2. OBJECTIVES
COURSE OUTLINE
Students should be able to:
• Define the following terms: tumour, neoplasm, neoplasia,
cancer
• Clasify tumours
• Outline risk factors to cancer formation
• Describe nomenclature of tumours
• Differentiate between benign and malignant tumours
• Describe Features of malignant cells/anaplasia
• Outline routes of tumour spread
3. • Discuss Molecular basis of tumours
• Discuss Carcinogenic agents
• Tumour angiogenesis
• Define and describe tumour staging and
grading
• Discuss Laboratory diagnosis of tumours
4. • Neoplasia means development of a new growth
• A neoplasm is an abnormal mass of tissue with
uncoordinated growth which exceeds that of
the normal tissue and persists in the same
manner after the stimuli that initiated it is
removed.
• Tumour: neoplasm (both benign and malignant)
• Cancer: Latin word for crab= common term for
malignant tumours.
5. General classification of tumours
Tumours are divided into:
a. Mesenchymal
a. Benign mesenchymal tumours
b. Malignant mesenchymal tumours
b. Epithelial.
a. Benign epithelial tumours
b. Malignant epithelial tumours
c. Combined Epithelial/mesenchymal
a.
7. Tissue of origin Benign tumour
Fibrous tissue fibroma
Adipose tissue Lipoma
Cartilage chondroma
Bone osteoma
Blood vessel hamangioma
Lymph vessel lymphangioma
Smooth muscle leiomyoma
Striated muscle rhabdomyoma
[Naming] Nomenclature of benign
mesenchymal tumours.
Named by attaching suffix -oma to the cell of origin.
8. Naming of benign epithelial tumours is more complex and
are named according to
– Cell of origin just like messenchymal tumours
– Microscopic architecture
– Macroscopic patterns
Adenoma
• Benign epithelial neoplasms derived from glands even if not forming
glandular pattern
Papilloma
• Benign epithelial tumours producing fingerlike projections macroscopically or
microscopically.
9. Cystadenoma
• Benign epithelial tumours forming large cystic masses as in the
ovary.
Papillary cystadenoma
• Benign epithelial tumours producing papillary pattern protruding into
cystic masses.
Polyp
• A benign tumour producing a macroscopically visible projection
above the mucosal surface as in the GIT, repiratory mucosae.
13. Nomenclature of malignant tumours
Those of mesenchymal origin are termed
sarcomas.
Those of epithelial origin are termed
carcinomas
Those of combined epithelial and
mesenchymal tissues are termed
carcinosarcomas
15. Tumours inappropriately named
Melanomas
• These are carcinomas of melanocytes. Should
correctly be called melanocarcinomas
Seminomas
• Malignant tumours arising from testis. Should be
testicular carcinoma but have always been
referred to as seminomas.
16. Differences between benign and
malignant tumours
• The following criteria are used:
• Metastasis
• Differentiation
• Anaplasia
• Rate of growth
• Necrosis
• Local invasion
17. 1) Differentiation
• Differentiation is the extent to which
parenchymal cells/neoplastic cells resemble
normal cells both morphologically and
functionally.
• Thus a well differentiated tumour has cells
resembling mature normal cells of the tissue of
origin
• A poorly differentiated tumour has cells that do
not resemble the cell of origin- are primitive
looking and unspecialised.
• Benign tumours are in general well differentiated
18. • Malignant tumours range from well
differentiated to moderately differentiated
to poorly differentiated to undifferentiated.
• Those composed of undifferentiated cells
are said to be anaplastic
19. 2) Anaplasia
Anaplasia means lack of differentiation
It is characterised by the following cell changes
Pleomorphism=Pleomorphism is variation in cell
size and shape.
Hyperchromasia= dark staining of the nuclei due
to abundance of DNA
Number of mitoses= Malignant tumours have a
large number of mitoses than the benign ones
but the most important thing is finding abnormal
mitoses.
20. Tumour giant cells=These are large
tumour cells having one or more nuclei
Loss of polarity= means lack of orientation.
Tumour cells are arranged in a
disorganized manner
• Presence of prominent nucleoli
• High nuclear-cytoplasmic ration
21.
22. 3) Rate of growth
• Generally benign tumours grow slowly while
malignant ones (cancer) grow faster.
• However the rate of growth is dependent on
factors such as blood supply, hormones and so
some benign tumours may grow faster than the
malignant ones. Eg leiomyoma of the uterus due
to dependence of estrogen.
• Since benign ones grow slowly, they compress
connective tissues around them forming a
fibrous capsule. Its thus easier to surgically
enucleate these tumours because of the
capsule.
24. 4) Local invasion
In general:
• malignant tumours (cancers) infiltrate,
invade, and destroy the surrounding tissue
while
• benign ones are localized to their site of
origin. They have no capacity to infiltrate
or metastasize, they push and compress
the surrounding tissues thus forming a
capsule.
25. 5) Metastasis
• It is the most reliable marker of
malignancy
• It is defined as tumour implants
discontinous with the primary tumour.
• All malignant tumours metastasise except
– Gliomas –glial cell neoplasms
– Basal cell carcinoma of the skin
• Difficult to cure metastatic spread
26. Benign tumours Malignant tumours
Do not metastasise Metastasise
Usually well differentiated Usually poorly differentited
Do not invade locally Usually invade locally
Rate of growth is slow Very high rate of growth
Do not show features of anaplasia Show features of anaplasia;
No necrosis Usually have necrosis
29. Spread of cancer
Three main routes
Lymphatic spread
• This is the main route for carcinomas (malignant
epithelial tumours ) but also for a few sarcomas.
Haematogenous spread
• Is the main route of spread for sarcomas but also for a
few carcinomas( eg renal cell carcinoma-renal vein; hepatocellular
carcinoma-hepatic vein; follicular carcinoma of thyroid; choriocarcinoma).
Seeding of body cavities and surfaces.
• This occur when a malignant tumour penetrates in to a
natural cavity like peritoneal, pleaural, pericardial cavities
e.g. tumours of the ovary.
30. Associated risk factors
• Age :Carcinomas generally arise at an older age >50yrs. Tumours
like neuroblastomas, Ewings tumour,
nephroblastomas,retinoblastomas are more common in children.
• Geographic factors: Some tumours are more common in certain
areas than others. Carcinoma of the stomach more common in
Japan. This is due to environmental influence.
• Environmental factors: Alcohol abuse is associated with many
cancers. Chemicals like asbestos, benzene, radiations
• Hereditary factors.
• Acquired preneoplastic lesions eg
Squamous metaplasia and dysplasia of the bronchial mucosa-lung
cancer
Endometrial hyperplasia and dysplasia-endometrial carcinoma
Leukoplakia of the oral cavity, vulva or penis- squamous cell
carcinoma
31. MOLECULAR BASIS OF CANCER
(Cell cycle should be understood first)
• Progression of cells through the cell cycle is
controlled by cyclins and cyclin-dependent
kinases (CDKs) and by their inhibitors.
• CDKs are expressed throughout the cell cycle
but are in an inactive form. Activation is by phos
phorylation by binding to protein cyclin.
• Cyclins are produced at specific phases of cell
cycle and once they activate the CDKs they
decline.
• Most important cyclins are D,E,A B.
32. • A critical stage in cell cycle is the progression
from G1 to S phase. Cyclin D binds to CDK4 and
the complex phosphoralates RB protein. This
eliminates the main barrier to cell cycle
progression.
• Thus RB protein acts like a gate.
Cell cycle inhibitors.
• They are called CDK inhibitors and function as
tumour suppressors. Examples are p21, p27,
and p57. Others are p161NK4a and p14ARF
33. Cell cycle check points.
• There are two main points:G1 to S transition and G2
to M transition
• S phase is the no return point.
• G1/S check point checks for DNA damage. If
present, cell cycle is arrested and DNA repair is
done. If not repairable the cell undergoes
apoptosis. This is by protein p53.
• G2/M check point checks completion of DNA
replication
34. MOLECULAR BASIS OF CANCER
• Carcinogenesis is the development of tumour
and is due to genetic change (mutations) of
cells.
• There are four classes of normal regulatory
genes that if any of them undergoes mutation,
may cause tumour. These genes are:
protooncogenes,
Tumour suppressor genes,
Genes that control programmed cell death,
Genes involved with DNA repair.
35. a) protooncogenes,
• Protooncogenes are cellular genes that
encode proteins that promote normal
growth
• When they undergo mutations they are
transformed into Oncogenes (cancer
causing genes) and they encode for
oncoproteins ( cancer causing proteins)
36. b) Tumour Suppressor Genes (Tsg)
• These are genes that suppress formation
of tumours so when they undergo
mutations tumours arise.
• Examples include:
• BRCA-1 and BRCA-2 : their mutation responsible
for breast cancer.
• RB gene: its mutation responsible for
retinoblastoma
• P53 gene: its mutation leads to many tumours
• NF-1, NF-2: neurofibromatosis
• APC: leads to intestinal adenomas
39. c) Genes That Regulate Apoptosis
• These genes regulate the programmed cell
death [apoptosis] When they undergo mutations
, tumours arise. Examples are:
Bcl-2: Bcl-2 over expression is seen in B-cell
lymphomas
P53: induces apoptosis by increasing the
transcription of proapoptotic gene bax
40. d) Genes That Regulate DNA Repair.
• These genes correct errors that occur in
DNA during cell division or those occurring
as a result of exposure to carcinogenic
chemicals.
• When they undergo mutations tumours
arise.
42. 1) Chemical carcinogenesis
• Port demonstrated higher incidences of scrotal
cancer to chronic exposure to soot.
• Today there are several chemicals that are
known to be carcinogenic.
• chemical carcinogenesis is a multistep process
involving several steps
• These are summed up as
– initiation stage and
– promotion stage in a sequential manner.
43. Initiation stage
• Initiation is due to exposure of cells to sufficient
dose of the initiator (carcinogenic agent ) and
the cell gets altered. However initiation alone is
not sufficient to tumour formation.
• Initiation causes permanent DNA damage. This
is usually rapid and irreversible and has
memory. Thus even if the promoting agent acts
several months latter, due to memory tumour
formation is still likely to occur.
44. Initiation of chemical carcinogenesis
Initiators fall in to two categories
1) Direct acting carcinogens.
– They do not need chemical transformation to become
carcinogenic. Include:
• Alkylating Agents like dimethyl sulfate and anticancer drugs.
• Acylating Agents like Acetyl imidazole and diepoxybutane.
2) Indirect acting carcinogens ( procarcinogens)
– Require metabolic conversion to produce
carcinogens. Include:
• Polycyclic and Heterocyclic Aromatic Hydrocarbons like
Benzopyrene
• AromaticAmines, Amides and Azo dyes like Benzidine and 2-
Acetylaminofluorene.
• Natural Plant and Microbial Products like Aflatoxin and betel
nuts.
45. Promotion of chemical carcinogenesis.
• After initiation, promoters are required to augment the
carcinogenicity of the chemicals.
• Promoters are not themselves mutagenic.
• Promoters lead to cell proliferation and clonal
expansion of the mutated (initiated) cells.
• The cells suffer more repeated damages (mutations)
leading to malignant tumours.
• Thus if a promoter is applied before the initiator, no
tumour arises. Promoters enhance the proliferation of
the initiated cells and their effect is reversible. Thus
there must be multiple application of promoters.
46. • Examples of promoters are the phenols,
hormones, phorbol eters, and some drugs.
48. 2) Radiation carcinogenesis
Ultra violet rays: From the sun:
Induces skin cancer especially in the fair-skinned people
leading to squamous cell carcinomas, basal cell
carcinomas and melanomas.
Ionizing radiation
• They cause mutations in the cells. Good example is the
high incidence of malignancies in Hiroshima.
• The most common tumours are the leukaemias and
thyroid cancer in children remotely followed by breast
cancer.
49.
50. .
3) Microbial carcinogenesis
viruses.
Human papilloma virus. (HPV)
– HPV types 1, 2, 4,and 7 cause squamous
papilloma/warts.
– HPV types 16 or 18 cause >90% of cervical cancer.
EBV virus ( Epstein- Barr Virus)
Associated with Burkitts lymphoma, Nasopharyngeal
carcinoma, B- cell lymphomas, Some types of Hodgkin
disease.
Hepatitis B virus Associated with liver cancer
HTLV-1 virus causes leukaemias and lymphomas.
52. Biology Of Tumor Growth
Tumor angiogenesis
Tumor cells need oxygen to survive and therefore there
must be neovascularization a process called
angiogenesis.
If the rate of growth exceeds the rate of vascularization, the
tumour cells undergo ischaemic necrosis like in
malignant tumours.
Angiogenesis is induced by factors called tumour
associated angiogenic factors (TAAF) produced by
tumour cells and inflammatory cells eg macrophages
53. TAAF induce angiogenesis through:
– recruitment of the endothelial cell precursors to form new
vessels
– sprouting of existing capillaries as in physiologic angiogenesis.
• Examples of TAAF:
– Vascular endothelial growth factor (VEGF)
– Basic fibroblastic growth factor (bFGF)
• Early in the growth tumor cells do not initiate
angiogenesis but after some time some tumor
cells undergo angiogenic switch leading to
angiogenesis.
54. • Tumour cells also induce anti-
angiogenesis molecules like angiostatin,
thrombospondin-1, endostatin and
tumstatin.
• Thus , tumour growth is controlled by the
balance between the angiogenic and anti-
angiogenic factors.
• anti-angiogenic factors are being
evaluated for therapy.
55. Invasion and metastasis
The are two main steps involved are:
• Invasion of extracellular matrix
• Vascular dissemination and homing
1) Invasion of extracellular matrix
• ECM consists of the basement membrane and
the interstitial connecting tissue.
• Tumour cell must first penetrate the bm and then
the interstitial ct in the following sequence.
56. • Detachment of tumour cells from each other
• Cells are adhered to each other by adhesion
molecules like cadherins. These are down regulated
and the cells become loose.
• Attachment to matrix components
• Tumour cells bind to laminin and fibronectin through
receptors.
• Degradation of ECM
• Tumour cells secrete protyolytic enzymes that
degrade the matrix and create passage ways.
• Migration of tumour cells.
57.
58. 2) Vascular dissemination and homing
• Tumour cells form emboli in circulation by
aggregation and by adhering to
lymphoid cells and platelets
• This tumour emboli adhere to the
endothelium, then extravasate and form a
metastatic deposit.
• Angiogenesis occur and tumour cells grow
59.
60.
61. Laboratory Diagnosis Of Cancer
Histologic methods
• Through excision or incision biopsy. The sample
must be adequate, representative, and well
preserved in formalin.
Cytologic methods.
• Interventional cytology: Through Fine Needle
Aspiration (FNA), Pap smear.
• Exfoliative cytology: eg fluid cytology.
62. Immunohistochemistry
• This is through the use of monoclonal antibodies to
identify cell markers.
Molecular diagnosis
• Though they are not the primary modes of cancer
diagnosis they are useful.
Flow cytometry.
• Widely used in classification of leukaemias and
lymphomas.
Tumour markers.
• They include cell-surface antigens, cytoplasmic proteins,
enzymes, and hormones. PSA for prostatic cancer, CA-
19-9 for colon and pancreatic cancers. CA-125 for
ovarian tumours and CA-15 for breast cancer.
63. Clinical features of tumour
.
1) Local and hormonal effects
• Pressure effects to the surrounding tissues.
• Hormonal effects; tumours of endocrine glands may
produce hormones that will have effect on the effector
organs.
2) Tumour cachexia
• This is loss of body fat, wasting and weakness due to the
tumour and is due to loss of appetite, production of
cachectin (Tumour Necrosis Factor) and metabolic
changes that lead to reduced synthesis and storage of
fat.
64. 3) Par neoplastic syndromes.
• Refers to symptoms not directly related to
spread of the tumour or elaboration of hormones
indigenous to the tissue from which the tumour
arose.
• They include
– Hypercalcaemia
– Endocrinopathies
– Acanthosis nigrans
– Thrombotic diathesis
– Clubbing of fingers and hypertrophic
osteoarthropathy.
65. Grading And Staging Of Tumours
• This gives the semi-quantitative estimate
and the anatomic extent of the tumour.
66. Importance of Staging
• Defines prognosis
• Determines appropriate treatment modalities
• Helps to evaluate results of treatments and clinical trials
• Facilitates in the exchange and comparison of information
among treatment centres. Uniformity and standardization
• Follow up of patients can be objectively planned depending
on the stage
• Serves as a basis for clinical cancer research
• Public health concern: by knowing at what stage a certain
tumour presents, public health education can objectively be
planned
• Useful in standardization of information.
67. • There are several cancer staging systems but
the most common one is the TNM
• It is maintained collaboratively by the
American Joint Committee on cancer AJCC
and the International Union for Cancer
Control UICC.
• TNM is periodically revised by the AJCC and
UICC every 6-8 years.
• Now in its 7th edition
• Staging is superior to grading.
68. • Staging is based on the
– Size of the primary tumour (T)
– Its extent of spread to regional lymph nodes
(N)
– Presence or absence of metastasis (M)
69. Grading
• Is based on the degree of differentiation of the tumour
cells and the number of mitosis within the tumour.
• Cancers are therefore put into four grades I to IV
• Grade I is the well differentiated tumour, grade II
moderately differentiated, grade III poorly differentiated,
and grade IV is the anaplastic tumour.
• NOTE grading is of less clinical value than staging.
