This document summarizes key concepts related to tumors and metastasis. It defines a tumor as abnormal cell proliferation. Metastasis occurs when tumor cells spread from the primary site to other parts of the body through routes like lymphatic or blood vessels. Common sites of metastasis include the liver, lungs, bones and brain. Carcinogens and genetic factors can cause carcinogenesis, the process of tumor formation. Grading and staging provide information on tumor characteristics and spread.

1. Melbia Shiny
First MDS

2.  Definition
 classification
 Difference between benign & malignant
 Metastasis
 Carcinogens & carcinogenesis

3.  A mass of tissue formed as a result of abnormal
,excessive , uncoordinated , autonomous , &
purposeless proliferation of cells.

6.  Spread of tumour by invasion in such a way
that discontinuous secondary tumour
mass/masses are formed at site of lodgement.
Routes of metastasis
 Lymphatic spread
 Haematogenous spread
 Other routes- transcoelomic
spread,implantation ,spread through
CSF,epithelium lined surface,

7.  Carcinomas – metastasise by lymphatics
 Sarcomas - metastasise by hamatogeneous
route.
 Two forms:
 Lymphatic permeation-walls of lymphatics
invaded by cancer cells & form continuous
growth

8.  Lymphatic emboli - malignant cell detach to
form tumour emboli & are carried along lymph
to next lymph node & get lodged in
subcapsular sinus.
 Regional nodal metastasis seen in:
 Carcinoma breast – to axillary lymph nodes
 Carcinoma thyroid – to lateral cervical lymph
node

10.  Skip metastasis – due to venous lymphatic
anastomosis/ due to obliteration of lymphatics
by inflammation or radiation lymphatic
metastasis do not occur in nearest node.
 Retrograde metastasis – due to obstruction of
lymphatics by tumour cells lymph flow is
disturbed & tumour cell spread against flow of
lymph.

11.  Virchow’s lymph node – nodal metastasis to
supraclavicular lymph node from cancer of
abdominal organs.

12.  Common sites are – liver ,lung ,brain,
bone,kidney, & adrenals
 These provide good soil for growth of good
seed - Seed soil theory
 Do not allow metastasis to grow – heart ,
spleen , skeletal muscle.
 Arterial spread is less likely because of thick
wall & elastic tissue.

13.  Systemic vein drain into vena cava from limbs
,head ,neck & pelvis.- metastasis to lungs
 Portal vein drain from bowel , spleen, &
pancreas – secondaries in lungs
 Retrograde spread due to venous obstruction
,seen in vertebral metastases in cancer of
thyroid & prostrate.

15. Transcoelomic spread
 Cancers invade serosal wall of coelomic cavity
so tumour fragments break & are carried in
coelomic fluid & get implanted in body cavity.
 Peritoneal cavity mostly involved
 Carcinoma of stomach into ovary
 Carcinoma of ovary into peritoneal cavity
 Carcinoma of bronchus & breast into pleura &
peritoneum

16.  Along epithelium lined surfaces
 Unusual because intact epithelium are resistant
to penetration by tumour cell
 Fallopian tube from endometrium to ovaries &
vice versa
 Through bronchus into alveoli
 Through ureters from kidney into lower
urinary tract

17.  Spread via CSF
 Malignant tumours of leptomeninges spread
by releasing tumour cells into CSF to produce
metastasis
 Implantation
 Due to implantation by needles , sutures, or
transfer from lower lip to upper lip.

19. steps a involved at cell molecular level:
 1)aggressive clonal proliferation and angiogenesis
rapidly proliferating clone of cancer cells
based on tumour heterogenicity.Tumour
angiogenesis (new blood vessels are formed from
pre existing ones) plays a important role,which
provide nourishment to growing tumours.The
morphologic features are:
i)microvascular density –the new capillaries add
to vascular density of tumour.
 ii)central necrosis –if tumour outgrows its
blood supply tumour angiogenesis fail & core
undergoes ischaemic necrosis.

20.  2)Tumour cell loosening
 Normally cell adhesion is due to
CAMs,E(epithelial)-cadherin.in carcinomas
there is loss or inactivation of E-cadherin &
other CAMs.
 3)tumour cell ECM interaction
 Loosened cancer cells are attached to
ECM proteins laminin & fibronectin.

21.  4)degradation of ECM
 Tumour cells overexpress proteases and
matrix degrading enzymes ,cathepsind
metalloproteinases(collagenase,gelatinase).
(dissolution of ECM).
5)entry of tumour cells into capillary lumen
This is by these mechanism:
 Autocrine motility factor (AMF)-this stimulate
receptor mediated motility of tumours cells
 Cleavage products of matrix components-these
promote chemotaxis,growth promotion &
angiogenesis.

22.  6)thrombus formation
 The protruding tumour cells are covered
with circulating blood and form
thrombus.Thrombus provide nourishment and
protect from immune attack.
 7)extravasation of tumour cells
 Tumour cells block these vascular
channels and attach to vascular endothelium.
 8)survival and growth of metastatic deposit
 The extravasated malignant cell on
lodgement grow further under growth
factors(PDGF, FGF, TGF-B & VEGF.

23.  Grading is defined as macroscopic &
microscopic degree of differentiation of tumour
 Based on :
 Degree of anaplasia
 Rate ofgrowth

24.  Borders grading
 Grade I – well differentiated (<25% anaplastic)
 Grade II – moderately differentiated (25-50%
anaplastic cells)
 Grade III – moderately differentiated(50-75%
anaplastic cells)
 Grade IV – poorly differentiated / anaplastic
(>75% anaplastic cells)

25.  Means extent of spread of tumour within the
patient
 TNM staging:
 T- primary tumour
 N- regional nodal involvement
 M- distant metastasis

27.  Carcinogenesis /oncogenesis/tumorigenesis
means mechanism of induction of tumours.
 Agents inducing tumours are called carcinogens
 The etiology & pathogenesis are discussed under
 1)molecular pathogenesis of cancer(genes &
cancer)
 2)chemical carcinogens & chemical carcinogenesis
 3)physical carcinogens & physical carcinogenesis
 4)biologic carcinogens & viral oncogenesis.

28.  The general concept of molecular mechanism
of cancer is below;
 1)monoclonality of tumours
 arise from single clone of cells by genetic
transformation or mutation.
 In multiple myeloma(malignant disorder of
plasma cell)there is production of single type of
immunoglobulin.
 benign uterine tumours contain either A or B
genotype,while normal myometrium is mosaic

30. 2)Genetic theory of cancer
There is either abnormality in genes of cell or
normal genes with abnormal expression.
3)genetic regulators of normal & abnormal mitosis
In normal cell growth four regulatory genes
 Proto oncogenes
 Anti oncogene
 Apoptosis regulatory genes
 DNA repair genes
In cancer transformed cells are produced by
activation of growth promoting oncogene

31.  Inactivation of cancer suppressor gene
 Abnormal apoptosis regulatory genes
 Failure of DNA repair
4)multi step processof cancer growth &
progression

32. i)excessive & autonomous growth –growth promoting
oncogenes.
ii)refractoriness to growth inhibition- growth suppressing
anti oncogenes.
iii)escaping cell death by apoptosis – genes regulating
apoptosis and cancer.
iv)avoiding cellular aging – telomeres & telomerase.
v)continued perfusion of cancer – cancer angiogenesis.
vi)invasion & distant metastasis- cancer dissemination
vii)DNA damage & repair system- mutator gene& cancer
viii)cancer progression & tumour heterogeneity.- clonal
aggressiveness.

36.  3)Gene regulating apoptosis & cancer:
 In cancer cells apoptosis is interfered due to
mutation in the gene.eg are
 BCL2 gene seen in B cell lymphoma removes
the apoptosis –inhibitary control on cancer
cells.
 CD95 receptors are depleted in hepatocellular
carcinoma.

37.  4)Telomereses & telomerase in cancer
 Telomerase is RNA enzyme that help in
repair of damage to DNA and maintain normal
telomere length in successive cell division.
 After repetitive mitosis telomeres are lost in
normal cell & cease mitosis.Cancer cell have
upregulated telomerase enzyme ,hence avoid
aging & mitosis does not slow down.

38.  5)Tumour angiogenesis
 The stimulus is provided by
 Promoters of tumour angiogenesis- vascular
endothelial growth factors(VEGF)& basic
fibroblast growth factors(bFGF)
 Antiangiogenesis factors – thrombospondin
1,angiostatin ,endostatin & vasculostatin.

39. 6)Mutated genes & cancer
The example mutated gene present are ;
Hereditary nonpolyposis colon cancer(lynch syndrome)
Ataxia telangiectasia(ATM)
Xeroderma pigmentosum
Bloom syndrome
Hereditary breast cancer

40.  7)Clonal aggressiveness
 With passage of time tumour cells
acquire more heterogenecity & leads to
tumour progression.


41.  The stages of chemical carcinogenesis is :
 i)Initiation of carcinogenesis
 there are two (direct acting & indirect
acting).
 The steps are involved to transform target cell to
initiated cell
 a)Metabolic activation
 procarcinogens needs activation & are
activated in liver by monooxygenase of
cytochrome& P-450 system in endoplasmic
reticulum

42.  b)Reactive electrophiles
 these bind to electron rich portions such
as DNA, RNA, other proteins.
 c)Target molecules
 the primary target is DNA producing
mutagenesis
 d)Initiated cell
 the changes produced in DNA become
fixed only if the altered cell undergoes one cell
cycle

43.  ii)Promotion of carcinogenesis
 they are not mutagenic
 need repeated dose exposure for long time
 produce slow response
 the change may be reversible
 applied after exposure to initiators
 is not effective alone
 there is a clonal expansion of mutated gene
 eg- hormones , phorbol esters

46.  They are of two types;
 Radiation & nonradiation
 i)Radiation carcinogenesis
 UV & ionizing radiation
 the UV radiation produce pyrimidine dimmers
in DNA which remains unrepaired in
exceesively exposed individuals.
 Ionizing radiation are X rays ,alpha
,beta,gamma rays radioactive isotopes ,protons
& neutrons can cause cancer.

47.  ii)Non radiation carcinogenesis
 these include mechanical injury from
stones in gallbladder, urinary tract, healed
scars from burns /trauma,implant materials
like plastic ,glass, or foreign bodies.

48.  BIOLOGIC CARCINOGENESIS
 THEY ARE
 Parasites- schistosoma haematobium cause
carcinoma of urinary tract
 Fungus – aspergillus flavus cause
hepatocellular carcinoma
 Bacteria – helicobacter pylori cause gastric
lymphoma

49.  Oncogenic viruses is transmitted by
Vertical transmission-from parent to offspring
 Horizontal transmission- one to another by
direct contact
 Two types of oncogenic viruses are DNA
oncogenic viruses & RNA oncogenic viruses

51. 1)Papova virus
Human papilloma virus
Papilloma virus
Polyoma virus
2)Herpes virus
EB virus
Human herpesvirus 8
3)Adeno virus
4)Pox virus
5)Hepadnavirus
HB virus

52.  1)Mode of DNA viral oncogenesis
Replication
 The DNA virus invade the host cell & is
incorporated into host nucleus & T antigen is
expressed.
 Virions are formed in cell nucleus.The new virions
released are accompanied by host cell lysis.
Integration
 Integration of viral genome into host
cell genome occurs which requires essential
presence of functional T antigen.

53.  2)Mode of RNA viral oncogenesis
 a)RNA virus invade the host cell ,the viral
envelope fuses with plasma membrane of host
cell,viral RNA genome as well as reverse
transcriptase are released into cytosol
 b)Reverse transcriptase act as template to
synthesise single strand of matching viral DNA
which is copied to form complementary DNA
resulting in double stranded viral
DNA(proviruses)
 c)The provirus is integrated into host cell genome
 d)Finally brings about replication of viral
components.

55.  1)histological methods
 2)cytological methods
 Exfoliative cytology
 FNAC
 3)histochemistry & cytochemistry
 4)immunohistochemistry
 5)electron microscopy
 6)tumour markers
 7)modern aids
 Flow cytometry
 In situ hybridization
 Molecular diagnostic techniques
 DNA micro assay analysis of tumours


56. Thank you