Neoplasia

Gerard Leaño Lamayra, MD, FPSP

Anatomic and Clinical Pathology

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 Neoplasia

-represents the uncontrolled proliferation of

cells that express varying degrees of fidelity to their
precursors.
neoplasms are irreversible; they are autonomous and
persistent after stimulus that produce it has been removed.
derived from cells that normally maintained a proliferative
capacity.
express varying degrees of differentiation.
stimulus responsible may not be identifiable.
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 Benign vs Malignant Tumors

-terms refer to overall biological behavior of tumor

rather than its morphological characteristics.

benign – do not penetrate/invade adjacent tissues nor

spread/metastasize to distant sites; more differentiated
(closely resemble their tissue of origin).

malignant – invade and metastasize.

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 Feature Benign Malignant

Rate of growth Progressive but slow. Variable. Mitoses

Mitoses few and more frequent and
normal may be abnormal

Differentiation Well differentiated Some degree of

anaplasia

Local invasion Cohesive growth. Poorly cohesive and

Capsule & BM not infiltrative.
breached

Metastasis Absent May occur

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 Differentiation
 Well-differentiated neoplasm -resembles mature cells of
tissue of origin.
 Poorly-differentiated neoplasm -composed of primitive
cells with little differentiation.

 Undifferentiated or “anaplastic” tumor

Correlation with biologic behavior:

Benign tumors are well differentiated
Poorly differentiated malignant tumors usually have worse
prognosis.
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 Classification of Neoplasms

Cell or tissue of origin – primary descriptor of any

tumor.

A. Benign tumors –identified by the suffix “oma”.

e.g. chondroma, papilloma, adenoma

hamartoma – localized disordered differentiation of

normal tissues.
choristoma – ectopic islands of normal tissue.

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 Classification of Neoplasms
B. Malignant tumors-
suffix “carcinoma” applied to epithelial cancers.
“sarcoma” to those of mesenchymal origin.

e.g. gastric adenocarcinoma

squamous cell carcinoma
osteosarcoma
fibrosarcoma

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 Classification of Neoplasms
Tissue Differentiation Benign Malignant

smooth muscle leiomyoma leiomyosarcoma

striated muscle rhabdomyoma rhabdomyosarcoma

fat lipoma liposarcoma

blood vessels hemangioma angiosarcoma

lymphatic vessels lymphangioma lymphangiosarcoma

fibrous tissue fibroma fibrosarcoma

peripheral nerves neurofibroma malignant peripheral

nerve sheath tumor8
 Classification of Neoplasms
B. Malignant tumors-
historical terms: hepatoma, melanoma, seminoma,
lymphoma

suffix “emia” relationship to blood, e.g. leukemia.

eponym –tumors with poorly understood histiogenesis.

e.g. Hodgkin disease
Ewing sarcoma

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 Classification of Neoplasms
B. Malignant tumors-
-secondary descriptors refer to tumor’s morphological and
functional characteristics.

e.g. papillary –frondlike structures.

medullary –soft cellular tumor with little connective tissue
scirrhous –dense fibrous stroma.
colloid – secrete abundant mucus.
comedocarcinoma – necrotic material expressed from
ducts.
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 Histological Diagnosis of
Malignancy
Benign tumors
-generally resemble their parent tissues histologically and
cytologically.

inability to invade
-definition resides above all in an
adjacent tissue and to metastasize.

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12
 Histological Diagnosis of
Malignancy
Malignant tumors
-depart from parent tissue morphologically and functionally but
diagnosis depends on resemblance to normal tissue .
-features the favor malignancy:
(1) anaplasia or cellular atypia.
-lack of differentiated features in a cancer cell.
-degree correlates with aggresiveness.
-cytological evidence include variation in size and shape
(pleomorphism), enlarged hyperchromatic nuclei with
clumped chromatin pattern and prominent nucleoli, atypical
mitosis, bizarre cells. 13
If cells LOOK BAD, they are probably going to
BEHAVE BAD!
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 “ANAPLASIA”
 Pleomorphism
 Size

 shape

 Abnormal nuclear morphology

 Hyperchromasia

 High nuclear cytoplasmic ratio

 Chromatin clumping

 Prominent nucleoli

 Mitoses
 Mitotic rate

 Location of mitoses
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 Loss of polarity
16
 Histological Diagnosis of
Malignancy
Malignant tumors

-other features that favor malignancy:

(2) mitotic activity
(3) invasion –particularly of blood vessels and
lymphatics.
(4) metastases

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 Features of Malignant Tumors
(1) Cellular features
-anaplasia
(2) Local invasion
-capsule
-basement membrane
(3) Metastasis
-unequivocal sign of malignancy
-seeding of body cavities
-lymphatic and hematogenous spread
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Breast carcinoma

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Breast carcinoma

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Breast carcinoma

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Breast carcinoma

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Breast carcinoma –lymph node
metastasis

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Breast carcinoma –liver metastasis

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 Histological Diagnosis of
Malignancy
Electron Microscopy of Tumors
-no specific determinants of malignancy can be detected by
electron microscopy.
-significant value in diagnosis of poorly differentiated
cancers problematic by routine microscopy.

carcinoma –exhibit desmosomes and junctional complexes

which are not typical of mesenchymal tumors and
absent in lymphomas.

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 Histological Diagnosis of
Malignancy
Electron Microscopy of Tumors

microvilli of carcinomas – short and blunt associated with

terminal web.
mesothelioma – long and slender.
microvilli of lymphoid and mesenchymal tumors – do not show
terminal web.

epithelial tumors – bundles of tonofilaments.

mesenchymal tumors –slender microfilaments.
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 Histological Diagnosis of
Malignancy
Tumor Markers
-no marker that allows unequivocal distinction between benign
and malignant cells.

(1) carcinomas- uniformly express cytokeratins.

lineage-associated markers:
prostrate-associated antigen prostatic cancers.
carcinoembryonic antigen  colon cancers
CA 19-9  pancreatic and GI cancers
CA 125  ovarian cancers
thyroglobulin  thyroid carcinomas 27
 Histological Diagnosis of
Malignancy
Tumor Markers

(2) neuroendocrine tumors –express chromogranin, neuron-

specific enolase, synaptophysin, leu-7 (CD57)

(3) Malignant melanoma

(+)vimentin, melanoma-associated antigen, S-100
(-) cytokeratin

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 Histological Diagnosis of
Malignancy
Tumor Markers
(4) Soft tissue sarcomas –express vimentin.
desmin smooth or striated muscle fibers.
muscle-specific actin marker for muscle tissue.
neurofilament proteins neuroblastomas and ganglioneuromas
glial fibrillary acidic protein astrocytes.

(5) Malignant lymphomas

–generally positive for leucocyte common antigen (CD45).
-markers grouped by cluster designations.
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 Histological Diagnosis of
Malignancy
Tumor Markers

(6) Vascular tumors –identified by antibodies against factor VIII-

related antigen or binding to certain lectins.

(7) Proliferating cells –display Ki67 and proliferating cell nuclear

antigen (PCNA).

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 Histological Diagnosis of
Malignancy
Tumor Markers

-serum tumor markers not disease-specific but allow tumor

monitoring for recurrence after surgery.
CEA
CA 19-9
CA 125
PSA
α-fetoprotein liver cancer or yolk sac tumor
human chorionic gonadotropin (hCG) trophoblastic tumors.
human placental alkaline phosphatase seminomas. 31
 Invasion and Metastasis

-characteristics unique to cancer cells; cause of most

cancer deaths.

A. Direct Extension
-in-situ stage – carcinomas confined to the epithelium; no
penetration of basement membrane; not defined for
connective tissue cells, lymphoid elements, and hepatocytes.

-growth within tissue of origin then enlarged and infiltrate normal

structures causing impairment of function.
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 Invasion and Metastasis
B. Metastatic spread
-refer to the transfer of malignant cells from one site to another
not directly connected with it.
-dissemination through vascular and lymphatic
channels.
1. hematogenous metastasis
-capillaries and venules commonly invaded.
-appearance of malignant cells in blood is not synonymous with
metastasis.
-must lodge in the vascular bed of metastatic site for it to
become viable.
-liver and lung are favored sites. 33
 Invasion and Metastasis
B. Metastatic spread

2. lymphatic metastasis
-basement membranes are lacking in lymphatic capillaries.
-regional lymphatic pattern of spread.

skip metastasis –metastases found in lymph nodes

distant from site of tumor.

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 Invasion and Metastasis
C. Biology of invasion and spread

steps required for establishment of metastasis:

1. Invasion of basement membrane

2. Movement through the extracellular matrix

3. Penetration of vascular and lymphatic channels

4. Survival and arrest within the circulating blood or lymph
 35
 Invasion and Metastasis

steps required for establishment of metastasis (continuation):

5. Exit from circulation into new tissue site

6. Survival and growth as a metastasis

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37
 Invasion and Metastasis
(1) invasion
-role of adhesion molecules:
integrins –confers metastatic potential; play a role in cell
migration, proliferation, and in angiogenesis.
expression of intercellular adhesion molecule-1 (ICAM-1)
correlates with tumor aggresiveness.
vascular cell adhesion molecule-1 (VCAM-1) is downregulated
in highly metastatic clones; decreased expression allows
detachment of tumor cells from parent tumor.
cadherins and catenins –cell-cell adhesion molecules that
suppress invasion and metastasis; expression lost or
reduced in most carcinomas. 38
 Invasion and Metastasis
(1) invasion

-autocrine motility factor tumor cell cytokine that stimulate

motility.

-proteolytic enzymes elaboration of proteases (e.g. matrix

metalloproteinases) that degrade basement membrane
components.

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 Invasion and Metastasis
(2) Metastasis

Invasion of circulation needed to establish new colony.

Escape from circulation adheres to endothelium causing

retraction with exposure of basement membrane and
subsequent binding and extravasation.

Local growth secretion of substances that stimulate

angiogenesis.
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 Invasion and Metastasis
(3) Target organs in metastatic disease

distribution depends on 2 factors:

(i) favorable environment
(ii) vascular anatomy

“homing” to specific organs –depends on surface

properties of the cells involved.

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 The Grading and Staging of
Cancers
A. Cancer Grading
-subjective and semi-quantitative.
-based on the degree of anaplasia and number of proliferating
cells.
(i) degree of anaplasia: shape and regularity of cells,
presence and distinct differentiated features

(ii) evidence of rapid growth: large number of mitosis,

presence of atypical mitoses, nuclear pleomorphism, tumor
giant cells.
-correlation of cytological grade and biological behavior is
variable. 42
 The Grading and Staging of
Cancers
B. Cancer Staging
-refers to the extent of tumor spread; influence choice
of surgical approach or treatment modalities.

-criteria used: tumor size

extent of local growth
presence of lymph node metastasis
presence of distant metastasis

TNM cancer staging

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 The clonal origin of cancer
-there is strong evidence that most cancers arise from a
single transformed cell.

The natural history of malignant tumor:

1. Malignant change in the target cell, referred to as
transformation.

2. Growth of the transformed cells

3. Local invasion

4. Distant metastases. 44
 Dysplasia
-literally means abnormal growth.

-malignant transformation is a multistep

process.

-in dysplasia ,some but not all of the features of malignancy are
present microscopically.

-dysplasia may develop into malignancy:

uterine cervix
colon polyps 45
 Dysplasia

-graded as low-grade or high-grade.

-dysplasia may not develop into malignancy.

-HIGH-grade dysplasia is often classified with carcinoma-in-situ.

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48
 Tumor Growth Rate
-doubling time of tumor cells
lengthens as tumor grows
30 doublings (109 cells) = 1 g
10 more doublings (1 kg) = lethal burden
-fraction of tumor cells in replicative pool
may be only 20% even in rapidly growing tumors
tumor stem cells
-rate at which tumor cells are shed or lost
apoptosis
maturation
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“clonal”

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Schematic Representation Of
Tumor Growth

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 Geographic & Environmental

 Sun exposure
 Melanomas 6x incidence New Zealand vs Iceland
 Blacks have low incidence of melanoma, so do normally
pigmented areas like areola on white people
 Smoking and alcohol abuse
 Body mass
 Overweight = 50% increase in cancer

52
 Geographic & Environmental

 Environmental vs racial factors

 Japanese immigrants to USA
 Viral exposure
 Human papilloma virus (HPV) and cervical cancer
 Hepatitis B virus (HBV) and liver cancer (Africa)
 Epstein-Barr Virus (EBV) and lymphoma

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Change In Incidence Of Various Cancers
With Migration From Japan To The United
States

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 Predisposing Factors for Cancer
 Age
 Most cancers occur in persons ≥ 55 years
 Childhood malignancies
 Leukemias & CNS neoplasms

 Bone tumors

 Genetic predisposition
 Familial cancer syndromes
 Early age at onset

 Two or more primary relatives with the cancer

 Multiple or bilateral tumors

 Polymorphisms that metabolize procarcinogens, e.g.,

nitrites
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 Predisposing Factors for Cancer

 Nonhereditary predisposing conditions

 Chronic inflammation
 Precancerous conditions
 Chronic ulcerative colitis

 Atrophic gastritis of pernicious anemia

 Leukoplakia of mucous membranes

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 The Growth of Cancer
A. Cell cycle kinetics
-tumor cells do not necessarily proliferate at a faster rate than
their normal counterparts.
-major determinant of tumor growth is more
cells
produced than die in a given time.

Doubling time-
-time taken for number of cells in mass to double.

detectable size = 1.0 cm3 (1.0 gram) = 108 to 109 cells

= doubles 30x

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 The Growth of Cancer
B. Tumor Angiogenesis
-sprouting of new capillaries from pre-existing blood vessels;
requirement for continued growth of cancers.

-absence of blood vessels tumor grow no larger than 1-2 mm

in diameter.
-angiogenic factors: FGF
TNF-α
EGF
VEGF
TGF
PDGF
angiogenin 58
 The Growth of Cancer

C. Tumor Dormancy
-cell proliferation is balance by apoptosis in the absence of
tumor angiogenesis; or may be due to cell cycle arrest.

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 The Molecular Genetics of Cancer

-unregulatedgrowth of cancer cells results

from sequential acquisition of somatic
mutations in genes that control and differentiation or that
maintains the integrity of the genome.

concept of “cancer gene”

hereditary predisposition
presence of chromosomal abnormalities in neoplastic cells
correlation of impaired DNA repair and occurrence of cancer
close association between carcinogenesis and mutagenesis

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 The Molecular Genetics of Cancer
-likely the most common mechanism of mutagenesis
relates to spontaneous errors in DNA replication
and repair.

-genes involved in the pathogenesis of cancer:

oncogenes positive effectors of neoplastic phenotype.

tumor suppressor genes loss of function permits

unregulated cell growth

mutator genes inactivation allow further mutations

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 The Molecular Genetics of Cancer
A. Oncogenes
1. Mechanisms of activation of cellular oncogenes
2 general mechanisms:
(i) alteration in structure of protooncogene results
in abnormal gene product.
change in nucleic acid sequence by point mutation,
deletions, chromosomal translocation which leads to the
synthesis of mutant protein that functions abnormally.
(ii) increase in expression of protooncogene causes
overproduction of normal gene product.
increased transcription occurs insertional mutagenesis,
chromosomal translocation and gene amplification.
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 The Molecular Genetics of Cancer
activation by mutation
e.g. C-ras in bladder cancer point mutation in codon 12
resulting in substitution of valine for glycine.

activation by chromosomal translocation

e.g. Philadelphia chromosome found in 95% of Chronic
Myelogenous Leukemia
c-abl protooncogene on chromosome 9 translocated to
chromosome 22 where it is place in juxtaposition to a site
known as breakpoint cluster region (bcr); aberrant protein
with very high kinase activity is coded.

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 The Molecular Genetics of Cancer

activation by gene amplification

-increase number of gene copies.
e.g. N-myc protooncogene found in neuroblastomas
erb protooncogene in breast and ovarian cancers

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 The Molecular Genetics of Cancer
A. Oncogenes
2. Mechanisms of actions of oncogenes

(a) extracellular growth factors, e.g. synthesis of PDGF-like

factors by neoplastic cells

(b) cell surface receptors generation of mitogenic signals that

override normal controls of signaling pathways

(c) intracellular signal transduction pathways, e.g. activation of

growth factor receptors

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 The Molecular Genetics of Cancer
A. Oncogenes
2. Mechanisms of actions of oncogenes

(d) DNA-binding nuclear proteins (transcription factors)

C-myc activation render cells competent to receive signals
for mitosis.

(e) cell cycle proteins (cyclins and cyclin-dependent protein

kinases)

(f) Inhibitors of apoptosis (bcl-2)

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 The Molecular Genetics of Cancer
B. Tumor Suppressor Genes
-loss of heterozygosity by deletion or somatic mutation
predispose to tumor development.
P53 gene
-located on small arm of chromosome 17; protein product
present in all normal tissues.
-seem to be the most common genetic change in human cancer
(deleted or mutated in 80% of cases of colon cancer,
frequently in breast cancer, small cell carcinoma of lung,
hepatocellular carcinoma, astrocytoma).
-negative regulator of cell division; levels rise in response to DNA
damage and prevent cells from entering the S phase allowing
time for DNA repair to take place.
-mutations allow cells with damage DNA to
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progress through the cycle.
 The Molecular Genetics of Cancer
B. Tumor Suppressor Genes

other tumor suppressor genes:

APC gene implicated in familial adenomatous polyposis coli
and colorectal cancers
WT-1 gene hereditary Wilm’s tumor.
NF-1 gene neurofibromatosis type 1.
DPC-4 gene 90% of pancreatic cancers
BRCA-1 and BRCA-2 genes breast and some ovarian cancers

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 The Molecular Genetics of Cancer
C. Mutator Genes
-caretaker genes which exercise surveillance over the
integrity of genetic information by participating in cellular
response to DNA damage.

-loss of these gene functions renders the DNA

susceptible to the progressive accumulations of
mutations; when these affect protooncogenes or tumor
suppressor genes, cancer will result.

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 Viruses and Human Cancer
It is estimated that viral infections are responsible for 15% of all
human cancers.

The strongest association includes:

(i) HTLV-1 virus and T-cell leukemia and lymphoma
(ii) HPV and squamous cell carcinoma of the cervix
(iii) Hepatitis B and hepatocellular carcinoma
(iv) EBV and Burkitt’s lymphoma
(v) Human herpesvirus-8 and Kaposi sarcoma

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Hepatocellular carcinoma

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Burkitt’s lymphoma

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 Chemical carcinogenesis
Many compounds known to be potent carcinogens are relatively
inert in terms of chemical reactivity; most require
metabolic activation before they can react with cell
constituents.

A. Chemical carcinogens as mutagens

epidemiological studies
animal studies
mutagen –is an agent that can permanently alter the genetic
constitution of a cell.

-about 90% of known carcinogens are mutagenic.

-most (but not all) mutagens are carcinogenic. 73
 Chemical carcinogenesis
B. Chemical carcinogenesis as a multistep process
4 stages of chemical carcinogenesis:
1. Initiation –the first step; mutations in a single cell.
2. Promotion –follows initiation and characterized by clonal
expansion of the initiated cell.
3. Progression –growth becomes autonomous; stage
where cancer is independent of the carcinogen or promoter;
mechanism is related to the instability of the genome with
the end result of further clonal expansion.
4. Cancer – end result of the entire sequence; established
when the cells acquire the capacity to invade and
metastasize.
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 Chemical carcinogenesis
C. Chemical carcinogenesis and their metabolism
-direct acting carcinogens are inherently reactive to bind
covalently to cellular macromolecules.
e.g. benzyl chloride

-conversion to a more reactive compound through

enzymatic reactions effected by cellular systems.
e.g. polycyclic aromatic hydrocarbons converted to epoxides
(cigarette smoke lung cancer).
aromatic amines and azo dyes converted to hydroxyl
derivatives (aniline dyes  bladder cancer)

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Bronchogenic carcinoma

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Bladder carcinoma

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 Physical carcinogenesis
A. UV radiation
-cancers attributed to sun exposure, namely: (1) basal cell
carcinoma, (2) squamous cell carcinoma, (3) melanoma.
-areas exposed to the sun are most prone to develop cancer.
-there is distinct correlation between total exposure to sunlight
and the incidence of cancer.
-carcinogenic effect occurs at wavelengths of 290nm to 320
nm.
-the effects of radiation on cells include enzyme inactivation,
inhibition of cell division, mutagenesis, cell death, and
cancer.
-most important biochemical effect is the formation of
pyramidine dimers on DNA which distorts the
backbone of the DNA helix (unless repaired; this genomic
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injury is mutagenic and carcinogenic).
Basal cell carcinoma

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 Physical carcinogenesis
B. Asbestos

-material widely used in construction, insulation, and

manufacturing.
‘serpentines’ – chrysotile
‘amphiboles’ – crocodolite and amosite
-deposition of asbestos fibers in the lung.
-characteristic tumor associated is malignant
mesothelioma of the pleura and peritoneal cavities.
-latent period between exposure and appearance of tumor is
usually 20 years.

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Malignant mesothelioma

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Epidemiology of Cancer

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Epidemiology of Cancer

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Epidemiology of Cancer

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Epidemiology of Cancer

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Epidemiology of Cancer

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