BISC 3150

General Pathology
Neoplasia
Wednesday, January 31, 2018
Friday, February 2, 2018

Judy Maloney, PhD

 Neoplasia is new, uncontrolled growth of
cells that is not under physiologic control

How does it differ from hypertrophy and

hyperplasia?

Cause Reversible?
Hypertrophy
or hyperplasia

Neoplasia
There are a couple of approaches to ‘curing
cancer’. One is to target the support tissue
of a tumor. This might involve:

A. Killing the neoplastic cells in the

parenchyma
B. Stopping the growth of new blood
vessels in the parenchyma
C. Killing the neoplastic cells in the stroma
D. Stopping the growth of new blood
vessels in the stroma
 Characteristics of benign and malignant
neoplasms

What distinguishes benign from

malignant tumors?

• Differentiation and Anaplasia

• Local invasion
• Metastasis
 What is differentiation?

Stem cell (relatively undifferentiated)

Divides

Develops specialized
structures (differentiate)

Fully mature cell that

assumes a specific (highly differentiated)
function
Differentiation and Anaplasia with neoplasms

Question to ask: How well do the tumor

cells resemble their cells of origin?

Closely resembles  well differentiated

Sort of resembles  moderately differentiated

Doesn’t resemble  poorly differentiated

Anaplasia  a state of complete

undifferentiation
 Benign tumors

Malignant tumors
Well
Anaplastic
differentiated

http://library.med.utah.edu/WebPath/NEOHTML/NEOPL069.html
With malignant neoplasms, the cells also
show atypical cytology

structure, function and

the chemistry of the cell
A normal
tissue

Is the size of the cells and

nuclei uniform or variable?
Is there a lot or a little
cytoplasm in proportion to
the nucleus?
How darkly stained are the
nuclei?
 Common features of malignant cells

Cytology Name
Cell size and Varies Pleomorphism
shape
Nuclear size Varies, many Nuclear
and shape large pleomorphism
Nuclear to Increased
cytoplasmic
ratio
Color or Intensely Hyperchromatic
intensity of staining or dark nuclei (high
nucleus DNA content)
 Identify some features of malignant cells

http://library.med.utah.edu/WebPath/NEOHTML/NEOPL044.html
 Dot in the nucleus = nucleolus

A normal
tissue

Are the nucleoli very

prominent?
Do you see any
mitotic figures?
 What are mitotic figures?
What happens to DNA during cell division?

Examples of ‘normal’ mitotic figures

Metaphase Anaphase
Mitosis at a Glance; J Oral Maxillofac Pathol. 2014 Sep; 18(Suppl 1): S2–S5.
 Common features of malignant cells
Cytology Name
Number of Increased
mitotic (rapidly
figures dividing)
Shape of Can be irregular Atypical mitosis
mitotic and bizarre
figures
Nucleolus Very prominent
 Examples of abnormal mitotic figures

Tripolar Tetrapolar or
formation Quadripolar
formation

Mitosis at a Glance; J Oral Maxillofac Pathol. 2014 Sep; 18(Suppl 1): S2–S5.
 Anaplastic neoplasm
Can you identify the abnormal mitosis?

http://library.med.utah.edu/WebPath/NEOHTML/NEOPL044.html
 Anaplastic neoplasm
Can you identify the very prominent nucleoli?

http://library.med.utah.edu/WebPath/NEOHTML/NEOPL041.html
 Is this A) benign or B) malignant?

http://library.med.utah.edu/WebPath/NEOHTML/NEOPL043.html
 Colon

Epithelial layer
Connective
tissue Cut
mucus
Lumen

Columnar cells
Benign neoplasm of the colon. Is it well-
differentiated or poorly differentiated?
Normal Benign neoplasm Not as
‘clear
looking’
by the
lumen

Cells are
columnar with
orderly
arrangement
Malignant neoplasms of the colon. Which is well-
differentiated, poorly differentiated, anaplastic?
 Identify the types of tumors

Normal adipose
tissue

Adipocyte
http://library.med.utah.edu/WebPath/NEOHTML/NEOPL013.html
http://library.med.utah.edu/WebPath/NEOHTML/NEOPL053.html
 Identify the types of tumors
Normal smooth
muscle

Which tumor will most likely

Smooth contract (i.e. retain its function)
muscle cell
http://library.med.utah.edu/WebPath/NEOHTML/NEOPL015.html
 A 62-year-old male has several episodes of
hematuria (blood in the urine) in the past week. He
has smoked a pack of cigarettes a week for the past
48 years. A urinalysis show hematuria, and cytologic
examination of the urine shows that atypical cells are
present. A cystoscopy is performed (a scope is put
in the bladder) and a 4 cm mass with a nodular,
ulcerated surface is seen in the dome of the bladder.
Which of the following best describes this lesion?
A. Adenoma
B. Carcinoma
C. Fibroma
D. Papilloma
E. Sarcoma
 Characteristics of benign and malignant
neoplasms

What distinguishes benign from

malignant tumors?

• Differentiation and Anaplasia

• Local invasion
• Metastasis
 What is characteristic about this tumor?
Benign tumor the thyroid
(thyroid adenoma)

Capsule

Homogeneous
cut surface

Grows as a cohesive mass and does

not invade surrounding tissue

https://library.med.utah.edu/WebPath/ENDOHTML/ENDO024.html
 What is characteristic about this tumor?
Malignant tumor
(thyroid carcinoma)
No capsule

There is progressive
infiltration, invasion
and destruction of
surrounding tissue

Tumor can penetrate blood vessels,

lymphatic vessels.
http://www.pathologyoutlines.com/topic/thyroidmedullary.html
Metastasis (secondary tumor) unequivocally
marks a tumor as malignant

Primary
tumor

Metastases
Tumor cell breaks off and spreads to a
different part of the body that is not directly
connected with it
 Identify the benign and malignant liver tumors?

http://library.med.utah.edu/WebPath
 Are these lung tumors benign or malignant?
Lymph Tan area
node

Tan
area

http://library.med.utah.edu/WebPath/NEOHTML/NEOPL028.html
http://library.med.utah.edu/WebPath/NEOHTML/NEOPL029.html
Ways cancer can spread

Seed into a body cavity

Lymphatics

Blood
 Spread of cancer – seeding into a body cavity

Mesentery

Many small,
tan tumor
nodules

More often from neoplasms that

GI tract
impinge upon body cavities
http://library.med.utah.edu/WebPath/NEOHTML/NEOPL060.html
 Lymphatic and Hematogenous Spread
If a person has surgery for breast cancer, why
are the axillary lymph nodes checked for cancer?
Breast cancers Sarcomas
are carcinomas
Commonly spread
Commonly spread via hematogenous
via lymphatics route
(sarcomas also (carcinomas also
use this route) use this route)
Note: there is also tissue specific homing of tumors
 For cancer to spread via the blood, it needs to
‘break through’ the vessel wall and then it often
stops at the first capillary bed. Veins have thin
walls, whereas arteries have thicker walls.
Therefore, which of the following is one of the 2
most common sites of metastasis from
hematogenous spread?
A. Bone
B. Breast
C. Colon
D. Kidneys
E. Lungs
 The largest percentage of liver metastases
arise from primary cancers in the:

A. Breast
B. Colon
C. Esophagus
D. Kidneys
E. Lungs

http://library.med.utah.edu/WebPath/LIVEHTML/LIVER059.html
 Carcinogenesis: the
molecular basis of cancer

or
Cancer Genes
 Principal targets of genetic damage in
most neoplasms
1. Proto-oncogenes (mutated  oncogenes)
2. Tumor suppressor genes
3. Genes that regulate apoptosis
4. Genes that regulate interactions between
tumor cells and host cells
Alteration in more
than one gene
Unregulated cell growth and
differentiation

Malignant transformation and neoplasm

 Proto-oncogenes (‘go’ signals for cell division)
Growth factor Growth factor
receptor
(e.g. HER2)
Signaling pathway
(e.g. Ras)

Transcription factor
(e.g. MYC)

Increase synthesis of a protein

that stimulates the cell cycle
(e.g. CDK 4)
 Growth promoting proto-oncogenes
e.g. HER2, Ras, MYC, CDK4
Mutation, translocation, or
amplification in one allele
Oncogene

Overexpressed Protein produced is

(too much always on or
protein is made) constitutively active

Cause uncontrolled growth or

progression through the cell cycle
 Tumor suppressor genes

Normally are a Normally sense

‘stop’ signal for genomic damage
cell division and cause an
(governors) appropriate
response
(e.g. RB)
(guardians)
(e.g. TP53)
 S +
Cyclin/CDK
G1 -
CDK inhibitor
Cell cycle
G2 -
Rb
(hypophosphorylated)
M
(first discovered in
retinoblastomas)

Phosphorylation and Cell cycle

inactivation of Rb progression
Growth inhibiting tumor suppressor genes
e.g. RB
A mutation in
both alleles

Non functional Rb protein produced

(When active  it is an important
brake on the cell cycle)

Uncontrolled growth or
progression through the cell cycle
Tumor suppressor genes that sense genomic damage
e.g. Tumor promoter p53 or TP53
Normal cell

Carcinogenic agent
DNA damage
(e.g. toxic chemicals,
p53
radiation, or UV light)
Decides if the
cell will either:

Undergo Cell cycle arrest

Die apoptosis and activate DNA
repair genes
 TP53
A mutation in
both alleles

Non functional p53

Allows the accumulation of mutations in other

oncogenes and tumor suppressor genes
 There are several pro-apoptotic (e.g. BAX)
and anti-apoptotic (e.g. BCL2) proteins.
BCL2 has been show to be mutated in some
lymphomas. The mutation is most likely a:
A. Gain of function mutation and both
alleles are mutated
B. Gain of function mutation and only one
allele is mutated
C. Loss of function mutation and both
alleles are mutated
D. Loss of function mutation and only one
allele is mutated
 BRCA1 and BRCA2 are genes involved in
breast cancer. They produce proteins that
interact with several other proteins to repair
double-stranded breaks in DNA. Based on
this, BRCA1 and BRCA2 would be considered:
A. Oncogenes
B. Tumor suppressor genes
Panitumumab is a monoclonal antibody that
inhibits the epidermal growth factor receptor
(EGFR) and is approved for the treatment of
K-Ras mutation-negative (wild-type), EGFR-
overexpressing metastatic colorectal cancer.
This drug will most likely lead to:
A. Activation of the downstream signaling
molecule, K-Ras
B. Cell cycle arrest
C. DNA repair
D. Increased transcription of anti-apoptotic
genes
E. Necrosis
Carcinogenesis: a multistep process

How do tumors become less well

differentiated and more aggressive with time?

Acquire more mutations!

Subpopulations of cells with

new genetic abnormalities

Progression
 Tumor Progession

Robbins Basic Pathology 9th Ed.

Progression and tumor heterogeneity can
explain:
• Why a primary tumor may respond to a
chemotherapeutic agent, but the
secondary tumor (metastases) may not
• Why, as time goes by, tumors are harder
to treat (more resistant to chemotherapy)
• Why a recurrent tumor is usually resistant
to therapy
 Hallmarks of Cancer
• Self-sufficiency in growth signals
• Insensitivity to growth inhibitory signals
• Altered cellular metabolism
• Evasion of apoptosis
• Limitless replicative potential (immortality)
• Sustained angiogenesis
• Invasion and metastasis
• Evasion of immune surveillance
Mutations in genes that regulate some or all of
these cellular traits are seen in every cancer
Most normal
 capacity for 60-70 doublings
cells

Cancer cells need to be able

to divide indefinitely

Henrietta Lacks
died in 1951 of
cervical cancer

HeLa cells
 How can cancer cells get the nutrients and
oxygen (i.e. blood supply) they need for survival?

Growth of
Angiogenic new blood
factor vessels
(e.g. VEGF) into the
Tumor tumor

(> 1-2 mm) Bevacizumab (Avastin)

VEGF - vascular endothelial growth factor

 Tumor cells need to develop strategies
that enable them to invade the
surrounding tissue and metastasize

Break through the basement membrane

and invade the interstitial connective tissue

Enter blood vessels or lymphatics

Evade the immune system

Deposit and grow in a new tissue

Clinical aspects
of neoplasia
 Problems with both malignant and benign
tumors
• Impingement on adjacent structures
• Functional activity (e.g. hormone
production)
• Ulceration through adjacent surfaces
causing bleeding and infections
 Cachexia
(loss of body mass that cannot be
reversed nutritionally)
Starvation Cancer cachexia
• Reduced food • Reduced food
intake intake
• Decreased basal • Increased basal
metabolic rate metabolic rate
Loss of fat and lean muscle

Profound weakness, anorexia, anemia

 FYI
Staging and grading

Gives an idea of Microscopic

how large or appearance
widespread the
cancer is
 Grading of Malignant Neoplasms
Grade Definition
I Well differentiated
II Moderately differentiated
III Poorly differentiated
IV Nearly anaplastic

http://library.med.utah.edu/WebPath/NEOHTML/NEOPL069.html
 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
Larger and/or invasive beyond margins of primary organ
T3
site
Very large and/or very invasive, spread to adjacent
T4
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
http://library.med.utah.edu/WebPath/NEOHTML/NEOPL069.html
What is the advantage of having a
staging and grading schema for
malignant neoplasms?

They can help determine the

treatment and the prognosis

Staging has greater clinical value

than grading
The End