Pathology Lecture 2 Neoplasia

LO 1: Recognise the dysplasia neoplasia pathway of malignancy, esp those related to the
oesophagus and colon
Underwood Ch.10 Carcinogenesis & neoplasia

Tumour (neoplasm) = lesion resulting from the autonomous abnormal growth of cells that persists in the absence of
an initiating stimulus

Neoplastic transformation of nucleated cells occurs via 2 mechanisms:

1. Genetic alterations 2. Epigenetic changes

- Mutations - Promoter methylation silencing
- Deletions transcription
- Translocations
- Rearrangements
- Amplifications

Cancer = malignant neoplasm which can invade or metastasise

Structure of tumours
Solid tumours consist of neoplastic cells and stroma (supportive connective tissue framework)
- Mechanical support
- Intercellular signalling
- Provides nutrition
Process of stroma formation = desmoplastic reaction
- V. fibrous due to induction of connective tissue fibroblast proliferation by GF

NB: stroma always contains blood vessels which perfuse the tumour angiogenesis stimulated by factors
secreted e.g. vascular endothelial growth factor (VEGF)

(this is counteracted by factors e.g. angiostatin & endostatin which slow down angiogenesis)

Stroma often contains lymphocytic infiltrate (may be host reaction to tumour)

Tumour morphology
Gross appearance Behaviour Features
Polypoid Benign Clearly defined borders

Sessile (flattened, broad-based) Precancerous

Papillary (irregular, well-differentiated solid mass) Benign Firmer than surrounding tissue

Cut surfaces due to:

Exophytic/fungating (grows outward from an epithelial Benign/malignant - Necrosis
surface) - Haemorrhage
- Fibrosis
Annular (scaly border with clear centre) Malignant - degeneration

Ulcerated (heaped up, irregular edges) Malignant

Tumour classification
Benign
Slow growing
Non-invasive/localised
Enveloped by thin layer of compressed
connective tissue (encapsulated)
Grows away from surface i.e. exophytic (will
form a polyp)
- Pedunculated have a stalk
- Sessile sits on the surface
Histologically resembles parent tissue
Carcinoma = epithelial
Sarcoma = connective tissue
Lymphoma = lymphoid organs
Leukaemia = haemopoietic organs
Malignant
Invasive & metastatic
Rapid growing
Irregular margins
Destroys surrounding tissue, allowing
penetration of neoplastic cells into vessels &
lymphatics
Will eventually grow into underlying tissue i.e.
endophytic
Often shows central necrosis due to
inadequate vascular perfusion
o Enlargement of nucleus
o Darker staining (hyperchromasia)
o Variability in nuclear size, shape &
chromatic clumping (pleomorphism)
 Benign Cells Cancer Cells

Within physiological limits reflecting

Variation in size and shape reflecting abnormal cell
Cell size and shape normal cell division and maturation
division and maturation (anisocytosis)
of the epithelium.

Significant variation in nuclear size (anisonucleosis)

Within normal limits reflecting
Nuclear size reflecting abnormal cell division and maturation
normal cell division and maturation.
(nuclear-cytoplasmic ratio)

Generally round, oval or bean

Nuclear shape Abnormal shape.
shaped.

Structure of chromatin in Finely granular chromatin evenly Coarse granular chromatin unevenly distribution

interphase nucleus distributed throughout nucleus. throughout nucleus.

Normal amount of chromatin for Chromatin often increased but the amount and
Chromatin content of
diploid cells evenly distributed in all distribution of chromatin varies from one nucleus to
interphase nucleus
cells. another due to abnormal cell division.

Rarely seen, if present reflects Common reflecting increased chromatin content or

Hyperchromasia
regenerative change. rapid cell turnover or both.

Not normally found. If present nuclei

Multinucleation Not uncommon. Nuclei vary is size and shape.
are of even size.

Large, irregular variable in size and shape and in

Nucleoli Small, even size, few in number.
number.

Cohesiveness Well-formed cell junctions. Loss of cohesiveness; loss of cell stratification

Occasionally seen in basal layer of Abnormal mitoses frequently found throughout

Mitoses
epithelium. epithelium.

Preserved (via proto-oncogenes &

Cell polarity Loss of cell polarity
tumour suppressors)
From the TORG

Dysplasia = disordered growth

Dysplastic changes form a mild severe spectrum; dysplasia = progression to malignancy (carcinoma in situ)

NB: there is no stromal invasion by abnormal cells seen in severe dysplasia;

no vessels in epithelium = no metastases

Mitotic changes will also be seen:

Occurs in superficial cell layers where not normally found

no. of mitoses
Abnormal no. of mitoses e.g. tripolar

NB: dysplasia only occurs in the epithelium; carcinoma in situ = malignancy that hasnt crossed the basement
membrane

Barretts Oesophagus
Caused by GORD
Characterised by metaplastic change from flat squamous epithelium tall columnar epithelium with goblet
cells & tall mucin-secreting cells
Epithelial dysplasia (pre-cancer) detected in 0.2-2% of pt

LO 2: Understand the adenoma-carcinoma sequence in the formation of colorectal cancer

Colonic adenoma
Precursors of most colorectal cancers (100% of untreated patients)
Strong hereditary factor with familial adenomatous polyposis (FAP)
- mutation of APC (tumour suppressor gene)
- Autosomal dominant
Mainly develop in the large intestine; can be in small bowel
Will undergo malignant change cancerous presentation by 35yrs
NB: diagnosis requires >100 polyps

Malignant development Molecular changes

size 1. Activation of oncogenes

Villous growth pattern - KRAS & c-MYC (proliferation)
severity of dysplasia - Age-related DNA hypomethylation may
Hx: adenomatous polyps/ulcerative colitis contribute to oncogene activation
 2. Loss/mutation of tumour suppressor genes
- Point mutations in APC (adenomatous
polyposis coli) gene
- Mutation in MCC gene (cell cycle control)
- Deleted DD gene (control of apoptosis)
- TP53 (nuclear protein that holds cell cycle
at G1/S phase for DNA repair/apoptosis)
- Deletions in the NME1 gene may facilitate
metastasis
3. Defective genes in DNA repair pathway
genomic instability i.e. easier to acquire
mutations
- Microsatellite instability- highly
conserved genes that recognise
nucleotide mismatch (every 1-5 bases) in
complementary DNA & triggers repairs is
faulty
- Mismatch repair genes hMLH1 &
hMSH2

Colonic adenocarcinoma
Adenoma carcinoma sequence occurs in >80% of patients
Proximal colon tumours = exophytic, rarely obstructive
Distal colon tumours = annular luminal narrowing (napkin ring constriction)
May result in Fe2+ deficiency anaemia due to silent bleeding (NB: fresh blood in stools)

2 most important prognostic factors:

i. Depth of invasion
ii. Presence/absence of lymph node metastases
Tumour staging (Dukes staging)

LO 3: Understand the differences between squamous carcinoma & adenocarcinoma

SSC = from squamous cells; preceded by dysplastic changes (immature cells near surface)

Adenocarcinoma = from glandular tissue

Treatment:

Non-small cell lung carcinoma with EGFR mutations (adenocarcinomas) = EGFR-targeting drugs e.g. erlotinib,
gefitinib

- Crizotinib (with ALK mutations)

LO 4: Describe the concept of benign & malignant neoplasms (clinical, gross & microscopic)
Behaviour of tumours
In epithelial neoplasms, invasion & metastasis requires motile/migratory properties of mesenchymal cells
shift in behaviour = epithelial-mesenchymal transition

Invasion

Easy to recognise in epithelial tumours basement membrane serves as line of demarcation b/w tissue
boundaries (pagetoid infiltration)

Difficult to recognise in CT tumours no clear vascular/lymphatic permeation

Factors influencing tumour invasion:

cellular adhesion (altered E-cadherin expression)

Secretion of proteolytic enzymes
Abnormal/ cellular motility
- Loss of normal mechanism that arrests/reverses normal cellular migration (contact inhibition)

Proteinases & inhibitors

Malignant neoplastic cells secrete matrix metalloproteinases which digest surrounding connective tissue

I. Interstitial collagenases
II. Gelatinases
III. Stromelysins

NB: Invasion often occurs along tissue plans of least resistance

to tumour growth

- Perineural spaces
- Vascular lumina

LO 5: Understand the potential pathways for spread of

a malignant tumour
Metastasis
The spread of malignant tumours from site of origin (primary
tumour) to other locations (secondary tumour)

Metastatic sequence = sequence of events that a neoplastic cell

must undergo before forming a metastatic tumour

1. Detachment of tumour cells from surrounding cells

2. Invasion of surrounding CT to reach means of metastasis
(blood & lymphatics)
3. Intravasation into lumen
4. Evasion of host defence mechanisms
5. Adherence to endothelium downstream
6. Extravasation from the vessel lumen into surrounding
tissue

Increase expression of integrins aids invasive migration

of neoplastic cells into CT
Routes of metastasis
Haematogenous = via blood
- Favoured by sarcoma
- Organs involved: liver, lung, bone, brain
- Bone favoured by 5 carcinomas
i. Lung
ii. Breast
iii. Kidney
iv. Thyroid
v. Prostate

Lymphatic = via lymph nodes (preferred by carcinoma)

- Tumour cells reach lymph n. via afferent lymphatic channel
- Cells grow in the periphery of the node
- Results in groups of enlarged/hardened lymph n

Sequence of events for lymphatic spread of carcinoma cells:

1. Primary malignant tumour with stromal invasion by carcinoma cells

2. Infiltration of lymphovascular channels
3. Malignant cells flow via lymph channels to sentinel/local/regional lymph n. and adhere to vessel-lining cells
via cell surface receptors
4. Emigration into receptive tissues

Transcoelomic = via pleural, pericardial & peritoneal cavities with malignant effusion
- Effusion is rich in protein (i.e. exudate) and may contain fibrin
- Peritoneal effusions (ascites) may be due to involvement of any abdominal tumour but most common
with ovarian cancer
- Pleural & pericardial effusions often caused by breast & lung carcinomas

Other pathways of spread

Direct tumour extension = spread to contiguous organs

Passive = via pre-existing lumen e.g. bronchi, fallopian tubes

LO 6: Discuss the concept of paraneoplastic effects of tumours

Local
Compression (e.g. pituitary adenoma compressing the gland, resulting in hypopituitarism)
Invasion (e.g. skin disfiguration in BCC)
Ulceration most commonly found on mucosal surfaces (e.g. peptic ulcer in gastric cancer anaemia)
Destruction of surrounding structures (e.g. pulmonary a. by carcinoma of the lung)

Metabolic
Tumour-specific

Well-differentiated (i.e. low grade) tumours often retain functional properties of the parent cell will often
enhance physiological effects of parent cell. E.g.

i. Thyrotoxicosis in thyroid adenoma

ii. Cushings Syndrome in adrenocortical adenoma
iii. Hyperparathyroidism in parathyroid adenoma
Non-specific

Generalised effects of disseminated malignancy

Cachexia (profound weight loss despite adequate nutrition)

- Macrophages TNF production
- TNF suppresses appetite & inhibits lipoprotein lipase, which inhibit release of FA from lipoproteins
- Protein-mobilising factor (proteolysis inducing factor) breaks down skeletal muscle

Normal cells have relatively low rate of glycolysis accompanied by oxidation of pyruvate in mitochondria
Cancerous cells display the Warburg effect high rate of glycolysis with fermentation of lactic acid
- can be used to image tumours by PET using FDG, as Warburg Effect FDG in tumours

LO 6: Discuss the concept of paraneoplastic effects of tumours

Paraneoplastic Syndrome
The remote, indirect but specific effect of a particular neoplasm occurring more frequently than by chance i.e.
unexpected or inappropriate consequences of a tumour

Rare <1% of cancer pt (10 15%? Robbins)

Usually manifests in >66y.o
Syndrome is a diagnosis of conclusion i.e. ruling out effects of primary tumour, infiltration, metastasis etc
Usually due to autoimmune response or ectopic hormone production

Most common syndromes include:

Hypercalcaemia (synthesis of PTHrP by tumour cells)

Cushings syndrome
Nonbacterial thrombotic endocarditis (hypercoagulabiity)

Type of cancer Paraneoplastic effect

Small cell (oat cell) carcinoma of the lung ACTH
Syndrome of inappropriate ADH secretion
Myasthenic (Eaton-Lambert) syndrome
(AI disease which attacks the NMJ, resulting in weakness of the legs, eyes,
face and throat sometimes improved with exercise)
Finger clubbing
Hypertrophic osteo-arthropathy (HPOA)
Ovarian cancer Subacute cerebellar ataxia
Ectopic ACTH secretion (Cushings syndrome)
LO 7 Interpreting pathology reports
See separate document

LO 8 Discuss some of the pathogenic mechanisms for the development of tumours in the body
Carcinogenesis
Neoplasms arise from single cells that transform following cumulative mutational events
- Require 3 6 genetic mutations to transform into a neoplastic cell
- Self-exacerbating changes account for:
o Intratumoural heterogeneity
o Competing cell-clones
o Malignant evolution
o Drug resistance
Approximately 85% of cancers are due to environmental agents i.e. 10 15% of cancers are inherited

NB: Due to a latent interval, exposure to carcinogen and appearance of signs/symptoms may be decades apart
Inherited

Germ-line mutations affect every cell in the body

Tumours arise at younger age
High incidence of specific cancer types
Synchronous/metachronous presentation of multiple primary tumours

Environmental

1. Chemical
a) Alkylating agents
b) Polycyclic hydrocarbons
c) Benzopyrenes

2. Radiation
a) UVL UVB > UVA
- Melanoma, SCC, BCC
b) Ionising radiation
- Myeloid leukaemia, thyroid cancer
- Particularly sensitive tissues:
o Thyroid
o Breast
o Bone
o Haemopoietic tissue

NB: Melanin has a protective effect against UVL darker skin = < chance of skin cancer

3. Viruses

4. Bacterial
- H. Pylori gastric MALT lymphoma & gastric adenocarcinoma

5. Fungal
- Aspergillus flavus mycobacteria leads to hepatocellular carcinoma

6. Familial/non-modifiable
- Familial Hx, age, gender, race
Common genetic molecular sequence

1. Mutation latency

2. Genomic instability
- Initiation = carcinogen induces genetic change that gives rise to neoplastic potential
- Promotion = stimulation of clonal proliferation of transformed cell
- Progression = accumulation of malignant characteristics

3. Activation (up-regulation) of oncogenes

4. Down-regulation of tumour suppressor genes

5. Loss of normal cell senescence & production of telomerase leads to cell-immortalisation

6. Secretion of autocrine GF

7. Cell transformation numerous malignant cell clones

8. Tumour heterogeneity & competing cell clones

Activation of oncogenes

1. Chromosomal translocations

2. Point mutation
Neoplasm Mutation
Bladder carcinoma Ras gene
Pancreatic cancer K-Ras gene

3. Gene amplification & over-expression

Neoplasm Mutation
Small cell (Oat cell) carcinoma Myc-family
Breast & ovarian cancer Erb-B
Neuroblastoma n-Myc
Tumour suppressor genes
Further categorised according to their mechanism of action:

Caretaker = genes that maintain the integrity of the genome by repairing DNA damage

Gatekeeper = genes that inhibit proliferation/promote cell death of cells with damaged DNA

e.g. Retinoblastomas

In hereditary retinoblastoma, there is a germline deletion on chromosome 13 (RB1 gene)

Therefore, one further mutational loss of the other RB1 gene = tumour development

NB: this is known as the two-hit hypothesis

First hit = inheritance of defective/mutated allele of TSG

Second hit = acquired mutational LoF of the remaining normal copy of the TSG

e.g. p53 mutation

Located on short arm of chromosome 17

Normal function:
- Repair of damaged DNA before S phase arrest in G1
- Apoptotic cell death in extensive DNA damage
Loss of function due to:
- Mutations (nonsense or missense mutations)
- Complexes (normal + mutated p53)
- Binding of p53 with oncogenic DNA viruses e.g. HPV