as estrogen, drugs
such as diethylstilbesterol, and chemicals

Causes of Neoplasia(3)Chemical carcinogenesis
36
 An example of chemical carcinogenesis involves grilled
meats
• Meats exposed to high temperatures (above 162°C, or 325°F),
either in an oven or over an open flame (grilling) undergo
changes in proteins that form compounds called heterocyclic
amines and polycyclic aromatic hydrocarbons  can be
carcinogenic (A char on meat indicates risk)
o Following ingestion of these compounds, not only directly exposed
tissues such as stomach and colon have an increased risk for cancer,
but also sites elsewhere, including pancreas, breast, and prostate

Causes of Neoplasia: Hereditary
37
Hereditary causes:
 Chromosomes which have absent or defective anti-oncogenes
that control growth (retinoblastoma results from defective
chromosome 13)
 Obscure defects: racial predilections (American women have
breast cancer more often than Japanese women; Japanese men
have stomach cancer far more often than American men)
 Age: older persons have a greater propensity to develop
neoplasms from lack of effective control mechanisms…see next
slide

38
Cancer and Ageing
Key Concepts:
 Ageing is key risk factor for cancer and it promotes cancer
 All normal cells undergo cellular senescence, a permanent
growth‐arrested phase
 Cellular senescence results due to intrinsic factors such as telomere
shortening or extrinsic factors such as stress
 Induction of senescence by intrinsic or extrinsic factors is mediated by
p53/p21 and p16INK4A/pRB tumor suppressor pathways
 Tumor suppressor pathways not only regulate cancer but also regulate
organismic ageing
 Cellular senescence contributes to ageing and cancer via its cell
autonomous and nonautonomous effects
 Cellular senescence can suppress or promote cancer via cell
autonomous and nonautonomous mechanisms
Source: Dimri, M. and Dimri, G.P. (2014). Cancer and the Ageing Process.
In eLS , John Wiley & Sons, Ltd (Ed.).
Molecular mechanism of cellular senescence.

Causes of Neoplasia: Altered DNA
39
Altered DNA:
 All of the above causes of neoplasia mentioned are mediated by
cause, whatever it is, producing a mutation in, or damage to, cell
DNA
 There can be mutations involving tumor suppressor genes (such
as p53) fail to exert a controlling influence on growth activation
 Majority of human neoplasms arise via this mechanism
NB: The p53 protein (“guardian of the genome”) is a tumor suppressor
gene protein responsible for promoting apoptosis (regulated cell death)
in cells with excessive DNA mutations or cellular damage.

Causes of Neoplasia: Altered DNA cont’ed.
40
 In some cases these mutations are mediated by proto-oncogenes
(genes which control cellular growth) undergo mutation to
oncogenes which give rise to neoplasia
• Proto-oncogenes can be activated by 1) point mutations, 2) translocations,
and 3) gene amplification
An example of this is chronic myelogenous leukemia (CML)  neoplastic
proliferation of WBCs
o All cases of CML have "Philadelphia chromosome" which is a
translocation betw chromosomes 9 and 22
• Translocation juxtaposes proto-oncogene ABL with breakpoint cluster region
(BCR) on chromosome 22
• The chimeric ABL-BCR gene leads to production of a mutant protein w enhanced
tyrosine kinase activity
• Protein plays a role in regulation of cell growth in CML

41
 About 15 to 20% of human cancers have been linked to oncogenic
activity
• The ras oncogene is transforming gene found most frequently in human
cancers
 Oncogenic viruses may bring oncogenes w them, so-called viral
oncogenes (typical of RNA containing "retroviruses" such as human
T-lymphotropic viruses (HTLV's)
 Growth factors such as epidermal growth factor (EGF), platelet-
derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1)
assist oncogene activity
• Transforming growth factor (TGF-α) also promotes tumor growth

42
 DNA repair mechanisms may be affected
• There are DNA excision repair genes that can be mutated,
introducing genomic instability and a greater likelihood that
mutations in other genes will occur to drive oncogenesis
Examples include:
o DNA mismatch repair genes: defective nucleotide "spell checker"
introducing "microsatellite instability" of tandem repeat sequences in
DNA. Seen in hereditary non-polyposis colon cancer (HNPCC)
o Nucleotide excision repair genes: defective function in xeroderma
pigmentosa, allowing DNA damage from pyrimidine dimer formation
induced by ultraviolet light

Familial vs Sporadic Neoplasia
43
Most human cancers are "sporadic" b/c there is no identifiable
inherited gene involved but cancers developed as a result of
environmental factors
 carcinogens such as cigarette smoke that randomly induced
mutations in cells led to uncontrolled growth
 Such factors are encountered throughout life and act over a long period
of time hence, most sporadic cancers occur in adults
 Most affected persons have one primary site, and that site is where you
would expect most cancers to be (breast, lung, prostate, colon, etc.)

Familial vs Sporadic Neoplasia cont’ed.
44
Familial CAs have a specific gene w a defined inheritance pattern
 Thus, one is born w "one strike" and it is a matter of years before
another event triggers cancer growth
• Tend to occur at a younger age than sporadic cancers
 One form of classic familial cancer syndrome involves a tumor
suppressor gene, w the "two hit" hypothesis
• A person inherits a bad p53 gene, for example, (first hit) but still has another
functional copy of this gene on other chromosome
• Sometime later, a mutation wipes out good gene (second hit) and growth control
is lost allowing a clone of neoplastic cells to arise multiple organs can be
affected
 Thus, familial cancers often involve more than one organ
• Affected individuals can have more than one cancer, and
• Malignancies other than epithelial are more likely (soft tissue sarcomas,
leukemias/lymphomas, nervous system tumors)

Familial vs Sporadic Neoplasia cont’ed.
45
The rare Li Fraumeni Syndrome illustrates difference
betw. "familial" and "sporadic" cancers
 In Li Fraumeni syndrome there is an inherited mutation in p53
gene, and a variety of cancers arise in persons w this mutation
 However, as indicated above, p53 mutations are most common
mutations in sporadic cancers too

Biologic Characteristics of
Neoplasms: Oncogenesis
46
Companion Video Edu:
Intro to Cancer Animations_Mechanisms of Medicine

Oncogenesis
47
What drives a cell into uncontrolled growth?
 Figuratively, as you drive your cell down the highway of life, you have several
factors controlling that journey
 You have an accelerator to speed up proliferation
 You have brakes to stop growth forward
 You have fuel in the tank to keep going
 Thus, you can have:
 Gene activation: accelerated cell proliferation
• When you have activation of an oncogene, accelerator can be stuck open
 Loss of tumor suppression: loss of the brakes on cell growth
• Tumor suppressor genes act as brakes associated with cell cycle regulation
 Persistence: accumulation of cells from lack of apoptosis
• Apoptotic mechanisms also serve as brakes on growth
 Replication: acquisition of ability to keep dividing
 Cancer cells often acquire telomerase activity ("immortality" )

Oncogene and Tumor Suppressor Gene
48
An oncogene is a mutated form of a normal gene (proto-
oncogene) Proto-oncogenes code for proteins that can lead to
cellular proliferation and neoplasia
 However, proto-oncogenes are normally silent (unexpressed)
Activating mutations convert proto-oncogenes into oncogenes and
predispose to neoplasia
 b/c only a single gene needs to be mutated, oncogenes are seen as
dominant mutations
 An example of a proto-oncogene is a gene for a growth factor
receptor that, when mutated, could lead to inappropriate
activation of receptor leading to uncontrolled cellular
proliferation in absence of excessive levels of that growth factor

Oncogenesis
Mechanism Action Example
Growth Promotion
Overexpression of growth factor receptors (such as epidermal
growth factor, or EGF) making cells more sensitive to growth
stimuli
HER2
(c-erb-B2)
Increased growth factor signal transduction by an oncogene
that lacks the GTPase activity that limits GTP induction of
cytoplasmic kinases that drive cell growth
RAS
Overexpression of a gene product by stimulation from an
oncogene (such as RAS) C-SIS
Lack of normal gene regulation through translocation of a gene
where it is controlled by surrounding genes to a place where it
is no longer inhibited
BCR-ABL
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle C-MYC

Oncogene Associated Neoplasms
HER2 Breast and ovarian carcinomas
RAS Many carcinomas and leukemias
C-SIS Gliomas
BCR-ABL Chronic myelogenous leukemia, acute lymphocytic leukemia
C-MYC Lymphomas
BRCA-1 Breast and ovarian carcinomas
APC Colonic adenocarcinomas
NF-1 Neurofibromas and neurofibrosarcomas
Rb Retinoblastomas, osteosarcomas, small cell lung carcinomas
P53* Many carcinomas
BCL-2 Chronic lymphocytic leukemia, lymphomas
*T Soussi and KG Wiman. TP53: an oncogene in disguise. Cell Death and Differentiation
(2015) 22, 1239–1249.
NB: In reference to Oncogenes and Tumor Suppressor Genes, for Board exam purposes, you
should use the classification provided on Pg. 224. of First AID for the USMLE Step 1, 2020.

Oncogene & Tumor Suppressor Gene cont’ed.
51
A tumor suppressor gene is a normally active gene (in contrast
with a proto-oncogene)
 Tumor suppressor genes encode proteins that suppress cellular
proliferation; therefore, if its function is lost (disinhibited),
cancerous cells are permitted to survive
 Mutations in tumor suppressor genes are said to be recessive b/c
mutation must occur in both alleles in order to completely knock out
the function of gene

Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition BRCA-1
Lack of regulation of cell adhesion with
loss of growth control through cell
interaction
APC
Loss of down-regulation of growth
promoting signal transduction NF-1
Loss of regulation of cell cycle activation
through sequestation of transcriptional
factors
RB
Loss of regulation of cell cycle activation
through lack of inhibition of cell
proliferation that allows DNA repair
p53
Limitation of Apoptosis Overexpression of gene, activated by
translocation, prevents apoptosis BCL-2
Oncogenesis
Mechanism Action Example

Oncogene & Tumor Suppressor Gene cont’ed.
Familial cancer syndromes mutations
53
 Tumor suppressor genes are more commonly involved in familial
cancer syndromes b/c an embryo w one mutated copy of a tumor
suppressor gene is likely to develop normally
 However, a second mutation may be acquired at a later date leading to
cancer (loss of heterozygosity)
• Eg., Knudson’s “two-hit hypothesis”
 On the other hand, an embryo is less likely to survive if it has
inherited an oncogene b/c effects of this dominant negative
mutation are typically much more disruptive to development

Tumor Suppressor Gene cont’ed
Knudson’s “two-hit hypothesis”
54
 Alfred Knudson studied retinoblastoma, which was later found to be a form of
cancer caused by mutation of retinoblastoma (Rb) tumor suppressor gene
 He observed that in familial forms of retinoblastoma, tumors formed in pts at a
much younger age than was typical for those arising in pts with no family history
of the disease
 He theorized that in familial cases, a germ-line mutation was inherited (the
first hit) and that a second sporadic mutation occurred early in life (the
second hit) thus deactivating both tumor suppressor genes and causing
tumor formation
• Theory was therefore called the two-hit hypothesis
 In nonfamilial cases, however, mutations of both tumor suppressor genes
(both hits) had to occur sporadically and thus took much longer to manifest
as tumor formation

Apoptotic mechanisms
55
Along with tumor suppressor genes, apoptotic mechanisms also
serve as brakes on growth
 There are cell receptors that, when contacting a ligand such as a
hormone, will signal the cell to self destruct
 There are genes encoding proteins that oppose this process
(antiapoptotic proteins)- thus, if you turn off apoptotic genes,
or turn on antiapoptotic genes then cells will continue to
accumulate (sort of like having all of your friends and relatives come to
your house, but never leave)

What about the fuel of oncogenesis?
56
One of most important cellular resources is DNA in order to keep
dividing, cells need to maintain their chromosomes
 However, the ends of chromosomes tend to "wear down" w repeated
divisions enzyme telomerase can maintain ends of chromosomes
• Ordinarily, only human stem cells have active telomerase
• Cancer cells often acquire telomerase activity makes them
"immortal" b/c they continue cell division indefinitely
Neoplastic cells also need local resources to continue growth, in the
form of structural support and blood supply

Cellular Transformation
57
 Some factor, as discussed above, causes a cell to be transformed
to a neoplastic cell  not controlled by normal body processes
• Most transformed cells die b/c they are too abnormal to function or are
abnormal enough for body's immune system to destroy them
• If, however, factors promoting neoplasia persist a transformed cell may
some day give rise to a clone that does continue to grow

Cellular Transformation cont’ed.
58
Malignant neoplasms do not tend to arise from benign
neoplasms (e.g., malignant melanomas do not come from
benign nevi)
 However, in some cases such as adenomas of colon, appearance
of benign neoplasm is a step toward possible malignancy, b/c
oncogenic forces are at work  producing additional
abnormalities in DNA in existing lesions

Cellular Transformation cont’ed.
59
There are "pre-cancerous" conditions in which malignant neoplasia
is more likely to occur (but not in every case): liver cirrhosis, chronic
ulcerative colitis, atrophic gastritis, epidermal actinic keratosis, and
oral leukoplakia (all are examples of "pre-cancerous” lesions)
 In these cases, there is ongoing cellular proliferation for repair of damaged
tissue (often from ongoing inflammation) abnormal cell proliferation
leads to a greater likelihood for mutation to occur

Clonality
60
Neoplastic cells tend to be monoclonal, or similar in genetic
makeup, indicating origin from a transformed cell
 Non-neoplastic proliferations (such as reactions to inflammation) have
cells that are polyclonal in origin
The concept of "tumor progression" holds that subclones may
arise over time from original malignant clone
 Subclones may differ from original clone in characteristics such as
invasiveness, metastatic potential, and response to therapy
 Subclones may arise from acquisition of additional mutations
NB: Clonality is a key characteristic of neoplastic cellular proliferations that
distinguishes them from reactive proliferations (such as inflammation).

61
Clonal expansion
Source: Momna Hejmadi. Introduction to Cancer Biology, 2nd Ed. 2010, Fig. 1.1, Pg. 8.
 Cancer is a multi-gene, multi-step disease
originating from single abnormal cell
(clonal origin)
 Changes in DNA sequences result in cell
progressing slowly to mildly aberrant
stage
 Successive rounds of mutation &
natural selection leads to a mass of
abnormal cells called tumors
 Some cells in tumor undergo further
rounds of mutations leading to formation
of malignant cells which cause metastasis

Tumor Genetics
62
 Neoplasms have a greater tendency to demonstrate
karyotypic abnormalities such as
 translocations, deletions, and gene amplifications (which
are also activators of proto-oncogenes)
 Leukemias and lymphomas are well known with chronic
myelogenous leukemia, and t(8:14) translocation in Burkitt
lymphoma being exemplary

Tumor Genetics cont’ed.
63
 The process of neoplasia begins w cell transformation
• A variety of chemical carcinogens , as stated above, i.e.,
benzene, cigarette smoke, and nitrites can initiate and/or
promote the cell transformation process
• As explained above, radiation, either as low level long-term
environmental gamma rays or as higher dose therapeutic
radiation, can also produce genetic mutations in cells
• And we said persistent infectious agents such as HPV can lead
to cellular transformation as well

64
 Genetic damage w DNA alterations leads to point
mutations of genes, translocations of genetic material
betw. chromosomes, and gene reduplication w
amplification
• These alterations transform proto-oncogenes into oncogenes
o Proto-oncogenes within cells may play a role in growth
promotion and regulation in normal cells (eg.
embryogenesis) but are "turned off" in adults
o Proto-oncogenes are "turned on" by transformation lead
to uncontrolled growth that defines neoplasia

65

Tumor growth
66
In general, less differentiated a neoplasm, faster it grows
 The cell cycle of neoplastic cells is not shortened, rather growth
fraction of cells proliferating is increased this is offset by
neoplastic cell death
 Tumor growth is expressed as a "doubling time" or time to
increase twice in volume (e.g., from 1 to 1.3 cm diameter)
• An aggressive malignant neoplasm doubles in 1 to 3 months, while
benign neoplasms double in years

Tumor growth cont’ed.
67
Some neoplastic growth is influenced by host factors
 Estrogenic hormones aid growth of breast fibroadenomas or carcinomas and
uterine leiomyomas b/c tumor cells have hormone receptors
Growth is also dependent upon ability of tumor to develop a blood
supply
 Factors secreted by neoplastic cells promote angiogenesis and fibroblast
proliferation
 Cancers must elaborate growth factors in order to produce an
environment for continued growth vascular endothelial growth
factor (VEGF) promotes angiogenesis that keep neoplasm supplied
w bld
 VEGF increases expression of ligands that active Notch signaling pathway

Characteristics of Transformed (Neoplastic) Cells
68
 Neoplastic cell growth is not inhibited by contact w surrounding
cells and is not dependent on anchorage to a solid surface
 Neoplastic cells are discohesive and transplantable favoring
invasion and metastasis
 Neoplastic cells can bind to laminin and fibronectin in connective
tissues then secrete collagenases or proteases, and then invade
 Neoplastic cells may attain "immortality" or ability to keep dividing
indefinitely

The Six Hallmarks of Cancer
A heterotypic model proposed by Douglas
Hanahan and Robert Weinberg in 2000, manifested
as the six common changes in cell physiology that
results in cancer:
1. Immortality: Continuous cell division and limitless
replication
2. Produce ‘Go’ signals (growth factors from
oncogenes)
3. Override ‘Stop’ signals (anti-growth signals from
tumor suppressor genes)
4. Resistance to cell death (apoptosis)
5. Angiogenesis: Induction of new blood vessel growth
6. Metastasis: Spread to other sites
Acquired Capabilities of Cancer
Hanahan, D ; Weinberg, R. The Hallmarks of Cancer. Cell, Vol. 100,
57–70, January 7, 2000.

70
The six hallmarks of CA (2)
 Almost all cancers share some or all 6 traits
described, depending on the tumor
 Some tumors may show all these changes b/c
of mutations in one key gene (e.g. the p53
gene controls at least 4 of the traits) whereas
other tumors may need more than 1 mutation
for progression
In Re of the Graphic:
 Arrows on right (orange and red) show signals
that regulate normal cell behavior
 Green arrows on left indicate abnormal
growth triggered by cancer cells
 The green boxes outline the 6 key
characteristics of cancer cells
Source: Momna Hejmadi. Introduction to Cancer Biology, 2nd Ed.
2010, Fig. 1.5, Pg. 15.

Updated to: The Eight Hallmarks of Cancer
It appears that all cancers display eight
fundamental changes in cell physiology, which are
considered the hallmarks of cancer.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next
generation. Cell 144:646, 2011.
These changes consist of the following:
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Altered cellular metabolism
4. Evasion of apoptosis
5. Limitless replicative potential (immortality)
6. Sustained angiogenesis
7. Invasion and metastasis
8. Evasion of immune surveillance
Eight cancer hallmarks and two enabling factors (genomic
instability and tumor-promoting inflammation). Most cancer cells
acquire these properties during their development, typically due
to mutations in critical genes.
Kumar V and Abbas AK. Robbins Basic Pathology 10th ed.
Phil: Saunders, 2018. Fig. 6.17;Pg. 205.

Development of cancer through stepwise accumulation of complementary driver
mutations. The order in which various driver mutations occur is usually unknown
and may vary from tumor to tumor.
72
Kumar V and Abbas AK. Robbins Basic Pathology 10th ed. Phil: Saunders, 2018. Fig. 6.17;Pg. 205.
What is driver mutation and passenger mutation?
 Identifying which mutations contribute to cancer development is a key step in understanding tumor
biology and developing targeted therapies.
 Mutations that provide a selective growth advantage, and thus promote cancer development, are
termed driver mutations, and those that do not are termed passenger mutations

73
The Cell Cycle and restriction point
 Most cells in human body are
quiescent(i.e., not actively
dividing)
 Exceptions include cells of the
hematopoietic system, the
integument, and the intestinal
mucosa
 However, those cells that divide
follow a well-defined cyclic pattern
 Major challenges in cell replication
include high-fidelity DNA duplication
(in the S phase) and segregation of
chromosomes into daughter cells
(during mitosis or the M phase)
 Different phases & checkpoints
help address these issues
 S phase: DNA synthesis
 G2 phase: gap period 2
 M phase: mitosis
 G1 phase: gap period 1
 R: restriction point
The restriction point occurs just prior
to S phase important b/c once
restriction point is passed, a cell is
committed to complete cell cycle
Multiple cellular factors interact to
allow a cell to pass the restriction point
(Fig. next slide)

Regulation of
the cell cycle
74
Brown, TA; Shah, SJ. USMLE Step 1 Secrets 4th Ed. Saunders, 2017. Pg. 225.

75
Cell Cycle Checkpoints (aka cell cycle arrests)
Most important function of cell cycle arrest is to allow for repair of cellular damage and DNA sequences
 If improperly duplicated DNA were not repaired at cell cycle checkpoints, then DNA mutations would quickly
propagate, and integrity of cellular homogeneity could not be maintained
• A cell may also arrest in absence of proper nutrients, growth factors, or hormones
 Cyclins are proteins that regulate progression from one phase of cell cycle to next
• Cyclins phosphorylate cyclin-dependent kinases (CDKs) to form cyclin-CDK complexes that must be in
either an activated or inactivated state for various cell cycle stages to commence or terminate
• CDKs are regulated by CDK inhibitors such as p16, p21, and p27
o If these CDK inhibitors are mutated cell cycle becomes deregulated and cancer can result
Brown, TA; Shah, SJ. USMLE Step 1 Secrets 4th Ed. Saunders, 2017. Pg. 225.

76
Cell Cycle and Cancer Phases, Hallmarks, and Development_Amboss
Online Version

What is the importance of p53?
77
 The p53 protein (“guardian of the genome”) is a tumor suppressor
gene protein responsible for promoting apoptosis (regulated cell
death) in cells w excessive DNA mutations or cellular damage
 p53 can
 activate DNA repair genes during DNA damage,
 initiate apoptosis in cells that cannot be repaired,
 activate CDK inhibitor p21, and
 prevent phosphorylation and inactivation of Rb protein
 Loss of p53 can lead to loss of apoptotic regulation and thus to
uncontrolled cellular proliferation
 normal p53 gene can be inactivated by hypermethylation aberrant
methylation of tumor suppressor genes is an epigenetic mechanism
 p53 gene (TP53) is most commonly mutated gene in human CAs

Function of retinoblastoma (Rb) protein?
78
Like p53, Rb is a tumor suppressor protein functions to prevent
cell cycle progression from G1 to S phase by binding to and inhibiting
transcription factor E2F
 Rb is heavily regulated via p53 and cyclin-CDK complexes
 When in a hypophosphorylated state (which is maintained by p53), Rb
functions as a tumor suppressor inhibits cell cycle progression until cell is
actively ready to divide
 During G1 to S transition, ↑ levels of cyclin D/CDK4 and CDK6 and cyclin
E/CDK2 phosphorylate Rb and prevent its binding to E2F (see slide 74)
 E2F then activates additional proteins that push cell cycle to S phase
Loss-of-function mutations of Rb present in several human cancers

Family members: E2F is a group of genes that encodes a family of transcription factors
(TF) in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others
act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation
and synthesis of DNA in mammalian cells.
Legend
•cyc A - Cyclin A binding domain
•DNA - DNA-binding domain
•DP1,2 - domain for dimerization
with DP1, 2
•TA - transcriptional activation
domain
•PB - pocket protein binding domain
https://www.wikiwand.com/en/E2F

80
Overview of signal transduction pathways involved in apoptosis.
Learn more via Video Edu: Cell Signaling_JJ Medicine

Tumor Markers
81
Marker Cancer
Alpha-fetoprotein (AFP) Hepatocellular carcinoma, testicular
carcinomas
Cancer Antigen (CA) 15-3 Breast
Cancer Antigen (CA) 19-9 Colon, pancreas, bladder
Cancer Antigen (CA) 125 Ovary
Carcinoembryonic antigen (CEA) Gastrointestinal carcinomas, other
adenocarcinomas
Hepatocyte growth factor
Marker of cell proliferation with therapy
resistance and metastasis in colorectal
carcinomas
Human Chorionic Gonadotrophin (HCG) Gestational trophoblastic disease,
testicular carcinomas
Monoclonal immunoglobulin Multiple myeloma
Myeloperoxidase Marker of oxidative stress in colorectal
carcinomas
Osteopontin Marker of cancer progression,
invasiveness and metastasis
Prostate specific antigen (PSA) Prostatic adenocarcinoma
Tissue Inhibitor of Matrix
Metalloproteinases 1 (TIMP1) Pancreas

82
The Cancer-Immunity Cycle
 Generation of immunity to cancer is a cyclic process
that can be self propagating, leading to an
accumulation of immune-stimulatory factors that in
principle should amplify and broaden T cell
responses.
 The cycle is also characterized by inhibitory factors
that lead to immune regulatory feedback
mechanisms, which can halt the development or
limit the immunity.
 This cycle can be divided into seven major steps,
starting with the release of antigens from the
cancer cell and ending with the killing of cancer
cells.
 Each step is described in the graphic, with the
primary cell types involved and the anatomic
location of the activity listed.
Source: Chen DS and Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 39, July 25, 2013.
Abbreviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T lymphocytes

83
Cancer-Immunity Cycle 7 Steps_Amboss
Online Version

Reversible to Irreversible
Cellular Alterations

85
Cellular adaptations Reversible changes that can be physiologic (eg, uterine enlargement during pregnancy)
or pathologic (eg, myocardial hypertrophy 2° to systemic HTN). If stress is excessive or persistent,
adaptations can progress to cell injury (eg, significant LV hypertrophy injury to myofibrils HF)
First AID for the USMLE Step 1 2020, Pg. 206.

86
Neoplasia and neoplastic progression: Uncontrolled, monoclonal proliferation of cells. Can be
benign or malignant. Any neoplastic growth has two components: parenchyma (neoplastic cells)
and supporting stroma (nonneoplastic; eg, blood vessels, connective tissue).
1. Normal cells Normal cells with basal apical polarity
2. Dysplasia Loss of uniformity in cell size and shape (pleomorphism); loss of tissue orientation; nuclear
changes (eg, ↑ nuclear: cytoplasmic ratio)
3. Carcinoma in situ/ preinvasive Irreversible severe dysplasia that involves entire thickness of epithelium
but does not penetrate the intact basement membrane
4. Invasive carcinoma Cells have invaded basement membrane using collagenases and hydrolases
(metalloproteinases); Cell-cell contacts lost by inactivation of E-cadherin
5. Metastasis Spread to distant organ(s) via lymphatics or blood
First AID for the USMLE Step 1 2020, Pg. 219.

87
Left Ventricular Cardiac Hypertrophy
 Any increase in tissue size is not necessarily
neoplasia
 Here is an example of left ventricular cardiac
hypertrophy in which there has been an increase
in size of myocardial fibers in response to an
increased pressure load from hypertension
 With hypertrophy, the cells increase in size, but
the cells do not increase in number
 Except for being larger, the cells are normal in
appearance
 Alterations in cell growth can be physiologic
(normal responses to stimuli) or pathologic
 Cardiac hypertrophy shown above is a
pathologic response to abnormally elevated
blood pressure
Source: https://webpath.med.utah.edu/NEOHTML/NEOPLIDX.html

88
Endometrial Hyperplasia
 Large fronds of endometrium seen in this
uterus opened to reveal endometrial cavity
are a result of hyperplasia
 This resulted from increased estrogen
 With hyperplasia, there is an increase in cell
numbers to produce an increase in tissue
size
• However, cells are normal in appearance
 Sometimes hyperplasias can be "atypical"
and cells not completely normal
• Such conditions can be premalignant
Source: https://webpath.med.utah.edu/NEOHTML/NEOPLIDX.html

Tissue evidence of carcinogenic factors at work
89
 Metaplasia: an initial change from normal cells to a different cell
type (such as chronic irritation of cigarette smoke causing ciliated
pseudostratified epithelium to be replaced by squamous
epithelium more able to withstand the insult)
 Dysplasia: an increasing degree of disordered growth or
maturation of tissue (often thought to precede neoplasia) such as
cervical dysplasia as a result of human papillomavirus infection
• Dysplasia is still a reversible process however, once transformation to
neoplasia has been made, process is not reversible…

…Thus, there is a natural history from metaplasia to dysplasia to neoplasia. This is
best evidenced in development of uterine, cervix and respiratory tract neoplasms
90
https://sphweb.bumc.bu.edu/otlt/MPH-Modules/PH/PH709_Cancer/PH709_Cancer5.html

91
Dysplasia
 Dysplasia is illustrated in histologic section
from a biopsy of the uterine cervix shown
to the right
 Area to the right encircled with red
illustrates dysplasia; the cells have not yet
progressed to cancer, but they are in
danger of doing so, so they would be
considered "pre-malignant"
 Dysplasia can revert back to hyperplasia,
but it may also become malignant
Therefore, dysplasia should be carefully
monitored or treated
Dysplasia on a Biopsy from the Uterine Cervix
http://library.med.utah.edu/WebPath/FEMHTML/FEM008.html

Dysplasia on a Pap Smear
92
https://sphweb.bumc.bu.edu/otlt/MPH-Modules/PH/PH709_Cancer/PH709_Cancer5.html
To continue this learning sequence see: Neoplasia and Oncologic Pathology
SDL Tutorial. Pgs. 10-70.

93
THE END
See next slide for links to tools and resources for further study.

Further study:
94
eLearning (Cloud)
Neoplasia Lecture Notes. pdf
Oncologic Pathology: A Case-based Organ Systems Review Ppt.
Oncologic Pathology Video Edu. Folder
Atlas:
Klatt EC. Robbins and Cotran Atlas of Pathology 3rd Ed. Elsevier-
Saunders, 2015.
Textbooks:
Kumar V and Abbas AK. Robbins Basic Pathology 10th ed. Phil:
Saunders, 2018.
Rubin R and Strayer DS Eds. Essentials of Rubin's Pathology, 6th Ed..
Baltimore: Lippincott Williams & Wilkins, 2012.

Neoplasia & Oncologic Pathology

Recommandé

Recommandé

Contenu connexe

Tendances

Tendances (20)

Similaire à Neoplasia & Oncologic Pathology

Similaire à Neoplasia & Oncologic Pathology (20)

Plus de Imhotep Virtual Medical School

Plus de Imhotep Virtual Medical School (20)

Dernier

Dernier (20)

Neoplasia & Oncologic Pathology