Basic Principles - Ústav Patologie 1.LFpau.lf1.cuni.cz/file/6387/18-oncology-1.pdf · Basic...
Transcript of Basic Principles - Ústav Patologie 1.LFpau.lf1.cuni.cz/file/6387/18-oncology-1.pdf · Basic...
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/