NEOPLASIA

Dr Mbayah Etabalé
Anatomical Pathologist and Lecturer of Pathology
Outline
• Definition

• Nomenclature

• Characteristics of Benign and Malignant Neoplasms

• Carcinogenesis

• Genetic Lesions in Cancer

• Pre-Malignancy

• Clinical Effects of Neoplasms

• Laboratory Diagnosis of Neoplasms

• Grading and Staging of Cancers

2
Definition

3
Neoplasm: Definition
• Pre-Molecular Era
 An abnormal mass of tissue
 Its growth exceeds and is
uncoordinated with that of normal
tissue
 Its growth persists in the same
excessive manner after cessation of
stimulus that evoked the change
• Molecular Era
 Disorder of cell growth triggered by a
series of mutations of a single cell
and its progeny
• A neoplasm consists of 2 basic
components:
 Parenchyma
 Composed of the proliferating tumour
cells
 Determines the nature and evolution of
the disease
 Stroma
 Composed of fibrous connective tissue
and blood vessels
 Provides the framework on which the
parenchymal tumour cells grow

4
Nomenclature

5
Nomenclature
• Neoplasms are named based:
 Behavioural patterns
 Benign
 Malignant
 Histological types (histogenesis)
 Epithelial
 Mesenchymal

6
Benign Epithelial Tumours
• Generally, the suffix –oma is used
• Epithelia can be gland-forming (glandular) or non-
glandular
• Non-glandular, lining, epithelial neoplasms produce
macroscopically or microscopically visible finger-like or
warty projections from surface – papillomas (nipple-
like/finger-like)
 Squamous epithelium → squamous cell papilloma
 Transitional epithelium → transitional cell papilloma

7
Benign Epithelial Tumours

Squamous Papilloma
8
Benign Epithelial Tumours
• Benign neoplasms of glandular epithelia are termed
adenomas
 Colon → colonic adenoma
 Thyroid → thyroid adenoma
 Kidney → renal adenoma
 Liver → liver adenoma

• Benign neoplasms of cyst-forming glandular epithelia are

termed cystadenomas
 Mucinous/serous cystadenoma of the ovary

9
Benign Epithelial Tumours

Ovarian Cystadenoma

10
Benign Mesenchymal Tumours
• Generally, the suffix –oma is used

Connective Tissue Tumours

Tissue of Origin Benign Tumour
Fibrous Tissue Fibroma
Bone Osteoma
Cartilage Chondroma
Adipose tissue Lipoma
Smooth muscle Leiomyoma
Skeletal muscle Rhabdomyoma
Blood vessel Haemangioma
Lymphatic vessels Lymphangioma

11
Misnomers
Non-Neoplastic Misnomers Neoplastic Misnomers
• Haematoma • Melanoma
• Granuloma • Lymphoma
• Hamartoma • Seminoma
• Glioma
• Hepatoma

12
Malignant Epithelial Tumours
• Generally, the suffix –carcinoma is used for malignant
epithelial tumours
 Carcinoma (Greek karkinos – crab)

• Malignant neoplasms of surface epithelia are simply

termed carcinomas
 Squamous epithelium → squamous cell carcinoma
 Transitional epithelium → transitional cell carcinoma

• Malignant neoplasms of glandular epithelia are termed

adenocarcinomas
 Colon → colonic adenocarcinoma

13
Malignant Mesenchymal Tumours
• The suffix –sarcoma is used for mesenchymal cancers

Connective Tissue Tumours

Tissue of Origin Benign Tumour Malignant Tumour
Fibrous Tissue Fibroma Fibrosarcoma
Bone Osteoma Osteosarcoma
Cartilage Chondroma
Adipose tissue Lipoma
Smooth muscle Leiomyoma
Skeletal muscle Rhabdomyoma
Blood vessel Haemangioma Angiosarcoma
Lymphatic vessels Lymphangioma
14
Nomenclature: Teratomas
• Tumours derived from totipotential germ cells
• The tumour cells can differentiate to tissues of the
various germ layers (ectoderm, mesoderm and endoderm)
• Arise in the ovary, testes or along the body midline e.g.
pineal gland, mediastinum, retroperitoneum,
sacrococcygeum
• Can be further classified as:
 Benign vs malignant
 Mature vs immature

15
Nomenclature: Teratomas

Mature Cystic Teratoma of the Ovary 16

Tumour Nomenclature: Mixed
Tumours
• Tumours composed of neoplastic proliferations of both
epithelial and mesenchymal components (biphasic)
• Examples
 Benign
 Fibroadenoma
 Pleomorphic adenoma/benign mixed tumour of the salivary gland
 Malignant
 Carcinosarcoma

17
Tumour Nomenclature: Blastoma
• A malignant tumour composed of immature cells
resembling those that form the foetal anlage or primordia
of adult organs (blasts)
• Commonly seen in the paediatric setting
• Examples
 Kidney →
 Cartilage →
 Retina →
 Medulla →
 Nerves →
 Liver →

18
 Tumour Nomenclature:
Harmatoma
• A mass of composed of cells and tissues indigenous to the
involved site but which are disorganised
 Mole (melanocytic naevus) – skin harmatoma representing an
aggregate of pigment cells that are normally dispersed in the skin
 Pulmonary harmatoma – this represents a nodule composed of
cartilage, bronchial epithelium and smooth muscle cells

19
Tumour Nomenclature: Choristoma
• A mass composed of normal cells and tissues found in the
wrong location
• It is also called ectopia or ectopic rest
• Examples:
 Ectopic brain tissue in the nasal cavity
 Pancreatic choristoma in the stomach or in the liver

20
Tumour Nomenclature: Eponyms
• With some tumours, proper names (usually of their
describers) are used:
 Hodgkin lymphoma Thomas Hodgkin (1832)
 Ewing sarcoma James Ewing (1866 – 1943)
 Wilms tumour Max Wilms (1867 – 1918)
 Kaposi sarcoma Moritz Kaposi (1872)
 Burkitt lymphoma Denis Burkitt (1958)

21
Benign vs Malignant
Neoplasms

22
Biological Differences
1. Differentiation and Anaplasia
2. Rate of Growth
3. Local Invasion
4. Metastasis

23
Differentiation
• Tumour grade
• Extent to which parenchymal cells resemble comparable
normal cells, morphologically and functionally
• Well-differentiated tumour cells resemble mature normal
cells of tissue of origin
• Poorly-differentiated or undifferentiated tumours have
primitive appearing, unspecialised cells

24
Differentiation: Benign Tumours
• Benign neoplasms are well-differentiated
 Mimic the structure of the parent tissue microscopically
 The neoplastic cells resemble their normal cell counterparts
 The neoplastic cells show remarkable uniformity in size, shape and
nuclear configuration
 Have relatively infrequent mitotic figures; these are of normal type

25
Differentiation: Benign Tumours

Normal Terminal Duct Lobular Unit Tubular Adenoma of the Breast

of the Breast 26
Differentiation – Malignant Tumours
• Malignant neoplasms range from well-differentiated to
undifferentiated/anaplastic (anaplasia = lack of differentiation)
• The level of differentiation speaks of the grade of the neoplasm
• Tumour grade is a prognosticator
 Low grade tumour – better prognosis
 High grade tumour – worse prognosis

4-Tier Grading 2-Tier Grading

G1 – Well Differentiated Low Grade
G2 – Moderately-Differentiated
G3 – Poorly-Differentiated High Grade
G4 - Undifferentiated
27
Anaplasia
1. Increased variation in shapes and sizes of cells (cellular
pleomorphism), sometimes with bizarre cells
2. Loss of polarity
3. Increased variation in shapes and sizes of nuclei (nuclear
pleomorphism)
4. Increase in density of staining of nucleus (nuclear
hyperchromasia)
5. Disproportionately large increase in size of the nuclei relative to
the size of the cell cytoplasm (high nucleocytoplasmic ratio)
6. Large, multiple nucleoli
7. Many/abnormal mitotic figures
28
Harsh Mohan Textbook of Pathology, 7e

29
30
Anaplastic Large Cell Carcinoma of the Lung
31
Rate of Growth – Benign vs
Malignant Tumours
• In general (but with the caveat that range of tumour
behaviour is wide)
1. Most benign tumours grow slowly whereas most cancers grow
rapidly
2. The growth rate of tumours correlates with their level of
differentiation
3. Rapid growth rate leads to tumour ischemia and necrosis

32
 Local Invasion
Benign Tumours
• Benign tumours grow as cohesive,
expansile masses that remain localised to
their site of origin
 Because they grow slowly, they develop a
rim of compressed connective tissue – a
capsule
 Cause problems by impingement on other
structures
Malignant Tumours
• Malignant tumours grow by infiltration
and invasion of the surrounding
structures
 Poorly demarcated from the surrounding
tissue
 Next to metastasis, invasion is the most
reliable feature of malignancy
 In-situ cancers display the cytologic
features of malignancy without invasion
33
Local Invasion and Benign Tumours

Robbins Basic Pathology, 10e

Fibroadenoma

34
Local Invasion and Malignant Tumours

Robbins Basic Pathology, 10e

Breast Carcinoma
35
Metastasis
• Spread of tumours to sites that are anatomically separate from their
site of origin
• Hallmark of malignant tumours
• Metastasize in 4 ways:
1. Direct/Local extension
2. Lymphatic spread
3. Haematogenous spread
4. Spread across body cavities and natural passages
i. Transcoelomic spread
ii. Spread along epithelial-lined surfaces
iii. Spread via CSF

36
Metastasis
Liver Metastasis Lymph Node Metastasis

Robbins Basic Pathology, 10e

37
 Benign Malignant

Behaviour Expansile / “pushing” growth Invasive growth

Grows locally May metastasise

Often encapsulated Not encapsulated

Generally, grow slowly Generally, grow rapidly

Histology Resembles cell of origin (well- May show failure of cellular differentiation
differentiated)
Few or no mitoses Many mitoses, some of which are abnormal
forms
Normal or slight increase in NC ratio High NC ratio

Cells are uniform throughout the tumour Cells vary in shape and size (cellular
pleomorphism) and/or nuclei vary in shape and
size (nuclear pleomorphism 38
Carcinogenesis

39
Carcinogenesis
• The process by which normal cells are converted to cancer cells
(oncogenesis)
• Initiated by a non-lethal genetic damage (mutation)
• Mutation may be acquired (chemicals, radiation or viruses) or inherited
in the germline
• Occurs through the sequential accumulation of multiple mutations
• The mutations are non-lethal
• Agents that cause carcinogenesis are called carcinogens
• The acquired mutations give the precursor cells a selective advantage
• Carcinogenic agents classified as follows:
 Chemical carcinogens
 Physical carcinogens
 Biological carcinogens
40
Carcinogenesis
• Stages:
 Exposure to carcinogen
 Interplay of factors:
 Route of exposure of carcinogen
 Dose of carcinogen
 Duration of exposure to carcinogen
 Host susceptibility
 Carcinogenic phenotype

• Stages of carcinogenesis
 Initiation
 Promotion
 Progression

41
Chemical Carcinogenesis: Initiation
• A non-lethal genetic change produced by a
carcinogen
• Can take place with:
 A single dose of the initiating agent for a short
time (less effective)
 A larger dose for longer duration (more
effective)
• During cell division, the mutation may be passed
to the daughter cell; this renders the mutation
irreversible/permanent
• Initiating agents can be classified into 2:
a. Directly-acting carcinogens
b. Indirectly-acting carcinogens
(procarcinogens)

42
Directly-Acting Chemical
Carcinogens
• These are the ultimate carcinogens

• They are highly-reactive electrophiles (have electron deficient atoms) that

can react with nucleophilic (electron-rich) sites in the cells e.g., DNA, RNA
and proteins

• Non-enzymatic reaction

• Results in the formation of covalent adducts (addition products) between the

chemical carcinogen and a nucleotide in DNA

• 2 classes:
 Alkylating agents (cyclophosphamide, chlorambucil, busulphan, melphalan,
nitrosourea, β-propiolactone, epoxides, etc.)
 Acylating agents (acetylimidazole, dimethylcarbamyl chloride)

• Implicated in the aetiology of leukaemias and lymphomas in humans

43
Indirectly-Acting Chemical
Carcinogens
• Constitute the majority of chemical carcinogens

• Require metabolic conversion in vivo to produce ultimate carcinogens

capable of transforming cells

• Most are metabolized by the CYP-450 system

• Categories
1. Polycyclic aromatic hydrocarbons
 Largest group
2. Aromatic amines and azo-dyes
3. Naturally occurring products
4. Miscellaneous agents

44
Indirectly-Acting Carcinogens

Harsh Mohan Textbook of Pathology, 7e

45
Chemical Carcinogenesis: Promotion
• Slow and gradual process, usually
occurring over years
• Promoters lack intrinsic carcinogenic
potential but their application subsequent
to initiator exposure helps the initiated cell
to proliferate further
• Examples
 Phorbol esters
 Phenol
 Hormones
 Drugs e.g. phenobarbital
• During this period of proliferation,
additional mutations may be acquired

46
Initiators and Promotors

Harsh Mohan Textbook of Pathology, 7e

NB: Some carcinogens may act as initiators and promoters

47
Chemical Carcinogenesis:
Progression
• Stage where the growth of the tumour
becomes autonomous
• The mutated proliferated cell shows
phenotypic changes of malignancy
• Consequence of serial accumulation of
genetic damage

48
Physical Carcinogens
• Radiation carcinogens
 Non-ionizing radiation – ultraviolet rays
 Ionising radiation – X-rays, α-rays, β -rays, γ-rays, radioactive
isotopes

• Non-Radiation carcinogens
 Gall bladder stones – gall bladder adenocarcinoma
 Urinary stones – urinary bladder squamous cell carcinoma
 Old scars (burns, chronic wounds) – squamous cell carcinoma

49
Carcinogenic Agents - Radiation
Source of Radiation Tumours Type of Radiation

Sunlight Melanoma, SqCC, BCC UV (non-ionising)

Nuclear events e.g. Leukaemia; Carcinomas Ionising

Nagasaki & Hiroshima of lung, breast, thyroid
Therapeutic Carcinomas, sarcomas, Ionising
irradiation leukaemia
Mining of radioactive Lung carcinoma Ionising
substances e.g.
uranium
X-ray workers Skin cancer, leukaemia X-rays (ionizing)
(historical)

50
Biological Carcinogens
• Parasites
 S. haematobium – squamous cell carcinoma of the urinary bladder
 C. sinensis – cholangiocarcinoma

• Fungi
 Aspergillus flavus > aflatoxin > HCC

• Bacteria
 H. pylori – gastric carcinoma / gastric lymphoma

• Viruses

51
Carcinogenic Agents – Oncogenic
Viruses
• Addition of new DNA to the nucleus of the host cells
resulting in mutants
• 2 types of oncoviruses
 DNA virus
 Invades the cell > direct incorporation of viral DNA in host DNA >
mutation > neoplasia
 RNA virus
 Invades the cell > production of reverse transcriptase > formation of
DNA > incorporation of viral DNA in host DNA > mutation > neoplasia

52
Carcinogenic Agents – Oncogenic
Viruses
Virus Type Mechanism Tumour Type

EBV DNA Products stimulate B-cell Burkitt lymphoma; NPC

proliferation/epithelial cell Hodgkin lymphoma;
proliferation Post-transplantation
lymphoma
HBV DNA Chronic inflammation and HCC
HCV DNA increased cell regeneration

HPV DNA Products neutralise Rb and p53 Anogenital Ca

proteins
HTLV RNA Products trigger cytokine-mediated Lymphoblastic T-Cell
proliferation of T-cells Leukaemia

53
54
Genetic Lesions in
Cancer

55
Outline
1. Point Mutations

2. Gene Rearrangements

3. Chromosomal Deletions

4. Gene Amplifications

5. Aneuploidy

6. Epigenetic Changes

56
 1. Point Mutations
• A point mutation is an alteration in a single base
• The alteration can be in the form of:
 Single base substitution
 Single base deletion
 Single base insertion

• Point mutation can activate (gain-of-function

mutation) or inactivate (loss-of-function mutation)
the protein products of the affected genes
• Gain-of-function mutations:
 Convert proto-oncogenes to oncogenes Zulhabri O, Rahman J, Ismail S, Isa MR, Wan Zurinah WN.
 RAS point mutation: colorectal cancer, pancreatic cancer, etc. Predominance of G to A codon 12 mutation K-ras gene in Dukes' B
colorectal cancer. Singapore Med J. 2012 Jan;53(1):26-31. PMID:
22252179.
• Loss-of-function mutations:
 Inactivation of TSGs
 p53 point mutation

57
2. Gene Rearrangements
• Due to chromosomal translocations and inversions

• Consequent activation of proto-oncogenes by two mechanisms:

 Removing a gene from its regulator and placing it next to a promoter / enhancer
 Creation of a novel fusion hyperactive oncogene

58
2. Gene Rearrangements
Placement of a Proto-Oncogene Next to an Enhancer / Promoter

• Follicular Lymphoma
 Chromosomal abnormality: t(14;18)(q32;q21), IGH::BCL2
 Ch 14 – promoter site for immunoglobulin expression
 Ch 18 – BCL2 gene (anti-apoptotic gene)

• Mantle Cell Lymphoma

 Chromosomal abnormality: t(11;14)(q13;q32), IGH::CCND1
 Ch 11 – CCND1 gene (cyclin D1 gene)
 Ch 14 – promoter site for immunoglobulin expression

• Burkitt Lymphoma
 Chromosomal abnormality: t(8;14)(q24;q32), IG::MYC
 Ch 8 – MYC gene (proto-oncogene)
 Ch 14 – promoter site for immunoglobulin expression

59
2. Gene Rearrangements
Creation of a Novel Fusion Hyperactive Oncogene

• Chronic Myeloid Leukaemia (CML)

 Chromosomal abnormality t(9;22)(q34.1;q11.2), BCR::ABL1
 Ch 9 – ABL gene
 Ch 22 – BCR gene
 Results in a new smaller chromosome 22 – Philadelphia chromosome
 BCR-ABL codes for a hyperactive tyrosine kinase

60
3. Chromosomal Deletions
• Loss of a portion of a chromosome

• Neoplasia ensues if deletion affects a tumour suppressor gene

 Autosomal recessive pattern

• Examples
 del 13q14, site for RB gene associated with Retinoblastoma
 del 17p, site for TP53 gene associated with many cancers

61
 4. Gene Amplification
• Increase in the number of copies of a gene sequence

• Result in increased protein coding and consequently

increased protein activity

• Examples in neoplasia:
1. HER-2 (ERBB2) positive breast carcinomas
 ~20% of breast carcinomas
 Worse prognosis
 Targeted therapy using trastuzumab (Herceptin)
2. NMYC amplified Neuroblastoma
 25 – 30% of neuroblastomas
 Poor prognosis

62
4. Gene Amplification

Robbins Basic Pathology, 10e Rubins Pathology: Clinicopathologic Foundations of Medicine, 7e

63
4. Aneuploidy
• Any chromosome number that is not a whole number multiple of haploid
state

• Due to errors in mitotic checkpoint

• Certain chromosome copies might increase while others decrease

 Increased copy numbers of chromosome 8 containing MYC gene
 Reduced copy numbers of chromosome 17 containing TP53 gene
 Reduced copy numbers of chromosome 13q containing RB gene

64
5. Epigenetic Changes
• DNA methylation

• Histone modification

• miRNAs

Quora

65
5. Epigenetic Changes: Histone
Modification
• These modifications provide either an ON or
OFF signature which result in the tight
regulation of gene expression (histone code)

• Histone modification can be targeted for cancer

therapy:
 HDAC inhibitors are examples of drugs used to
reverse these changes

https://doi.org/10.1093/femsml/uqad032

66
5. Epigenetic Changes: DNA Methylation
• Involves covalent modification of cytosine nucleotides at the C5
position in specific areas of CpG dinucleotides

• Hypermethylation results in gene silencing

 Directly interfering with the binding of transcription factors to DNA
 Attracts proteins that specifically bind modified DNA, thus blocking
access to other factors required for gene induction

• Hypermethylation of CpG islands in promoter regions of anti-

cancer genes is at the origin of many cancers (e.g., ↓Rb protein
expression, ↓BRCA1 expression)

• At the genome level hypomethylation is associated with

chromosomal instability and development of mutations

• DNA methylation are targets for cancer therapy:

 DNMT inhibitors are examples of drugs used to reverse these changes

Researchgate
67
5. Epigenetic Changes: MicroRNAs
• Non-coding, single-stranded RNAs

• MicroRNAs (miRNAs) function to regulate messenger RNA (mRNA) by binding to the

3' untranslated region (3' UTR) of the mRNA and triggering degradation or inhibiting
translation

• Overactive MiRNAs targeting TSG promotes oncogenesis

• Inactive / underactive MiRNAs targeting proto-oncogenes promotes carcinogenesis

68
5. Epigenetic Changes

N Engl J Med 2008; 358: 1148-59

69
Pre-Malignancy

70
Pre-Malignancy
• Conditions associated with the development of a
malignancy
1. Benign tumours undergoing malignant transformation
2. Chronic inflammatory disease states
3. Hyperplasia
4. Intra-epithelial Neoplasia (Dysplasia)

• Removal of the lesion (or initiating stimulus) eradicates

the risk of malignant transformation

71
Malignant Transformation of Benign
Tumours
• Patients with multiple colonic adenomas have a high incidence of developing
colonic carcinoma

• Neurofibromas in NF-1 patients may undergo malignant transformation

• Pleomorphic adenoma of the salivary gland may complicate with malignant

transformation (carcinoma ex pleomorphic adenoma)

72
Chronic Inflammation
1. Hashimoto Thyroiditis Diffuse
complicating to Thyroid Large B
Cell
H. Pylori
infection
Lymphoma Lymphoma

2. H. pylori Gastritis
complicating to:
Reactive
1. Gastric MALToma Distant polyclonal
spread immune
2. Gastric Carcinoma stimulation

3. Ulcerative Colitis
complicating with Colorectal
Carcinoma Monoclonal
MALToma B-Cell
neoplasm

73
Hyperplasia
• Endometrial hyperplasia is associated with an increased risk of
progression to endometrial carcinoma
 Nonatypical endometrial hyperplasia confers a 2 – 4-fold increased risk
compared to the general population
 Atypical endometrial hyperplasia confers a 45-fold increased risk
compared to the general population

74
Intraepithelial Neoplasia
• Commonly called DYSPLASIA

• An epithelial lesion characterised by

presence of cytological features of
malignancy without invasion into the
surrounding tissue
 Cellular and nuclear pleomorphism
 Disordered orientation (loss of polarity)
 Increased mitoses
 Atypical mitotic figures

• Represents intermediate stage in

carcinogenesis Mild Moderate Severe
Dysplasia Dysplasia Dysplasia

• Acronym __IN: Low Grade

Dysplasia High Grade Dysplasia
 CIN – Cervical Intraepithelial Neoplasia
Low Grade High Grade Squamous

75
Squamous
Intraepithelial Intraepithelial Lesion
Lesion (LSIL) (HSIL)
Cervical Intraepithelial Neoplasia

76
Hallmarks of Cancer

77
Hallmarks of Cancer
• Fundamental changes in cell
physiology found in all cancer cells
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory
signals
3. Evasion of apoptosis
4. Altered cellular metabolism
5. Limitless replicative potential
(immortality)
6. Sustained angiogenesis
7. Invasion and metastasis
8. Evasion of immune surveillance

• There are 2 enablers of these

hallmarks
1. Tumour promoting inflammation
2. Genomic instability
Robbins Basic Pathology, 10e
78
1. Self-Sufficiency in Growth Signals
• Conversion of proto-oncogenes to oncogenes by GOF mutations
• Oncogenes code for oncoproteins which promote cell growth even in the absence of
normal growth promoting signals
 Increased growth factor synthesis
 Glioblastomas secreting PDGF for their PDGFR
 Sarcomas secreting TGF-α for their TGF-αR
 Increased growth factor receptor action:
 EGFR overexpression in lung SqCC (80%), glioblastoma (50%)
 Her-2 overexpression in breast carcinoma (20%)
 Increased 2nd messenger activity:
 RAS overexpression in pancreatic Ca, colorectal Ca, etc.
 ABL overexpression in CML
 Activation of nuclear transcription factors
 MYC overactivity in Burkitt lymphoma, neuroblastoma (NMYC), small cell lung carcinoma (LMYC)
 Persistent cell cycling
 GOF mutations involving cyclin D in mantle cell lymphoma
 LOF mutations involving CDK-Is e.g. CDKN2 (p16) mutation in pancreatic carcinoma, melanoma,
oesophageal carcinoma, glioblastoma, leukaemia
79
1. Self-Sufficiency in Growth Signals
• Normal growth-promoting genes are called proto-oncogenes
• These genes code for GF; GFR; pro-growth enzymes and 2 nd messengers;
transcription factors and cell cycle regulatory proteins
• A GOF mutation to a proto-oncogene results in an oncogene; oncogenes
encode oncoproteins
• Oncogenes are expressed in a dominant fashion
• Oncogene expression results in excessive growth even in the absence of
normal growth promoting signals

Harsh Mohan Textbook of Pathology, 7e

80
Proto-Oncogenes and Oncogenes
1. Increased growth factor synthesis
 Glioblastomas secreting PDGF for their PDGFR
 Sarcomas secreting TGF-α for their TGF-αR

2. Increased growth factor receptor action:

 EGFR overexpression in lung SqCC (80%), glioblastoma (50%)
 Her-2 overexpression in breast carcinoma (20%)

3. Increased 2nd messenger activity:

 RAS overexpression in pancreatic Ca, colorectal Ca, etc.
 ABL overexpression in CML

4. Activation of nuclear transcription factors

 MYC overactivity in Burkitt lymphoma, neuroblastoma (NMYC), small cell lung carcinoma
(LMYC)

5. Persistent cell cycling

 GOF mutations involving cyclin D in mantle cell lymphoma
 LOF mutations involving CDK-Is e.g., CDKN2 (p16) mutation in pancreatic carcinoma,
melanoma, oesophageal carcinoma, glioblastoma, leukaemia

81
Proto-Oncogenes and Oncogenes

Harsh Mohan Textbook of Pathology, 7e 82

2. Insensitivity to Growth-Inhibitory
Signals
• Growth inhibitory signalling proteins prevent
uncontrolled growth
• They are coded by Tumour Suppressor Genes (TSGs) aka
Anti-Oncogenes
 Rb, p53, APC, NF-1, NF-2
• When mutated (LOF) or lost from a cell, allow the
transformed phenotype to develop
• Both normal alleles of tumor suppressor genes must be
damaged for transformation to occur (AR behaviour)
• Inactivation of TSG is the key event in carcinogenesis

83
Tumour Suppressor Genes

84
Harsh Mohan Textbook of Pathology, 7e
2. Retinoblastoma Gene and Protein
• Locus: 13q
• RB, a key negative regulator of the cell cycle, is directly or indirectly inactivated
in most human cancers
 Binds to and sequester E2F transcription factor thereby preventing DNA replication (S
Phase)

• Clinical examples
 Retinoblastoma
 Inherited germline LOF mutation in one allele, 13q, followed by a “second hit” in the remaining
allele
 First hit may be an inherited germline mutation (hereditary retinoblastoma) or acquired (sporadic
retinoblastoma)
 HPV-induced squamous cell carcinoma
 High-risk HPV-associated protein E7 displaces E2F from the RB protein binding site; E2F is
therefore free to mediate DNA replication
 Osteosarcoma
 Sarcomas
 Small cell lung carcinoma

85
2. p53 Gene and Protein
• Locus: 17p
• > 70% of human cancers have defect in the p53 gene; the remaining 30% have defects in
the genes upstream or downstream p53
• p53 protein regulates the cell cycle by:
 Triggering temporary cell cycle arrest (quiescence) to allow for DNA repair
 p53 also upregulated the expression of DNA repair genes to allow for DNA repair
 Triggering permanent cell cycle arrest (replicative senescence) of cells with irreparable DNA
damage
 Triggering apoptosis of cells with irreparable DNA damage

• Examples:
 Acquired bi-allelic p53 mutations present in many carcinomas: breast, lung, colon, etc.
 In some sarcomas, p53 gene is normal but MDM gene is overexpressed (MDM protein inhibits
p53)
 Germline p53 mutation (Li-Fraumeni syndrome) is associated with a 25-fold increased risk
relative to the general population of development of a variety of cancers by age 50: sarcomas,
breast cancer, leukaemia, brain tumours, etc.
86
3. Evasion of Apoptosis
• Pro-apoptotic genes e.g. Bax, Bad, Bid, p53
 Mutations express in a recessive fashion
 LOF mutations in genes encoding pro-apoptotic proteins leads to
evasion of apoptosis thereby giving the tumour cells a survival
advantage
 Fas (CD 95) mutation in HCC

• Anti-apoptotic genes e.g. Bcl-2, Bcl-X

 Mutations express in a dominant fashion
 GOF mutations can occur in anti-apoptotic genes leading to evasion
of apoptosis:
 Bcl-2 mutation in Follicular Lymphoma

87
3. Evasion of Apoptosis
• Due to acquired abnormalities that interfere with the
intrinsic (mitochondrial) pathway of apoptosis
1. Loss of TP53 function: every tumour
 TP53 activates PUMA which opposes BCL2 (anti-apoptotic protein) >
tilts towards BAX/BAD A0 > mitochondrial permeability > escape of
cytochrome c into cytoplasm > caspase A0
2. Overexpression of anti-apoptotic genes: BCL2
 In follicular lymphoma, BCL2, an anti-apoptotic gene is overexpressed
leaving to increased B-cell survival
 In chronic lymphocytic leukaemia, loss of expression miRNA that target
BCL2 leading to increased anti-apoptotic activity

88
4. Altered Cellular Metabolism - Warburg
Effect
• With adequate O2 levels, normal cells metabolise each molecule
of glucose aerobically to generate 36 ATP molecules (aerobic
respiration)

• In the absence of sufficient O 2, they break down glucose to lactic

acid while releasing only 2 ATP molecules (anaerobic glycolysis)

• Cancer cells preferentially engage in anaerobic respiration even

when there is adequate O2 and mitochondria are working –
Warburg Effect

• Aerobic glycolysis generates metabolic intermediates whose

carbon moieties can be used by proliferating cells as building
blocks for cellular macromolecules:
 pyruvate – proteins
 acetylCoA – lipids
 ribose 5-phosphate - DNA, RNA, etc.

• Oncoproteins such as RAS and MYC induce the WE

• Tumour suppressor proteins such as PTEN, NF1 and p53 oppose

the WE 89
5. Limitless Replicative Potential
(Immortality)
• Normal cells have a limited capacity for cell division, up to 70 times, after which they enter
replicative senescence
 With every cell division, telomeres shorten progressively until they are exhausted
 The host DNA repair machinery interprets shortened telomeres as chromosome breaks and cell cycle
arrest and exit initiated by TP53 and RB proteins

• Tumor cells are capable of limitless replication

1. LOF mutations in TP53 and RB genes
 Absence of TP53 and RB activity removes restriction from the cell cycle
 DNA repair machinery attempts to repair lost telomeres by end-to-end joining of chromosomes causing
further severe mutations and aneuploidy with each anaphase and risking apoptosis
2. Activation of telomerase
 Activation of telomerase in neoplastic cells usually occurs before the cell reaches mitotic catastrophe and
activates apoptosis
 Telomerase synthesise more telomeres allowing unlimited cell cycling (immortality)

90
5. Limitless Replicative Potential
(Immortality)

Robbins Basic Pathology, 10e

91
6. Sustained Angiogenesis
• Tumour cells require close access to blood vessels, ~ 1 – 2 mm
maximum, to supply O2 and nutrients, to fuel tumour growth, and
remove waste products
1. Tumour growth results in areas of hypoxia → induction of hypoxia
inducing factor-1α (HIF-1α) → activates transcription of VEGF gene →
proangiogenic stimulation to hypoxic areas
2. VEGF synthesis is stimulated by signaling pathways that involve RAS
and MYC proteins, ergo GOF mutations in RAS and MYC protooncogenes
lead to increased angiogenesis
3. p53 activity stimulates expression of antiangiogenic proteins such as
thrombospondin-1 and suppresses expression of VEGF. LOF mutations
in TP53 tilt the balance towards angiogenesis

92
7. Invasion and Metastasis
• Invasion and metastasis are defining features of
malignancies
• 3 steps:
1.Invasion of extracellular matrix (ECM)
 Invasion of basement membrane
 Invasion through interstitial matrix
 Intravasation into blood vessels and lymphatics
2.Vascular dissemination
3.Homing of tumour cells
 Extravasation from blood vessels
 Formation of micrometastases
 Growth into macrometastases

Robbins Basic Pathology, 10e

93
 7. Invasion and Metastasis
A. Loosening of intercellular connections between tumour cells
 E-cadherin is lost in carcinomas
 E-cadherin is a cell adhesion molecule mediates homophilic cell-cell attachment
 Its intracellular portion binds to β-catenin, an intracytoplasmic protein that has
growth promoting activity; this binding sequesters β-catenin thereby inhibiting growth
and proliferation
 Loss of E-cadherin promotes proliferation due to increased intracellular activity of
β-catenin

B. Local degradation of the basement membrane and interstitial

connective tissue
 Due to secretion of proteolytic enzymes e.g., matrix metalloproteases,
cathepsin D, urokinase plasminogen activator, etc.
 Enzymes may be produced by neoplastic cells or by stromal cells e.g., fibroblasts,
inflammatory cells, etc.
 Breakdown of ECM releases sequestered pools of GFs which have chemotactic,
angiogenic and growth-promoting activity e.g., VEGF

Robbins Basic Pathology, 10e

94
8. Evasion of Immune Surveillance –
Tumour Antigens
• Cancer cells express a variety of antigens – Tumour Antigens - that stimulate the host immune
system:
Proteins from Mutated Genes
 Driver mutations and random (passenger) mutations (due to genetic instability) in neoplastic cells result in the
formation of neoantigens
Overexpressed Cellular Proteins
 Neoplastic cells may also produce excessive amounts of proteins that are normally in very low concentrations
thereby triggering an immune response e.g., tyrosinase in melanomas
Abnormally Expressed Cellular Proteins
 Certain genes present in all cells are not normally expressed but during neoplastic transformation may become
abnormally expressed e.g., testis antigens
Viral Oncoproteins
 Oncogenic viruses express viral proteins which can be recognized by the immune system e.g., EBNA protein
(EBV), E6 and E7 proteins (HPV), etc.

95
8. Evasion of Immune
Surveillance – Anti-Tumour
Mechanisms
• Host dendritic cells ingest dying tumour cells

• Dendritic cells then present the tumour antigens to naïve CD8

lymphocytes

• Sensitised CD 8 cells undergo clonal expansion

• Cell-mediated immune reaction against tumour cells

presenting tumour antigens on the MHC I

Robbins Basic Pathology, 10e

96
8. Evasion of Immune Surveillance –
Mechanisms of Immune Evasion
1. Darwinian selection of antigen-negative tumour cells
2. Acquired mutations in β2-microglobulin that prevent the assembly of functional MHC
class I molecules
 NK cells can initiate CMI in cells that do not present MHC I proteins by releasing perforins

3. Expression of proteins that inhibit CTL function (immune check-point inhibitors)

 Tumour CTL4A competes with CD 28 for binding with CTL B7 ligand thereby abrogating co-
stimulation during MHC-1 antigen presentation leading to anergy
 When PD-L1 engages its receptor, PD-1, on CTLs, the CTLs become unresponsive and lose their
ability to kill tumour cells

4. Secretion of immunosuppressive substances e.g., TGF-β, IL-10, PGE2, VEGF, etc. but
tumour cells and stromal cells
5. Induction of regulatory T cells (T regs)

97
 Hallmarks of Cancer
• Fundamental changes in cell physiology found in all
cancer cells
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Altered cellular metabolism
5. Limitless replicative potential (immortality)
6. Sustained angiogenesis
7. Invasion and metastasis
8. Evasion of immune surveillance

• There are 2 enablers of these hallmarks

1. Tumour promoting inflammation
2. Genomic instability

Robbins Basic Pathology, 10e

98
Tumour Promoting Inflammation
• Infiltrating cancers evoke chronic inflammation

1. Infiltrating leucocytes produce growth factors:

a. EGF that can be trophic to tumour cells (hallmark)
b. EGF, TNF, TGF-β that stimulate tumour cell motility hence allowing tumour cell invasion and metastasis
(hallmark)
c. VEGF that stimulates angiogenesis (hallmark)
d. TGF-β stimulates recruitment of Treg cell and suppresses CTL activity leading to an immunosuppressive
microenvironment i.e., evasion of immune surveillance (hallmark)

2. Infiltrating leucocytes produce proteases that breakdown the ECM

a. Releasing sequestered growth factors that can be trophic to tumour cells
b. Breaking down cell-cell and cell-matrix adhesion molecules thereby abrogating contact inhibition and
promoting proliferation
c. Allowing tumour cell invasion and metastasis (hallmark)

3. Infiltrating macrophages help detached cells (due to proteases breaking down cell-cell and cell-
matrix interaction) evade cell death (hallmark) by providing alternative adhesion molecules:
integrins
99
Genomic Instability
• Despite frequent mutagenic exposure, cancer occurs infrequently due to a system of DNA damage
sensing and repair

• DNA repair proteins include:

 Base excision repair (BER) proteins – no known cancer association
 Nucleotide excision repair (NER) proteins – xeroderma pigmentosum
 Double-strand break repair (DSBR) proteins – BRCA breast cancer
 Mismatch repair (MMR) proteins – Hereditary Nonpolyposis Colon Cancer Syndrome (HNPCC)

• These proteins are coded by DNA repair genes (“spell-checker” genes)

• Loss of function mutation leading to loss of proof-reading activity

• Individuals with defects in DNA damage repair system are prone to development of accumulating
numerous mutations over time (genomic instability)

100
MMR Syndromes
1. Xeroderma Pigmentosum
 Inherited germline mutation of genes coding for nucleotide excision repair enzymes
 NER enzymes critical in repairing damage caused by UV radiation (CT crosslinking)
 Consequent decreased ability to repair UV-associated DNA damage
 High risk of skin cancers: squamous cell carcinoma, basal cell carcinoma

2. Familial Breast Cancer Syndrome

 Inherited germline mutation of BRCA genes
 BRCA genes required for DNA repair via homologous recombination
 Loss of BRCA protein activity leads to repair by non-homologous chromosome joining contributing to
chromosomal structural and numerical abnormalities (aneuploidy)
 Associated with breast carcinoma, ovarian carcinoma, prostatic carcinoma

3. Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer)

 One inherited defective MMR allele (germline mutation)
 MSH2, MLH1 genes
 Subsequent sporadic mutation of normal MMR allele leading to complete loss of MMR function
 Associated with colonic carcinomas
101
MMR Defects and Cancers

Rubin’s Pathology – Clinicopathologic Foundations of Medicine, 7e

102
Clinical Effects of
Neoplasms

103
Effects of the Tumour on the Host
• Local Effects
• Systemic Effects

104
Local Effects of the Tumour
• Mass effect e.g. palpable breast mass deforming the breast
• Compression of normal tissue with loss of function e.g. pituitary atrophy and
hypopituitarism due to pituitary adenoma
• Pain due to compression of nerves
• Destruction of normal tissue
 Punched-out bone lesions in multiple myeloma
 Perforation of a hollow organ
• Obstruction of a hollow organ
• Irritation and inflammation e.g. bronchial cancer causing coughing
• Bleeding due to erosion of blood vessels e.g. vaginal bleeding
• Necrosis e.g. ischaemic necrosis due to obstruction of a nutrient vessel
105
Systemic Effects of the Tumour
• Cancer cachexia
• Fever
• Paraneoplastic syndromes
• Tumour lysis syndrome

106
Cachexia
• Clinical constellation: ii. IL-1
 Progressive fat and muscle loss iii. IFN-α

 Profound weakness 4. PIF (Proteolysis Inducing

Factor) production by
 Anorexia tumour
 Anaemia 5. Lipid Mobilising Factor
• Causes: 6. Other possible causes
Pain, insomnia, anxiety,
1. Reduced diet, malabsorption pyrexia
2. Increased basal metabolic
rate
3. Systemic inflammation
i. TNF-α – originally termed
“cachectin”

107
Paraneoplastic Syndromes
• Signs and symptoms produced by tumours at sites not
anatomically related to the tumour or produced by hormones
that are not indigenous to the normal counterparts of the
tumours
• 10% of cancer cases
• Classification
1. Endocrine
2. Neuromuscular
3. Haematologic
4. Dermatologic
5. Renal
6. Idiopathic

108
Endocrine Paraneoplastic Syndromes
• Small cell carcinoma of the lung → Cushing syndrome
 Secrete ACTH and pro-opiomelanocortin

• Squamous cell carcinoma of the lung → hypercalcaemia

 Secrete PTH-like peptide

• Uterine leiomyosarcoma → hypoglycaemia

 Secret insulin-like growth factor (IGF)

• Renal cell carcinoma → polycythaemia

 Secrete erythropoietin

109
Haematologic Paraneoplastic
Syndromes
• Pancreatic carcinoma → migratory thrombophlebitis
(Trousseau syndrome)
 Secrete thromboplastin

• Lymphoma → anaemia
 Cryoglobulin (“cold antibodies”) production

110
Neuromuscular Paraneoplastic
Syndromes
• Thymoma → myasthenia gravis
 Antibodies to ACh receptors

• Small cell carcinoma of the lung → Lambert-Eaton

syndrome
 Antibodies to presynaptic Ca+2 channels

111
Dermatologic Paraneoplastic
Syndromes
• Gastric carcinoma → acanthosis
nigricans (hyperpigmentation on
the neck and intertriginous areas)

112
Renal Paraneoplastic Syndromes
• Nephrotic syndrome caused by the deposition of tumour
antigen-antibody immune complex in the glomerular
basement membranes

113
Osseous Syndromes
• Hypertrophic osteoarthropathy
 Largely lung cancer
1. Periosteal new bone formation at the
ends of long bones, metatarsals,
metacarpals, proximal phalanges
2. Arthritis of adjacent joints
3. Digital clubbing

114
Laboratory Diagnosis
of Tumours

115
Laboratory Diagnosis
• Tumour markers
• Cytological evaluation
 Exfoliative
 Abrasive
 Aspiration

• Biopsy / tumour resection for

 Light Microscopy
 Electron Microscopy
 Immunohistochemistry

• Flow cytometry
• Liquid Biopsy
• Molecular techniques
 Cytogenetics
 Fluorescent in-situ hybridisation (FISH)
 PCR-technology
 Microarrays

116
Tumour Markers
• These are substances found
at higher-than-normal levels
in biological fluids or tissues
in individuals with certain
cancers
• Tumour cells produce
substances, many of which
are proteins, which enter the
bloodstream (and/or urine)
where it can be measured

117
Histological Assessment of
Neoplasms
1. Guide to tumour behaviour: benign vs malignant
2. Guides treatment
3. Can inform on response to treatment

118
Histological Assessment of
Neoplasms
1. Benign
2. Malignant
a) Tumour Type
b) Degree of Differentiation (Grading)
i. Architectural and cytological similarity to normal counterpart
ii. Cellular and nuclear pleomorphism
iii. Mitotic activity of tumour
c) Completeness of Resection
d) Extent of Tumour Spread (Staging)

119
Immunohistochemistry (IHC)
• An immunological method of recognising a cell by one or more of its specific components (antigens)

• Monoclonal antibodies specific to the antigen of interest are introduced into the paraffin–embedded tissue

• The antibodies are labelled with a chromogen

• If the antigen is present, the antibody binds to it; the chromogen becomes visible

Antigen Tissue/Lineage Type

Cytokeratin
CD 45 Leucocytes
Vimentin Mesenchymal cells, leucocytes
Desmin
Smooth muscle actin
Neurofilament
Chromogranin Neuroendocrine cells
Glial fibrillary acid
protein
Chromogranin positivity in carcinoid tumour of the stomach

Rosai and Ackerman’s Surgical Pathology, 10e 120

Liquid Biopsy
• Detection, quantification and characterization of rare circulating tumour
cells (CTC) or circulating tumour DNA (ctDNA) in blood

• Principles:
 Antibody-antigen reaction
 Nucleic acid amplification studies

• Can detect changes in tumour burden months or years before conventional imaging
modalities

• Role
 Disease diagnosis by detecting tumour cells
 Quantification of metastatic burden
 Monitoring response to therapy

121
Flow Cytometry
• Computerised technique by which
individual cell characteristics are
recognized and quantified:
 Cytoplasmic antigen
 Cell membrane antigen
 Nuclear antigens

• Single cell suspensions are required to flow

through the cytometer
• Best for fluid samples: blood, bone marrow
aspirates, body fluids Rosai and Ackerman’s Surgical Pathology, 10e

122
In-Situ Hybridisation
• Hybridisation refers to the process of binding two
complementary strands of DNA
• In-situ refers to the hybridisation taking place in
the actual tissue (vs in extracted DNA)
• A probe (short commercially prepared
complementary DNA strand) specific to a DNA
sequence of interest is used
• Once a probe has been deployed and has
hybridized to its target, it has to be visualised

123
FISH
• Fluorescent In-Situ Hybridisation
• The probe has a specialised dye
molecule that will fluoresce when
exposed to ultraviolet light
• Requires a specialized FISH
microscope

124
CISH
• Chromogenic In-Situ Hybridisation
• The probe is visualized following an
enzymatic reaction which produces
a coloured substance
• Can be interpreted using
conventional light microscopy

125
Chromosomal Microarray (CMA)
• CMA looks for extra (duplicated) or missing (deleted) chromosomal segments

• These chromosomal segments are called copy number variations – CNVs

• Can identify the following genetic abnormalities

 Microdeletions
 Microduplications
 Trisomies, monosomies, etc.
 Unbalanced translocations
 Excessive homozygosity
 Triploidy, tetraploidy

126
Chromosomal Microarray (CMA)
1. A platform (microchip) with spots is used
2. Each spot contains probes (nucleotide
sequences) complementary to known DNA
sequence in each chromosome
3. Patient’s DNA sample labelled with a
fluorescent dye e.g., green
4. A reference DNA sample (normal, control) 8.
labelled with a different fluorescent dye
e.g., red
5. Both DNA samples are mixed and then
placed on the microchip platform;
hybridisation follows; laser scanning is
used visualize the fluorescent pattern
6. If both test and control sample contain
same gene at a given locus, both will bind
evenly (1:1 ratio) with the probes and a new
colour e.g., yellow, will form from the
combination of test and control colours
7. If test sample has a deletion at a given
locus, the reference sample will be in excess
(negative variance), and the spot will be red
If the patient sample has a duplication at a
given locus, it will be in excess (positive
variance) and the spot will light green
9. A computer programme analyses the data:
nature of variance (+ve or –ve), location of
the variance, magnitude of the variance,
etc.
127
Chromosomal Microarray (CMA)

Researchgate

Robbins Basic Pathology, 10e

128
Grading and Staging
of Cancer

129
Tumour Grading
• This is an assessment of the cytological differentiation of a neoplasm i.e. how well it
resembles the normal tissue counterpart
• Parameters used in tumour grading:
 Formation of specialised structures associated with the normal tissue counterpart e.g.
formation of glands / tubules in colonic adenocarcinoma
 Degree of nuclear pleomorphism
 Rate of mitotic activity
 Presence or absence of necrosis (sarcomas)

• Several grading systems:

 Two-tiered – low grade vs high grade
 Four-tiered – G1 (well-differentiated), G2 (moderately-differentiated), G3 (poorly-
differentiated), G4 (undifferentiated)
 Three-tiered – G1 (well-differentiated), G2 (moderately-differentiated), G3 (poorly-
differentiated / undifferentiated)
4-Tier Grading 2-Tier Grading
• Has predictive and prognostic value G1 – Well Differentiated Low Grade
G2 – Moderately-Differentiated
G3 – Poorly-Differentiated High Grade
G4 - Undifferentiated
130
Tumour Staging
• This refers to the extent of anatomical spread of a tumour
• This is the strongest predictive and prognosticating
measure of a malignancy
• Two methods of staging
 TNM
 AJCC (American Joint Committee on Cancer)

131
TNM Staging System
• Three parameters used in staging:
 Tumour Size (T)
 Regional Nodal Metastasis (N)
 Distant Metastasis (M)

132
Example of Tumour Staging – Colorectal
Carcinoma
T N M
TX Cannot be assessed NX Cannot be assessed MX Cannot be assessed
T0 No evidence of primary tumour N0 No regional lymph node metastasis M0 No distant metastasis
Tis Intraepithelial or intramucosal tumour N1 Metastasis to 1 – 3 regional nodes M1 Distant metastasis
T1 Tumour invades the submucosa N2 Metastasis to ≥ 4 regional nodes
T2 Tumour invades the muscularis propria
T3 Tumour invades the serosa
T4 Tumour invades beyond the serosa

AJCC Stage pT pN pM

Stage 0 Tis N0 M0

Stage I T1 to T2 N0 M0

Stage II T3 to T4 N0 M0

Stage III T1 to T4 N1 to N2 M0

Stage IV Any T Any N M1

133
Example of Tumour Staging – Carcinoma
of the Kidney
T N M
T0 No evidence of primary N0 No regional lymph M0 No distant
tumour node metastasis metastasis
T1 Tumour ≤ 7 cm ø and N1 Spread to 1 node M1 Distant
confined to the kidney metastasis
T2 Tumour ≥ 7 cm ø and N2 Spread to ≥ 2 nodes
confined to the kidney
T3 Spread to local tissue
T4 Spread beyond local AJCC T N M
tissue Stage
I T1 N0 M0
II T2 N0 M0
III T1/T2 N1 M0
T3 N0/N1 M0
IV T4 Any N M0
Any T Any N M1 134
References
• Robbins Basic Pathology 10th Edition
• Pathology Illustrated 7th Edition
• Harsh Mohan Textbook of Pathology 7th Edition
• Rubin’s Pathology – Clinicopathologic Foundations of
Medicine, 7e
• www.pathologyoutlines.com
• ilovepathology YouTube Channel

135