Download Oncology - Dr. Tamas Tornoczki

Oncology (Oncopathology)
Nomenclature, definitions
Neoplasia
• „new growth” → leads to NEOPLASM
Tumor
• Was originally used for the „swelling” phenomenon in relation to inflammation
• the non-neoplastic, inflammatory use of this expression is almost vanished today
Oncology
• (Greek oncos = tumor), study of tumors/neoplasms
• medical discipline dealing with the diagnosis, the genesis and therapy of neoplasms
What is neoplasm?
British oncologist, Willis:
„A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated
with that of the normal tissues and persists the same excessive manner after cessation of the
stimuli which evoked the change”
Clonal proliferation, shows evolution, autonomous proliferation (not in nutrition, blood supply)
Dignity of the tumors
(behavioral nature)
Benign
Malignant
•
•
•
•
•
considered to be rather innocent
remains localised
does not spread to other sites
easily amenable with local surgical
removal
•
•
•
•
the „cancer” (latin: „crab”) because they
adhere to other parts of the body
invade and destroy other adjacent
structures
spread to distant sites - metastasis
cause death
many of them however are
treatable/curable with the modern
diagnostics and therapy, mainly in early
stages.
Nomenclature of benign tumors
Nomenclature of benign tumors – suffix ~oma to the cell of origin,
•
•
•
Mesenchymal examples:
Fibroma - fibrous tissue, fibroblasts
Chondroma – made of chondrocytes, cartilage tumor
Lipoma – benign tumor of the fat tissue
Leiomyoma/rhabdomyoma – benign tumor of the smooth or striated muscles
respectively
Benign tumors epithelial origin
The nomenclature is a bit more complex
Adenoma – glandular tumors
Papillary cystadenoma - eg. ovary glandular tumor projects into cysts
Papilloma (squamous) – fingerlike/warthy projections from squamous epithelium
Polyp – benign/malignant developed an mucosal sufaces of luminal organs
However exceptions exist: ~oma ending, but represent malignancies (inapropriate, but
deeply entrenched expressions).
Lymphoma, melanoma, seminoma, mesothelioma, synovioma (synovial sarcoma)
All are highly malignant neoplasms, but their name does not reflect on malignancy.
Benign tumors, epithelial and
mesenchymal
Nomenclature of tumors
Malignant mesenchymal – SARCOMA („sar” greek – fleshy)
According to the tissue origin:
fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, chondrosarcoma, osteogen sarcoma.
Malignant epithelial – CARCINOMA
squamous cell carcinoma – tumor cells are resemble stratified squamous epithelium.
adenocarcinoma – tumor cells arrange in glandular structures
Mixed origin – divergent differentiation of the same neoplastic clone originate from single germ layer – pleiomorphic adenoma (mixed tumor)
– developed from the ectoderm: duct cells, myoepithelial cells, epidermoid cells, myxoid
background with mesenchymal cells, chondroid tissue, bone
Mixed origin, but from multiple two or more germ layers (all the three) – TERATOMA
– from totipotential cells
– normally present in OVARIES and TESTES
– abnormally present in sequestred form in the midline – EMBRYONIC RESTs
– may consist of mature cells/tissues – benign, MATURE TERATOMA, e.g. dermoid cysts or
teratoma adultum cysticum
– may consist of immature cells/tissues – malignant, IMMATURE, potentialy/overtly malignant
TERATOMA (or some of the components show true malignant component –a carcinoma)
Benign tumors, adult teratoma
Tissue of Origin
COMPOSED OF ONE PARENCHYMAL CELL TYPE
Tumors of Mesenchymal Origin
Connective tissue and derivatives
Endothelial and Related Tissues
Blood vessels
Lymph vessels
Synovium
Mesothelium
Brain coverings
Blood Cells and Related Cells
Hematopoietic cells
Lymphoid tissue
Muscle
Smooth
Striated
Tumors of Epithelial Origin
Stratified squamous
Basal cells of skin or adnexa
Epithelial lining of glands or ducts
Benign
Malignant
Fibroma
Lipoma
Chondroma
Osteoma
Fibrosarcoma
Liposarcoma
Chondrosarcoma
Osteogenic sarcoma
Hemangioma
Lymphangioma
Angiosarcoma
Lymphangiosarcoma
Synovial sarcoma
Mesothelioma
Invasive meningioma
Meningioma
Leukemias
Lymphomas
Leiomyoma
Rhabdomyoma
Leiomyosarcoma
Rhabdomyosarcoma
Squamous cell papilloma
Squamous cell carcinoma
Basal cell carcinoma
Adenoma
Adenocarcinoma
Papilloma
Papillary carcinomas
Cystadenoma
Cystadenocarcinoma
Respiratory passages
Bronchial adenoma
Bronchogenic carcinoma
Renal epithelium
Renal tubular adenoma
Renal cell carcinoma
Liver cells
Liver cell adenoma
Hepatocellular carcinoma
Urinary tract epithelium (transitional)
Transitional-cell papilloma
Transitional-cell carcinoma
Placental epithelium
Hydatidiform mole
Choriocarcinoma
Testicular epithelium (germ cells)
Seminoma
Embryonal carcinoma
Tumors of Melanocytes
Nevus
Malignant melanoma
MORE THAN ONE NEOPLASTIC CELL TYPE—MIXED TUMORS, USUALLY DERIVED FROM ONE GERM CELL LAYER
Salivary glands
Pleomorphic adenoma (mixed tumor of salivary origin) Malignant mixed tumor of salivary gland origin
Renal anlage
Wilms tumor
MORE THAN ONE NEOPLASTIC CELL TYPE DERIVED FROM MORE THAN ONE GERM CELL LAYER—TERATOGENOUS
Totipotential cells in gonads or in embryonic rests Mature teratoma, dermoid cyst
Immature teratoma, teratocarcinoma
HAMARTOMA, CHORISTOMA
HAMARTOMA
• benign mass, composed of dysorganised tissues/cell componens, which are normally present in
the given site.
• originally regarded as not true tumor, but rather developmental defect, although the name
contains the „~oma” ending.
Eg.: CHONDROID HAMARTOMA of the lung
– islands of dysorganised, but mature/normal cartilage + blood lessels +
bronchialepithelium/tissue layers
– but recently a recurrent translocation in this lesions was discorvered – true neoplasm
CHORISTOMA
– heterotopic cell/tissue
– Eg.: small nodules of normal pancreas tissue within the submucosa of the stomach,
duodenum, small bowel (Meckel diverticulum)
CHARACTERISTICS OF NEOPLASMS
Dignity of a neoplasm: this is the behaviour.
(What can we expect from this neoplasm?) This is one of the first questions what the clinician ask from the
pathologists, and the patient from the clinician.
BENIGN or MALIGNANT? (its a drastic simplification of the things)
Benign:
–
–
–
–
–
–
well circumscribed
capsule (true or pseudo)
expansile growth
differentiated cells/tissues
do not metastatise (rare exceptions)
do not usually recur
Malignant:
– infiltrative growth
– destructive or pushing
– may, or may not have capsule
– variable differentiation
– may metastatise
– easily recur locally
Behaviour of a certain neoplasm is infuenced by numerous factors hidden
in the tumour or the surrounding host tissues. The rules above are just general,
not necessarily true in all the cases.
Characteristics
Differentiation/anaplasia
Benign
Malignant
Well differentiated; structure
Some lack of differentiation with
sometimes typical of tissue of origin anaplasia; structure often atypical
Rate of growth
Usually progressive and slow; may
come to a standstill or regress;
mitotic figures rare and normal
Erratic and may be slow to rapid;
mitotic figures may be numerous and
abnormal
Local invasion
Usually cohesive expansile welldemarcated masses that do not
invade or infiltrate surrounding
normal tissues
Locally invasive, infiltrating
surrounding tissue; sometimes may
be seemingly cohesive and expansile
Metastasis
Absent
Frequently present; the larger and
more undifferentiated the primary,
the more likely are metastases
Benign tumors
Malignant tumors
Differentiation status of the tumors
Benign: usually differentiated, cells/tissues are resemble to the normal counterpart
Malignant, variable: well differentiated, moderately differentiated, poorly/undifferentiated (this
is the basic principle of grading malignant neoplasms.
Poorly or undifferentiated tumors show the signs of ANAPLASIA.
Anaplasia (lack of differentiations), these tumors develop from undifferentiated „CANCER STEM
CELLS”
Well differentiated tumors
Well, poorly or undifferentiated tumors
Well differentiated malignant tumors:
•
Cancer cells are very similar, they are morphologically close to the normal corresponding cells
•
They may secrete/elaborate the same proteins/hormons/biogenic amines than the normal cells
•
These are useful biomarkers for the clinical and laboratory diagnosis
Eg.:
•
produced hormons: insulin, glucagon, gastrin (NETs), pituitary stimulating hormons, beta HCG
(choriocarcinoma), AFP (teratoma), NSE, chromogranin (tumors of the PNS, NETs), NA, A (tumors of the
adrenal medulla -pheochromocytoma), PTH (parathyroid adenoma), calcitonin, procalcitonin (MTC,
medullary carcinoma of thyriod
Poorly differentiated/undifferentiated tumors:
„Despite the exceptions, the more rapidly growing and the more anaplastic a tumor, the less likely it will have
specialised functional activity”
Ancillary technics should be applied to define the „line of differentiation” (IHC, ISH, molecular technics).
Characteristics of anaplasia (anaplastic tumors)
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•
•
•
•
•
•
•
•
•
pleomorphism (polymorphism, variation in size and shape of the cells)
anisonucleosis (irregular nuclear shape, variably sized, coarsely clumped chromatin to the
nuclear membrane)
hyperchromatism (dark staining nuclei)
enlarged nuclei (nuclear/cytoplasm ratio is 1:1 instead of the normal 1:4; 1:6)
anisochromasia (variable chromatin content and staining)
large nucleoli (activated nuclei)
mitoses (large number, atypical figures: tripolar, multipolar)
loss of polarity (mainly in epithelial tumors, orientation of the cells is disturbed)
tumor giant cells (polymorphic, large or polylobated, multiple nuclei, not to be mistaken
with the multinucleated inflammatory giant cells)
presence of mainly central coagulation type of necrosis
Anaplasia
METAPLASIA and DYSPLASIA
Metaplasia:
• „replacement of a cell type with another one, which later is not characteristic of the
actual/corresponding site”
• almost always found in association with tissue damage or repair
• the „new metaplastic” cell type is more suited for the environmental change
• EXAMPLES: Barett metaplasia (gastric or intestinal epithelium in the lower part of
oesophagus), squamous cell metaplasia of the cervical glands, that of the gallbladder,
bronchial respiratory epithelium
Dysplasia:
• altered, „not normal” growth of cells
• often occures in metaplastic epithelium
• often in the near of carcinomatous foci (flanking region)
• mainly in epithelial structures (but in haemopoetic cells as well)
• morphology of dysplasia: loss of uniformity of cells, disturbed orientation, pleomorphism
with large hyperchromatic nuclei, loss of normal maturation.
Eg.:
• In the cervical squamous epithelium: CIN I-II-III (grades of dysplasia), in Barrett’s epithelium,
in the larynx, in adenomatous polyps of GIT, etc.
DYSPLASIA
Rate of tumor cell growth
•
Rate of tumor growth is determined by
– doubling time of tumor cells
– replicative (proliferative) fraction of the tumor
– death rate of the tumor cells
•
•
The doubling time of tumor cells is highly variable
Growth fraction: experimental data  majority of the cells in early/submicroscopic stage are
in the proliferative fraction
As the tumour grows, the proliferation fraction is decreasing
A clinically detectable tumour shows cca. 20% of proliferation fraction
Tumours with the highest proliferative rate: Burkitt lymphoma, AL, SCLC, NBoma
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Growth fraction of tumours has profound effect on susceptibility to chemotherapy 
Chemotherapy is effective on tumour cells in cycle.
The smaller the tumour the higher the growth fraction.  That’s the reason of usefulness of
the DEBULKING.
Growth rate is not constant, it is changing, eg. UTERINE leiomyoma: over the span of years it
grows slowly  in menopause stops growing  fibrosis/calcification
in pregnancy cell growth speed up.
Local invasion of tumors
•
•
•
•
•
Benign tumours  expansil growth, capsule formation (from the surrounding atrophized
stroma), pseudocapsule formation (compressed surrounding host tissue).
Exceptions: pleomorph adenoma, pituitary adenoma, fibromatosis.
Malignant tumours  infiltrative growth, beside metastasis this is one of the most reliable
factor for malignancy.
Malignant tumor penetrate the wall of colon, uterus, bladder.
Brakes through the surface of skin
Metastasis:
• Malignant tumours can metastasize, all of them (with rare exceptions)
• Exceptions: glioma, BCC  do not metastasize.
Types of Metastases
•
•
•
•
Seeding of body cavities/serous membranes.
Peritoneal: ovarium cc., GIST, pseudomyxoma peritonei
Pleural: breast and lung cc.
Pericardial: melanoma, breast and lung cc., SCC of head and neck.
Lymphatic spread
Almost all cancers can spread through the lymphatics
eg. Breast cc.  upper outer quadrant  axillary LN, medial quadrant  internal
mammary artery
Concept of sentinel lymph nodes (breast cc., melanoma).
Tumours like to metastasize to the first „filtrating” lymph node, that’s the sentinel
lymph node  examination of sentinel lymph nodes may prevent the unnecessary
extensive axillary surgery with the possible axillary morbidity.
Exceptions: SKIPPING metastasis  due to fibrosis or inflammatory obstruction of
lymphatics.
Hematogenous spread
Portal type  metastasis to the liver (GIT, eg. CRC, GIST)
Cava type  metastasis to the lung (kidney, soft tissues, liver, etc.)
Paravertebral plexus type  vertebrae (prostate adenocarcinoma, thyroid cancers)
Invasion of great veins and continuus spread in the lumen (RCC, HCC)
Types of Metastases
EPIDEMIOLOGY
•
•
study of cancer incidence/deaths in geographical, cultural, race relations
contributes substantially to the knowledge about the origin/pathogenesis
INCIDENCE (occurence) of a cancer
MORTALITY RATE (death) of a cancer
2008, USA:
about 1.4 million new cancer cases
about 566.000 deaths from cancer
cancer deaths represented 23% of all mortality (surpassed only by deaths caused by
CARDIOVASCULAR diseases)
Frequency:
Women: BREAST CANCER, LUNG CANCER, COLORECTAL CANCER
Man: PROSTATIC CANCER, LUNG CANCER, COLORECTAL CANCER
These above constitutes more than 50% of cancer diagnoses and deaths
2011, Hungary:
Mortality rate for cancer: 333,7/100.000 people
For cardiovasculare diseases: 644,3/100.000 people
EPIDEMIOLOGY
Incidence of cancer in the USA is increased over the XX. century, but at 1995 the overall cancer
incidence rate in man and in women have stabilized (did not increase) and the death rate has
decreased 18,4% in man, and 10,4% in women.
It was due to
– decreased use of tobacco:
it is responsible for the decreased lung cancer death rate
– improved detection/treatmant:
it is responsible for the decrease in death rates in CRC, female breast cancer, prostate
cancer
– in the last half century:
a decline in cervical cancer deaths was due to the application of PAP smear
– reduced number of stomach cancer deaths: was caused by the better food preservation
methods and change in the dietary habits
– death from primary liver cancers: increased (doubled) from 1970 due to the increased
incidence of HCV infection
Daganatos halálozás, 2011
C00–D48
C00–C15
C16
C18
C19–C21
C22–C24
C25
C33–C34
C91–C95
Daganatok
Ajak, szájüreg, garat, nyelőcső
rosszindulatú daganata
Gyomor rosszindulatú
daganata
Vastagbél rosszindulatú
daganata
Végbél rosszindulatú daganata
Máj, epehólyag, epevezetékek
rosszindulatú daganata
Hasnyálmirigy rosszindulatú
daganata
A légcső, hörgő és tüdő
rosszindulatú daganata
Fehérvérűség
Összes egyéb daganatok
Férfi, nő együtt
36
60
163
699
3 194
8 585
9 276 11 261
33 274
–
–
1
45
436
952
429
227
2 090
–
1
8
42
137
324
472
717
1 701
–
1
10
44
171
587
919
1 563
3 295
–
–
4
31
114
388
518
704
1 759
–
1
3
11
111
308
435
570
1 439
–
1
2
26
154
476
540
651
1 850
–
–
9
109
997
2 943
2 593
1 882
8 533
16
20
11
44
18
81
26
230
68
686
154
1 754
268
2 147
387
2 926
948
7 888
MOLECULAR BASIS OF CANCER DEVELOPMENT
FUNDAMENTAL PRINCIPLES
1. Nonlethal genetic demage (due to environmental agents like chemicals, irradiation,
viruses or inherited problems in the germ line).
2. Clonal expansion of a single precursor cell (monoclonal proliferation)
3. Principle targets of genetic demage
• Protooncogens (normally they are growth promoting gens, mutant forms
considered to be dominant)
• Tumor suppressor genes (phisiologically blocks cell proliferation, usually
both allels should be mutated/deleted)
• Apoptosis regulator genes (regulates programmed cell death, could be
suppressors or oncogenes)
• Genes involved in DNA repair (do not transform cells directly, but indirectly
influence the repair of other genes. „Mutator phenotype” → cells with mutation
in DNA repair genes)
• Micro RNAs → regulatory small RNA molecules
Fundamental changes which together determine malignant
phenotype
A. SELF SUFFICIENCY in GROWTH SIGNALS (no external stimuli is needed
for the activation)
B. INSENSIVITY TO GROWTH INHIBITORS
C. ESCAPE FROM APOPTOSIS
D. LIMITLESS REPLICATIVE POTENTIAL
E. SUSTAINED ANGIOGENESIS
F. ABILITY TO TO INVADE AND FORM METASTASIS
G. INABILITY TO REPAIR DNA DEMAGE
ONCOGENES
Oncogenes → genes that promote autonomous cell growth
Protooncogenes → unmutated cellular counterpart of oncogenes, which have important functions
in promoting cell cycle.
Oncoprotein → product of oncogenes, which plays a role in cancer development, they are often
devoid of internal regulatory elements.
What are these genes/proteins in the reality?
– Growth factor
– Growth factor receptor
– Proteins involved in signal transmission
– Nuclear regulatory proteins, which initiate DNA transcription
– Cell cycle regulators
Category
GROWTH FACTORS
PDGF-β chain
Proto-oncogene
Mode of Activation
Associated Human Tumor
SIS (official name PBGFB)
Overexpression
Fibroblast growth factors
HST1
INT2 (official name FGF3)
Overexpression
Amplification
TGF-α
TGFA
Overexpression
HGF
GROWTH FACTOR RECEPTORS
EGF-receptor family
HGF
Overexpression
Astrocytoma
Osteosarcoma
Stomach cancer
Bladder cancer
Breast cancer
Melanoma
Astrocytomas
Hepatocellular carcinomas
Thyroid cancer
ERBB1 (EGFR), ERRB2
Overexpression
Squamous cell carcinoma of lung, gliomas
FMS-like tyrosine kinase 3
Receptor for neurotrophic factors
FLT3
RET
Amplification
Point mutation
Point mutation
Breast and ovarian cancers
Leukemia
Multiple endocrine neoplasia 2A and B,
familial medullary thyroid carcinomas
PDGF receptor
Receptor for stem cell (steel) factor
PDGFRB
KIT
Overexpression, translocation
Point mutation
Gliomas, leukemias
Gastrointestinal stromal tumors,
seminomas, leukemias
Point mutation
Colon, lung, and pancreatic tumors
HRAS
NRAS
Point mutation
Point mutation
Bladder and kidney tumors
Melanomas, hematologic malignancies
Nonreceptor tyrosine kinase
ABL
Translocation
Chronic myeloid leukemia
Acute lymphoblastic leukemia
RAS signal transduction
WNT signal transduction
BRAF
β-catenin
Point mutation
Point mutation
Overexpression
Melanomas
Hepatoblastomas, hepatocellular
carcinoma
C-MYC
N-MYC
Translocation
Amplification
PROTEINS INVOLVED IN SIGNAL TRANSDUCTION
GTP-binding
KRAS
NUCLEAR-REGULATORY PROTEINS
Transcriptional activators
L-MYC
Amplification
Burkitt lymphoma
Neuroblastoma, small-cell carcinoma of
lung
Small-cell carcinoma of lung
CELL CYCLE REGULATORS
Cyclins
Cyclin D
Cyclin-dependent kinase
Cyclin E
CDK4
Translocation
Amplification
Overexpression
Amplification or point mutation
Mantle cell lymphoma
Breast and esophageal cancers
Breast cancer
Glioblastoma, melanoma, sarcoma
GROWTH FACTOR/GROWTH FACTOR RECEPTOR
–
Mutations converts these genes (protooncogenes) to oncogenes, which are
constitutively active.
Eg.:
– Glioblastoma → synthesize PDGF and express PDGFR (the recept protein),
which make them responsive for they own growth factors
– Many sarcomas are able to elaborate TGFα and it receptors TGFαR
GROWTH FACTOR RECEPTORS
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Most important growth factor receptor class: the TRANSMEMBRANE RECEPTOR PROTEINS with
cytoplasmic TYROSIN KINASE DOMAIN
Normal function: GF binds to GF receptor → activation → phosphorylation of substrates → signal transduction
Oncogenic versions of receptors are constitutively activated (able to work without binding substrate) by mutations,
gene rearrangement, overexpression of the gene
Result: permanent signal independently of growth factors
- RET protooncogene (receptor tyrosin kinase for gial cell derived neurotropic factor)
- Normally expressed in neuroendocrine cells (parfolliculare C-cells, adrenal medulla cells,
parathyroid cells)
- RET germ line point mutation:
MEN2a → RET extracellular domain, MTC+phaeochromocytoma+parathyreoid adenoma,
MEN2b → RET cytoplasmic catalytic domain, MTC+pheochromocytoma
Familiar medullary thyreoid carcinoma, multinodular MTC only
- RET somatic point mutation, sporadic MTC
- FLT point mutation → myeloid leukaemia
- t(5-12) (PDGFR/ETS fusion) → CMyMOL
- ~85% of GISTs KIT or PDGFRα mutation, constitutive activation of receptor tyrosin kinase
- Good bases for targeted therapy: IMATINIB MESILATE, sunitinib etc.
Overexpression of normal forms of growth factor receptors
Her2/Neu (17q22) high amplification
– More common than mutation
– Due to gene amplification
Example:
ERBB1 (EGF receptor gene):
Overexpressed in 80% of lung SCC-s!
Overexpressed in more than 50% of GLIOBLASTOMAS
80-100% of HEAD and NECK carcinomas
ERBB2 (HER2/neu, also an EGF receptor family genes)
amplified in 15-25% of BREAST carcinomas, adenocarcinomas of OVARY, LUNG,
STOMACH, SALIVARY GLAND
Utilized in therapy of breast carcinoma, monoclonal antibody against HER2 called
HERCEPTINE, which is another example of targeted therapy
GENES/PROTEINS IN SIGNAL TRANSDUCTION
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RAS protooncogene, located on the inner surface of plasma membrane, endoplasmic
reticulum and Golgi membrane
ras protein → GTP binding protein (G-protein)
There are three RAS in the human genom: KRAS, NRAS, HRAS
Originally discovered in transforming retroviruses
MUTATION IN RAS and RAS SIGNALING PROTEINS
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Point mutation of RAS family genes → most common, about 15-20% of human cancers
contain one of the mutated version.
90% of pancreas adenocarcinomas, cholangiocellulare carcinomas → KRAS mutation
50% of CRC, endometrial carcinoma thyroid carcinoma (follicular) → KRAS mutation
30% of lung adenocarcinomas, myeloid leukaemias show RAS mutation
Bladder cancers → HRAS mutation
Haemopoietic tumors → NRAS mutation
Place of point mutation:
1. In the GTP binding pocket,
2. In the enzymatic region essential for GTP hydrolysis
Mutated RAS remains activated → contributes cell proliferation
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Mutation of GAPs (GTP-ase activating proteins) may mimic the effect of RAS mutation
As in case of neurofibromatosis type 1
NF1 product → neurofibromin, it is a GAP
Mutations of the RAS downstream signaling cascade: RAS/RAF/MAP kinase
Mutations in BRAF (RAF family) is detected in 60% of melanomas
ALTERATIONS in NONRECEPTOR TYROSIN KINASES
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In CML and ALL → c-ABL tyrosin kinase
ABL gene is translocated to BCR gene → chimeric gene BCR/ABL
t(9-22), Philadelphia chromosome
detection: karyotyping, FISH, PCR
IMATINIB MESILATE (Glivec) inhibits the fusion tyrosin kinase protein which is another
example of TARGETED THERAPY
In PV and PMF (progressiv mylofibrosis) → activating mutation of JAK2 nonreceptor tyrosin
kinase gene
BCR-ABL1 translocation
(9;22)(q34.1;q11)
bcr/abl RT-PCR
Alterations in nuclear transcription factors
MYC, MYB, JUN, FOS, REL
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–
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MYC is most commonly involved in human tumors
Belongs to immediate early response gene → becomes rapidly induced when resting cells
receive proliferation signal
MYC function is not entirely understood
Range of activities modulated by MYC
– Histon acetylation
– Reduced cell adhesion
– Increased cell motility
– Increased telomerase activity
– Increased protein synthesis
– Decreased proteinase activity
– Other changes
– MYC is one of the handful transcription factors, that can reprogram somatic cells back
into pluripotent stem cells
– MYC activation is linked to proliferation
– In the absence of growth factors MYC activation leads to APOPTOSIS in cell cultures
– MYC oncoprotein has separate domains for growth promoting and apoptotic activity
Role of MYC oncogene in tumors
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Persistent expression, or overexpression of myc oncoprotein in tumors is common
Dysregulation of MYC by translocation of the gene: t(8-14) MYC/IgH in Burkitt lymphoma
MYC is amplified in breast, colon, lung carcinomas
NMYC is amplified in neuroblastomas
LMYC is amplified in small cell lung cancers (SCLC)
MYCN amplification
CELL CYCLE REGULATORS
CELL CYCLE REGULATORS
A. Cyclins/cyclin dependent kinases (cyclin/CDK) → drive cell cycles
-Mishaps in cyclin D/CDK4 complex → COMMON EVENT in neoplastic trasnsformation
-Cyclin D genes → overexpression in many cancers like: breast, oesophagus, liver, lymphomas
-CDK4 gene amplification → in melanomas, sarcomas, glioblastomas
-Cyclin B, E, other CDK mutations → much rare
B. Cyclin dependent kinase inhibitors (CDKI) → blocks cell cycle by blocking cyclin/CDK
complexes
-CDKI-s → normally silence the CDK-s → negative control on cell cycle
-They are p21, p27, p57 (CIP/WAF family) → inhibit cyclinE/CDK2, cyclinA/CDK1,
cyclinA/CDK2
-Or p16, p15, p18, p19 (INK4 family) → inhibit cyclinD/CDK4, cyclinD/CDK6
-Frequently mutated or otherwise silenced in human malignances
-Germline mutation of p16 → associated with 25% of melanoma-prone children
-Somatic deletion or inactivation of p16 → 75% of pancreas cc, 40-70% of glioblastoma,
50% of oesophageal cc, 20-70% of ALL, 20% of NSCLC
TUMOR SUPPRESSOR GENES
Cell cycle checkpoints: there are two: G1/S and G2/M
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G1/S → checks for DNA demage
G2/M →checks for DNA replication and monitors whether it is safe to let the cell into mitosis
It is particularly improtant in the cells, which are expressed to ionizing irradation
These checkpoints are regulated by tumor suppressor genes
Tumor suppressor genes are brakes in the cell proliferation, their product are tumor
suppressor proteins → form a kind of network of chekpoints that prevent uncontrolled
growth
Several important tumor supressor genes:
– RB, p53, APC/β-catenin, NF1, NF2, VHL, WT1/WT2
Gene
Function
Tumors Associated with
Somatic Mutations
Tumors Assocated with
Inherited Mutations
TGF-β receptor
Growth inhibition
Carcinomas of colon
Unknown
E-cadherin
Cell adhesion
Carcinoma of stomach
Familial gastric cancer
Inner aspect of plasma
membrane
NF1
Inhibition of RAS signal
transduction and of p21 cell Neurofibromas, GIST
cycle inhibitor
Cytoskeleton
NF2
Cytoskeletal stability
Schwannomas and
meningiomas
APC/β-catenin
Inhibition of signal
transduction
Carcinomas of stomach,
Familial adenomatous
colon, pancreas; melanoma polyposis coli/colon cancer
PTEN
PI3 kinase signal
transduction
Endometrial and prostate
cancers
Cowden syndrome
SMAD2 and SMAD4
TGF-β signal transduction
Colon, pancreas tumors
Unknown
RB1
Regulation of cell cycle
Retinoblastoma;
osteosarcoma carcinomas
of breast, colon, lung
Retinoblastomas,
osteosarcoma
p53
Cell cycle arrest and
apoptosis in response to
DNA damage
Most human cancers
Li-Fraumeni syndrome;
multiple carcinomas and
sarcomas
WT1
Nuclear transcription
Wilms' tumor
Wilms' tumor
P16/INK4a
Regulation of cell cycle by
inhibition of cyclindependent kinases
Pancreatic, breast, and
esophageal cancers
Malignant melanoma
Unknown
Carcinomas of female
breast and ovary;
carcinomas of male breast
Subcellular Locations
Cell surface
Cytosol
Nucleus
BRCA1 and BRCA2
DNA repair
Neurofibromatosis type 1
and sarcomas
Neurofibromastosis type 2,
acoustic schwannomas, and
meningiomas
RETINOBLASTOMA GENE (RB)
–
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–
–
–
–
RB gene, the first tumor suppressor gene, maps to 13q14 locus, found at first in retinoblastoma
Retinoblastoma: tumor of the eye (retinoblasts) in children, AD inheritance of the gene
Approximately 60% of retinoblastomas are sporadic, 40% are familial
Sporadic: two somatic mutations, hereditary/familial: germline mutation+somatic mutation
1970 Knudson: „Two-hit hypothesis of oncogenesis”
A child carrying one inherited mutant RB allele in all somatic cells is perfectly normal at
phenotypical level, she/he is heterozygous for the defect allele
Cancer developes, when the cell becomes homozygous for mutant allele → loss of heterozygosity
(LOH)
RETINOBLASTOMA GENE (RB)
Active RB-protein → hypophosphorylated, hyperphosphorylated is the inactive form
Activ protein (hypophosphorylated) controls G1/S transition by inhibiting E2F gene product, this way
active protein blocks transcription
If RB is mutant → becomes inactive
Mutations map to the „RB pocket” of the protein, which is responsible for E2F binding
Oncogenic human DNA viruses can neutralize RB protein by binding of viral proteins: HPV-E7 protein,
adenovirus EIA protein, polyoma virus large T-antigen
–All bind to hypophosphorylated, active form of protein
p53: GUARDIAN OF THE GENOME
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–
–
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p53 gene maps to 17p13.1
Over 50% of human tumors contain mutation in these gene
Homozygous loss of p53 occurs: in lung, colon, breast carcinomas
Mutation (point mutations, deletions, rearrangements) of the gene in both alleles → loss of
function
Function of p53 protein → cell cycle arrest at G1/S and G2/M phase, makes the cell repair
possible, if the cell is unrepairable → it triggers apoptosis
Nuclear protein, very short half life, WT-p53 can not be detected by IHC, mutant form
accumulates
p53: GUARDIAN OF THE GENOME
–
–
–
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Mutational status resulting in inactivity: two somatic or one germline+one somatic mutations
p-53 germline mutation: Li-Fraumeni syndrome, 25x greater chance of developing malignant tumor
by age 50 than the general population, the spectrum is wide: sarcomas, breast cancer, leukaemia,
brain tumors, carcinomas of the adrenal cortex
80% of p53 point mutations in human cancers maps to DNA-binding domain of the protein
Similarly to RB, transforming proteins of several DNA viruses (HPV-E6) binds to WT-p53 and
inactivate, degrade it.
Also MDM2 and MDMX (regulators of WT-p53) if overexpressed, accelerate p53 degradation
MDM2 gene is amplified is 33% of human sarcomas
Other tumor suppressor genes
NF1 gene, maps to chr. 17, it’s product called neurofibromin → it is a GAP (GTP-ase activating protein)
• Neurofibromin facilitates GTP-active-RAS to GDP-inactive-RAS transition
• Related syndrome: neurofibromatosis type 1 (Recklinghausens disease)
• 1882, von Recklinghausen, 1:2500-3000, AD, high penetrance, in 50% there is new mutation,
deletion, (more, than 200 types of mutations, insertions or deletions in the NF-1 gene)
•
Clinical setting: 2 or more of the following criteria are diagnostic to NF-1
-six or more café au lait
-two or more neurofibromas (of any type)
-one plexiform neurofibroma,
-axillary or inguinal pigmentation
-optic glioma,
-two or more Lisch nodules on the iris
-bone lesion (sphenoid dysplasia, kyphoscoliosis),
-NF-1 in first degree relatives
Other tumor suppressor genes
NF2, Neurofibromatosis type 2, maps to chr. 22, it’s protein product is merlin
– Characterised by acoustic nerve Schwannomas (bilateral)
– Somatic mutations affecting both allels of NF2 have also been found in sporadic meningeomas and
ependymomas
VHL, von Hippel-Lindau gene maps to chr. 3p
– syndrome: von Hippel-Lindau syndrome
– Characterised by hereditary RCC, phaeochromocytoma, haemangioblastoma of the CNS, retinal
angiomas, renal cysts
– Mutations of VHL also found in sporadic RCC-s
– The gene product is VHL protein
– In the presence of oxygen, HIF1α binds to VHL protein leading to proteosomal degradation
– In hypoxia HIF1α does not bind to VHL, travels to the nucleus, turns on many genes responsible for
cellular growth and angiogenesis, like VEGF and PDGF → vascular proliferation
Other tumor suppressor genes
WT1, locates on chr. 11p13, associated with development of Wilms’ tumor (nephroblastoma)
– Mutational inactivation of WT1 has been seen in inherited and sporadic form of Wilms’ tumor
– WAGR syndrome: germline del. WT1, Wilms +Aniridia +Genital abnormalities +mental
Retardation (chance for Wilms is 33%)
– Second hit: somatic mutation of the gene
– WT1 protein is a transcriptional activator, which plays important role in renal and gonadal
differentiation
– Regulates the mesenchymal-to-epithelial transition, that occures in kidney development
– Danys-Drash syndrome: 90% chance to have Wilms, germline mutation of WT1 gene
Wilms+gonadal dysgenesis (male pseudohermaphroditism) +early nephropathy (diffuse
mesangial sclerosis) + increased risk of gonadoblastoma
– Germline mutation is enough for development of genitourinary abnormalities but not for Wilms.
Development of nephroblastoma needs inactivation of the other allele.
– Only about 15% of patients with nonsyndromic Wilms tumor has WT1 mutation
Another Wilms’ tumor gene is WT2, which locates on 11p15.5, and its associated with BeckwithWeidemann syndrome characterized by hemihypertrophy +macroglossia +organomegaly
+omphalocele +adrenal cytomegaly
Chemical cancerogenesis
•
•
Animal model for chemical cancerogenesis
Mouse skin cancer (SCC) INITIATION and PROMOTION phases  basic model of „multistep”
cancerogenesis
– INITIATION: by initiators, which
 causes permanent DNA damage
 alone is not sufficient to produce tumor
 highly electrophilic agents
 bind to DNA, RNA, proteins
 they could be direct acting or indirect acting
 Direct acting  require no metabolic conversion for it’s cancerogenic potential
they are week cancerogenes chemotherapeutic drugs (alkylating agents) 
useful drugs in controlling/treating certain type of tumours (leukemia, lymphoma,
ovarian cc.). Alkylating agents can cause AML!!!
 Indirect acting  require metabolic conversation by eg. cytochrom P450
 polycyclic hydrocarbons: present is fossil fuels, present in cigarette smoke
(benzpyrene), present in animal fats after grilling/boiling
 aromatic amine, azo-dyes  formerly widely used in dye and rubber industry
Molecular targets of chemical cancerogenes
•
•
•
•
Initiators are mutagenic  DNA is the primary target in chemical cancerogenesis
Any of the genes could be mutated
Particularly important targets are RAS, p53
Eg. AFLATOXIN B1 (from Aspergillus strains)  increases the incidence of HCC in Africa
– Aflatoxin B1 causes p53 mutation in codon 249 (G:C T:A, called 249 (Ser) p53 mutation
– Signature mutation
– Vinyl-chloride, Arsenic, Nickel, Chromium, insecticides, fungicides, polychlorinated
biphenyles  all are potential cancerogenes in workplace and at home
– Nitrites used as food preservatives  nitrosylation of amines  NITROSAMINE 
CANCEROGENIC COMPOUND
Radiation cancerogenesis
•
•
•
•
•
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•
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Radiant energy independently it’s forms (UV ray, sun, ionising electromagnetic, particulate) is
well established to be cancerogenic
UV-light  skin cancers  SCC, BCC, melanoma
Ionising irradiation (medical, occupational, accidental like nuclear bomb or nuclear
catastrophes)  cause a variety of cancers
Effect of UV-light depends on the
1. type of UV-light
2. intensity of exposure
3. quantity of protective melanin in the skin
White skinners, patients living in „high exposure” places, like Australia are at highest risk
Nonmelanoma cancers (SCC, BCC) are associated with total cummulative exposure to UV
radiation
Melanomas are associated with intense intermittent UV exposure (sunbath)
Sunlight’s UV spectrum: UVA (320-400 nm), UVB (280-320 nm), UVC (200-280 nm)
The UVB is believed to be responsible for skin cancers.
UVB  cancerogenecity is attributed to formation of pyrimidin (timin) dimers in DNA
– It is postulated that with increased exposure the capacity of the repair is overwhelmed.
– DNA repair is extremely important in protection (nucleotid excision repair).
– Hereditary disease Xeroderma pigmentosum (high frequency of skin cancers) underlies
the importance of DNA repair
Radiation cancerogenesis
•
•
•
•
•
Ionising radiation (X-ray, γ-ray) , particulate radiation (α, β, proton, neutron)  are all
cancerogenic
X-ray pioneers  developed skin cc.
Uranium miners in CE, USA have 10x risk of lung cc.
Inhabitants at Hiroshima/Nagasaki  the follow up of these people revealed increased risk of
leukaemia (AML, CML, 7 years after the event), later increased risk of breast, colon, lung,
thyroid cc.
Chernobyl  increased risk of thyroid cc. (I131 isotop).
Microbial carcinogenesis
•
•
•
RNA virus (HTLV-1, HCV)
DNA viruses (EBV, HPV, HBV)
Bacteria (Helicobacter pylori)
RNA viruses
• HTLV-1 (Human T-cell Leukaemia Virus)
This is the only retrovirus, sufficiently proved to be oncogenic is human.
• HTLV-1 causes T-cell leukaemia/lymphoma that is endemic in Japan and the Caribbean Islands
• Sporadic in the USA
• HTLV-1 has tropism for CD4 positive cells (similarly to HIV)  this is the major target of
cancerogenesis here.
• It has a latency from primary infection which is about 40-60 years.
• Human infection occurs after
– SEXUAL intercourse
– BLOOD transfusion
– BREAST FEEDING
• Tumorigenesis is not clear
• In leukaemic cells the virus is found to be integrated
– No oncogene is identified, no predilection sites of integration
– Viral integration is clonal, identical in all the leukemic tumor cells
– TAX gene could be the transforming gene
Microbial carcinogenesis: DNA viruses
EBV (Burkitt ly. NPC, Hodgkin)
HPV (cervical cc., oropharyngeal cc., laryngeal cc.)
HBV (HCC)
HHV8 (Kaposi sarcoma virus, Kaposi sarcoma, PEL)
Merkel cell polyoma virus
Oncogenic DNA viruses
HPV (Human papilloma virus)
– At least 70 different genotypes.
– Low risk viruses
 HPV1, 2, 4, 7  cause benign squamous lesions (papilloma, wart)
 HPV 6, 11, episomal localisation, lesions with low malignant potential (papilloma,
CIN I.)
– High risk viruses
HPV 16, 18, 31, 33, 51  integrated to the host DNA  malignant transformation
• site of integration is „random”, variable from case to case, but the pattern is clonal
(in the same place in all tumor cells of the same neoplasm)
• the cells with integrated viral DNA show genomic instability.
• malignant squamous cell lesions like SCC the cervix, anogenital or oropharyngeal
SCC.
Mechanism of oncogenesis:
E7 oncoprotein
 acts on RB protein (deactivates RB protein)
 inactivate P21, P27 (CDKI-s) increase cell proliferation
E6 oncoprotein
 acts on WTp-53 protein
Infection with HPV itself is not sufficient for carcinogenesis
HPV infection in cell cultures transfected HPV types 16, 18, 31+ mutant RAS transfection
full malignant transformation.
EBV (Epstein-Barr Virus)
EBV (Ebstein-Barr Virus)
•
Burkitt lymphoma
•
B-cell lymphomas in immunodeficient host (mainly in those with HIV infection)
•
Hodgkin’s lymphoma
•
NPC (nasopharyngeal carcinoma)
•
some gastric carcinomas
•
rare NK/T cell lymphomas
•
•
•
EBV infects B cells and epithelial cells of oropharyngx through CD21 (complement receptor)
Infection is latent (means no viral replication, no cell necrosis is seen)
B-cells are immortalized  polyclonal B-cell proliferation (autonomous without TH cells)
EBV-Oncogenes:
LMP1 (latent membrane protein-1)  activates NF-κB and JAK (STAT signalling)
behaves like a constitutively active CD40 receptor
EBNA-2  encodes a protein which behaves like a constitutively active Notch receptor  transactivate
cyclin D
Result: proliferation of the virus infected, polyclonal, immortalized, EBV-harbouring B-cell population
– Clinically it may be SILENT or prominent called MONONUCLEOSIS INFECTIOSA
– This was the first step in cancerogenesis
– 2nd step:  genetic involvement of c-myc oncogene
– by translocations: t(8;14) (c-myc/IgH), t(8;22), t(2;8)
EBV (Epstein-Barr Virus)
Burkitt lymphoma
High grade/agressive B-cell lymphoma
Most common tumour in childhood in Central Africa and
New Guinea
African type: 90-100% association with EBV
European type: 15-20% association with EBV
EBV (Epstein-Barr Virus)
•
•
B-cell lymphoma of immunodeficient patients  HIV positive AIDS patients, in transplant
patients
Starts as polyclonal  becomes monoclonal  express EBNA2, LMP-1
Nasopharyngeal carcinoma
– Endemic in South China, in some parts of Africa, in Inuit population of Arctic
– 100% of NPC contains EBV DNA
– clonal viral integration
– antibody to EBV VCA is greatly elevated
– EBV plays central role in the genesis
– genetic or environmental cofactors also play important role in tumorigenesis
– LMP-1 expression
– LMP-1 activates NF-KB pathway, and also activates VEGF, FGF2, MMP9, COX2
HBV, HCV (Hepatitis B and C Viruses)
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Close association of HBV and hepatocellular carcinoma (HCC)
cca.: 70-85% of HCC is due to HBV or HCV infection
HBV and HCV genomes do not harbour oncoproteins
HBV is endemic in countries of Far East and Africa  these have the highest incidence of
HCC
HBV is integrated to the genome
there is no consistent pattern of integration
oncogenic effect of HBV, HCV  multifactorial  immun-mediated chronic inflammation
 hepatocyte death  regeneration (at cellular level)  cirrhosis  HCC
molecular pathogenesis is not clear
one of the key molecular steps in infected hepatocytes is: activation of NF-κB  blocks
apoptosis  proliferating/regenerating hepatocytes accumulate mutations
The HBV genome contains a gene called HBx  may activate a variety of transcription
factors and members of cell signaling
HCV  RNA virus
much less understood
chronic liver cell demage  regeneration
HCV core protein may have a role in tumorigenesis
Helicobacter pylori
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The first bacterium which was implicated in carcinogenesis
HP infection  key role in gastric adenocarcinomas and gastric lymphomas (MALT
lymphoma)
chronic unresolved/persistent inflammation  mucosal atrophy  cellular regeneration
(proliferation)  genotoxic agents  intestinal metaplasia  dysplasia  cancer
this sequence of events takes decades and only in 3% of the affected individuals
H. pylori  genome contains pathogenecity islands  CagA (cytotoxin-associated gene A)
 initiation of signal in cascade  mimics unregulated GF stimulation
MALT lymphomas development is not fully understood
H.pylori infection  HP reactive T-cells (immunresponse)  stimulate polyclonal B-cell
proliferation  accumulation of mutations  „monoclonal” MALToma (proliferation of
„tumour cells” remain dependent on T-cell stimulation of B-cell pathways)  at this stage the
tumour is reversible, eradication of H.pylori by antibiotics removes the antigen stimulus for Tcells  stops proliferation  the tumour disappear
at later stages: additional mutations like t(11;18)  renders NF-κB constitutively active 
H.pylori is no more needed for progression.
Multistep cancerogenesis: CRC
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Epidemiology and research data indicate: this is a multistep process
Full genom sequencing of tumors (breast, CRC) revealed: an average 90 mutant gene
11 from above genes are mutated in high frequency
A single gene does not transform the non-immortalized cells, but several together can
Eg.: ras+myc together are able to transform fibroblasts in cell culture
Clinical aspects of neoplasia
•
•
Effect of neoplasm on the host (patients)
Clinical problems, even in the case of a benign tumor due to
– Location of the tumor
compression of the surrounding tissues, dislocation, effect on local organs)
• Small pituitary adenoma  compresses, destroys surrounding normal gland 
PANHYPOPITUITARISM
• primary or metastatic tumour in an endocrin gland  may couse endocrine
insufficiency
• neoplasm in GIT  enlarge  obstruction  ileus
– Functional activity (hormons, paraneoplasia)
• hormone production  rather in benign tumors or well differentiated malignant
tumours, eg. INSULOMA  insulin production of even a small adenoma  may
cause even fatal HYPOGLYCAEMIA
– Bleeding, infections (erosion, ulceration)
• GIT tumours, urinary passage tumours, airways tumours  melaena, haematuria,
haemoptisis, blood aspiration
– Rupture or necrosis of the tumor
Clinical aspects of neoplasia
– Cachexia
• common event
• loss of body fat and weight  loss of fat and also muscle
• profound weakness
• anorexia
• anaemia
In cachexia the basal metabolic rate is increased (contrary to starvation, where the basal
metabolic rate is decreased, which is an adaptive reaction).
Cachexia is due to certain cytokin production, like TNF (tumour necrosis factor),
produced by macrophages in response to tumour cells.
– TNF
Mobilizes fat from stores, reduces appetite
In conjunction with TNF, IL1, IF γ also plays important role in development of cachexia.
They are synergistic.
Reduce proteins synthesis and stimulate protein catabolism (through the activation of
ATP-dependent ubiquitin proteasome pathway)
1/3 of death in cancer is due to cachexia and not the tumor burden itself.
Paraneoplastic syndromes
•
Symptom complexes, which can not be explained by local/metastatic spread of the tumour or
hormone production of the host tissue where the tumour arose.
Important to recognize because:
•
It may represent the earliest manifestation of an occult neoplasm
•
Maybe clinically significant lading to death
•
May mimic metastatic (systemic) disease
Paraneoplastic syndromes:
Ectopic hormone production
Hypercalcaemia
Neuromyopathies
Acanthosis nigricans
Hypertrophyic osteoartropathy
Vascular/haematologic manifestations.
Clinical Syndromes
ENDOCRINOPATHIES
Cushing syndrome
Syndrome of inappropriate antidiuretic hormone
secretion
Hypercalcemia
Hypoglycemia
Carcinoid syndrome
Polycythemia
NERVE AND MUSCLE SYNDROMES
Myasthenia
Disorders of the central and peripheral nervous
system
DERMATOLOGIC DISORDERS
Acanthosis nigricans
Major Forms of Underlying Cancer
Causal Mechanism
Small-cell carcinoma of lung
ACTH or ACTH-like substance
Pancreatic carcinoma
Neural tumors
Small-cell carcinoma of lung; intracranial neoplasms Antidiuretic hormone or atrial natriuretic hormones
Squamous cell carcinoma of lung
Breast carcinoma
Renal carcinoma
Adult T-cell leukemia/lymphoma
Ovarian carcinoma
Fibrosarcoma
Other mesenchymal sarcomas
Hepatocellular carcinoma
Bronchial adenoma (carcinoid)
Pancreatic carcinoma
Gastric carcinoma
Renal carcinoma
Cerebellar hemangioma
Hepatocellular carcinoma
Parathyroid hormone–related protein (PTHRP),
TGF-α, TNF, IL-1
Bronchogenic carcinoma
Breast carcinoma
Immunological
Gastric carcinoma
Lung carcinoma
Uterine carcinoma
Dermatomyositis
Bronchogenic, breast carcinoma
OSSEOUS, ARTICULAR, AND SOFT-TISSUE CHANGES
Hypertrophic osteoarthropathy and clubbing of the Bronchogenic carcinoma
fingers
VASCULAR AND HEMATOLOGIC CHANGES
Venous thrombosis (Trousseau phenomenon)
Pancreatic carcinoma
Bronchogenic carcinoma
Other cancers
Nonbacterial thrombotic endocarditis
Advanced cancers
Red cell aplasia
Thymic neoplasms
OTHERS
Nephrotic syndrome
Various cancers
Insulin or insulin-like substance
Serotonin, bradykinin
Erythropoietin
Immunological; secretion of epidermal growth factor
Immunological
Unknown
Tumor products (mucins that activate clotting)
Hypercoagulability
Unknown
Tumor antigens, immune complexes
•
•
•
•
•
•
Ectopic hormon production
– Cushing syndrome  50% of patients has bronchus cc. (SCLC) ACTH , corticotrophin like peptide ,
ACTH precursor  (PROOPIOMELANOCORTIN) only in case of ectopic hormone production
– Carcinoid syndrome (flush, asthmatic events, diarrhoea, endocardial fibrosis)
Hypercalcaemia
– Production of PTHRP (parathormon related protein)  normal tissues produce in small concentrations
(epithelial cells, muscles, bone tissue, ovary, lung and breast)
– Carcinomas of lung (SCC of lung), breast cc. may produce
Neuromyopathies
– Peripheral neuropathy, cortical cerebellar degeneration, polymyopathy, myasthenic syndrome
– Pathogenesis: poorly understood  perhaps autoimmun reaction, autoantibodies generated against tumour
cells antigens  cross react with neuronal antigens.
Acanthosis nigricans
– Normally genetic disorder charatherised by gray-black patches on the skin  verrucose hyperkeratoses in
juveniles and young adults.
– Over 40 years of age  it appears as paraneoplastic syndrome which sometimes appears earlier than the
disease itself.
Hypertrophyic osteoartropathy
– 1-10% of lung cancers: periosteal new bone formation on distal end of long tube bones, arthritis, clubbing of
digits.
Vascular/haematologic manifestations
– Migratory thrombophlebitis (Trousseau syndrome): carcinoma of pancreas and lung.
– DIC (APL, prostatic adenocarcinoma)
– Deep vein thrombosis
– NBTE (mucin-secreting adenocarcinoma)
Tumour Markers
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•
Biochemical assays for tumour-associated enzymes, hormones, other markers in the blood
may contribute to detection of a cancer, they are very useful in determining the effectiveness
of therapy and the recurrency.
Examples:
– PSA (prostata specific antigen /prostatic adenocarcinoma/)
– CEA (carcinoembryonic antigen)  CRC (colorectal adenocarcinoma), pancreas cc.,
stomach cc. breast cc.
– AFP (alphafoetoprotein)  HCC, yolk sac tumour, teratocarcinoma, embryonal
carcinoma
– All of those markers above do not rule out and do not disclose the presence of a tumor
in 100% chance.
Tumor markers
Laboratory diagnosis of cancer
• Clinical information: extremely important
– Radiation changes (skin, mucosa), regeneration (healing after bone fracture) all can mimic
dysplastic changes, malignancy
• Sampling:
– excision biopsy (open/laparoscopic surgery), sampling errors, question of representativity
– true-cut biopsy (core biopsy specimen)
– FNAB (palpable lesions of breast, lymph node, thyroid, salivary gland, US/CT guided from
deeper structures), less invasive, rapid
– exfoliative cytology (cervical/endocervical smear/PAP staining, bronchus brush cytology,
urine/sputum/CSF)
• Appropriate preservation of the specimen (formaline, glutaraldehyde, ASAP)
• Frozen technique: determining the nature of a mass lesion, evaluation of the
resection margin
• Ancillary techniques: IHC, ISH, PCR, molecular profiling
Ancillary techniques
• IHC: identification of cell products, intermediate filaments, surface markers
– To identify line of differentiation in undifferentiated neoplasms (CK, vim., desmin, lymphoid
markers)
– Identification of home/organ/tissue specific antigens in metastatic tumors (PSA,
thyreoglobulin)
– Identification of molecules having prognostic, therapeutic significance (ER/PR, Her2, c-kit)
• Flow cytometry: rapid and quantitative measurement of cell characteristics
– DNA content
– Membrane proteins
– Useful to identify T and B cells, and other haematopoietic cells
• PCR: quick and effective amplification of a given DNA sequence
– clonality of a lymphoid population (T and B), indication of residual disease (CML),
identification of translocations, gene mutations (KRAS, NRAS, KIT, BRAF), deletions
• ISH: in situ study of gene/chromosome alterations (translocations,
amplifications
• CGH: study of gains and losses
• Karyotyping: (the basic method of studying chromosomes)
• Spectral karyotyping: (24-color) detects chromosomal changes
Grading and staging of tumours
•
Indicates the probable clinical agressiveness of a given neoplasm
•
and it’s apparent extent and spread in the individual patient
•
Staging and grading is necessary for making an accurate diagnosis
•
Both are necessary for comparing the end results of various treatment protocols.
•
Grading of a neoplasm: the level of differentiation of tumour tissue
• Staging of a neoplasm: local extents and spreading type of the cancer in a given patient.
Grading of a cancer: degree of differentiation of the tumour cells, the number of mitoses and some architectural
features (like formation of glands)
•
Grades are: low grade, high grade (two categories), low, intermediate and high grade (three categories) and
grade 1, 2, 3, 4 (four categories).
•
Criteria for individual grades vary with each form of neoplasia
•
In general with a few exceptions, such as soft tissue sarcomas, grading of cancers has proved less clinical
value than has staging.
Staging of cancers:
•
1. Based on the size of the primary lesion
•
2. The extent of spread to regional lymph nodes and
•
3. The presence or absence of blood born metastasis
•
AJCC (American Joint Committee on Cancer Staging) developed the TNM system
•
T stands for primary tumour, N for regional lymph node involvement and M for metastases.
•
T goes from T1 up to T4, T0 (no evidence of tumour), Tis (means in situ lesion), N goes N1 up to N3
indicating the involvement of lymph nodes in number and in different region, M means presence or absence
of metastases (M0 or M1)
Mandatory parameters
T: size or direct extent of the primary tumor
Tx: tumor cannot be evaluated, Tis: carcinoma in situ, T0: no signs of tumor
T1, T2, T3, T4: size and/or extension of the primary tumor
N: degree of spread to regional lymph nodes
Nx: lymph nodes cannot be evaluated, N0: tumor cells absent from regional, N1: regional
lymph node metastasis present; (at some sites: tumor spread to closest or small number of
regional lymph nodes)
N2: tumor spread to an extent between N1 and N3 (N2 is not used at all sites)
N3: tumor spread to more distant or numerous regional lymph nodes (N3 is not used at all
sites)
M: presence or absence of distant metastasis, M0: no distant metastasis, M1: metastasis to
distant organs
Prefix modifiers
c: stage given by clinical examination. The c-prefix is implicit in absence of the p-prefix
p: stage given by pathologic examination of a surgical specimen
y: stage assessed after chemotherapy and/or radiation therapy (neoadjuvant therapy)
r: stage for a recurrent tumor in an individual that had some period of time free from the
disease.
a: stage determined at autopsy
u: stage determined by US. Clinicians often use this modifier although it is not an officially
defined one
Staging of CRC
Staging of bladder cancer