Assist Prof.

Mustafa Gheni

Neoplasia

Definition and Nomenclature

Literally, neoplasia means new growth and technically, it is defined as
abnormal mass of tissues the growth of which exceeds and persists in the
same excessive manner after cessation of the stimulus, evoking the
transformation.

Nomenclature: Neoplasms are named based upon two factors

on the histologic types : mesenchymal and epithelial


on behavioral patterns : benign and malignant neoplasms

Thus, the suffix -oma denotes a benign neoplasm. Benign mesenchymal

neoplasms originating from muscle, bone, fat, blood vessel nerve, fibrous
tissue and cartilages are named as Rhabdomyoma, osteoma, lipoma,
hemangioma, neuroma, fibroma and chondroma respectively. Benign
epithelial neoplasms are classified on the basis of cell of origin for example
adenoma is the term for benign epithelial neoplasm that form glandular
pattern or on basis of microscopic or macroscopic patterns for example
visible finger like or warty projection from epithelial surface are referred
to as papillomas.

This nomenclature has, however, some exceptions

(I) Nonneoplastic misnomers hematoma, granuloma, hamartoma 


(II) Malgnant misnomers melanoma, lymphoma, seminoma, glioma,

hepatoma. 


Malignant neoplasm nomenclature essentially follows the same scheme

used for benign neoplasm with certain additions. Malignant neoplasms
arising from mesenchymal tissues are called sarcomas (Greed sar =fleshy).

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Thus, it is a fleshy tumour. These neoplasms are named as fibrosarcoma,
liposarcoma, osteosarcoma, hemangiosarcoma etc.

Malignant neoplasms of epithelial cell origin derived from any of the

three germ layers are called carcinomas.

Eg. Ectodermal origin: skin (epidermis squamous cell carcinoma, basal cell
carcinoma)Mesodermal origin: renal tubules (renal cell
carcinoma).Endodermal origin: linings of the gastrointestinal tract
(colonic carcinoma) Carcinomas can be furtherly classified those
producing glandular microscopic pictures are called Aden carcinomas and
those producing recognizable squamous cells are designated as squamous
cell carcinoma etc furthermore, when possible the carcinoma can be
specified by naming the origin of the tumour such as renal cell
adenocarcinoma etc

Tumors that arise from more than tissue components:

- Teratomas contain representative of parenchyma cells of more

than one germ layer, usually all three layers. They arise from
totipotential cells and so are principally encountered in ovary and
testis. 


- Mixed tumors containing both epithelial and mesenchymal

components Examples include pleomorphic adenoma and
fibroadenoma 


Characteristics of Benign and Malignant Neoplasms 


1. The difference in characteristics of these neoplasms can be conveniently
discussed under the following headings: 


1. Differentiation & anaplasia 


2. Rate of growth 

3. Local invasion 

4. Metastasis 


1. Differentiation and anaplasia 


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Ø Differentiation refers to the extent to which parenchymal cells
resemble comparable normal cells both morphologically and
functionally. Thus, well-differentiated tumours cells resemble
mature normal cells of tissue of origin. Poorly differentiated or
undifferentiated tumours have primitive appearing, unspecialized
cells. In general, benign neoplasms are well differentiated.
Malignant neoplasms in contrast, range from well differentiated,
moderately differentiated to poorly differentiate types. Malignant
neoplasm composed of undifferentiated cells are said to be
anaplastic, literally anaplasia means to form backward.

Ø Morphology of anaplastic cell includes large Pleomorphic;

hyperchromatic nucleus with high nuclear cytoplasmic ratio
1:1(normally 1:4 to 1:6). The cell usually reveals large nucleoli with
high and often abnormal mitoses. Tumour giant cells and frequent
loss of polarity of epithelial arrangements are encountered. 


Ø On functional differentiation, the well differentiated the neoplasm,

the more completely it retains the functional capabilities found in
its normal counterparts thus, endocrine tumours produce hormone
(ex. Thyroid, adrenal) so also, well differentiated squamous cell
carcinoma and well differentiated hepatocellular carcinomas
produce keratine and bile respectively. 


Ø However, highly anaplastic or undifferentiated cells of what cell

tissue of origin come to resemble each other functionally and
morphologically more than the normal cells which they have arisen
this is called chemical convergence. 


2.Rate of growth 


Ø Most benign tumours grow slowly whereas; most malignant

tumours grow rapidly sometimes, at erratic pace. Some benign
tumours for example uterine leiomyoma increase in size during
pregnancy due to probably steroidal effects (estrogen) and regress
in menopause. In general, the growth rate of neoplasms correlate
with their level of differentiation and thus, most malignant

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 neoplasms grow more rapidly than do benign neoplasms. On
occasions, cancers have been observed to decrease in size and even
spontaneously disappear. Examples include renal cell carcinoma,
malignant melanoma, choriocarcinoma.

3. Local invasion

Ø Nearly all benign neoplasms grow as cohesive expansile masses that

remains localized to their site of origin and do not have the capacity
to invade or metastasize to distant sites, as do malignant neoplasms.



Rims of fibrous capsules encapsulate most benign neoplasms. However,

hemangiomas and neurofibromas are exceptions. Thus, such
encapsulations tend to contain the benign neoplasms as a discrete, rapidly
palpable and easily movable mass that can

easily surgically enucleated.

Ø The growth of malignant neoplasms is accompanied by progressive

infiltration, invasion 
and destruction of the surrounding tissue.
Generally, they are poorly demarcated from 
the surrounding
normal tissue (and a well-defined cleavage plane is lacking). 


Ø Next to the development of metastasis, invasiveness is the most

reliable feature that 
differentiates malignant from benign
neoplasms. 


Ø Even though, malignant neoplasms can invade all tissues in the

body, connective 
tissues are the favoured invasive path for most
malignant neoplasms, due to the elaboration of some enzymes such
as type IV collagnases & plasmin, which is specific to collagen of
basement membrane. Several matrix-degrading enzymes including
glycosidase may be associated with tumour invasion. 


Ø Arteries are much more resistant to invasion than are veins and
lymphatic channels due to its increased elastic fibers contents and its
thickened wall. Densely compact collagens such as membranous
tendons, and joint capsules. Cartilage is probably the most resistant

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 of all tissues to invasions and this is may be due to the biologic
stability and slow turnover of cartilage. 


Sequential steps in mechanisms of tumor invasion & metastasis: 


a. Carcinoma in-situ 

b. Malignant cell surface receptors bind to basement membrane
components (ex 
laminin). 

c. Malignant cell disrupt and invade basement membrane by releasing
collagenase 
type IV and other protease. 

d. Invasion of the extracellular matrix 

e. Detachment 

f. Embolization 

g. Survival in the circulation 

h. Arrest 

i. Extravasation 

j. Evasion of host defense 

k. Progressive growth 

l. Metastasis 


Most carcinomas begin as localized growth confined to the epithelium

in which they arise. As long as this early cancers do not penetrate the
basement membrane on which the epithelium rests such tumours are
called carcinoma in-situ.

In those situations in which cancers arise from cell that are not confined
by a basement membrane, such as connective tissue cells, lymphoid
elements and hepatocytes, an in-situ stage is not defined.

4. Metastasis

It is defined as a transfer of malignant cells from one site to another

not directly connected with it (as it is described in the above steps).



Metastasis is the most reliable sign of malignancy. The invasiveness

of cancers permits them to penetrate in to the blood vessel,

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 lymphatic and body cavities providing the opportunity for spread.



Most malignant neoplasm metastasies except few such as gliomas in

the central nervous system, basal cell carcinoma (Rodent ulcer) in
the skin and dermatofibrosarcoma in soft tissues. 


Organs least favoured for metastatic spread include striated muscles

and spleen. 


Since the pattern of metastasis is unpredictable, no judgment can be

made about the 
possibility of metastasis from pathologic
examination of the primary tumour. 


Approximately 30% of newly diagnosed patients with solid

tumours (excluding skin 
cancers other than melanoma) present
with metastasis in the studied populations. 


Pathways of spread: 


Dissemination of malignant neoplasm may occur through one of the

following pathways. 


1. Seeding of body cavities and surfaces (transcoelomic spread) 


Ø This seeding may occur wherever a malignant neoplasm
penetrates into a natural “open field”. Most often involved
is the peritoneal cavity, but any other cavities such as pleural,
pericardial, sub-arachnoid and joint spaces-may be affected.
Ø Particular examples are krukenberg tumour that is a classical
example of mucin producing signet ring adenocarcinomas
arising from gastrointestinal tract, pancreas, breast, and gall
bladder may spread to one or both ovaries and the peritoneal
cavities.
Ø The other example is pseudomyxoma peritoni which are
mucus secreting adrocarcinoma arising either from ovary or
appendix. These carcinomas fill the peritoneal cavity with a
gelatinous soft, translucent neoplastic mass. It can also be
associated with primaries in the gallbladder and pancreas.

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2. Lymphatic spread

Ø Lymphatic route is the most common pathway for the initial

dissemination of carcinomas
Ø The pattern of lymph node involvement follows the natural routes
of drainage. Lymph nodes involvement in cancers is in direct
proportion to the number of tumour cell reaching the nodes.
Ø Due to numerous inter connections between vascular and
lymphatic channels the emphasis that used to be given, lymphatic
spread for carcinomas and vascular spread for sarcomas is
misreading.
Ø Metastasis to lymph nodes first lodge in the marginal sinus and then
extends throughout the node. The cut surface of this enlarged
lymph node usually resembles that of the primary tumour in colour
and consistency. The best examples of lymphatic spread of
malignant neoplasm can be exemplified by breast carcinoma.
Ø Skip metastasis may occur when local lymph nodes may be by-
passed and occasionally found in lymph node distant from the site
of the primary malignant neoplasm. Skip metastasis happen to
occur because of venous lymphatic anastomoses or because
inflammation or radiation has obliterated the lymphatic channels
for example abdominal cancer (gastric cancer) may be initially
signaled by supra clavicular (sentinel node).
Ø A clinical presence of enlarged lymph node is not necessarily
synonymous with a metastasis. Conversely, the absence of tumour
cells in reseated lymph nodes does not guarantee that there is no
underlying cancer.

3. Hematogenous spread

Ø Typical for all sarcomas and certain carcinomas- the spread appears
to be selective with seed and soil phenomenon. Lung & liver are
common sites of metastasis because they receive the systemic and
venous out flow respectively. Other major sites of hematogenous
spread include brain and bones. 


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 Ø In the circulation, tumour cells form emboli by aggregation and by
adhering to circulating leukocytes particularly platelets. The site
where tumour cell emboli lodge and produce secondary growth is
influenced by 

• Vascular (and lymphatic) drainage from the site of the primary
tumour 

• Interaction of tumour cells with organ specific receptors 

• The microenvironment of the organ or site, example a tissue rich
in protease 
inhibitors might be resistant to penetration by
tumour cells. 


Cancer Epidemiology
• The only certain way to avoid cancer is not to be born, to live is to
incur the risk. 


• Thus, In USA one in five deaths is due to cancers. Over the years
cancer incidence increased in males while it slightly decreased in
females (due to largely screening Procedures-cervical, breast etc.).
In the studied populations the most common cancer in 
males is
broncogenic carcinoma while breast carcinoma in females. 


• Most cancers in adults occur in those over 55 years of age. 


• Children under 15 years of age however, are susceptible to acute
leukemia, central 
nervous system tumours, neuroblastoma, wilm's
tumour, retinoblastoma, rhabdo myosarcoma and etc. Acute
leukemias and neoplasms of the central nervous system accounts for
about 60% of the deaths. 


Geographic factors (geographic pathology): 


Specific differences in incidence rates of cancers are seen worldwide.For

example, 


Stomach carcinoma Japan

Lung cancer
 USA

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Skin cancer New zeland & Australia


Liver cancer Ethiopia

Environmental factors (occupational hazards) include:

Asbestos-----Lung cancer, mesothelioma,esophagus and, stomach

carcinomas;

Vinyl chloride----Angiosarcoma of liver


Benzene ---Leukemias


Cigarette smoking-----Brochogenic carcinomas

Venereal infection (HPV)--Cervical carcinoma

Premalignant disorders


a) Heredity premalignant disorders

Inherited predisposition to cancer is categorized in to three groups:

i. Inherited cancer syndromes (Autosomal dominant) with strong familial

history include

- Familial retinoblastomas usually bilateral, and a second cancer risk

particularly osteogenic sarcoma. Oncosupressor gene is the basis for this
carcinogenesis

- Familial adenomatous polyps of the colon. virtually all cases are fatal to
develop carcinoma of the colon by the age of 50.

ii. Familial cancers:

Evidence of familial clustering of cancer are documented E.g. Breast,

ovarian, colonic, and brain cancers

iii. Autosmal recessive syndromes of defective DNA repair Characterized

by chromosomal or DNA instability syndrome such as xeroderma
pigmentosium, Ataxia telaangietasia, Bloom syndrome and Fanconi

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anemia

B) Acquired preneoplastic disorders

V. Molecular Basis of Cancer (Carcinogenesis)

Basic principles of carcinogenesis:

The fundamental principles in carcinogenesis include

1) Non-lethal genetic damage lies at the heart of carcinogenesis. Such

genetic damage (mutation) may be acquired by the action of
environmental agents such as chemicals, radiation or viruses or it
may be inherited in the germ line.
2) The three classes of normal regulatory genes are:

i) The growth promoting proto-oncogenes


Activation of proto-oncogenes activation gives rise to oncogenes (cancer

causing genes).Proto


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- oncogenes are activated by


- Point mutation


- Chromosomal rearrangements ranslocation Inversion


- Gene amplification

ii) Cancer suppressor genes (anti oncogenes)


Ø Its physiologic role is to regulate cell growth however, the

inactivation of cancer suppressor genes is the key event in cancer
genesis

Ø Examples of tumour suppressor genes include-Rb, P53, APC and
NF-1&2 genes

iii) Genes that regulate apoptosis


Ø Genes that prevent or induce programmed cell death are also

important variables in the cancer equation. These genes include bcl-
2 that inhibits apoptosis whereas, others such as bax. Bad, and bcl-
x5 favour programmed cell death. Genes that regulate apoptosis
may be dominant as are proto- oncogenes or may behave as cancer
suppressor genes (recessive in nature)

iv) Genes that regulate DNA repair

Inability to DNA repair can predispose to mutations in the genome and

hence, to neoplastic transformations


 3) Carcinogenesis is a multifactorial process

Ø at both the phenotypic and genotypic levels.

Types of carcinogenesis:

A large number of agents cause genetic damages and induce neoplastic

transformation of cells. They fall into the following three categories:

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 a) Chemical carcinogenesis 


b) Radiation carcinogenesis 


c) Viral carcinogenesis 


A) Chemical carcinogenesis

An enormous variety of chemicals may induce tumours and this was

exemplified by Sir Percival Pott’s observation in the last century that
astutely related the increased incidence of scrotal skin cancer in chimney
sweeps to chronic exposure to soot.

Steps involved in chemical carcinogenesis

Ø appropriate dose of a chemical carcinogenic agents to a cell results

in the formation of initiation –promotion sequence 

Ø Initiation causes permanent DNA damage (mutation) which, is
rapid and irreversible. However, initiation alone is not sufficient for
tumour formation and thus, promoters can induce tumours in
initiated cells, but they are non-tumourogenic by themselves.
Furthermore, tumours do not result when a promoting agent
applied before, the initiating agent. 

Ø In contrast to the effects of initiators, the cellular changes resulting
from the application of promoters do not affect DNA directly and
are reversible. 

Ø Promoters render cells susceptible to additional mutations by
causing cellular proliferation. Examples of promoters include
phorbol ester, hormones, phenols and drugs. 


Chemical carcinogenic agents fall into two categories 


1. Directly acting compound 


Ø These are ultimate carcinogens and have one property in

common:

Ø They are highly reactive electrophiles (have electron deficient

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 atoms) that can react with nucleophilic (electron-rich) sites in
the cell. This reaction is non-enzymatic and result in the
formation of covalent adducts (addition products) between
the chemical 
carcinogen and a nucleotide in DNA. 

Ø Electrophilic reactions may attack several electron-rich sites
in the target cells including DNA, RNA, and proteins.
Ø Only a few alkylating and acylating agents are directly acting
carcinogens
2 Indirect acting compounds (or pro-carcinogens)
Ø Requires metabolic conversion in vivo to produce ultimate
carcinogens capable of transforming cells. 

Ø Most known carcinogens are metabolized by cytochrome p-450
dependent mono- oxygenase. 

Ø Examples of this group include polycyclic and heterocyclic aromatic
hydocarbones, and aromatic amines etc.... 

Ø These chemical carcinogens lead to mutations in cells by affecting
the functions of oncogenes, onco-suppressor genes and genes that
regulate apoptosis.

B) Radiation carcinogenesis

Radiant energy whether in form of ultraviolet (UV) sun light or ionizing

electromagnetic (X rays and gamma (δ ) rays) and particulates (α,β,
protons and neutrons) radiation can transform and induce neoplasm in
both humans and experimental animals.

Two types of radiation injuries are recognized:

i) Ultraviolet rays (UV light)

Ø UV rays are examples of non-ionizing radiation that cause

vibration and rotation of atoms in biologic molecules 

Ø UV rays induce an increased incidence of squamous cell
carcinoma, basal cell carcinoma and possibly malignant
melanoma of skin. 

Ø Risk factors for developing UV rays related disorders depend

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 on
- Type of UV rays – UV type B
- Intensity of exposure
-
Quality of light absorbing “protective mantle” of melanin
in the skin 
Ex. Australians (queen's land etc.) 

Ø UV rays’ effects on cell nucleus are: 
-The carcinogenesis of
UV type B rays is attributable to its formation of pyrimidine
dimmers in DNA 
- However, UV rays can also cause
inhibition of cell division, inactivation of enzymes, Induction
of mutation and sufficient dose kill cells. 


As with other carcinogens, UVB also cause mutations on oncogenes and

tumour suppressor genes mutant forms of P53 and ras genes have been
detected.

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