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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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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