General Pathology

Basic Principles of Cellular and Organ

Pathology

Oncology - I

Jaroslava Dušková

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

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General Oncology 1

Definition

History note

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

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Tumour

swelling of any kind

NEOPLASIAJaroslava Duško

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NEOPLASIA

Definition - descriptive:

persistentabnormalrelatively autonomous

proliferation of cells Jarosla

va Dušková

NEOPLASIA

Definition - pathogenetic:

DNA disease

Stepwise accumulation

of genetic abnormalities

Escape of immunological

clearing systems

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NEOPLASIA – history I.

Ramayana – 2000 B.C.

therapy with knife

chemotherapy - arsenical

compoundsJarosla

va Dušková

NEOPLASIA – history II.

Galen – AD 129–216TUMOURS

according to naturepregnancy

exceeding natureinflammatory, reparative, callus

against naturetrue neoplasms

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Eutopic

pregnancy

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Macrocystosis renum

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Ependymoma

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Growth Disturbances

&

Their Relation

to NeoplasmsJaroslava Duško

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Nonneoplastic

Growth Disturbances – I

MALFORMATIONS

complete or partial lack of

development (aplasia, hypoplasia)

asymmetry oversize-------- hamartia - hamartoma choristia - choristoma

ectopic tissue

-

+Jarosla

va Dušková

phocomelia

cheilo-gnatho-

palato-schisis

rhachischisis

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Hamartia – Hamartoma

Def.:

A mass of disorganized

tissue indigenous to the

particular site. Jaroslava Duško

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C

h

o

n

dr

o

h

a

m

ar

to

m

a

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Chondrohamartoma

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Choristia - Choristoma

Def.:

A mass of ectopic tissue

(cells) with a limmited

growth potency Jaroslava Duško

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1. Rathke´s pouch

& proc.

infundibularis

2. separation

3. final status

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squamous

epithelium

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Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy -

(incl.pseudohypertrophy)

hyperplasia

metaplasia------------ dysplasia anaplasia – undifferentiation

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Cell Proliferation in the

Gastrointestinal Tract

a Oesophagus

b Stomach

c Sm Bowel

d L Bowel

e Anus

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repair

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Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy -

(incl.pseudohypertrophy)

hyperplasia

metaplasia dysplasia* anaplasia – undifferentiation

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Urocystolithiasis

Hyperplasia

adenomyomatosa

prostatae

Hypertrophia

trabecularis

tunicae

muscularis

vesiace

urinariae

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Atrophia

gl.suprarenalium

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Pseudohypertrophia (atrophia) lipomatosa

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Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy

hyperplasia

metaplasia dysplasia* anaplasia – undifferentiation

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Metaplasia

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Metaplasia

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ecc-tubar meplasianormal endocervical cells.

reactive ecc

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von Brunn´s nests

Mucinous metaplasia - alc. blue pH2,5

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Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy

hyperplasia

metaplasia dysplasia = intraepithelial

neoplasia = precancerosis anaplasia – undifferentiation

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dysplasia

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Urotel normální stavby

Urothelium

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Urocystitis chronica(mild reactive urothelial changes)

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Urocystitis chronica (reactive hyperplasia)

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LG IUN – mild dysplasia

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HG IUN

moderate dysplasia

severe dysplasia

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Nonneoplastic

Growth Disturbances – II

repair

hypertrophy / atrophy

hyperplasia

metaplasia dysplasia anaplasia – undifferentiation

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ASC – H – atypical immature squamous metaplasia

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EMA

TGB

vimentin

Undifferentated (anaplastic) carcinoma

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Relation of the Non-neoplastic Growth Disturbances to Neoplasms

1. differential diagnosis pseudotumours

2. precursors precanceroses

(preblastomatoses)

3. both 1. and 2.

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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

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Tissue stem cells- assymetric division:

a) differentiation, b) stem cells

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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

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Oncogenic Viruses

DNA

HPV

SV 40 – polyoma

Adenoviruses

Herpesviruses

Epstein– Barr

Hepatitis B

RNA

Rous sarcoma

Leukemia

HIV

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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…

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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 (other than linked to BRCA 1 or BRCA 2,

ovary, pankreas…)

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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

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Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-674.

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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

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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

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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

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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 – pankreas, colon

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Carcinoma vesicae urinariae non differentiatum p53

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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

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Block of apoptosis

inactivation of the death receptors – FAS

( leukemia, neuroblastoma) ;

overexpression of Bcl2 antiapoptotic

protein - Follicular cell lymphoma

t(14;18)

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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

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Limitless replicative potential activation of telomerase – immortality – advanced cancers

John Maciejowski J, and de Lange T:

Telomeres in

cancer: tumour

suppression and

genome instability.NATURE REVIEWS | MOLECULAR

CELL BIOLOGY VOLUME 18 |

MARCH 2017 | 175-186

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Carcinoma vesicae urinariae non differentiatum Ki-67 – MIB1

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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

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Defective DNA repair – genom instability

silenced genom repair genes –

hereditary non- polypose colon cancer -

Lynch syndrome

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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

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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

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Angiogenesis

Endogenous Inhibitors

Angiostatin

Brain Angiogenesis Inhibitor 1 BAI1

Endostatin

Interferons

Platelet factor-4 cleavage products

Prolactin fragment (16kd)

Thrombospondin-1

VEG I

Vasostatin

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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.

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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 proteasesJaroslava Duško

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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

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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) – block of apoptosis

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Host - Neoplasm Interactions

immune

surveillance

immune response

spontaneous regression

local pressure

cachexia

anaemia

immunodepression

products of

neoplastic cells

Cancer Immune Escape

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Pathologist´s Role in Cancer

Immunotherapy

Neoplastic antigens on tumour cells are

recognized by the host immune cells.

Immune checkpoints can be both stimulatory and

inhibitory

Tumours use the checkpoints to escape immune

control. Jarosla

va Dušková

Testing of Lung Cancer for PD-L1 (Programmed Death-1 Ligand)

Interaction of PD-L1 on tumour cells with

PD-1 on T-lymphocytes blocks T-lympho

signals and attacking of neoplastic cells

PD-1 inhibitors (Nivolumab, Pembrolizumab)

and PD-L1 inhibitors (Atezolizumab,

Durvalumab, Avelumab) increase T-

lymphocytic ability to kill cancer cells.

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78

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Pathologist´s Role in Cancer Immunotherapy

For certain

types/stages

of cancer, knowing

PD-L1 expression

may help identify

patients that will

benefit most from

immune checkpoint

blockade.

79

Reasons for testing PD-L1 expression in patients

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Tasuku HonjoJ.P. Allison

Nobel Prize 2018

Antibodies blocking the brake molecules CTLA-4 and PD-1

enhance the immune response to cancer

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T-Cell Interaction With Dendritic Cells and Tumor Cells:

The Immune Checkpoints CTLA-4 and PD-1/PD-L1

Cytotoxic T-Lymphocyte Antigen -4

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NEOPLASIA – „function“

NEOPLASTIC CELL PRODUCTS:

immunoglobulin

osteoid

keratin

mucus

melanin

hormones

…rather a key

to either

clinical or

morphology

DIAGNOSIS

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Adenocarcinoma

apicis vesicae

urinariae

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Adenocarcinomaapicis vesicae

urinariae

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B 12841/05 neoplasma vesicae urinariae non

differentiatum

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

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B 12841/05 carcinoma vesicae urinariae non differentiatum p53

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Adenocarcinomaapicis vesicae

urinariae

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NEOPLASIA – „function“

NEOPLASTIC CELL PRODUCTS:

immunoglobulin (AL amyloid)

osteoid

keratin

mucus

melanin

HORMONES neoplastic & paraneoplastic endocrine symptoms

AA amyloid, hormonal amyloid

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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

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Prl

GH

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TGB+

HE

Carcinoma glandulae thyreoideae

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kalcitonin

chromogranin

Carcinoma medullare gl. thyeoideae

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Frank NY, Schatton T, Frank MH:

The therapeutic promise of the cancer stem cell concept J Clin Invest. 2010;120(1):41-50.

Makena MR, Ranjan A, Thirumala V, Reddy A.

Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance.Biophys Acta Mol Basis Dis. 2018 Nov 24. pii: S0925-4439(18)30476-9. doi: 10.1016/j.bbadis.2018.11.015.

[Epub ahead of print]

Cancer Stem CellsJaroslava Duško

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