General Pathology

Basic Principles of Cellular and Organ

Pathology

Oncology - I

Jaroslava Dušková

Inst. Pathol. ,1st Med. Faculty, Charles Univ. Prague

General Oncology – 1 : topics

Disorders of the cell proliferation and

growth (hypertrophy, hyperplasia,

metaplasia)

Neoplasms – disorders of cell

proliferation and differentiation

Molecular biology of neoplasia -

oncogenesis

Host - neoplasm interactions

Tumour

swelling of any kind

NEOPLASIA

NEOPLASIA

Definition - descriptive:

persistentabnormalrelatively autonomous

proliferation of cells

NEOPLASIA

Definition - pathogenetic:

DNA disease

Stepwise accumulation

of genetic abnormalities

Escape of immunological

clearing systems

NEOPLASIA – history I.

Ramayana – 2000 B.C.

therapy with knife

chemotherapy - arsenical

compounds

NEOPLASIA – history II.

Galen – AD 129–216TUMOURS

according to naturepregnancy

exceeding natureinflammatory, reparative, callus

against naturetrue neoplasms

Eutopic

pregnancy

Macrocystosis renum

Ependymoma

Growth Disturbances

&

Their Relation

to Neoplasms

Nonneoplastic

Growth Disturbances – I

MALFORMATIONS

complete or partial lack of

development (aplasia, hypoplasia)

asymmetry oversize hamartia - hamartoma choristia - choristoma

ectopic tissue

-

+

phocomelia

cheilo-gnatho-

palato-schisis

rhachischisis

Hamartia – Hamartoma

Def.:

A mass of disorganized

tissue indigenous to the

particular site.

C

h

o

n

dr

o

h

a

m

ar

to

m

a

Chondrohamartoma

Choristia - Choristoma

Def.:

A mass of ectopic tissue

(cells) with a limmited

growth potency

1. Rathke´s pouch

& proc.

infundibularis

2. separation

3. final status

squamous

epithelium

Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy -

(incl.pseudohypertrophy)

hyperplasia

metaplasia dysplasia anaplasia – undifferentiation

Cell Proliferation in the

Gastrointestinal Tract

a Oesophagus

b Stomach

c Sm Bowel

d L Bowel

e Anus

repair

Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy -

(incl.pseudohypertrophy)

hyperplasia

metaplasia dysplasia anaplasia – undifferentiation

Urocystolithiasis

Hyperplasia

adenomyomatosa

prostatae

Hypertrophia

trabecularis

tunicae

muscularis

vesiace

urinariae

Atrophia

gl.suprarenalium

Pseudohypertrophia (atrophia) lipomatosa

Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy

hyperplasia

metaplasia dysplasia anaplasia – undifferentiation

Metaplasia

Definition:

- transformation of one differentiated cell type into another differentiated type

Metaplasia

Metaplasia

ecc-tubar meplasianormal endocervical cells.

reactive ecc

von Brunn´s nests

Mucinous metaplasia - alc. blue pH2,5

Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy

hyperplasia

metaplasia dysplasia anaplasia – undifferentiation

Dysplasia

Definition:

- disturbance of cell growth, maturation, architecture

(frequently, but not always preneoplastic condition)

dysplasia

Urotel normální stavby

Urothelium

Urocystitis chronica(mild reactive urothelial changes)

Urocystitis chronica (reactive hyperplasia)

LG IUN – mild dysplasia

HG IUN

moderate dysplasia

severe dysplasia

Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy

hyperplasia

metaplasia dysplasia anaplasia – undifferentiation

ASC – H – atypical immature squamous metaplasia

EMA

TGB

vimentin

Undifferentated (anaplastic) carcinoma

Relation of the Non-neoplastic Growth Disturbances to Neoplasms

1. differential diagnosis pseudotumours

2. precursors precanceroses

(preblastomatoses)

3. both 1. and 2.

NEOPLASIA

Def.:

persistentabnormalrelatively autonomous

proliferation of cells

Tissue stem cells- assymetric devision:

a) differentiation, b) stem cells

Characteristics of Neoplastic Growth

self-sufficiency in growth signals

insensitivity to growth inhibitory signals

block of apoptosis

limitless replicative potential– block of

mitotic catastroph

defective DNA repair – genom instability

development of sustained angiogenesis

ability to invade and metastasize

Neoplasia - causes

External

Irradiation

chemical

cancerogens

oncogenic bacteria

& viruses

Internal

genetic predisposition (15% of tumours)

immunosupression

(inborn, acquired)

chronic irritation

(inflammation)

non-lethal genom changes

Oncogenic Viruses

DNA

HPV

SV 40 – polyoma

Adenoviruses

Herpesviruses

Epstein - Barr - HHV4

KSHV - HHV8

Hepatitis B

RNA

Rous sarcoma

(chicken, 1911)

Leukemia (many

different in animals)

HTLV-1

HIV

Hepatitis C

Inherited Predispositions to Cancer -1/2

Autosomal dominant: – retinoblastoma (RB gene)

– Li- Fraumeni (TP53) – breast, brain, sarcoma, leukemia…

– melanoma (p16 ink4A)

– Familial Adenomatosis of Colon (APC)

– BRCA1, BRCA 2

– others…

Inherited Predispositions to Cancer 2/2

Autosomal recessive – defective DNA repair –

chromosomal instability

– xeroderma pigmentosum - nucleotid excision

repair – NER pathways :

Global Genom Repair - GGR, and

Transcription Coupled Repair - TCR skin tumours in

UV exposed locations + neurology symptoms –

microcephaly

Familial cancers of uncertain inheritance breast (not linked to BRCA 1 or BRCA 2, ovary,

pancreas…)

Characteristics of Neoplastic Growth

self-sufficiency in growth signals

insensitivity to growth inhibitory signals

block of apoptosis

limitless replicative potential– block of

mitotic catastroph

defective DNA repair – genom instability

development of sustained angiogenesis

ability to invade and metastasize

Cell Cycle Regulators– control of cellular proliferation

polypeptide growth factors EGF, PDGF , FGF, TGFα, β

(protooncogenes)

ligand receptor binding

activation via conformation alteration (kinase)

signal transduction – second messengers (tyrosine

kinases)

activation of transcription factors

DNA synthesis initiation

cyclins and cyclin dependent kinases cdk

cdk associated inhibitors cki

Cell Cycle Regulators – growth factors

Polypeptide growth stimulators

EGF, PDGF, TGF α (protooncogenes)

– ERBB1 – EGFR – overexpressed in 80-

100% sq. ca of lung, head& neck,

glioblastoma

– ERBB2 – EGFR – HER2/NEU

overexpressed in 30% of breast ca

Routine testing in biopsies

Cell Cycle Regulators – growth factors

Polypeptide growth stimulators

EGF, PDGF, TGF α (protooncogenes)

– ERBB1 – EGFR – overexpressed in 80-

100% sq. ca of lung, head& neck,

glioblastoma

– ERBB2 – EGFR – HER2/NEU

overexpressed in 30% of breast ca

Routine testing in

biopsies

Characteristics of Neoplastic Growth

self-sufficiency in growth signals

insensitivity to growth inhibitory signals

block of apoptosis

limitless replicative potential– block of

mitotic catastroph

defective DNA repair – genom instability

development of sustained angiogenesis

ability to invade and metastasize

Insensitivity to growth inhibitory signals

Governors and Guardians of

the cell cycle:

retinoblastoma (RB gene)

Li- Fraumeni (TP53) – breast,

brain, sarcoma,

leukemia…Transforming Growth Factor – β –

pancreas, colon

Characteristics of Neoplastic Growth

self-sufficiency in growth signals

insensitivity to growth inhibitory signals

block of apoptosis

limitless replicative potential– block of

mitotic catastroph

defective DNA repair – genom instability

development of sustained angiogenesis

ability to invade and metastasize

Block of apoptosis

inactivation of the death receptors – FAS

( leukemia, neuroblastoma) ;

overexpression of Bcl2 antiapoptotic

protein - Follicular cell lymphoma

t(14;18)

Burkitt´s Lymphoma

the virus uses complement receptor CD21 ( B- cell

activation pathway!)

viral latent membrane protein 1 – LMP-1 activates

signaling pathways ( NF κB, JAK/STAT)

LMP-1 activates bcl 2 – antiapoptotic effect

v IL-10 viral cytokine that prevents macrophages

and monocytes from activating T-cells – EVASION

from immune system

t14-18 activation of MYC oncogene

Burkitt´s Lymphoma (1964)EBV

DNA

t(8;14)

Burkitt´s Lymphoma

Characteristics of Neoplastic Growth

self-sufficiency in growth signals

insensitivity to growth inhibitory signals

block of apoptosis

limitless replicative potential– block of

mitotic catastroph

defective DNA repair – genom instability

development of sustained angiogenesis

ability to invade and metastasize

Limitless

replicative

potential

activation of

telomerase –

immortality –

advanced cancers

Review Open Access

Roles of telomeres and telomerase in

cancer, and advances in telomerase-

targeted therapies

Mohammad A. Jafri,

Shakeel A. Ansari,

Mohammed H. Alqahtani and

Jerry W. ShayEmail author

Genome Medicine 2016 8:69

DOI: 10.1186/s13073-016-0324-x

B 12841/05 carcinoma vesicae urinariae non differentiatum MIB1

Characteristics of Neoplastic Growth

self-sufficiency in growth signals

insensitivity to growth inhibitory signals

block of apoptosis

limitless replicative potential– block of

mitotic catastroph

defective DNA repair – genom instability

development of sustained angiogenesis

ability to invade and metastasize

Defective DNA repair – genom instability

silenced genom repair genes –

hereditary non- polypose colon cancer -

HNPCC

Lynch syndrome : colon, ovary, uterus

Variations in the MLH1, MSH2, MSH6,

PMS2, or EPCAM gene increase the

risk of developing Lynch syndrome.

ROUTINE TESTING IN BIOPSIES

Characteristics of Neoplastic Growth

self-sufficiency in growth signals

insensitivity to growth inhibitory signals

block of apoptosis

limitless replicative potential– block of

mitotic catastroph

defective DNA repair – genom instability

development of sustained angiogenesis

ability to invade and metastasize

Angiogenesis

Endogenous Promotors

VEGF - A,B,C,D

Angiopoietins

Angiogenin

Basic fibroblast growth factor bFGF

Hepatocyte Growth Factor HGF

Interleukin-8

PDGF

Transformation Growth Factor ß TGF ß

TNF

Angiogenesis

Endogenous Inhibitors

Angiostatin

Brain Angiogenesis Inhibitor 1 BAI1

Endostatin

Interferons

Platelet factor-4 cleavage products

Prolactin fragment (16kd)

Thrombospondin-1

VEG I

Vasostatin

Avastin - Bevacizumab – humanized

monoclonal antibody against VEGF

Avastin is approved for:

Metastatic colorectal cancer (mCRC)

Advanced nonsquamous non–small cell lung cancer (NSCLC)

Metastatic kidney cancer (mRCC)

Glioblastoma (GBM) in adult patients whose cancer has progressed after prior treatment.

Molecular Biological and Morphological

Tumour Progression

Normal cell

Loss of

growth

control

Loss of

apoptosis

control

Loss of Senescence

control

Metastasising tumour cell

dysplasia

adenoma

infiltrating

carcinoma

Molecular biological Morphological

Tumour Progression

genomic instability activation proteases

Cellular characteristics of neoplastic cells

1. Growth factors independence (paracrine and autocrine regulations instead)

2. Loss of inhibitory regulations (e.g. cdk-I)

3. Block of apoptosis (e.g. FAS inactivation, caspases mutations)

4. Uncontrolled replication potency (exceeding the usual 60-70 cell cycles – stabilisation of telomeres)

5. DNA repair defects & genom instability (either in the germ cell line or somatic e.g. BRCA + epigenetic KRAS mutations)

6. Angiogenesis

7. Invasion & metastasizing

Cell Cycle Regulation Disorders– uncontroled cellular proliferation

polypeptide growth factors (e.g. EGF, PDGF , FGF,…)

acting as oncogenes via overexpression

ligand receptor amplification

signal transducing proteins (e.g. ras oncoproteins) -

activation of the mitogenic signaling pathway

nuclear DNA synthesis regulators (myc, jun, fos)

mitochondrial oncogenes (bcl-2) – prevention of

apoptosis

Host - Neoplasm Interactions

immune

surveillance

immune response

spontaneous regression

local pressure

cachexia

anaemia

immunodepression

products of

neoplastic cells

NEOPLASIA – „function“

NEOPLASTIC CELL PRODUCTS:

immunoglobulin

osteoid

keratin

mucus

melanin

hormones

Adenocarcinoma

apicis vesicae

urinariae

Adenocarcinomaapicis vesicae

urinariae

B 12841/05 neoplasma vesicae urinariae non

differentiatum

B 12841/05 ca vesicae urinariae non differentiatum CK AE1-3

B 12841/05 carcinoma vesicae urinariae non differentiatum p53

Adenocarcinomaapicis vesicae

urinariae

NEOPLASIA – „function“

NEOPLASTIC CELL PRODUCTS:

immunoglobulin (AL amyloid)

osteoid

keratin

mucus

melanin

HORMONES neoplastic & paraneoplastic endocrine symptoms

AA amyloid, hormonal amyloid

ENDOCRINE NEOPLASIAHormone Production and Function

may or may not be present

unregulated – may be excessive

benign tumours more likely to be active

size of tumour not related to the

degree of function

metastases may cause hyperfunction

Acromegalia19 23

Acromegalia

28 32

m. Cushing

Internationally standardized cancer reporting

http://www.iccr-cancer.org/