Neoplasia

Dr.K.Vijaya
Professor
Department of Pathology
MIMS,VKB
 Class -2
• Metastasis
• Pathways of spread
 Metastasis
• Spread of the tumor to sites that are physically
discontinous with the primary tumor
• Invading to blood vessels ,lymphatics and body
cavities.
• All malignant tumors metastasize except -
Gliomas of CNS and Basal cell carcinoma of skin
• 30% of newly diagnosed malignant tumors present
with metastases.
 Pathways of spread
• Dissemination of cancer can occur through one
of these Pathways.
• 1.Direct seeding of body cavities and surfaces.
• 2.Lymphatic Spread
• 3.Hematogenous Spread
 1.Direct seeding of body cavities and surfaces

• Peritoneal ,pleural ,pericardial ,subarachnoid

and joint spaces.
• Example-
• Mucus secreting carcinomas of appendix and
ovary fill the peritoneal cavity with a gelatinous
neoplastic mass called –pseudomyxoma
peritonei
 2.Lymphatic spread
• Principle mode of spread in carcinomas
• Sarcomas may also use this route
• Wall of lymphatics is thin and penetrated by
the tumor cells
• They are carried by the lymphatics to the
sentinel lymph node
• They may reach the thoracic duct and enter
the SVC and spread into the blood stream
• Virchow’s Lymph node Nodal metastasis to
supraclavicular lymph node from cancers of
abdominal organs eg-colon, stomach ,
gallbladder
• Retrograde –due to obstruction of the
lymphatics the lymph flow is disturbed and
the tumor cells spread against the flow of
lymph ex-ca prostate to supraclavicular l.n
 Sentinel lymph node
• A sentinel lymph node is defined as first node
in the regional lymphatic basin that receives
lymph flow from the primary tumor.
• Sentinel lymph node mapping –by injecting
radio labelled dyes or color dyes
• Frozen section of the lymph node during
surgery
• It is useful in detecting the spread of Ca Breast
melanoma, colon cancer, other tumors.`
 3.Hematogenous spread
• Typical of sarcomas
• But can be seen in carcinomas
• There may be arterial spread or venous spread.
• Venous spread –metastasis are seen in Lung or
Liver
• Cancers arising in proximity to vertebral column
embolize through paravertebral plexus
• example -carcinoma of thyroid and prostrate .
 Metastatic cascade
Metastatic cascade-sequential steps involved in the
hematogenous spread of cancer
• Result of complex interaction between cancer cells
and Stroma
• Major cause of cancer related morbidity and
mortality
• It is divided into two phases
1.Invasion of the extracellular matrix
2.Vascular dissemination ,homing of tumor cells and
colonization
 2.Vascular dissemination , homing of tumor
cells and colonization
Vascular dissemination- occurs in the first capillary bed they
encounter
Related to the anatomic location and vascular drainage of the
tumor cells.
Colonization
Tropism of particular tumors for specific tissues is due to expression
of Adhesion or Chemokine receptors on the tumor cells
whose ligands are expressed by endothelial cells at the site of Mets
Example- Prostatic ca-spread to the bone
Bronchogenic CA – adrenals
Neuroblastomas- liver and bone
Genes that promote epithelial and mesenchymal transition –TWIST
and SNAIL are imp mets genes in epithelial tumors.
 Molecular genetics of metastasis
1.Clonal evolution theory – a subset of tumor cells
acquire metastatic potential
2.Metastatic signature — these cells develop mets
at an early stage
3.Metastatic signature with Mutations-
4.Characters of microenvironment like stromal
response ,infiltrating immune cells, and
angiogenesis.
 Molecular basis of cancer
• Nonlethal genetic damage lies at the heart of
carcinogenesis .
• A tumor is formed by single expansion of precursor
cells with genetic damage
• The principle targets of cancer causing mutations are
• Four classes of normal regulatory genes
• 1.The growth promoting proto oncogenes ,
• 2.The growth inhibiting tumor suppressor genes,
• 3.Genes that regulate programmed cell death
(apoptosis) and
• 4.Genes involved in DNA repair
 Molecular basis of cancer-Mutations
multi step process of cancer growth
• Carcinogenesis results from accumulation of complementary
mutations in a step wise fashion over time
• Normal cell-
• Carcinogen induced initiating mutation - initiated
precursor with stem like properties- cancer stem cells
• Driver Mutation effecting genomic integrity-
precursor with mutator phenotype -
• Additional driver mutations- Cancer cell –
additional mutation-
• Emergence of subclones – Genetically
heterogenous cancer
 Cancer -Hall marks
• Malignant neoplasms have certain phenotypic
attributes called cancer hall marks
• Excessive growth
• Local invasiveness
• Distant metastases
• They arise from genomic alterations which
change the expression and function of key
genes
 Tumor progression
• The tendency of tumor cells to become more
aggressive over time is called Tumor Progression
• It is due to genomic instability and cancer promoting
inflammation
• Two types of mutations were identified based on DNA
Sequencing
• 1.Ubiquitous –present in all tumor cells , present at
the time of Transformation
• 2.Unique-present in few tumor cells ,aquired after
transformation during the outgrowth and spread of
the tumor .
 Molecular basis of cancer-Epigenetic Modifications

• 1.DNA Methylation- silence gene expression

• 2.Histone modifications –enhance or dampen
gene expression
 Cellular and Molecular Hallmarks of Cancer
• All cancer phenotypes display 8 fundamental
changes in cell physiology called Hallmarks of
cancer
• 1.Self sufficiency in growth signals –activation of
oncogene
• 2.Insensitivity to growth inhibitory signals-
inactivation of tumor suppressor genes
• 3.Altered cellular metabolism –tumor cells switch
to aerobic glycolysis- warburg effect-synthesis of
the macromolecules and organelles that are needed
for the rapid cell growth.
• 4.Evasion of Apoptosis-Tumors are resistant to
programmed cell death
• 5.Immortality –unrestricted replicative potential
• 6.Sustained angiogenesis
• 7.Ability to invade and metastasize
• 8.Ability to evade the host immune response
 1.Self sufficiency in growth signal
Oncogenes
• Proto-oncogenes – unmutated counterparts of
Oncogenes –genes that promote autonomous
cell growth in cancer cells
• They encode – Oncoproteins which promote
cell growth in the absence of growth
promoting signals
• Cells expressing oncogenes proliferate
excessively
• Proto oncogenes -participate in signaling
pathways that drive proliferation .
• They encode
• 1.Growth factors eg-PDGF, TGFα
• 2.Growth factor receptors- EGF receptor-ERBB1
• 3.Signal transducers- RAS, ABL-BCR,BRAF,
• 4.Transcription factors - MYC, or
cell cycle components- CDK4
• 1.erb1-
 1.Growth factors
• Paracrine and autocrine action
• The cancer cells have the ability to synthesize
the same growth factor to which they are
responsive
• Example-
• PDGF and PDGF receptor tyrosine kinases
produced by Glioblastoma
• TGFα and its receptor EGFR- Sarcomas
 2.Growth factor receptors
• Tyrosine kinases –Transmembrane proteins , with
an extracellular ligand binding domain and a
cytoplasmic tyrosine kinase domain
• The receptor is activated by binding of a growth
factor to the extracellular domain
• It auto phosphorylates tyrosine residues in its tail
and they in turn serve as sites for recruitment of a
number of signaling molecules –RAS and PI3K
• These deliver mitogenic signals to the cell even in
the absence of GF
• Receptor TK is activated in cancer cells by point
mutations, gene rearrangements and gene
amplifications