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General Pathology
Pathology of Organels I.
– Introduction
The Secretory
Process
and
Its DisordersInst. Pathol. ,1st Med. Faculty, Charles Univ. Prague
Jaroslava Dušková
http://pau.lf1.cuni.cz/en/texts-from-the-lectures-and-seminars-presentations
Jaroslava Dusko
va
Pathology of Organels I - table of contents
Cell components & their function
Pathomorphology of the cell nucleus
quantitative
qualitative
Pathomorphology of the cytoplasm
cytosol
organelles
intracellular accumulations
water
proteins
lipids
glycogen
pigments,foreign bodies
Cellular secretion
types
organelles involved
sense
Jaroslava Dusko
va
The Cell Components &Their Function
1. nucleus (incl. nucleolus and
nuclear envelope)
2. cytoplasm
cytoplasmic matrix
cytoplasmic organelles
3. plasma membranes
Jaroslava Dusko
va
Main Cell
Organelles
Jaroslava Dusko
va
The Cell Components &Their Function
The nucleus(incl. nucleolus and nuclear
envelope)
chromosomes
DNA, RNA, histones
Jaroslava Dusko
va
Nuclear envelope
with pores
Jaroslava Dusko
va
The Cell Components &Their Function
The nucleus functions
– cell division
– genetic information
transcription & controlJaroslava Dusko
va
Cell Nucleus Pathology (1)
Related to genom changes
quantitative:
– binucleation, multinucleation – regular
polyploidy (4n, 8n… 2nn) - reactive change eg.
in inflammation –adaptation
qualitative:
– translocations, deletions, amplifications –
aneuploidy – often in neoplasms
(DNA densitometry, FISH, CGH, NGS…)
Jaroslava Dusko
va
Neoplasia (Tumour)
DNA disease
Stepwise accumulation
of genetic abnormalities
Escape of immunological
clearing systems
Jaroslava Dusko
va
Neoplasia (Tumour)
DNA disease Stepwise accumulation of genetic abnormalities
self sufficiency in growth signals
insensitivity to anti-growth signals
limitless replicative potential
sustained angiogenesis
tissue invasion and metastasis
Escape of immunological clearing systems
evading apoptosis
Jaroslava Dusko
va
L SIL
HR HPV stimulates loss of tumour supressor genes,
activates cyclins, inhibits apoptosis, combats celular
senescence
Jaroslava Dusko
va
p16INK4a protein
inhibitor of cyclin
dependent kinase
controled in healthy
cells – undetectable
overexpressed as a
result of HPV E7
protein
MARKER OF
DYSPLASTIC CELLSJarosla
va Duskova
Jaroslava Dusko
va
Jaroslava Dusko
va
Jaroslava Dusko
va
Apoptotic bodies
Jaroslava Dusko
va
ATM/p53 Signaling Pathway
Jaroslava Dusko
va
Ca ovarii p53
Jaroslava Dusko
va
Ca ovarii MIB1 (Ki67)
Ki-67 is an excellent marker to determine the growth
fraction of a given cell population.
The fraction of Ki-67-positive tumor cells (the Ki-67
labelling index) is often correlated with the clinical course
of cancer.
The best-studied examples in this context are carcinomas
of the prostate, brain and the breast. For these types of tumors, the
prognostic value for survival and tumor recurrence have repeatedly been proven in uni-
and multivariate analysis.
Jaroslava Dusko
va
Lymphocyti &
mesothelia
Carcinosis
peritonei
AgNORs
Jaroslava Dusko
va
Pleuritis
carcinomatosa
Alc. Blue pH2,5
AgNORs
Jaroslava Dusko
va
Jaroslava Dusko
va
Jaroslava Dusko
va
CSF carcinosis
Jaroslava Dusko
va
Cell Nucleus Pathology (2)
Related to nucleolemma
quantitative:
– invaginations - pseudoinclusions
qualitative:
– thickening (irregular)
– chromatin margination
Nuclear inclusions (real)
– viral, lipids, glycogen
Jaroslava Dusko
va
Cytoplasmic nuclear pseudoinclusions
Jaroslava Dusko
va
papillary ca of thyroid
Jaroslava Dusko
va
Jaroslava Dusko
va
grooves
Jaroslava Dusko
va
CytomegalovirusJarosla
va Duskova
Cowdry A inclusion – herpetic encephalitis
Jaroslava Dusko
va
glycogen nuclei
Jaroslava Dusko
va
The Cell Components &Their Function
ribosomes
endoplasmic
reticulum
Golgi complex
lysosomes
peroxisomes
mitochondria
cytoskeleton
caveolae
The cytoplasm (cytosol)cytoplasmic matrix
cytoplasmic organelles
Jaroslava Dusko
va
The Cell Components &Their Function
The cytoplasm (cytosol)aqueous solution with enzymes
Jaroslava Dusko
va
The Cell Components &Their Function
The cytoplasm function
– proteosynthesis (in coop. with organelles)
– storage unit (fat, carbohydrates and
secretory vesicles)Jaroslava Dusko
va
Intracellular Accumulations
water –hydropic degeneration
proteins – hyaline droplets
lipids – steatosis
glycogen – glycogenosis
pigments – melanin, ceroid, lipofuscin,
hemosiderin
foreign bodies, crystals
microorganisms
Jaroslava Dusko
va
Hydropic Degeneration
intoxications
sepsis
anoxia
starvation
functional overload
autolysis
ENERGY DEFICIENCY
Jaroslava Dusko
va
Jaroslava Dusko
va
Jaroslava Dusko
va
Intracellular Accumulations
water –hydropic degeneration
proteins – hyaline droplets
lipids – steatosis
glycogen – glycogenosis
pigments – melanin, ceroid, lipofuscin,
hemosiderin
foreign bodies, crystals
microorganisms
Jaroslava Dusko
va
Jaroslava Dusko
va
Intracellular Accumulations
water –hydropic degeneration
proteins – hyaline droplets
lipids – steatosis
glycogen – glycogenosis
pigments – melanin, ceroid, lipofuscin,
hemosiderin
foreign bodies, crystals
microorganisms
Jaroslava Dusko
va
Steatosis myocardii (oil red)
Jaroslava Dusko
va
Adenoma corticis glandulae suprarenalis
Jaroslava Dusko
va
Jaroslava Dusko
va
Intracellular Accumulations
water –hydropic degeneration
proteins – hyaline droplets
lipids – steatosis
glycogen – glycogenosis
pigments – melanin, ceroid, lipofuscin,
hemosiderin
foreign bodies, crystals
microorganisms
Jaroslava Dusko
va
PAS
Jaroslava Dusko
va
Intracellular Accumulations
water –hydropic degeneration
proteins – hyaline droplets
lipids – steatosis
glycogen – glycogenosis
pigments – melanin, ceroid, lipofuscin,
hemosiderin
foreign bodies, crystals
microorganisms
Jaroslava Dusko
va
Melanoma
Jaroslava Dusko
va
Ceroid - pseudomelanosis intestini crassi
Jaroslava Dusko
va
HEHS
Jaroslava Dusko
va
Jaroslava Dusko
va
Haemosiderosis hepatis
Jaroslava Dusko
va
Intracellular Accumulations
water –hydropic degeneration
proteins – hyaline droplets
lipids – steatosis
glycogen – glycogenosis
pigments – melanin, ceroid, lipofuscin,
hemosiderin
foreign bodies, crystals
microorganisms
Jaroslava Dusko
va
Asbestosis
Jaroslava Dusko
va
Sinus pilonides
Jaroslava Dusko
va
Intracellular Accumulations
water –hydropic degeneration
proteins – hyaline droplets
lipids – steatosis
glycogen – glycogenosis
pigments – melanin, ceroid, lipofuscin,
hemosiderin
foreign bodies, crystals
microorganisms
Jaroslava Dusko
va
Cytomegalovirus inclusions in the GER
Jaroslava Dusko
va
Chlamydia
Jaroslava Dusko
va
The Cell Components &Their Function
ribosomes
endoplasmic
reticulum
Golgi complex
lysosomes
peroxisomes
mitochondria
cytoskeleton
caveolae
vaults
The cytoplasm -cytoplasmic organelles
Jaroslava Dusko
va
The Cytoplasmic Organelles Functions (1)
Organelle Composition Function
ribosomes RNA –protein
complexes
proteosynthesis
endoplasmic
reticulum
cisternae,tubular
channels
proteosynthesis
& transport
Golgi complex
(GC)
smooth
membranes &
vesicles
processing and
packaging
lysosomes sacklike GC
derived
digestion
Jaroslava Dusko
va
GC
ER
N
Jaroslava Dusko
va
Autophagosomes
Jaroslava Dusko
va
2016
Jaroslava Dusko
va
The Cytoplasmic Organelles Functions (2)
Organelle Composition Function
peroxisomes lysosomes like
producing or
using H2O2
detoxication
mitochondria membrane
bound energy
production
Oxydative
fosforylation, cell
signaling, pH
control, Ca
homeostasis
Jaroslava Dusko
va
Oncocytus
Jaroslava Dusko
va
MGG
HE
Oncocytes
Jaroslava Dusko
va
The Biology and the Genetics of Hürthle Cell Tumors of the Thyroid
Máximo V et al, Endocrine-Related Cancer, 2012, 19, R131-R147
• Hürthle cell appearance - a phenotype superimposed on the
genotypic and conventional histopathologic features of the
tumors.
• large deletions of mitochondrial DNA (mtDNA), mutations of
mtDNA genes and nuclear genes coding for OXPHOS proteins
• energy production defects in Hürthle cell tumors;
• the increased proliferation of mitochondria a compensatory
mechanism
• predisposition for necrosis instead of apoptosis which seems to
be blocked in most Hürthle cell tumors.
Jaroslava Dusko
va
The biology and the genetics of Hürthle cell tumors of the thyroid
Máximo V et al, Endocrine-Related Cancer, 2012, 19, R131-R147
Hypoxia Inducible Factor 1α
Jaroslava Dusko
va
Peroxisomes - microbodiesup to 2 microns - catalase
FunctionDegradation: substrate oxidation
(etanol)
Anabolism: synthesis of
prostaglandin , cholesterol,
billiary acids, plasmalogens,
gluconeogenesis,
transamination
Jaroslava Dusko
va
The Cytoplasmic Organelles Functions (3)
Organelle Composition Function
Cytoskeleton Microtubules & actin
microfilaments
Microvilli, cilia,
flagella
Caveolae Membrane
indentationsShuttling
material
Vaults Octagonal barrrels
like
ribonucleoproteins
Shuttling
molecules
Jaroslava Dusko
va
Jaroslava Dusko
va
Trichomonas vaginalis
Jaroslava Dusko
va
carcinoma
Mesothelioma
Mesothelioma
Jaroslava Dusko
va
Cilia
Jaroslava Dusko
va
The Cell Components &Their Function
The plasma membranes– cell surrounding
– organelles enclosing
– bilayer of lipids and proteinsJaroslava Dusko
va
Cell
mechanismMembrane function
Structure Compartmentalization, cytoskeleton & ER
contacts, fluid & electrolyte balance
Protection Barrier to toxins & foreign organisms/cells
Activation of
cell
Hormones, mitogens, antigens, growth
&proliferation factors
Storage Receptors, transport, diffusion, exocytosis,
endocytosis
Cell to cell
interaction
Communication & attachment –junctional
complexes, nutritive relationship, enzymes
and antibody release
Jaroslava Dusko
va
Tasuku HonjoJ.P. Allison
Nobel Prize 2018
Antibodies blocking the brake molecules CTLA-4 and PD-1
enhance the immune response to cancer
Jaroslava Dusko
va
Estrogen
receptors
Jaroslava Dusko
va
Carcinoma mammae ductale invasivum IDC
HE PRER
MIB1 e-cadherin c-erbB2 / Her2-neu
Jaroslava Dusko
va
Secretion
– exocrine (apical pole of the cell lumen, duct)
– endocrine (basal pole of the cell blood)
– paracrine influencing neighbouring cells
– autocrine self influencing
Jaroslava Dusko
va
Organelles Involved in Secretion
membrane type
maternal origin (ovum cytoplasm)
autoreplicative
– granular (rough) endoplasmic reticulum
– Golgi apparatus
– lysosomesJarosla
va Duskova
Exocytosis and Its Disorders
protein secretion on the granular
endoplasmic reticulum
cis Golgi network
trans Golgi network (signal molecules
attachment)
Golgi Endoplasmic Reticulum
Lysosomes
Jaroslava Dusko
va
Jaroslava Dusko
va
Secretion
continual - permanent -unregulated
pulsatory - regulatedJarosla
va Duskova
Secretion
continual - permanent– unregulated vesicle transport
– protocollagen, proteoglycans, viral
particles
Targetting:immunoglobulins without and after stimulation
Jaroslava Dusko
va
C
o
ll
a
g
e
n
p
r
o
d
u
c
ti
o
n
Jaroslava Dusko
va
Secretion pulsatory - regulated
– exocrine mucin or zymogen granules secretion
– endocrine cells– neurons– T-lymphocytes– heparinocytes– thrombocytes– granulocytes
– endothelia
membrane budding
coating proteinsJarosla
va Duskova
Jaroslava Dusko
va
Secretion Disordersdefects of synthesis product itself
auxilliary proteins
retention in GER(inborn endoplasmic reticulum storage
diseases)
hyaline droplets (Russel bodies)
Jaroslava Dusko
va
Sinusitis chronica
Jaroslava Dusko
va
Autophagosomes
Jaroslava Dusko
va
Neuroendocrine
Secretion Disorders
defects of synthesis product itself
auxilliary proteins
regulation disorders on the receptor level
Jaroslava Dusko
va
Neuroendocrine Secretion
dense core granules
secretory vesicles
(small synaptic vesicles)Jaroslava Dusko
va
Membrane Componentsof Secretory Granules and Vesicles
– Synaptophysin (synaptic vesicle protein)
– Neuron Specific Enolase
– S-100 protein
– chromogranin
identification of neuroendocrine
neoplasms
Jaroslava Dusko
va
Juxtacrine Secretion (?) /Signaling
contact (- dependent) signalling
cell adhesion (inflammatory cells… neoplastic cells…
transmitted via oligosaccharide, lipid, or protein
components of a cell membrane
Unlike other types of cell signaling (such as paracrine
and endocrine), juxtacrine signaling requires physical
contact between the two cells involved.
Juxtacrine signaling has been observed for some
growth factors, cytokine and chemokine cellular
signals.
pathology of INFLAMMATION,
TUMOURS
Jaroslava Dusko
va
Jaroslava Dusko
va