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Neoplasia
 Neoplasm
Definitions
Neoplasia: literally means “new growth.” A neoplasm often is referred to as a
tumor, and the study of tumors is called oncology (from oncos, “tumor,” and
logos, “study of”).
The division of neoplasms into benign and malignant categories is based on
their potential clinical behavior.
Classification of Tumors:

Benign(‫)ﺣﻤﯿﺪ‬: the microscopic and gross characteristics of

the lesion are considered to be relatively innocent.

• Tumors remain localized (well-circumscribed).

• Tumors are amenable (responsive) to local surgical removal.
• Patients generally survive.

Malignant: lesions can invade (cell membrane base) and

destroy adjacent structures and spread to distant sites
(metastasize) to cause death.

• Usually not capsulated.

• Has the ability to spread.
• Hard to treat and remove.
• invades\destructs the surrounding structure.
• Not well-circumscribed.

All tumors, benign and malignant, have two basic components:

1. The parenchyma, made up of transformed or neoplastic cells.

2. The supporting stroma, host-derived, non-neoplastic stroma, made up of

connective tissue, blood vessels, and host-derived inflammatory Cells.
(important for growth)
Nomenclature of
Tumors

The nomenclature of tumors and their biologic

behavior are based primarily on the parenchymal
component.
However, the growth and evolution of tumors is
critically dependent on their stroma as an adequate
stromal blood supply is a requisite for the tumor cells
to live and divide.

Benign tumors are designated by attaching the suffix -oma to the cell type from
which the tumor arises.

The nomenclature of mesenchymal tumors usually apply this rule:

• Benign tumor arising in fibrous tissue: Fibro + oma = Fibroma.
• Benign tumor arising in fatty tissue: Lipo + oma = lipoma.
• Benign tumor arising in cartilage: chondro + oma = chondroma.
• Benign tumor arising in skeletal muscle: Rhabdomyo + oma = rhabdomyoma.
• Benign tumor arising in smooth muscle: Leiomyo + oma = leiomyoma.
• Benign tumor arising in bone tissue: Oste + oma = Osteoma.

Exceptions!!
Some glaring inconsistencies may be noted. For example the terms: are used
for malignant tumors.

• Melanoma (from the melanocytes of the skin).

• Mesothelioma (from the peritoneal cavity…mesothelium).
• Seminoma (from the testis).
• Lymphoma (from lymphoid tissue).

The nomenclature of benign epithelial tumors is more complex: cell of origin,

microscopic pattern or macroscopic appearance.

Adenoma: is generally applied to benign epithelial neoplasms producing gland

patterns and to neoplasms derived from glands but not necessarily exhibiting
glandular patterns.
Nomenclature of Tumors - Benign
Papillomas: Benign epithelial neoplasms producing microscopically or
macroscopically visible finger-like (projections) or warty projections from
epithelial surfaces.

Cystadenomas: Benign epithelial neoplasms forming large cystic masses

(bag like), as in the ovary (very common there).

Some of the latter produce papillary patterns that protrude into cystic spaces
and are called papillary cystadenomas. (combining both type “more
complicated”)

Cystadenoma – Macroscopically Cystadenoma – Microscopically

Papillary cystadenoma – Macroscopically Papillary cystadenoma – Microscopically

Nomenclature of Tumors - Benign
Polyp: is a mass that projects above a mucosal surface, as in the gut(from the
mouth till the anus), to form a macroscopically visible structure. (it is not
tumor)

Nomenclature of Tumors - Malignant

Sarcomas: Malignant neoplasms arising in mesenchymal tissue.
• Fibrosarcoma: a malignant tumor arising in fibrous tissue.
• Chondrosarcoma: a malignant tumor arising in cartilaginous tissue.
• Osteosarcoma: a malignant tumor arising in bone tissue.

Carcinoma(cancer): Malignant neoplasms arising from epithelial cells.

Carcinomas include:

• Carcinomas that arise from glandular epithelial cells (with or without forming
glands): adenocarcinomas.

• Carcinomas that arise from squamous cells (some producing keratin):

squamous cell carcinomas.

• Carcinomas that show little or no differentiation: poorly differentiated or

undifferentiated carcinoma.

Squamous cell carcinoma Adenocarcinoma

Nomenclature of Tumors - Malignant
Not infrequently, however, a cancer is composed
of undifferentiated cells of unknown tissue
origin,and must be designated merely as an
undifferentiated malignant tumor.

The transformed cells in a neoplasm, whether benign or malignant, often

resemble each other, as though all had been derived from a single progenitor,
consistent with the monoclonal origin of tumors. (All tumor cells are similar to
each other)(tumor arise from one cell “gone crazy”)
In some unusual instances, however, divergent differentiation of a single
neoplastic clone along two lineages occurs, creating the so-called mixed
tumors.

The best example is the mixed tumor of the salivary gland. These tumors have
obvious epithelial components dispersed throughout a fibromyxoid (mucousy
fiber) stroma, sometimes harboring islands of cartilage or bone.

All of these diverse elements are thought to derive from a single clone capable
of giving rise to epithelial cells or myoepithelial cells, or both, and the preferred
designation for these neoplasms is pleomorphic adenoma.
Pleomorphic adenoma ‫ ﺣﻤﯿﺪ ﻣﺘﻌﺪد اﻷﺷﻜﺎل‬: is a mixed tumor has the ability to produce two
types of cells:
1- epithelium
2- myoepithelium : has properties of smooth muscle.

Macroscopically Microscopically
Teratoma

Teratoma is a special type of mixed tumor that contains recognizable mature

or immature cells or tissues representative of more than one germ cell layer and
sometimes all three. (trilaminar disc)
Teratoma originates from totipotential cells such as those normally present in
the ovary and testis and sometimes abnormally present in sequestered midline
embryonic rests. Such cells have the capacity to differentiate into any cell type
found in the adult body.
Teratoma: has the ability to give any type of cell or tissue.
more abnormalities mean more faster to grow poorly differentiated.
“Mixed is not teratoma”
When all the components within the teratoma are well differentiated,
It is a benign (mature) teratoma.
when they are less differentiated, it is an immature, potentially or overtly,
malignant teratoma.
Macroscopically Macroscopically

Hamartoma
Hamartoma is a mass of disorganized benign-looking tissue indigenous to the
particular site.

pulmonary chondroid hamartoma, which contains islands of disorganized, but

histologically normal smooth muscles, cartilage, bronchi, and vessels,
epithelium.
Hamartomas have traditionally been considered developmental malformations,
but some genetic studies have shown the presence of acquired
translocations, suggesting a neoplastic origin.
(normal tissue and in the right place but disorganized)
Choristoma

Choristoma is a congenital anomaly consisting of a heterotopic rest of cells.

(normal histological structure, normal funtional tissue but is in abnormal “wrong”
location)

a small nodule of well-developed and normally organized pancreatic tissue may

be found in the submucosa of the stomach, duodenum, or small intestine.
Choristoma has usual trivial significance (Developmental annomiles)
Differentiation & Anaplasia

Features to distinguish between benign & malignant tumors:

● Differentiation & anaplasia
● Rate of growth
● Local invasion
● Metastasis

Differentiation & anaplasia are characteristics seen only in the parenchymal

cells that constitute the transformed elements of neoplasms.
Differentiation: the extent to which the parenchymal cells of the tumor
resemble their normal counterparts morphologically and functionally.
● Well differentiated (the only bening)
● Moderately differentiated
● Poorly differentiated
● Undifferentiated (Anaplasia)

Benign neoplasms are composed of well-differentiated cells that closely

resemble their normal counterparts.

• Lipoma: mature fat cells laden with cytoplasmic lipid vacuoles.

• Chondroma: mature cartilage cells that synthesize their usual cartilaginous
matrix (evidence of morphologic and functional differentiation).
In well-differentiated benign tumors, mitoses are usually rare and are of normal
configuration. benign neoplasms and even well-differentiated cancers of
endocrine glands frequently elaborate the hormones characteristic
of their origin.

The stroma carrying the blood supply is crucial to the growth of tumors but
does not aid in the separation of benign from malignant ones. the amount of
stromal connective tissue determines the consistency of a neoplasm.

certain cancers induce a dense, abundant fibrous stroma (desmoplasia) , making

them hard, so-called scirrhous tumors.

Lipoma Chondroma
Differentiation & Anaplasia

Malignant neoplasms are characterized by a wide range of parenchymal cell

differentiation: from well differentiated to completely undifferentiated.
Between the two extremes lie tumors loosely referred to as moderately
differentiated.

Malignant neoplasms that are composed of undifferentiated cells are said to be

anaplastic which means loss of the structural and functional differentiation. It
is a hallmark of malignancy.

leiomyosarcoma Squamous Cell carcinoma

Anaplasia

It is important to recognize the following histopathological

features in any neoplasm:

● Pleomorphism: variation in size and shape

● Enlarged nuclei resulting in an increase of nuclear to cytoplasm ratio
(that may approach 1:1 instead of the normal 1:4 or 1:6)
● Hyperchromasia (dark nuclei) due to coarse & clumped chromatin
● Prominent nucleoli
● Mitoses (typical or atypical forms)
● Giant cells: larger than their neighbors & possess either one
enormous nucleus or several nuclei.

Tumor Giant Cell Atypical Mitosis

Dysplasia

Dysplasia is a loss in the uniformity of the individual cells and a loss in their
architectural orientation. It is a non-neoplastic process but a premalignant
condition. It occurs mainly in the epithelia.

Dysplastic cells show a degree of: pleomorphism, N:C ratio, Hyperchromasia,

irregular nuclei, increased mitoses, loss of polarity & a disordered maturation or
total failure of maturation. (N= Nucleus C= cytoplasm)

Dysplasia does not mean cancer, and does not necessarily progress to cancer, it
may be reversible.

The risk of invasive cancer varies with:

• grade of dysplasia (mild, moderate, severe)
• duration of dysplasia
• site of dysplasia

Differences between dysplasia & cancer:

• Lack of invasiveness.
• Reversibility

Carcinoma in Situ
If dysplastic changes involve the entire thickness of the epithelium it is called:
carcinoma in-situ an intraepithelial malignancy in which malignant cells
involve the entire thickness of the epithelium without penetration of the
basement membrane.

It is applicable only to epithelial neoplasms, It is a true neoplasm with all of the

features of malignant neoplasm except invasiveness, It displays the cytological
features of malignancy without invading the basement membrane.
Rate of Growth
Benign tumors they usually grow Malignant tumors They usually
slowly. Their growth is affected by: grow fast, the rate of growth of
adequate blood supply, location or malignant tumors usually correlates
hormones e.g. leiomyoma of the inversely with their level of
uterus. differentiation.Malignant tumors
usually infiltrative ( irregular)
● They remain localized.
● They cannot invade. ● They invade the underlying
● They are usually encapsulated basement membrane or
stroma.
● They are destructive.
● They are usually not
encapsulated.
 Metastasis
it is the development of secondary implants of a tumor that are discontinuous
with the primary tumor & located in remote tissues. More than any other
attribute, the property of metastasis identifies a neoplasm as malignant. (the
most important sign of malignancy)

Cancer have different ability to metastasize. Approximately 30% patients

present with clinically evident metastases. Generally, the more anaplastic and
the larger the primary tumor, the more likely it metastasizes.

Malignant neoplasms disseminate by one of three pathways:

● seeding within body cavities occurs when neoplasms invade a natural

body cavity. This mode of dissemination is particularly characteristic of
cancers of the ovary, which often cover the peritoneal surfaces widely.
● lymphatic spread is more typical of carcinomas.
- Breast carcinoma axillary lymph node
- Lung carcinomas bronchial lymph nodes
● hematogenous spread ( the blood vessels) is favored by sarcomas but can
also occur in carcinomas. Veins are more commonly invaded.

The liver and lungs are the most

frequently involved secondary sites.

Cancer Incidence
Cancer Incidence:
The most common cancer in lung
cancer for both genders.
The second is prostate cancer to male
and breast cancer to female.
The thirds is colon cancer for both
genders.

Geographic and Acquired

Hereditary
environmental Age preneoplastic
factors
factors conditions

Geographic & environmental factors:

● Exposure to asbestos mesothelioma
● Smoking lung cancer
● Multiple sexual partners cervical carcinoma
● fat-rich diet colon carcinoma
Cancer Incidence
Age: Generally, the frequency of cancer increases with age. Most cancer
mortality occurs between 55 and 75 years of age and it also increases
during childhood
The most common malignant tumors in children are:
○ Leukemia
○ CNS tumors
○ Lymphomas
○ Soft tissue & bone sarcomas

Hereditary factors:

● Autosomal dominant cancer syndromes Several well-defined cancers in

which inheritance of a single mutant gene greatly increases the risk of
developing a tumor.
- retinoblastoma in children

40% of retinoblastoma are familial in nature.

Carriers of this mutation have 10000 fold increase in the risk of

developing retinoblastoma

- multiple endocrine neoplasia (MEN) syndrome

-
● Autosomal recessive syndromes of defective DNA repair. A group of rare
autosomal recessive disorders is collectively characterized by
chromosomal or DNA inability and high rates of certain cancers

xeroderma pigmentosum

● Familial cancers of uncertain inheritance: All the common types of

cancers that occur sporadically have been reported to occur in familial
forms where the patterns of inheritance is unclear.

E.g. breast, colon, ovary, brain

Familial cancers usually have unique features:

- They start at early age

- They are multiple or bilateral (for ex: if it was a breast cancer it will be
found in the two breasts)
- They occur in two or more relatives
Cancer Incidence
Acquired pre-neoplastic conditions (predispose to cancer):
● Dysplastic bronchial mucosa in smokers lung carcinoma
● Liver cirrhosis liver cell carcinoma
● Margins of chronic skin fistulae squamous cell carcinoma
● Endometrial hyperplasia endometrial carcinoma
● Leukoplakia of the oral cavity, vulva or penis squamous cell
carcinoma
● Villous adenoma of the colon or rectum colorectal adenocarcinoma

Carcinogenic agents

Chemicals Radiant energy Microbial agents

Chemical Carcinogens
Chemical carcinogens can be natural or synthetic.
They can cause cellular damage via:
● Direct
They require no metabolic conversion to become carcinogenic.
They are in general weak carcinogens but are important because
some of them are cancer chemotherapy drugs
e.g. alkylating agents
● Indirect
They require metabolic conversion of the chemical compound
(procarcinogen) to active & carcinogenic products (ultimate
carcinogen).
e.g. benzo[a]pyrene, aromatic amines, azo dyes & Aflatoxin B1

Mechanism of the action:

Most chemical carcinogens are mutagenic (cause genetic mutations).
The commonly mutated oncogenes & tumor suppressors are RAS and TP53.

All direct chemical carcinogens & ultimate chemical carcinogens are

highly reactive as they have electron-deficient atoms. They react with the
electron rich atoms in RNA, DNA & other cellular proteins.
 Radiation
Radiation, whatever its source (UV rays of sunlight, x-rays, nuclear fission,
radionuclides) is an established carcinogen. Radiation has mutagenic effects:
chromosomes breakage, translocations and point mutations.

UV rays of sunlight: It causes skin cancers: melanoma, squamous cell

carcinoma & basal cell carcinoma. It is capable of DNA damage & mutations of
p53 tumor suppressor gene.
When extensive exposure to UV rays occurs, the repair system is overwhelmed
causing skin cancer.

Viral & Microbial Oncogenes

Viral & microbial oncogenes include:
• RNA viruses
• DNA viruses
• Other micro-organisms e.g. H. Pylori bacteria
Host cells have endogenous gene to maintain a normal cell cycle.
Oncogene viruses induce cellular proliferation, mimic or block cellular signals
necessary for the cell cycle regulation.

RNA oncogenic viruses:

Human T cell lymphotropic virus-1 (HTLV-1), a retrovirus, infects & transforms
T-lymphocytes.
It causes T-Cell leukemia/Lymphoma after a prolonged latent period (20-30
years). It is endemic in Japan & the Caribbean.
It is transmitted like HIV but only 1% of infected patients develop T cell
leukemia/Lymphoma. No cure or vaccine to HTLV-1 and Treatment:
chemotherapy with common relapses.
Viral & Microbial Oncogenes
DNA oncogenic viruses:
DNA viruses form stable associations with hosts DNA, thus the transcribed
viral DNA transforms the host cells.
• Human papilloma virus (HPV)
• Epstein Barr virus (EBV)
• Hepatitis B virus (HBV)
• Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus-8
[HHV-8])
HPV infection: HPV has more than 70 serotypes, It is a sexually transmitted. It
causes benign warts, squamous cell carcinoma of the cervix, anogenital region,
mouth & larynx.

HPV types 6 and 11 Genital warts

HPV types 16, 18, 31 85% of cervical carcinomas are caused by HPV 16 or 18 •
High risk HPV types integrates with the host’s DNA

The oncogenic potential of HPV 16 and 18 can be related to products of two

early viral genes, E6 and E7.
E6 protein binds to Rb tumor suppressor and releases the E2F transcription
factors that normally are sequestered by Rb, promoting progression through
the cell cycle.
E7 protein binds to p53 & facilitates its degradation

HPV infection alone is not sufficient to cause carcinoma and other factors also
contribute to the development of cervical carcinoma e.g. cigarette smoking,
coexisting infections, and hormonal changes
.

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Viral & Microbial Oncogenes
EBV infection: It is a common virus worldwide, It infects B lymphocytes &
epithelial cells of the nasopharynx, causing infectious (flu like symptoms)
mononucleosis and It several malignant tumors.
• Burkitt’s Lymphoma
• B-cell lymphoma in immunosuppressed
• Nasopharyngeal carcinoma

Nasopharyngeal carcinoma is a malignant neoplasm arising from the

nasopharyngeal epithelium.
It is endemic in South China and parts of Africa, 100% of cases contain EBV
genome in these endemic areas.

Burkitt’s lymphoma, a highly malignant B-cell tumor. However, rare sporadic

cases occur worldwide. EBV-related Burkitt’s lymphoma is the most common
childhood tumor in Africa.
All cases have t(8:14) genetic mutation.

B lymphocyte cellular proliferation, It causes loss of growth regulation

predisposes the cells to genetic mutations, especially t(8:14).
Viral & Microbial Oncogenes
HBV infection: has a strong association
with liver cell carcinoma (HCC). It is
present world-wide, but most commonly in
the far East & Africa. HBV infection incurs
up to 200-fold risk of HCC.

Helicobacter Pylori bacteria: It is bacteria

that infects the stomach, It causes:
• Peptic ulcers
• Gastric lymphoma “ Mucosal Associated
Lymphoid Tumor” (MALT)
• Gastric carcinoma

Carcinogenesis
Carcinogenesis is a multistep process at both the phenotypic and the genetic
levels.

It Starts with Genetic damage Mutation single cell which has the
genetic damage undergoes neoplastic proliferation forming the tumor mass.

Genetic Damage

Environmental Inherited
➔ Chemical
➔ Radiation
➔ Infectious
Carcinogenesis
Regulatory genes are the main targets of the
genetic damage:
● Growth promoting protooncogenes.
Protooncogene > mutation > oncogene.
● Growth inhibiting suppressor genes
● Genes regulating apoptosis
● DNA repair genes

Main changes in the cell physiology

that lead to formation of the
malignant phenotype:

Insensitivity to
Self-sufficiency in growth-inhibitory
Evasion of
growth signals. apoptosis.
signals.

Limitless replicative Sustained Ability to invade

potential. angiogenesis. and metastsize.

Self-sufficiency in growth signals:

Oncogene: Gene that promote autonomous cell growth in cancer cells.
They are derived by mutations in protooncogenes, and characterized by the
ability to promote cell growth in the absence of normal growth promoting
signals. (causing abnormal cell growth)
Oncoproteins : are the products.

The cell cycle:

1. Binding of a growth factor to its
receptor on the cell membrane.
2. Activation of the growth factor
receptor leading to activation of
signal-transducing proteins.
3. Transmission of the signal to the
nucleus
4. Induction of the DNA transcription
5. Entry in the cell cycle and cell
division
A)Self-sufficiency in growth signals
Growth Factors:
Cancer cells are capable to synthesize the same growth factors to which they are
responsive.
Sarcomas TGF-α
Glioblastoma PDGF

Growth Factors Receptors: (two pathways can happens)

1- Receptors mutation continuous signals to cells and uncontrolled
growth.
2- Receptors overexpression cells become very sensitive
hyperresponsive to normal levels of growth factors.

Example:
Epidermal Growth Factor ( EGF ) Receptor family HER2
Amplified in breast cancers and other tumors, High levels of HER2 in breast
cancer indicate poor prognosis.
Anti- HER2 antibodies are used in Treatment. (blocking the receptor)

Signal-transducing proteins :
They receive signals from activated growth factors receptors and transmit them
to the nucleus. Examples : RAS, ABL.

RAS:
30% of all human tumors contain mutated RAS gene. (Colon, Pancreas cancers)
Mutations of the RAS gene is the most common oncogene abnormality in human
tumors.
Mutations in RAS cells continue to proliferate.
A)Self-sufficiency in growth signals
ABL gene:
ABL protooncogene has a tyrosine kinase activity,
Its activity is controlled by negative regulatory
mechanism.
chronic myeloid leukemia ( CML ):
t(9,22) ABL gene transferred from ch.9 to ch.22
ABL fusse with BCR BCR-ABL
BCR-ABL has tyrosine kinase activity (oncogenic).
CML patients are treated with Gleevec which is
inhibitor of ABL kinase.

Nuclear transcription factors:

Mutations may affect genes that regulate transcription of DNA growth
autonomy.
Example: MYC (inside the nucleus)
MYC protooncogene produce MYC protein when cell receives growth signals and
then MYC protein binds to DNA leading to activation of growth-related gene.
Normally MYC decrease when cell cycle begins but in tumors there is sustained
expression of MYC which continuous proliferation.
Burkitt Lymphoma MYC is dysregulated due to t( 8,14).

Cyclins and cyclins- dependent kinases (CDKs):

Progression of cells through cell cycles is regulated by CDKs after they are
activated by binding with cyclins.
Mutations that dysregulate cyclins and CDKs will lead to cell proliferation.

Cyclin D genes are overexpressed in breast, esophagus and liver cancers.

CDK4 is amplified in melanoma and sarcomas.

24
 B)Insensitivity to growth-inhibitory signals

Tumor suppressor genes control ( apply brakes)

cell proliferation
If mutation caused disruption to them cell
becomes insensitive to growth inhibition
uncontrolled proliferation
Examples: RB, TGF-b, APC, P53

RB ( retinoblastoma ) gene: First tumor supressor gene discovered. It was

discovered initially in retinoblastomas but it is found in other tumors, e.g. breast
cancer.
RB gene is a DNA-binding protein and located on chromosome 13
RB gene exists in “ active “ and “ inactive” forms
If active will stop the advancing from G1 to S phase in cell cycle.
If cell is stimulated by growth factors inactivation of RB gene brake is
released cells start cell cycle (G1, S , M) RB gene is activated again.
Retinoblastoma is an uncommon childhood tumor. Retinoblastoma is either
sporadic (60%) (scattered or isolated) or familial ( 40% ) (relating to or occurring in a
family or its members)
Two mutations required to produce retinoblastoma. Both normal copies of the
gene should be lost to produce retinoblastoma.

Transforming Growth Factor- b pathway: TGF-b is an inhibitor of proliferation. It

regulate RB pathway. Inactivation of TGF-b lead to cell proliferation.

Mutations in TGF-b pathway are present in:

100% of pancreatic cancers
83% of colon cancers

25
B)Insensitivity to growth-inhibitory signals
Adenomatous Polyposis Coli – b Catenin pathway: APC is tumor suppressor
gene. APC gene loss is very common in colon cancers. It has anti-proliferative
action through inhibition of beta-Catenin which activate cell proliferation.
Individuals with mutant APC develop thousands of colonic polyps. One or more
of the polyps will progress to colonic carcinoma.
APC mutations are seen in 70% to 80% of sporadic colon cancers.

P53: It has multiple functions Mainly:

- Tumor suppressor gene (anti-proliferative)
- Regulates apoptosis
P53 senses DNA damage Causes G1 arrest to give chance for DNA repair
Induce DNA repair genes If a cell with damaged DNA cannot be repaired, it
will be directed by P53 to undergo apoptosis.
With loss of P53, DNA damage goes unrepaired, Mutations will be fixed in the
dividing cells, leading to malignant transformation.
C) Evasion of apoptosis

Mutations in the genes regulating apoptosis

are factors in malignant transformation.
Cell survival is controlled by genes that
promote and inhibit apoptosis.
Reduced CD95 level inactivate death–induced
signaling cascade that cleaves DNA to cause
death tumor cells are less susceptible to
apoptosis.
DNA damage induced apoptosis (with the
action of P53 ) can be blocked in tumors.
loss of P53 and up-regulation of BCL2 prevent
apoptosis e.g. follicular lymphoma.

D) limitless Replicative potential

Normally there is progressive shortening of telomeres at the ends of

chromosomes.
Telomerase is active in normal stem cells but absent in somatic cells.

In tumor cells: activation of the enzyme telomerase, which can maintain normal
telomere length.
E) Sustained angiogenesis
Neovascularization has two main effects:
● Perfusion supplies oxygen and nutrients
● Newly formed endothelial cells stimulate the growth of adjacent tumor
cells by secreting growth factors, e.g PDGF, IL-1
Angiogenesis is required for metastasis.

How do tumors develop a blood supply?

Tumor-associated angiogenic factors, These factors may be produced by tumor
cells or by inflammatory cells infiltrating.
the tumor e.g. macrophages.
Important factors :
● Vascular endothelial growth factor (VEGF)
● Fibroblast growth factor

E) Ability to invade and metastsize

Tow Phases:
1) Invasion of extracellular matrix: (Four Steps):
1) Detachment of tumor cells from each other. 2) Attachments of tumor cells to matrix
components.

3) Degradation of ECM by collagenase 4) Migration of tumor cells.

enzyme

2) Vascular dissemination and homing of tumor cells:

● May form emboli.
● Most travel as single cells.
● Adhesion to vascular endothelium.
● Extravasation.
Genomic Instability
Enabler of malignancy due to defect in DNA repair genes.
Examples:
● Hereditary Nonpolyposis colon carcinoma(HNPCC)
● Xeroderma pigmentosum.
● Familial breast cancer:
Due to mutations in BRCA1 and BRCA2 genes, these genes regulate DNA
repair, Account for 80% of familial breast cancer They are also involved
in other malignancies.

Cancer results from accumulation of

multiple mutations.
All cancers have multiple genetic
alterations, involving activation of
several oncogenes and loss of two or
more tumor suppressor genes.

Tumor progression

Many tumors become more aggressive

and acquire greater malignant
potential this is called tumor
progression.
By the time, the tumor become
clinically evident, their constituent
cells are extremely heterogeneous.

Karyotypic Changes in Tumors

Translocations:
- In CML : t(9,22) (Philadelphia
chromosome) Deletions Gene amplification:
- In Burkitt Lymphoma : t(8,14) - Breast cancer :
- In Follicular Lymphoma: t(14,18) HER-2

Gene amplification Translocation Deletions

Summary -From team 436

30
 Tumor Antigen
Tumor Antigens:
- Tumor-specific antigen: found only on tumor cells.
- Tumor-associated antigen (nonspecific): found on tumor cells and some
normal cells.

Classes of tumor antigens:

● Products of mutated oncogenes and tumor suppressor genes. P53 tumor
suppressor gene, RAS oncogene
● Products of amplified genes. HER2-NEU
● Tumor antigens produced by oncogenic viruses. HPV, EBV
● Oncofetal antigens: expressed during embryogenesis (fetal life) but not in
normal adult tissues. CEA in colon and CEA liver carcinomas.
● Cell type–specific differentiation antigens: Tumors express molecules that
normally are present on the cells of origin. These antigens are called
differentiation antigens, because they are specific for particular lineages
or differentiation stages of various cell types. PSA in prostatic carcinoma
(specific screening)

Host Defense Against Tumors: (Antitumor effector mechanisms)

- Cytotoxic T lymphocytes
- Natural killer cells
- Macrophages

Humoral mechanisms:
- Complement system
- Antibodies

Clinical Aspects of Neoplasia

Both malignant & benign tumors may cause problems because of:
• Location and impingement on adjacent structures
• Bleeding, secondary fractures or infections
• Symptoms that result from rupture, obstruction or infarction
• Functional activity such as hormone synthesis or the development of
paraneoplastic syndromes
• Cachexia or wasting.
Clinical Aspects of Neoplasia
Location and impingement on adjacent structures: it is crucial in both benign
and malignant tumors.
A small (1-cm) pituitary adenoma can compress and destroy the surrounding
normal gland, giving rise to hypopituitarism. (due to the location benign tumor can
cause problems)
A 0.5-cm leiomyoma in the wall of the renal artery may encroach on the blood
supply, leading to renal ischemia and hypertension.

Bleeding, secondary fractures and infections: A tumor may ulcerate through a

surface or adjacent structures causing consequent bleeding or secondary
infection or fracture.

Symptoms that result from rupture, obstruction or infarction:

Clinical Aspects of Neoplasia
Functional activity such as hormone synthesis or the development of
paraneoplastic syndromes:
Hormone production is seen with benign and malignant neoplasms arising
in endocrine glands.

Adenomas and carcinomas arising in the beta cells of the pancreatic islets
of Langerhans can produce hyperinsulinism, sometimes fatal.

Some adenomas and carcinomas of the adrenal cortex elaborate corticosteroids

that affect the patient (e.g., aldosterone, which induces sodium retention,
hypertension, and hypokalemia).

Such hormonal activity is more likely with a well-differentiated benign tumor

than with a corresponding carcinoma.

Paraneoplastic syndromes:
They are symptoms that occur in cancer patients & cannot be explained.
• They are diverse and are associated with many different tumors.
• They appear in 10% to 15% of patients.
• They may represent the earliest manifestation of an occult neoplasm.
• They may represent significant clinical problems & may be lethal.
• They may mimic metastatic disease

The most common paraneoplastic syndrome are:

• Hypercalcemia
• Cushing syndrome
• Nonbacterial thrombotic endocarditis

The most often neoplasms associated with these syndromes:

• Lung and breast cancers and hematologic malignancies
Clinical Aspects of Neoplasia

Cancer cachexia(severe weight loss):

It is usually accompanied by weakness, anorexia and anemia. The severity of
cachexia is generally correlated with the size and extend of spread of the cancer.

The origin of cancer cachexia is multifactorial:

• Anorexia (reduced calorie intake): TNF suppresses appetite.
• Increased basal metabolic rate & calorie expenditure.
• General metabolic disturbance.
Grading and staging of cancer
Grading: It is based on the cytologic differentiation of tumor cells and the number
of mitoses within the tumor.
Malignant tumors are classified as:
• Grade I : well differentiated
• Grade II : moderately differentiated
• Grade III : poorly differentiated
• Grade IV : anaplastic (undifferentiated)

Staging: is based on the size of the primary lesion, its extent of spread to
regional lymph nodes, and the presence or absence of metastases.Two methods
of staging are currently in use: the TNM system (T,primary tumor; N, regional
lymph node involvement; M, metastases) and the AJC (American Joint
Committee) system.

TNM staging system:

• T0 (no tumor), Tis, T1, T2, T3, and T4 describe the increasing size of the primary
lesion
• N0 (no node involvement) , N1, N2, and N3 indicate progressively advancing node
involvement
• M0 (no metastases) and M1 (present of metastases) reflect the absence and
presence, respectively, of distant metastases.
Laboratory Diagnosis of Cancer
Laboratory diagnosis of cancer can be achieved by:
• Morphologic methods
• Biochemical assays
• Molecular tests

Morphologic methods include microscopic tissue or cellular diagnosis: It is

the gold standard for cancer diagnosis.
Several sampling approaches are available:
• Biopsy, excision & frozen section
• Fine-needle aspiration
• Cytologic smears
• Immunohistochemical stains
• Flow cytometry

Sampling approaches:
• Biopsies
• Surgical excisions
• Frozen section: a method in which a sample is quick-frozen and sectioned,
permits histologic evaluation within minutes.

Laboratory Diagnosis of Cancer:

• Fine needle aspiration: it involves aspiration of cells from a mass, followed by
cytologic examination of the smear.
• Cytologic (Papanicolaou) smears provide another method for the detection of
cancer. Neoplastic cells are less cohesive than others and are therefore shed into
fluids or secretions.
FNA Pap smear Frozen Section
Laboratory Diagnosis of Cancer

Immunocytochemistry offers a powerful adjunct to routine histologic

examination.
Flow cytometry is used routinely in the classification of leukemias and
lymphomas.

Biochemical assays: They are useful for measuring the levels of tumor
associated enzymes, hormones, and tumor markers in serum.
They are useful in screening, determining the effectiveness of
therapy & detecting tumor recurrences.
Elevated levels may not be diagnostic of cancer e.g. PSA.(not specific)
Only few tumor markers are proven to be clinically useful e.g. CEA & AFP.

Molecular tests:
• Polymerase chain reaction (PCR): PCR is useful for the detection of BCR-ABL
transcripts in chronic myeloid leukemia.
• Fluorescent in situ hybridization (FISH)
• FISH is useful for detecting chromosomal translocations characteristic of
many tumors.
• Both PCR and FISH can show amplification of oncogenes e.g.HER2-NEU &
N-MYC.

DNA microarray analysis:

• It evaluates the expression of thousands of genes.
•Different tissues have different patterns of gene expression.
• It is a powerful tool for subcategorizing diseases e.g. lymphomas.
• It confirms the morphologic diagnoses.
• It is useful in illustrating genes involved in certain disease & help plan
possible therapies.
 Team Team
leaders members
‫ا‬ ‫دا‬ ● ‫ح‬ ‫رزان ا‬ ● ‫اوي‬ ‫ا‬ ‫إ ا‬ ●

‫أ‬ ● ‫ي‬ ‫ا‬ ● ‫ا‬ ●

‫ا‬ ‫أ ةا‬ ● ●

‫ا ا‬ ● ‫ا‬ ●

‫ر‬ ‫ا‬ ● ‫رق ا‬ ●

‫ا‬ ●
Special ‫آل داوود‬ ●
thanks to:

Pathology
Team 436

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