pathology

2. Plan of the lecturePlan of the lecture
1. Neoplastic growth. Definition.
2. Features of benign and malignant tumors.
3. Classification of cancerogens.
4. Pathogenesis of tumors.
5. Stages of cancerogenesis.
6. Characteristic of tumor cells.
7. Mechanism of immunological response
against tumor cells.
8. Treatment of tumors.

3. Actuality of the lectureActuality of the lecture
By the prognoses of Worldwide health protectionBy the prognoses of Worldwide health protection
organization morbidity and death rate from oncologicorganization morbidity and death rate from oncologic
diseases in the whole worlddiseases in the whole world will grow in 2 timeswill grow in 2 times forfor
period from 1999 year for 2020period from 1999 year for 2020: from 10 to the 20: from 10 to the 20
million new cases and from 6 to the 12 millionmillion new cases and from 6 to the 12 million
registered deaths.registered deaths.
Taking into account that in the developed countriesTaking into account that in the developed countries
there is a tendency to deceleration of growth ofthere is a tendency to deceleration of growth of
morbidity and death rate from malignant tumors (due tomorbidity and death rate from malignant tumors (due to
the prophylaxis and due to the improvement of earlythe prophylaxis and due to the improvement of early
diagnostics and treatment), clearly, that a basicdiagnostics and treatment), clearly, that a basic
increase will be at developing countries (countries ofincrease will be at developing countries (countries of
former USSR). That is why doctors have to expectformer USSR). That is why doctors have to expect
serious increase of morbidity and death rate fromserious increase of morbidity and death rate from
oncopathology.oncopathology.
From data of Committee of cancer prophylaxis 90%From data of Committee of cancer prophylaxis 90%
tumors are related to influencing of external factors, andtumors are related to influencing of external factors, and
10% - depend on genetic factors.10% - depend on genetic factors.

4. Neoplasia –Neoplasia –
““new growth”new growth” && newnew
growth is calledgrowth is called
aa neoplasmneoplasm..
 NeoplasiaNeoplasia is new tissue growth that is:is new tissue growth that is:
 unregulated,unregulated,
 irreversible,irreversible,
 monoclonal.monoclonal.
 Monoclonal means that the neoplastic cells are derivedMonoclonal means that the neoplastic cells are derived
from a single mother cell.from a single mother cell.
 CancerCancer is anis an overgrowthovergrowth of cellsof cells
bearing cumulativebearing cumulative genetic injuriesgenetic injuries thatthat
confer growth advantage over theconfer growth advantage over the
normal cells.normal cells. [[Nowell’s LawNowell’s Law]]
these featuresthese features
distinguish it fromdistinguish it from
hyperplasia and repairhyperplasia and repair

5. • Oncology (Greek oncos = tumor) is the
study of tumors or neoplasms.
• Cancer is the common term for all
malignant tumors.
• Although the ancient origins of this term
are somewhat uncertain, it probably
derives from the Latin for crab, cancer —
presumably because a cancer "adheres to
any part that it seizes upon in an obstinate
manner like the crab."

6.  Believe it or not, cancer has affected people for several
centuries. It is not a new disease.
 The word cancer came from the father of medicine, Hippocrates,
a Greek physician. He used the Greek words, carcinos and
carcinoma to describe tumors, thus calling cancer “karkinos.”
 Hippocrates (460-377 BC) coined the term karkinos for
cancer of the breast.
 The word ‘cancer’‘cancer’ means crabcrab, thus reflecting the true
character of cancer since ‘it sticks to the part stubbornly like a
crabcrab’. He was certainly not the first to discover the disease.
 The history of cancer actually begins much earlier.
The History of Cancer, Lisa Fayed, About.com July,2008

7. • The world's oldest documented case of cancer hailsThe world's oldest documented case of cancer hails
from ancient Egypt, infrom ancient Egypt, in 3000 b.c.3000 b.c.
• The details were recorded on a papyrus, documentingThe details were recorded on a papyrus, documenting
8 cases of tumors occurring on the breast.8 cases of tumors occurring on the breast.
• It was treated by cauterization. It was also recordedIt was treated by cauterization. It was also recorded
that there was no treatment for the disease, onlythat there was no treatment for the disease, only
palliative treatment.palliative treatment.
• There is evidence that the ancient Egyptians wereThere is evidence that the ancient Egyptians were
able toable to tell the difference between malignant andtell the difference between malignant and
benign tumors.benign tumors.
• In ancient Egypt, it was believed cancer wasIn ancient Egypt, it was believed cancer was
caused by the Gods.caused by the Gods. The History of Cancer, Lisa Fayed, About.com July,2008

8. Ebers PapyrusEbers Papyrus treatment
for cancer: recounting a "
tumortumor against the god
Xenus", it recommends
"do nothing there against"
http://en.wikipedia.org/wiki/Ancient_Egyptian_medicine
Ancient Egyptian
medical instruments
depicted in a Ptolemaic
period inscription on
the Temple of Kom
Ombo.

9. TerminologyTerminology
 HyperplasiaHyperplasia -- increase in theincrease in the
number of cells,number of cells,
 HypertrophyHypertrophy - increase in the- increase in the
sizessizes of individual cellsof individual cells..
 AtrophyAtrophy isis an adaptivean adaptive
response in which there is aresponse in which there is a
decrease in the size anddecrease in the size and
function of cells.function of cells.
 AnaplasiaAnaplasia - lack of differentiation.- lack of differentiation.

10. MetaplasiaMetaplasia ::
TransformationTransformation
of a certainof a certain
type oftype of
differentiateddifferentiated
tissue intotissue into
another typeanother type ofof
differentiateddifferentiated
tissue.tissue.
HeteroplasiaHeteroplasia ::
Occurrence ofOccurrence of
non-neoplasticnon-neoplastic
tissue at atissue at a
location wherelocation where
it does notit does not
normallynormally
occur, either inoccur, either in
a heterotopiaa heterotopia
or as a resultor as a result ofof
tissuetissue
dissemination.dissemination.

12. All tumors,All tumors, benignbenign as well asas well as
malignantmalignant, have 2 basic components:, have 2 basic components:
““Parenchyma”Parenchyma”
comprised bycomprised by
proliferating tumor cells;proliferating tumor cells;
parenchymaparenchyma
determines the naturedetermines the nature
and evolution of theand evolution of the
tumortumor.
“Supportive stroma”Supportive stroma”
composed of fibrouscomposed of fibrous
connective tissueconnective tissue
and blood vessels; itand blood vessels; it
provides the frameworkprovides the framework
on which theon which the
parenchymal tumorparenchymal tumor
cells grow.cells grow.

13. NOMENCLATURENOMENCLATURE
BenignBenign tumors are designatedtumors are designated
by attaching the suffixby attaching the suffix -oma-oma to the cellto the cell
of origin. Tumors ofof origin. Tumors of mesenchymalmesenchymal
cellscells generally follow this rule.generally follow this rule.
For exampleFor example, a benign tumor arising, a benign tumor arising fromfrom
fibroblastic cellsfibroblastic cells is calledis called aa fibromafibroma,, aa
cartilaginous tumocartilaginous tumor isr is aa chondromachondroma, a, a
tumor oftumor of osteoblastsosteoblasts is anis an osteomaosteoma..
AdenomaAdenoma is the term applied to ais the term applied to a
benign epithelial neoplasm that formsbenign epithelial neoplasm that forms
glandularglandular patterns as well as topatterns as well as to
tumors derived from glands but nottumors derived from glands but not
necessarily reproducing glandularnecessarily reproducing glandular
patterns.patterns.
Benign epithelialBenign epithelial neoplasmsneoplasms
producing microscopically orproducing microscopically or
macroscopicallymacroscopically visible finger-likevisible finger-like oror
warty projectionswarty projections from epithelialfrom epithelial
surfaces are referred to assurfaces are referred to as papillomaspapillomas
MalignantMalignant tumours of epithelialtumours of epithelial
origin are calledorigin are called carcinomascarcinomas, while, while
malignantmalignant mesenchymalmesenchymal tumourstumours
are namedare named sarcomas (sarcos =sarcomas (sarcos =
fleshy)fleshy)
For exampleFor example,, fibrosarcoma,fibrosarcoma,
liposarcomaliposarcoma,, leiomyosarcomaleiomyosarcoma forfor
smooth muscle cancersmooth muscle cancer, and, and
rhabdomyosarcomarhabdomyosarcoma for a cancer thatfor a cancer that
differentiates towarddifferentiates toward striated musclestriated muscle).).
However, some cancers areHowever, some cancers are
composed of highlycomposed of highly undifferentiatedundifferentiated
cells and are referred to ascells and are referred to as
undifferentiated malignant tumours.undifferentiated malignant tumours.
TeratomasTeratomas (can be benign)(can be benign),, inin
contrast, are made up of a variety ofcontrast, are made up of a variety of
parenchymal cell typesparenchymal cell types
representative of more than onerepresentative of more than one
germ layer, usually all three.germ layer, usually all three.

14. "Knapsack” tumor: lipoma
Pleural sarcomatosis:Pleural sarcomatosis:
metastatic sarcoma of the uterusmetastatic sarcoma of the uterus

15. CANCER CELLS AND NORMAL
CELLS
CANCER CELLSCANCER CELLS NORMAL CELLSNORMAL CELLS
Loss of contact inhibitionLoss of contact inhibition
Increase in growth factor secretionIncrease in growth factor secretion
Increase in oncogene expressionIncrease in oncogene expression
Loss of tumor suppressor genesLoss of tumor suppressor genes
Oncogene expression is rareOncogene expression is rare
Intermittent or co-ordinatedIntermittent or co-ordinated
growth factor secretiongrowth factor secretion
Presence of tumor suppressorPresence of tumor suppressor
genesgenes
NormalNormal
cellcell
FewFew
mitosesmitoses
FrequentFrequent
mitosesmitoses
NucleusNucleus
Blood vesselBlood vessel
AbnormalAbnormal
heterogeneous cellsheterogeneous cells

16. Characteristics of Benign and Malignant NeoplasmsCharacteristics of Benign and Malignant Neoplasms
CharacteristicsCharacteristics BenignBenign MalignantMalignant
CellCell
characteristicscharacteristics
Well-differentiated cells that resemble
normal cells of the tissue from which
the tumor originated
Cells are undifferentiated and often bear little
resemblance to the normal cells of the tissue
from which they arose
Mode of growthMode of growth
Tumor grows by expansion and does
not infiltrate the surrounding tissues;
usually encapsulated by a fibrous
capsule (exception – uterine leiomyomas do(exception – uterine leiomyomas do
not have fibrous tissue capsule)not have fibrous tissue capsule)
Grows at the periphery and sends out
processes that infiltrate and destroy the
surrounding tissues
Rate of growthRate of growth Rate of growth usually is slow
Rate of growth is variable and depends on
level of differentiation; the more anaplastic the
tumor, the more rapid the rate of growth
MetastasisMetastasis Does not spread by metastasis
Gains access to the blood and lymph channels
and metastasizes to other areas of the body
General effectsGeneral effects
Usually is a localized phenomenon that
does not cause generalized effects
unless its location interferes with vital
functions
Often causes generalized effects such as
anemia, weakness, and weight loss
TissueTissue
destructiondestruction
Usually does not cause tissue damage
unless its location interferes with blood
flow
Often causes extensive tissue damage as the
tumor outgrows its blood supply or
encroaches on blood flow to the area; also
may produce substances that cause cell
damage
Ability to causeAbility to cause
deathdeath
Usually does not cause death unless its
location interferes with vital functions
Usually causes death unless growth can be
controlled

17. Principal Pathways of
Malignancy
1. Proliferation
2. Cell-Cycle Progression
3. DNA Repair
4. Immortalization
5. Apoptosis
6. Angiogenesis
7. Metastasis and Invasion

18. 1)External factors:1)External factors: tobacco,
alcohol, chemicals,
radiation, pathogens
2) Internal factors:2) Internal factors: hormones,
immune conditions, inheriled
mutations
 1. Age > 55 years - more than 75% of cancers.
 2. Causes:
3. Blacks
a. Greatest risk for cancer
and cancer-related
deaths of any other racial
group or ethnicity
b. Applies to almost all
cancers except
malignant melanoma
4. Hispanics and Asians
Lower incidence rates for all
cancers combined than
whites
b. Exceptions are for cancers
associated with infections –
cervix (human papillomavirus),
liver (hepatitis B and C),
stomach (Helicobacter pylori)
5. Native Americans
• Highest incidence and
cancer-related deaths
due to kidney cancer
than all racial and
ethnic populations.
Cancer incidenceCancer incidence
1. Cancers in children1. Cancers in children
a.a. Second most common cause of deathSecond most common cause of death inin
children (accidents most common cause)children (accidents most common cause)
b.b. Acute lymphoblastic leukemiaAcute lymphoblastic leukemia (-33%),(-33%),
central nervous system (CNS) tumors (-21%),central nervous system (CNS) tumors (-21%),
neuroblastoma (~7%), Wilms' tumor (-5%).neuroblastoma (~7%), Wilms' tumor (-5%).
•• These are not common tumors in adults.These are not common tumors in adults.
2.2. Cancers in menCancers in men
(in decreasing order)(in decreasing order)
•• ProstateProstate, lung, colorectal, lung, colorectal
3.3. Cancers in womenCancers in women
(in decreasing order)(in decreasing order)
•• BreastBreast, lung, colorectal, lung, colorectal

19. Cancer GeographyCancer Geography
1. Worldwide
•• Malignant melanoma isMalignant melanoma is
increasing at the most rapidincreasing at the most rapid
rate of all cancers.rate of all cancers.
2. China2. China
•• NasopharyngealNasopharyngeal
carcinoma secondary tocarcinoma secondary to
Epstein-Barr virus (EBV)Epstein-Barr virus (EBV)
3. Japan3. Japan
•• StomachStomach
adenocarcinomaadenocarcinoma
due t0 smoked foodsdue t0 smoked foods
4. Southeast Asia4. Southeast Asia
•• Hepatocellular carcinomaHepatocellular carcinoma
due to hepatitis B virus plusdue to hepatitis B virus plus
aflatoxins (produced byaflatoxins (produced by
Aspergillus) in foodAspergillus) in food
5. Africa5. Africa
•• Burkitt's lymphoma due to EBV andBurkitt's lymphoma due to EBV and
Kaposi's sarcoma due t0 humanKaposi's sarcoma due t0 human
herpes virus 8.herpes virus 8.
Epidemiology of Endometrial CancerEpidemiology of Endometrial Cancer

20. CausalCausal
TumorigenesisTumorigenesis
 CancerCancer is ais a genetic disordergenetic disorder that arises from athat arises from a
single body cell (monoclonal disorder).single body cell (monoclonal disorder).
 In humansIn humans and other animals, it may beand other animals, it may be
triggeredtriggered byby noxious chemicalnoxious chemical,, viralviral, and, and
physical agentsphysical agents withwith mutagenic effectsmutagenic effects..
 Cells acquire severalCells acquire several characteristics duringcharacteristics during
the course of this disease.the course of this disease.

21. CARCINOGENCARCINOGEN
METABOLISMMETABOLISM
Three Main Categories:Three Main Categories:
I. Chemical Carcinogens
II. Physical Carcinogens
III. Viral Agents
CarcinogensCarcinogens MutationsMutations CancerCancer
??EnvironmentalEnvironmental
factorsfactors

22. CARCINOGENSCARCINOGENS
• Occupation related causesOccupation related causes
• Lifestyle related causesLifestyle related causes
– TobaccoTobacco
– DietDiet
– Sexual practicesSexual practices
• Multifactorial causesMultifactorial causes
• Chemical carcinogensChemical carcinogens
• Ionizing radiationIonizing radiation
• Viral carcinogensViral carcinogens

23. CHEMICAL CARCINOGENESISCHEMICAL CARCINOGENESIS
Direct-acting CarcinogensDirect-acting Carcinogens
A.A. Alkylating agents
• Anti-cancer drugs: cyclophosphamide
(transitional cell carcinoma of urinary bladder)(transitional cell carcinoma of urinary bladder),
chlorambucil, busulfan, melphalan,
nitrosourea etc.
• β-propiolactone;
• Epoxides
B. Acylating agents:
• Acetyl imidazole
• Dimethyl carbamyl chloride
PromotersPromoters
 saccharine & cyclamatessaccharine & cyclamates
 EstrogenEstrogen ((endometrial carcinoma.
Adenocarcinoma of the vagina is seen with
increased frequency in adolescent daughters of
mothers who had received estrogen therapy
during pregnancy).

Anabolic steroids (↑ the risk of
developing benign and malignant tumors of the
liver)

Contraceptive hormonesContraceptive hormones ((↑ the risk of
developing breast cancer. For long durations
are benign tumors of the liver, and a few
patients have been reported to have developed
hepatocellular carcinoma.
Gregg Valentino

24. ProcarcinogensProcarcinogens
1. Polyclic,1. Polyclic, aromatic hydrocarbons (in tobacco, smoke, fossil fuel, soot, tar, minerals
oil, smoked animal foods, industrial and atmospheric pollutants)
(Lung cancer, skin cancer, cancer of upper aerodigestive tract)
• Anthracenes (benza-, dibenza-, dimethyl benza-)
• Benzapyrene;
• Methylcholanthrene
2.2. Aromatic amines and azo-dyes:
• β-naphthylamine; Benzidine (Bladder cancer)
• Azo-dyes (e.g. butter yellow, scarlet red) (hepatocellular carcinoma)
3. Naturally-occurring products
 Aflatoxin B1Aflatoxin B1 ((Hepatocellular carcinoma in association with hepatitis B virusHepatocellular carcinoma in association with hepatitis B virus))
 Actinomycin D; Mitomycin C; Safrole; Betel nutsActinomycin D; Mitomycin C; Safrole; Betel nuts
4. Miscellaneous
 Nitrosamine & AmidesNitrosamine & Amides
 AsbestosAsbestos ((Bronchogenic carcinoma, pleural mesotheliomaBronchogenic carcinoma, pleural mesothelioma))
 Vinyl chlorideVinyl chloride ((Angiosarcoma, liverAngiosarcoma, liver))
 Chromium, nickel, other metalsChromium, nickel, other metals ((Bronchogenic carcinomaBronchogenic carcinoma))
 ArsenicArsenic ((Squamous cell carcinoma of skin, lung cancer, liver angiosarcomaSquamous cell carcinoma of skin, lung cancer, liver angiosarcoma))
3,4-benzopyrene3,4-benzopyrene
This lady chews betel nuts the fruit of a palm

25. Stages:Stages:
InitiationInitiation - primary exposure- primary exposure
PromotionPromotion - transformation- transformation
ProgressionProgression - Cancer growth- Cancer growth
CancerCancer

26. InitiationInitiation
 normal cells are exposed to a carcinogennormal cells are exposed to a carcinogen
 not enough to cause malignant transformationnot enough to cause malignant transformation
 requires one round of cell divisionrequires one round of cell division
 normal cells are exposed to a carcinogennormal cells are exposed to a carcinogen
1. Direct-acting carcinogens1. Direct-acting carcinogens
2. Indirect-acting carcinogens2. Indirect-acting carcinogens
ProcarcinogenProcarcinogen CytochromeCytochrome
P450P450
UltimateUltimate
carcinogencarcinogen
PromotionPromotion
 initiated cells are exposed to promotersinitiated cells are exposed to promoters
 promoters are not carcinogens !promoters are not carcinogens !
 properties of promotersproperties of promoters  reversiblereversible
 dose-dependentdose-dependent
 time-dependenttime-dependent

27. 1. Radiation1. Radiation
1). Ionizing radiation-induced cancers1). Ionizing radiation-induced cancers
a. Mechanism:a. Mechanism:
•• Hydroxyl free radical injury to DNAHydroxyl free radical injury to DNA
b. Examplesb. Examples
(1)(1) Acute myelogenous or chronic myelogenousAcute myelogenous or chronic myelogenous
leukemia (leukemia ( risk of leukemia in radiologists andrisk of leukemia in radiologists and
individuals exposed to radiation in nuclear reactors);individuals exposed to radiation in nuclear reactors);
(2) Papillary thyroid carcinoma(2) Papillary thyroid carcinoma
(3) Lung, breast, and bone cancers(3) Lung, breast, and bone cancers
(4) Liver angiosarcoma(4) Liver angiosarcoma (Due to radioactive thorium(Due to radioactive thorium
dioxide used to visualize the arterial tree)dioxide used to visualize the arterial tree)
2). UV light-induced cancers2). UV light-induced cancers
a. Mechanisma. Mechanism
•• Formation of pyrimidine dimers, which distort DNAFormation of pyrimidine dimers, which distort DNA
b. Basal cell carcinoma, squamous cell carcinoma,b. Basal cell carcinoma, squamous cell carcinoma,
malignant melanomamalignant melanoma
2. Physical injury2. Physical injury
1). Squamous cell carcinoma may develop in third-1). Squamous cell carcinoma may develop in third-
degree burn scars.degree burn scars.
2). Squamous cell carcinoma may develop at the2). Squamous cell carcinoma may develop at the
orifices of chronically draining;orifices of chronically draining;
sinuses (e.g., chronic osteomyelitis),sinuses (e.g., chronic osteomyelitis),
Physical CarcinogenesisPhysical Carcinogenesis
PRE-IRRADIATIONPRE-IRRADIATION POST-IRRADIATIONPOST-IRRADIATION
ChondrosarcomaChondrosarcoma

28. Ultraviolet RaysUltraviolet Rays
UV-A = 320 - 400 nm
UV-B = 280 - 320 nm
UV-C = 200 - 280 nm
UV-CUV-C ⇒⇒ filtered by ozonefiltered by ozone
UV-BUV-B
Inhibition of cell divisionInhibition of cell division
inactivation of enzymesinactivation of enzymes
induction of mutations cellinduction of mutations cell
death at high dosesdeath at high doses
Squamous cell cancerSquamous cell cancer
Basal cell cancerBasal cell cancer
MelanocarcinomaMelanocarcinoma

29. Virus MECHANISM ASSOCIATED CANCER
RNA Viruses
HCV Produces postnecrotic cirrhosis Hepatocellular carcinomaHepatocellular carcinoma
HTLV-1 (human
T-cell lympho-
tropic virus)
Activates TAX gene, stimulates
polyclonal T-cell proliferation,
inhibits TP53 suppressor gene
T-cell leukemia and lymphomaT-cell leukemia and lymphoma
DNA VirusesDNA Viruses
EBV (Epstein-
Barr virus)
Promotes polyclonal B-cell
proliferation, which increases risk
for t(8:14) translocation
Burkitt's lymphoma, CNS lymphomaBurkitt's lymphoma, CNS lymphoma
in AIDS, mixed cellularity Hodgkin'sin AIDS, mixed cellularity Hodgkin's
lymphoma, nasopharyngeallymphoma, nasopharyngeal
carcinomacarcinoma
HBV (hepatitis B
virus)
Activates proto-oncogenes,
inactivates TP53 suppressor gene
Hepatocellular carcinomaHepatocellular carcinoma
HHV-8 (human
herpesvirus)
Acts via cytokines released from
HIV and HSV
Kaposi's sarcoma in AIDSKaposi's sarcoma in AIDS
HPV types 16
and 18, 31, 33
(human
papillomavirus)
Type 16 (-50% of cancers); E6 gene
product inhibits; TP53 suppressor
gene
Type 18 (-10% of cancers); E7 gene
product inhibits; RB suppressor
gene
Squamous cell carcinoma of vulva,Squamous cell carcinoma of vulva,
vagina, cervix, anus (associatedvagina, cervix, anus (associated
with anal intercourse), larynx,with anal intercourse), larynx,
oropharynxoropharynx
Viral CarcinogenesisViral Carcinogenesis

30. VirusesViruses
(in brackets)(in brackets)
in humanin human
tumors.tumors.

31. Burkitt's lymphomaBurkitt's lymphoma
Viral carcinogenesisViral carcinogenesis
Laryngeal papillomatosisLaryngeal papillomatosis
Oral cancerOral cancer
Kaposi's sarcomaKaposi's sarcoma

32. A, Replication: Step 1. The DNA virus invades the host cell.
Step 2. Viral DNA is incorporated into the host nucleus and T-
antigen is expressed immediately after infection. Step 3.
Replication of viral DNA occurs and other components of virion
are formed. The new virions are assembled in the cell nucleus.
Step 4. The new virions are released, accompanied by host cell
lysis. B, Integration: Steps 1 and 2 are similar as in
replication. Step 3. Integration of viral genome into the host cell
genome occurs which requires essential presence of functional
T-antigen. Step 4. A ‘transformed (neoplastic) cell’ is formed.
Step 1. The RNA virus invades the host cell. The viral envelope
fuses with the plasma membrane of the host cell; viral RNA
genome as well as reverse transcriptase are released into the
cytosol. Step 2. Reverse transcriptase acts as template to
synthesise single strand of matching viral DNA which is then
copied to form complementary DNA resulting in double-stranded
viral DNA (provirus). Step 3. The provirus is integrated into the
host cell genome producing ‘transformed host cell.’ Step 4.
Integration of the provirus brings about replication of viral
components which are then assembled and released by

33. Lifestyle RiskLifestyle Risk
FactorsFactors
Tobacco-related:Tobacco-related:
 Lung cancerLung cancer
 Pancreatic cancerPancreatic cancer
 Bladder cancerBladder cancer
 Renal cancerRenal cancer
 Cervical cancerCervical cancer
LungLung
carcinomacarcinoma
in situin situ
Penetration of the vena cava:Penetration of the vena cava:
renal carcinomarenal carcinoma

34. Diet-Related Risk Factors
Nitrates
Salt
Low vitamins A, C, E
Low consumption of
yellow-green
vegetables
Gastric Cancer
Esophageal
Cancer

35. Diet-Related RiskDiet-Related Risk
FactorsFactors
High fat
Low fiber
Low calcium
High fried foods
Colon Cancer
Pancreatic Cancer
Prostate Cancer
Breast Cancer
Uterine Cancer
Mycotoxins Liver Cancer
Carcinoma of the prostateCarcinoma of the prostate

36. Sexual PracticesSexual Practices
Risk FactorsRisk Factors
Cervical Cancer
Sexual promiscuity
Multiple partners
Unsafe Sex
Human Papillomavirus

39. MultifactorialMultifactorial
FactorsFactors
Oral Cavity CancerOral Cavity Cancer
Esophageal CancerEsophageal Cancer
Tobacco + Asbestos
Tobacco + mining
Tobacco + uranium +
radium
Respiratory TractRespiratory Tract
CancerCancer
Lung CancerLung Cancer
Tobacco + Alcohol

40. CHARACTERISTICS OF CANCERCHARACTERISTICS OF CANCER
• ClonalityClonality
• AutonomyAutonomy
• AnaplasiaAnaplasia
• MetastasisMetastasis

41. CHARACTERISTICS OF CANCERCHARACTERISTICS OF CANCER
ClonalityClonality
 Clonality can be determined by glucose-6-Clonality can be determined by glucose-6-
phosphate dehydrogenase (G6PD) enzymephosphate dehydrogenase (G6PD) enzyme
isoforms.isoforms.
 1. Multiple isoforms (e.g., G6PD1. Multiple isoforms (e.g., G6PDAA, G6PD, G6PDBB, and, and
G6PDG6PDCC) exist; only one isoform is inherited) exist; only one isoform is inherited
from each parent.from each parent.
 2. In females, one isoform is randomly2. In females, one isoform is randomly
inactivated in each cell by lyonization (G6PD isinactivated in each cell by lyonization (G6PD is
present on the X chromosome).present on the X chromosome).
 3. Normal ratio of active isoforms in cells of any3. Normal ratio of active isoforms in cells of any
tissue is 1:1 (e.g., 50% of cells have G6PDtissue is 1:1 (e.g., 50% of cells have G6PDAA,,
and 50% of cells have G6PDand 50% of cells have G6PDGG).).
 4. 1:1 ratio is maintained in hyperplasia, which4. 1:1 ratio is maintained in hyperplasia, which
is polyclonal (cells are derived from multipleis polyclonal (cells are derived from multiple
cells).cells).
 5. Only one isoform is present in neoplasia,5. Only one isoform is present in neoplasia,
which is monoclonal.which is monoclonal.
 6. Clonality can also be determined by6. Clonality can also be determined by
androgen receptor isoforms, which are alsoandrogen receptor isoforms, which are also
present on the X chromosome.present on the X chromosome.

42. • Cancer cells are able to proliferate despiteCancer cells are able to proliferate despite
regulatory influences.regulatory influences.
• Unrestricted proliferation results in tumorUnrestricted proliferation results in tumor
formation.formation.
• Mechanisms:Mechanisms:
– Growth factor secretionGrowth factor secretion
– Increased number of cell receptorsIncreased number of cell receptors
– Independent activation of key biochemical processIndependent activation of key biochemical process
• Proliferation depends on the cell cycle.Proliferation depends on the cell cycle.
CHARACTERISTICS OF CANCERCHARACTERISTICS OF CANCER
AutonomyAutonomy

43.  A tumor usually isA tumor usually is
undetectable until itundetectable until it
has doubled 30has doubled 30
times and containstimes and contains
more than 1 billionmore than 1 billion
(10*9) cells. At this(10*9) cells. At this
point, it ispoint, it is
approximately 1 cmapproximately 1 cm
in size.in size.
 After 35 doublings,After 35 doublings,
the mass containsthe mass contains
more than 1 trillionmore than 1 trillion
(10*12) cells, which(10*12) cells, which
is a sufficientis a sufficient
number to kill thenumber to kill the
host.host.

44.  The concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at theThe concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at the
Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normalWistar Institute in Philadelphia. Hayflick demonstrated that a population of normal
human fetal cellshuman fetal cells in a cell culturein a cell culture will divide between 40 and 60 timeswill divide between 40 and 60 times. The. The
population will then enter a senescence phase, which refutes the contention bypopulation will then enter a senescence phase, which refutes the contention by
Nobel laureate Alexis CarrelNobel laureate Alexis Carrel that normal cells are immortal.that normal cells are immortal.
 Hayflick found thatHayflick found that cells go through three phasescells go through three phases::
 TheThe firstfirst is rapid, healthy cell division.is rapid, healthy cell division.
 In theIn the secondsecond phase, mitosis slows.phase, mitosis slows.
 In theIn the thirdthird stage,stage, senescencesenescence, cells stop dividing entirely. Once a cell reaches the, cells stop dividing entirely. Once a cell reaches the
end of its life span, it undergoes a programmed cellular death calledend of its life span, it undergoes a programmed cellular death called apoptosisapoptosis..
 EachEach mitosismitosis slightly shortens each of theslightly shortens each of the telomerestelomeres on the DNA of the cells.on the DNA of the cells.
 Telomere shortening in humans eventually makes cell division impossible, and thisTelomere shortening in humans eventually makes cell division impossible, and this
aging of the cell population appears to correlate with the overall physical aging ofaging of the cell population appears to correlate with the overall physical aging of
the human body.the human body.
 This mechanism also appears toThis mechanism also appears to prevent genomic instabilityprevent genomic instability..
 Telomere shorteningTelomere shortening may alsomay also prevent the development of cancerprevent the development of cancer in human agedin human aged
cells by limiting the number of cell divisions.cells by limiting the number of cell divisions.
 However,However, shortened telomeresshortened telomeres impair immune functionimpair immune function thatthat might also increasemight also increase
cancer susceptibilitycancer susceptibility..
The Hayflick limit is the number of times a normal
human cell population will divide until cell division stops.

45. I)I) Epidermal growth factor (EGF)Epidermal growth factor (EGF)
II)II) Fibroblast growth factor (FGF)Fibroblast growth factor (FGF)
III)III) Platelet-derived growth factor (PDGF)Platelet-derived growth factor (PDGF)
IV)IV) Colony stimulating factor (CSF)Colony stimulating factor (CSF)
V)V) Transforming growth factors-β (TGF-β)Transforming growth factors-β (TGF-β)
VI)VI) Interleukins (IL)Interleukins (IL)
VII)VII) Vascular endothelial growth factorVascular endothelial growth factor
(VEGF)(VEGF)

46. 1)1) Activation of growth-promoting oncogenesActivation of growth-promoting oncogenes causingcausing transformation of cell (mutanttransformation of cell (mutant
form of normal protooncogene in cancer is termedform of normal protooncogene in cancer is termed oncogene). Many of these canceroncogene). Many of these cancer
associated genes, oncogenes, were first discovered inassociated genes, oncogenes, were first discovered in viruses, and hence named asviruses, and hence named as
v-oncv-onc. Gene products of oncogenes are. Gene products of oncogenes are calledcalled oncoproteinsoncoproteins..
2)2) Inactivation of cancer-suppressor genesInactivation of cancer-suppressor genes (i.e. inactivation of(i.e. inactivation of anti-oncogenes)anti-oncogenes)
permitting the cellular proliferation of transformed cells. Anti-oncogenes are active inpermitting the cellular proliferation of transformed cells. Anti-oncogenes are active in
recessive formrecessive form i.e. they are active only if both alleles are damaged.i.e. they are active only if both alleles are damaged.
3)3) Abnormal apoptosis regulatory genesAbnormal apoptosis regulatory genes which may act aswhich may act as oncogenes or anti-oncogenes or anti-
oncogenes. Accordingly, these genes may be active in dominant or recessive form.oncogenes. Accordingly, these genes may be active in dominant or recessive form.
4)4) Failure of DNA repair genesFailure of DNA repair genes and thus inability to repair theand thus inability to repair the DNA damage resultingDNA damage resulting
in mutations.in mutations.
1)1) Proto-oncogenesProto-oncogenes are growth-promoting genes i.e. theyare growth-promoting genes i.e. they encode for cell proliferationencode for cell proliferation
pathway.pathway.
2)2) Anti-oncogenesAnti-oncogenes are growth-inhibiting or growth suppressorare growth-inhibiting or growth suppressor genes.genes.
3)3) Apoptosis regulatory genesApoptosis regulatory genes control the programmed cellcontrol the programmed cell death.death.
4)4) DNA repair genesDNA repair genes are those normal genes which regulateare those normal genes which regulate the repair of DNA damagethe repair of DNA damage
that has occurred during mitosis and also control the damage to proto-oncogenesthat has occurred during mitosis and also control the damage to proto-oncogenes
and antioncogenes.and antioncogenes.

47. MOLECULAR CARCINOGENESISMOLECULAR CARCINOGENESIS
MutationMutation
 the molecular hallmark of cancerthe molecular hallmark of cancer
Gene Families in Cancer DevelopmentGene Families in Cancer Development
11 - Oncogenes- Oncogenes
22 - Tumor Suppressor genes- Tumor Suppressor genes
33 - Mutator genes- Mutator genes

48. + oncogenes
Oncogenes
 promote cell proliferation
 dominant & highly conserved
 types: viral oncogenes [v-oncs]
cellular oncogenes [c-oncs]
Proto-oncogene ⇒ “Mutation” ⇒ Oncogene

50. Classification of OncogenesClassification of Oncogenes
E. Regulators of the Cell CycleE. Regulators of the Cell Cycle
Components ofComponents of
signalsignal
transductiontransduction
pathwayspathways
A. Secreted Growth FactorsA. Secreted Growth Factors
B. Cell Surface ReceptorsB. Cell Surface Receptors
C. Intracellular TransducersC. Intracellular Transducers
D. DNA-binding Nuclear ProteinsD. DNA-binding Nuclear Proteins
c-sis, hstc-sis, hst
erb B, fms, ret, trk, fes, fmserb B, fms, ret, trk, fes, fms
c-src, c-abl, mst, rasc-src, c-abl, mst, ras
myc, jun, fosmyc, jun, fos
bcl, bax, badbcl, bax, bad

51. PROTPROTOO--
ONCOONCOGGENEENE
FUNCTIONFUNCTION MUTATIONMUTATION CANCERCANCER
ABLABL
Nonreceptor tyrosineNonreceptor tyrosine
kinase activitykinase activity
TranslocationTranslocation
tt(9:22(9:22))
Chronic myelogenousChronic myelogenous
leukemialeukemia (chromosome(chromosome
22 is Philadelphia22 is Philadelphia chrchr..))
HERHER ((ERBB2)ERBB2) RecepRecepttor synor syntthesishesis AmplificationAmplification
Breast carcinomaBreast carcinoma
(marker of(marker of
aggressiveness)aggressiveness)
MYCMYC Nuclear transcriptionNuclear transcription
TranslocaTranslocattionion
tt(8:14)(8:14)
Burkitt's lymphomaBurkitt's lymphoma
N-MYCN-MYC Nuclear transcriptionNuclear transcription AmplificationAmplification NeuroblastomaNeuroblastoma
RASRAS
GuanosineGuanosine
triphosphatetriphosphate signalsignal
transductiontransduction
Point mutationPoint mutation
Leukemia; lung, colon,Leukemia; lung, colon,
pancreaticpancreatic carcinomascarcinomas
RETRET Receptor synthesis PoinPointt mulationmulation
Multiple endocrine
neoplasia lla/llb
syndromes
SIS’SIS’
Growth factor
synthesis
OverexpressionOverexpression
Osteogenic sarcoma,
astrocytoma

52. Mechanisms of Oncogene ActivationMechanisms of Oncogene Activation
H-ras
GTP
Perpetual cell division
1. Point Mutation
H-ras [codon 12]
Normal CGC → Gly
Bladder ca CTC → Val
2. Gene Amplification
Double minutes
HSRs
Normal copy Multiple copies

53. Mechanisms of Oncogene ActivationMechanisms of Oncogene Activation
3. Gene Translocation3. Gene Translocation
Ex. Chronic Myelogenous Leukemia [CML]Ex. Chronic Myelogenous Leukemia [CML]

54. Mechanisms of Oncogene ActivationMechanisms of Oncogene Activation
4. Viral Gene Integration4. Viral Gene Integration
promoter
Viral promoter

55. ONCOGENS
Categories of oncogenes include growth factors, growth factor receptors, signal
transducers, nuclear regulators, and cell cycle regulators
Mechanisms of activation of protooncogenes to formMechanisms of activation of protooncogenes to form
growth promoting oncogenes.growth promoting oncogenes.

56. Tumor Suppressor Genes
 Synonym:Synonym: anti-oncogenes
 Definition:Definition: Collective term for genes whose products physiologically inhibit
cell proliferation, promote cell differentiation, and also suppress certain
steps in tumorogenesis and metastasis.
 A. Regulate cell growth and, hence, decrease ("suppress")decrease ("suppress") the risk
of tumor formation;
 p53p53 and Rb (retinoblastoma) are classic examples.
 B. p53p53 regulates progression of the cell cycle from G1 to S phase,
 1. In response to DNA damage, p53 slows the cell cycle and upregulates
DNA repair enzymes.
 2. If DNA repair is not possible, p53 induces apoptosis.
 a). p53 upregulates BAX, which disrupts Bcl2.
 b). Cytochrome c leaks from the mitochondria activating apoptosis,
 3. Both copies of the p53 gene must be knocked out for tumor formation
(Knudson two-hit hypothesis).
 a). Loss is seen in > 50% of cancers.
 b). Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic),
characterized by the propensity to develop multiple types of carcinomas and
sarcomas.

57. TUMOR SUPPRESSOR GENETUMOR SUPPRESSOR GENE
FAMILYFAMILYRetinoblastoma gene [Retinoblastoma gene [RB1RB1 gene]gene]
 rare form of childhood malignancyrare form of childhood malignancy
 forms: hereditary & sporadicforms: hereditary & sporadic
pRb
 location: 17p13.1
 105-KDa nuclear protein
 function: induces DNA repair or apoptosis; inhibits E2F [prevents G1 → S
transition]
 inhibited by: phosphorylation, viral oncoproteins [E1A, E1B, HPV E6, E7]
 mutation: point mutation > deletion
 results to: loss of function & extended lifespan of p53
 Clinical conditions: carcinomas, Li Fraumeni Syndrome

58. Cell Cycle RegulationCell Cycle Regulation
► Process assures that cell accurately duplicates itsProcess assures that cell accurately duplicates its
contents.contents.
► Important checkpointsImportant checkpoints are present atare present at G1G1 andand G2G2 and areand are
regulated by protein kinasesregulated by protein kinases calledcalled cyclinscyclins (cdk).(cdk).
► Checkpoints determineCheckpoints determine
whether the cell proceeds twhether the cell proceeds t
next phase of the cycle.next phase of the cycle.

59. The role ofThe role of p53 inp53 in
maintaining the integrity ofmaintaining the integrity of
the genome.the genome.
Activation of normal p53 byActivation of normal p53 by
DNA-damaging agents or byDNA-damaging agents or by
hypoxia leads to cell-cyclehypoxia leads to cell-cycle
arrest in G1 and induction ofarrest in G1 and induction of
DNA repair, by transcriptionalDNA repair, by transcriptional
up-regulation of the cyclin-up-regulation of the cyclin-
dependent kinase inhibitordependent kinase inhibitor p21,p21,
and the GADD45 genes,and the GADD45 genes,
respectively.respectively.
Successful repair of DNASuccessful repair of DNA
allows cells to proceed with theallows cells to proceed with the
cell cycle; if DNA repair fails,cell cycle; if DNA repair fails,
p53-induced activation of thep53-induced activation of the
BAX gene promotes apoptosis.BAX gene promotes apoptosis.
In cells with loss or mutations ofIn cells with loss or mutations of
p53, DNA damage does notp53, DNA damage does not
induce cell-cycle arrest or DNAinduce cell-cycle arrest or DNA
repair, and hence geneticallyrepair, and hence genetically
damaged cells proliferate,damaged cells proliferate,
giving rise eventually togiving rise eventually to
malignant neoplasms.malignant neoplasms.

60. SOME TUMOR SUPPRESSOR GENES, THEIRSOME TUMOR SUPPRESSOR GENES, THEIR
FUNCTIONS, AND ASSOCIATED CANCERSFUNCTIONS, AND ASSOCIATED CANCERS
GENE FUNCTION ASSOCIATED CANCERS
APC
(adenomatous
polyposis coli)
Prevents nuclear transcriplion
(degrades catenin, an activator of
nuclear transcription)
Familial polyposis (colorectal carcinoma)
BRCA1/BRCA2BRCA1/BRCA2
(breast cancer)
Regulates DNA repairRegulates DNA repair Breast, ovary, prosBreast, ovary, prosttate carcinomasate carcinomas
RB
(retinoblastoma)
Inhibits G1 to S phase
Relinoblastoma, osteogenic sarcoma, breast
carcinoma
TGF-TGF-ββ
((transforming
growth factor-β)
Inhibits GInhibits G11 to S phaseto S phase PancreaPancreattic and colorectal carcinomasic and colorectal carcinomas
TP53
Inhibits G1 to S phase. Repairs
DNA, activates BAX gene (initiates
apoptosis)
Lung, colon, breast carcinomas. Li-
Fraumeni syndrome: breast carcinoma,
brain tumors, leukemia, sarcomas
VHLVHL ((VonVon
Hippel-LindauHippel-Lindau ))
Regulates nuclear transcriptionRegulates nuclear transcription
Von Hippel-Lindau syndrome: cerebellarVon Hippel-Lindau syndrome: cerebellar
hemangioblasloma, retinal angioma, renalhemangioblasloma, retinal angioma, renal
cell carcinoma (bilateral),cell carcinoma (bilateral),
pheochromocytoma (bilateral)pheochromocytoma (bilateral)
WT1 (Wilms'
tumor) Regulates nuclear transcription Wilms' tumor

61.  Antiapoptosis genes;Antiapoptosis genes; BcL2 family of genesBcL2 family of genes
 Prevent apoptosis in normal cells, but promote apoptosis in mutated cellsPrevent apoptosis in normal cells, but promote apoptosis in mutated cells
whose DNA cannot be repaired (e.g., Bcl2)whose DNA cannot be repaired (e.g., Bcl2)
 a. Protein products prevent cytochromea. Protein products prevent cytochrome c from leaving mitochondria.c from leaving mitochondria.
•• CytochromeCytochrome cc in the cytosol activates caspases initiating apoptosis.in the cytosol activates caspases initiating apoptosis.
b. Mutation causes increased gene activity (e.g., over expression), which preventsb. Mutation causes increased gene activity (e.g., over expression), which prevents
apoptosis; e.g..apoptosis; e.g.. B-cell follicular lymphoma.B-cell follicular lymphoma.
 (1)(1) BcL2 gene familyBcL2 gene family (chromosome 18) produces gene products that prevent(chromosome 18) produces gene products that prevent
mitochondrial leakage ofmitochondrial leakage of cytochrome ccytochrome c (signal for apoptosis).(signal for apoptosis).
 (2) Translocation t(14; 18) causes over expression of the BcL2 protein product.(2) Translocation t(14; 18) causes over expression of the BcL2 protein product.
•• Prevents apoptosis of B lymphocytes causingPrevents apoptosis of B lymphocytes causing B-cell follicular lymphomaB-cell follicular lymphoma
 Apoptosis genesApoptosis genes
a.a. Regulate programmed cell deathRegulate programmed cell death (ex. BAX apoptosis gene)(ex. BAX apoptosis gene)
 (1) Activated by a(1) Activated by a TP53TP53 suppressor gene product if DNA damage is excessivesuppressor gene product if DNA damage is excessive
 (2)(2) BAX proteinBAX protein product inactivates theproduct inactivates the BcL2 antiapoptosis gene.BcL2 antiapoptosis gene.
 (3) Mutation inactivating(3) Mutation inactivating TP53 suppressor gene renders the BAX gene inoperative,TP53 suppressor gene renders the BAX gene inoperative,
which prevents apoptosis.which prevents apoptosis.

62. Anaplasia
The third characteristic feature of tumor cells – is
anaplasiaanaplasia, which is cells structural and biochemical
organization simplification, coming back to embryonic state.
Neoplastic cells lose a capacity for differentiation and can
not form the specific tissue complexes.
Tumor arisesTumor arises from one mutational maternal cell. However
such cells differ from their general ancestor by much
parameters. These distinctions consearn the cell structure, its
organelles, metabolism, specific properties and functions.
Therefore the following kinds of anaplasiakinds of anaplasia are
distinguished:
 morphological,
 biochemical,
 physical and chemical,
 functional,
 immunological.

63.  The essence of morphological anaplasiamorphological anaplasia is in
appearance of atypic cultural and tissue.
 Description of cultural atypic – lays in:
℘ cellular polymorphism,
℘ nuclear size increase,
℘ polynuclear state,
℘ nuclear hyperchromatosis,
℘ nucleoluses amount increase,
℘mitochondrias changes –
quantative size decrease,
℘ crests disappearance
 Tissue atypism – is sizes and shapes of tissue
structures change, sometimes is the total loss
of morphological tissue signs.
Conjunctival melanoma

64.  Biochemical anaplasiaBiochemical anaplasia – is the tumor cells metabolism peculiarities.– is the tumor cells metabolism peculiarities.
Its are arose their genetic system changes, enzymic spectrum of suchIts are arose their genetic system changes, enzymic spectrum of such
cells gets changed. All cells get alike by enzymic admission (unificationcells gets changed. All cells get alike by enzymic admission (unification
of isoenzymic spectrum).of isoenzymic spectrum).
 The most typical biochemical feature of neoplasticThe most typical biochemical feature of neoplastic cellscells
concern proteins and carbohydrates metabolism.concern proteins and carbohydrates metabolism. Proteins metabolismProteins metabolism
peculiarities are:peculiarities are:
℘ synthesis activation of nucleic acids,synthesis activation of nucleic acids,
℘ DNA-polymerase inactivation,DNA-polymerase inactivation,
℘ increase of proteins synthesis,increase of proteins synthesis,
℘ decrease of proteins disintegration.decrease of proteins disintegration.
 Carbohydrates metabolism and energeticCarbohydrates metabolism and energetic of tumor cells is alsoof tumor cells is also
differ of norm. Thediffer of norm. The main energy sourcesmain energy sources in normal cells arein normal cells are
anaerobic and aerobic carbohydrates disintegrationanaerobic and aerobic carbohydrates disintegration, that is, that is
glycolysis and Krebs cycle. Neoplastic cell also receives the energyglycolysis and Krebs cycle. Neoplastic cell also receives the energy
owing to glycolysis and Krebs cycle. However glycolysis role in tumorowing to glycolysis and Krebs cycle. However glycolysis role in tumor
cell is more, than in normal one.cell is more, than in normal one.
 TheThe tumor cells energetic supply includetumor cells energetic supply include::
℘ anaerobic glycolysis activation,anaerobic glycolysis activation,
℘ aerobic glycolysis presence,aerobic glycolysis presence,
℘ oppression of Krebs cycle by powerful glycolytical enzymes systemoppression of Krebs cycle by powerful glycolytical enzymes system..

65.  Functional anaplasiaFunctional anaplasia
displays in loss or perversiondisplays in loss or perversion
of tumor cells function.of tumor cells function.
℘ For example, inFor example, in
neoplastic thyroid cells aneoplastic thyroid cells a
surplus amount ofsurplus amount of
hormones thyroxine andhormones thyroxine and
triiodothyronine can betriiodothyronine can be
synthesized, thyrotoxicosissynthesized, thyrotoxicosis
arises.arises.
℘℘ In other cases separate functions of tumor cells fall out, forIn other cases separate functions of tumor cells fall out, for
example, bilirubin does not get conjugated in hepatocyte.example, bilirubin does not get conjugated in hepatocyte.
 In veryIn very malignant neoplastic cellsmalignant neoplastic cells functions are totally lostfunctions are totally lost..
Sometimes such cells begin doing the functions, which areSometimes such cells begin doing the functions, which are
not specific for them (bronchus cancer synthesizes thenot specific for them (bronchus cancer synthesizes the
gastrointestinal hormones).gastrointestinal hormones).

66.  Immunological anaplasiaImmunological anaplasia –– isis change of tumor cellchange of tumor cell
antigen propertiesantigen properties. In such cells antigen admission is. In such cells antigen admission is
changed. Several deviation kinds of antigen out of normchanged. Several deviation kinds of antigen out of norm
admission are distinguishedadmission are distinguished antigen simplificationantigen simplification,,
antigen divergenceantigen divergence andand antigen reversionantigen reversion..
 Antigen simplificationAntigen simplification – is the general number of– is the general number of
neoplastic cells antigens diminution. For example, theneoplastic cells antigens diminution. For example, the
cells of normal tissue synthesize up to 7 typical antigens,cells of normal tissue synthesize up to 7 typical antigens,
while same tissue tumor cells synthesize only 2-3while same tissue tumor cells synthesize only 2-3
antigens.antigens.
 The idea ofThe idea of antigen divergenceantigen divergence is in the fact of neoplasticis in the fact of neoplastic
cells starting to synthesize heterologous antigens. Forcells starting to synthesize heterologous antigens. For
example, hepatoma (liver tumor) begins synthesizingexample, hepatoma (liver tumor) begins synthesizing
organospecific spleenic antigens, or other organsorganospecific spleenic antigens, or other organs
antigens.antigens.
 Antigen reversionAntigen reversion means neoplastic embryonic antigensmeans neoplastic embryonic antigens
synthesis. For example, human liver cancer synthesizes asynthesis. For example, human liver cancer synthesizes a
special embryonic protein, which is a-fetoprotein.special embryonic protein, which is a-fetoprotein.

67. Invasion and MetastasisInvasion and Metastasis
• The defining
characteristic of a
malignancy.
• InvasionInvasion: active
translocation of
neoplastic cells across
tissue barriers.
• Critical pathologic point:
local invasion and
neovascularization.
These events may occur
before clinical detection.

68. MetastasisMetastasis
• 1. Benign tumors doBenign tumors do not metastasizenot metastasize.
• 2. Malignant tumors metastasize.
• 3. Pathways of dissemination:
• a. Lymphatic spreadLymphatic spread to lymph nodes (usual(usual
mechanism of dissemination of carcinomas)mechanism of dissemination of carcinomas)
• b. Hematogenous spreadHematogenous spread:
1) Usual mechanism of dissemination for sarcomas
2) Cells entering the portal vein metastasize to the
liver.
3) Cells entering the vena cava metastasize to the
lungs.

69. MetastasingMetastasing
 The final progression stage of anyThe final progression stage of any
tumor is its transformation into thetumor is its transformation into the
malignant neoplasm. The major criteriamalignant neoplasm. The major criteria
of malignant tumor is its ability toof malignant tumor is its ability to
generalisation, that is – to metastasing.generalisation, that is – to metastasing.
 Metastasing includes three stageMetastasing includes three stage::
℘ neoplastic invasion into the surroundingneoplastic invasion into the surrounding
tissues,tissues,
℘ tumor cells transport with the blood andtumor cells transport with the blood and
lymphatic vessles,lymphatic vessles,
℘ their implantation in different organstheir implantation in different organs
and tissues.and tissues.
 Separate cells evacuation out of theSeparate cells evacuation out of the
neoplastic node takes place in case ofneoplastic node takes place in case of
intercellular contacts relaxation.intercellular contacts relaxation.
 Tumor loses calcium, which must turnTumor loses calcium, which must turn
intercellular spaces cementated inintercellular spaces cementated in
malignisation process. Diminishedmalignisation process. Diminished
amount of desmosomes, which createamount of desmosomes, which create
the intercellular contacts arises inthe intercellular contacts arises in
pernicious neoplasms. The amount ofpernicious neoplasms. The amount of
gangliosides is disranked on the cellulargangliosides is disranked on the cellular
surface of malignant tumor.surface of malignant tumor.

70. ATTRIBUTES OFATTRIBUTES OF
CANCERCANCER
MetastasisMetastasis
 Two basic steps:
Destruction of the BM
Attachment to the laminin of distant BM
 Genes up-regulated among good metastasizers:
EDGF receptor
Basic Fibroblast Growth Factor
Type IV Collagenase
ε-Cathepsin (under-expressed)
Cathepsin B (a lamininase)
Heparanase

72. STAGING OF CANCERSTAGING OF CANCER
• A. Assessment of size and spread of a cancerA. Assessment of size and spread of a cancer
• B. Key prognostic factor; more important thanB. Key prognostic factor; more important than
gradegrade
• C. Determined after final surgical resection ofC. Determined after final surgical resection of
the tumorthe tumor
• D. Utilizes TNM staging systemD. Utilizes TNM staging system
• 1.1. TT—tumor (size and/or depth of invasion)—tumor (size and/or depth of invasion)
• 2.2. NN—spread to regional lymph nodes;—spread to regional lymph nodes; secondsecond
most important prognostic factormost important prognostic factor
• 3.3. MM—metastasis; single most important—metastasis; single most important
prognostic factorprognostic factor

73. Metastasis:Metastasis: cervical lymph nodecervical lymph node
Lymph node metastasis
Tissue destruction:Tissue destruction:
carcinoma of the maxillary sinuscarcinoma of the maxillary sinus
Cancer "crater”:
liver metastases

74. ANGIOGENESISANGIOGENESIS
 Formation of new blood vessels fromFormation of new blood vessels from
existing vascular bedexisting vascular bed
 Carried out by endothelial cells (EC)Carried out by endothelial cells (EC)
and extra cellular matrix (ECM)and extra cellular matrix (ECM)
 Regulated by angiogenic factorsRegulated by angiogenic factors
(inducers and inhibitors)(inducers and inhibitors)
** A tumor is unable to grow largerA tumor is unable to grow larger
than 1 mm3 w/o developing a newthan 1 mm3 w/o developing a new
blood supplyblood supply

75. Components of AngiogenesisComponents of Angiogenesis
1)1) ENDOTHELIAL CELLSENDOTHELIAL CELLS
 FenestratedFenestrated
 Increased cell adhesion molecules (E-Increased cell adhesion molecules (E-
selectin)selectin)
 Increased integrinsIncreased integrins αγβαγβ33 essential foressential for
viability during growthviability during growth
 Activated ECs release: bFGF PDGFActivated ECs release: bFGF PDGF
IGF-1IGF-1

76. Components of AngiogenesisComponents of Angiogenesis
2)2) INDUCERS OF ANGIOGENESISINDUCERS OF ANGIOGENESIS
VEGF – main inducerVEGF – main inducer
TGF-TGF- ββ
TNF-TNF-αα low concentration - inducerlow concentration - inducer
high concentration - inhibitorhigh concentration - inhibitor
PDGF/thymidine phosphorylasePDGF/thymidine phosphorylase
TGF-TGF-αα
EGFEGF
IL-8IL-8

77. Components of AngiogenesisComponents of Angiogenesis
3) CELL ADHESION MOLECULES (CAM)3) CELL ADHESION MOLECULES (CAM)
 Mediate cell-cell adhesion processesMediate cell-cell adhesion processes
 SelectinsSelectins
 IG Supergene family- ICAM, VCAMIG Supergene family- ICAM, VCAM
 CadherinsCadherins
 Integrins- vitronectin receptorIntegrins- vitronectin receptor
4) PROTEASES4) PROTEASES
 Degrade ECM to provide suitableDegrade ECM to provide suitable
environment for EC migration thru adjacentenvironment for EC migration thru adjacent
stroma Ex: Metalloproteinases (MMP)stroma Ex: Metalloproteinases (MMP)

78. Components ofComponents of
AngiogenesisAngiogenesis
5)5) ANGIOGENESIS INHIBITORSANGIOGENESIS INHIBITORS
 InterferonInterferon
 TSP-1TSP-1
 AngiostatinAngiostatin
 EndostatinEndostatin
 VasostatinVasostatin
CLINICAL SIGNIFICANCECLINICAL SIGNIFICANCE::
Tumor angiogenesis switch is triggered asTumor angiogenesis switch is triggered as
a result of shift in the balance ofa result of shift in the balance of
stimulators to inhibitorsstimulators to inhibitors

79. Immune system andImmune system and
neoplastic growthneoplastic growth Tumor cells are heterologous for the organism. They synthesizethe proteins, whichTumor cells are heterologous for the organism. They synthesizethe proteins, which
are not character for normal cells.are not character for normal cells. Neoplasms productNeoplasms product specific swelling antigenspecific swelling antigen ..
Their specificity is conventional, but it is still sufficient for immune reactionTheir specificity is conventional, but it is still sufficient for immune reaction
development. A final result depends on immune attack intensity greatly: that means,development. A final result depends on immune attack intensity greatly: that means,
if the transformed cell is going to reproduct or not; is the tumor going to arise, or not.if the transformed cell is going to reproduct or not; is the tumor going to arise, or not.
 Neoplasms are observed in people with congenital immunodeficiency 10000 timesNeoplasms are observed in people with congenital immunodeficiency 10000 times
more often, than in persons with normal immune system. The malignant neoplasmsmore often, than in persons with normal immune system. The malignant neoplasms
arise in patients, with transplanted organ (for example, kidney) very often.arise in patients, with transplanted organ (for example, kidney) very often.
Immunodepressive drugs are being prescribed with the purpose of transplantedImmunodepressive drugs are being prescribed with the purpose of transplanted
organ rejection prophylaxy in such patients. Tumors in are observed in such casesorgan rejection prophylaxy in such patients. Tumors in are observed in such cases
100 times more frequent, than in the rest of population.100 times more frequent, than in the rest of population.
 These facts testify, that the transformed cells underlie the organism immune systemThese facts testify, that the transformed cells underlie the organism immune system
supervision. In most people they eliminate in time. A transformed cell exists,supervision. In most people they eliminate in time. A transformed cell exists,
reproducts, and produces the neoplasm in a fact of immune supervision insolvency.reproducts, and produces the neoplasm in a fact of immune supervision insolvency.
 Tumor renders an oppressive action upon the organism immune system in its ownTumor renders an oppressive action upon the organism immune system in its own
way. Immunodepression gets developed.way. Immunodepression gets developed.
 The matters, which render immunodepressive action are produced in neoplasticThe matters, which render immunodepressive action are produced in neoplastic
cells. Low-molecular metabolites (oligopeptides, unsaturated fatty acids), embryoniccells. Low-molecular metabolites (oligopeptides, unsaturated fatty acids), embryonic
antigens (antigens (a-fetoproteina-fetoprotein), glucocorticoids belong to them.), glucocorticoids belong to them.
 Т-suppressors activityТ-suppressors activity in patients with tumorsin patients with tumors is increasedis increased. They slow down. They slow down
antineoplastic immunityantineoplastic immunity . One more reason of immunodepression in. One more reason of immunodepression in
oncologic patients is the disparity between neoplastic growth speedoncologic patients is the disparity between neoplastic growth speed
and immune answer development speedand immune answer development speed . Lymphoid cells reproduct slower,. Lymphoid cells reproduct slower,
than tumor cells do. Adequate immune answer is late.than tumor cells do. Adequate immune answer is late.

80. Systemic neoplastic action uponSystemic neoplastic action upon
the organismthe organism
Tumor is not locally isolated process. It renders an influence upon theTumor is not locally isolated process. It renders an influence upon the
diverse organism functions. This is concerning the malignantdiverse organism functions. This is concerning the malignant
neoplasms especially. Their systemic action displays theneoplasms especially. Their systemic action displays the cancercancer
cachexycachexy. There are a few components of its development.. There are a few components of its development.
Tumor absorbs the glucose reinforcelyTumor absorbs the glucose reinforcely.. Chronic hypoglycaemiaChronic hypoglycaemia
tendencytendency arisesarises. Glycogen disintegrates in liver and muscles. Glycogen disintegrates in liver and muscles
reinforcely.reinforcely. Glyconeogenesis gets increasedGlyconeogenesis gets increased. However, this. However, this
compensatory mechanism has the negative characteristics. Firstly,compensatory mechanism has the negative characteristics. Firstly,
glucocorticoids cause the albumens disintegration ofglucocorticoids cause the albumens disintegration of
immunocompetence organs (thymus, spleen, lymphoid tissue of otherimmunocompetence organs (thymus, spleen, lymphoid tissue of other
organs). Secondly, of big amount of amino acids in glyconeogenesisorgans). Secondly, of big amount of amino acids in glyconeogenesis
usage gets the organic albumens synthesis limited. Diverse organsusage gets the organic albumens synthesis limited. Diverse organs
dystrophy develops, muscles – first of all.dystrophy develops, muscles – first of all.
Neoplastic growth can be described with the intensive syntheticNeoplastic growth can be described with the intensive synthetic
processes. Plastic material (amino acids, nucleic acids) is veryprocesses. Plastic material (amino acids, nucleic acids) is very
important for this. Neoplasm absorbs these matters not only nutritional,important for this. Neoplasm absorbs these matters not only nutritional,
but from other organs also. It is named as nitrogen snare. all of otherbut from other organs also. It is named as nitrogen snare. all of other
tissues are havingtissues are having amino acid deficiencyamino acid deficiency. They can not synthesize their. They can not synthesize their
own proteins in a necessary volume. This is one more link ofown proteins in a necessary volume. This is one more link of cancercancer
cachexy pathogens.cachexy pathogens.

81. Neoplastic Tumors

82. Tumor ComplicationsTumor Complications
 The lesions described below complicate theThe lesions described below complicate the
simple growth of the tumor. The combinationsimple growth of the tumor. The combination ofof
such lesions with tumor expansion andsuch lesions with tumor expansion and
metastasismetastasis constitute neoplastic disease thatconstitute neoplastic disease that
extendsextends beyond the tumor as such.beyond the tumor as such.
Local ComplicationsLocal Complications
 Stenosis:Stenosis: Tumors can lead to severalTumors can lead to several
compressioncompression syndromes.syndromes.
 —— Expansion of the tumorExpansion of the tumor compressescompresses thethe
surroundingsurrounding tissuetissue (A(A11)) and causesand causes stenosis instenosis in
hollow organshollow organs (A2(A2)), compression of the, compression of the smallsmall
bowel by a mesenterial liposarcoma;bowel by a mesenterial liposarcoma;
Complications may include difficultiesComplications may include difficulties inin
swallowing, impaired micturition,swallowing, impaired micturition, disruption ofdisruption of
intestinal motility, and also increasedintestinal motility, and also increased intracranialintracranial
pressurepressure..
 —— Infiltration of the tumor can causeInfiltration of the tumor can cause congestioncongestion
in a hollow organ. Complications mayin a hollow organ. Complications may includeinclude
prestenotic dilation of the duct, stasisprestenotic dilation of the duct, stasis andand
congestion of secretions or excretions,congestion of secretions or excretions, andand
bacterial infestation of the congestedbacterial infestation of the congested area.area.
A 2
1
Tumor compression
(mesenterial liposarcoma)
Budd-Chiari Syndrome

83. Tumor ComplicationsTumor Complications
 —— BleedingBleeding due to erosion of vasculardue to erosion of vascular
structuresstructures may lead to spitting of bloodmay lead to spitting of blood
fromfrom the lungs or bronchi (the lungs or bronchi (hemoptysishemoptysis),),
vomitingvomiting of blood (hematemesis),of blood (hematemesis),
passage of bloodypassage of bloody stools (stools (melenamelena), blood), blood
in the urine (hematuria),in the urine (hematuria), acyclic bleedingacyclic bleeding
from the uterus (metrorrhagia),from the uterus (metrorrhagia), andand
hemorrhagic effusionshemorrhagic effusions (B).(B).
Hemorrhagic effusion (lung cancer)
B
Circulatory Disruption: Tumor growth that compromises or
infiltrates vascular structures produces a variety of lesions.
— Obstruction of venous drainage is common and
successively leads to varicose changes in the walls of the
veins and thrombosis.
— Vascular thrombosis may result from vascular stenosis
and/or substances produced by the tumor itself that promote
coagulation.

84. Tumor NecrosisTumor Necrosis (C):(C): occurs as a result ofoccurs as a result of the interplay ofthe interplay of
several factors. These include:several factors. These include:
 —— Thrombotic arterial obstruction;Thrombotic arterial obstruction;
 —— Vascular compression by the tumor;Vascular compression by the tumor;
 —— Twisting of the tumor pedicle;Twisting of the tumor pedicle;
 —— Cytokines (macrophagic TNF-a);Cytokines (macrophagic TNF-a);
 —— Aggressive tumor therapy.Aggressive tumor therapy.
Complications of tumor necrosis:Complications of tumor necrosis:
 –– Ulceration of the inner or outer body surface mayUlceration of the inner or outer body surface may
occur, primarily in gastrointestinal, skin, and breastoccur, primarily in gastrointestinal, skin, and breast
cancercancer (D).(D).
 –– Perforation of the tumor necrosis may occur intoPerforation of the tumor necrosis may occur into
hollow organs or through the surface of the skinhollow organs or through the surface of the skin (E).(E).
 –– Fistulas may form that communicate with adjacentFistulas may form that communicate with adjacent
organs.organs.
 Disruption of Organ Function: occurs especiallyDisruption of Organ Function: occurs especially inin
tumors that not only mechanically altertumors that not only mechanically alter the organthe organ
parenchyma and its supporting tissueparenchyma and its supporting tissue but also destroybut also destroy
them.them.
 Particularly susceptible tissues include:Particularly susceptible tissues include:
 —— Neurovascular structures;Neurovascular structures;
 —— Urinary tract,Urinary tract,
 —— Intestinal tract;Intestinal tract;
 —— Skeletal system, where boneSkeletal system, where bone
tumors can causetumors can cause pathologicpathologic
fracturesfractures (F).(F).
C
D
E
Perforation of the cheek:
cancer of the tongue
F
Bone destruction:
Ewing sarcoma
Skin ulceration:
breast cancer
Necrosis: uterine sarcoma

85. Systemic ComplicationsSystemic Complications
Advanced neoplastic disease regularly producesAdvanced neoplastic disease regularly produces four types of systemicfour types of systemic
lesions.lesions.
 Tumor MetastasesTumor Metastases : occasionally: occasionally occur even in the early phases ofoccur even in the early phases of
neoplastic disease.neoplastic disease.
 Cancer CachexiaCancer Cachexia : involves weight loss in: involves weight loss in cancer patients. Causescancer patients. Causes
include:include:
—— Impaired swallowing due to the tumor;Impaired swallowing due to the tumor;
—— Impaired digestion due to the tumor;Impaired digestion due to the tumor;
—— Generation of TNF-a by macrophages stimulatedGeneration of TNF-a by macrophages stimulated by tumor-associatedby tumor-associated
antigens.antigens.
—— Generation of leptin (fat-cell hormoneGeneration of leptin (fat-cell hormone)). This results in loss of appetite. This results in loss of appetite
(anorexia),(anorexia), reduced intake of nutrients, decreasedreduced intake of nutrients, decreased body fat, andbody fat, and
increased energy consumption.increased energy consumption.
 Tumor AnemiaTumor Anemia : produces the characteristic: produces the characteristic pale skin of cancerpale skin of cancer
patients. It is due to severalpatients. It is due to several factors, including:factors, including:
—— Blood loss due to internal bleeding;Blood loss due to internal bleeding;
—— Lack of substances that promote maturationLack of substances that promote maturation of blood cells;of blood cells;
—— Autoreactive antibodies against erythrocytes;Autoreactive antibodies against erythrocytes;
—— Displacement of bone marrow by tumorousDisplacement of bone marrow by tumorous infiltrates.infiltrates.

86. Paraneoplastic SyndromesParaneoplastic Syndromes
Definition: Collective term for a group of generalized pathologic
manifestations that are not attributable to the local effects of a tumor but
are linked to the existence of a tumor and can regress after the tumor has
been removed.
Pathogenesis: Often unclear.
— Cell destruction occurs due to formation of autoreactive antibodies
against tumor antigens and “self” antigens and as a result of apoptosis
caused by certain tumor proteins.
— Dysfunction results from synthesis of peptides with endocrine and
enzymatic effects.
Endocrinopathies
General pathogenesis: Tumors synthesize ectopic hormones of
substances similar to hormones.
The most important forms are as follows:
— Cushing’s syndrome is caused by formation of ACTH and occurs in
patients with bronchial cancer.
— Flush’s syndrome is caused by formation of serotonin and leads to
facial erythema, diarrhea, colic, and bronchospasm. It occurs in patients
with bronchial or ileal carcinoid.
— Schwartz-Bartter’s syndrome is caused by formation of proteins
resembling ADH and leads to hyponatremia. It occurs in patients with
small cell bronchogenic carcinoma.
— Hypercalcemia syndrome is caused by formation of parathormone-like
protein. It occurs in patients with squamous cell bronchogenic carcinoma
or renal cell carcinomas.

87. PARANEOPUSTIC SYNDROMESPARANEOPUSTIC SYNDROMES
SYNDROME ASSOCIATED CANCER COMMENT
Acanthosis nigricans Stomach carcinomaStomach carcinoma Black, verrucoid-appearing lesion
Eaton-Lambert
syndrome
Small cell carcinoma ofSmall cell carcinoma of
lunglung
Myasthenia gravis-like
symptoms(e.g., muscle weakness);
antibody directed against calcium
channel
Hypertrophic
osteoarthropathy
Bronchogenic carcinomaBronchogenic carcinoma
Periosteal reaction of distal phalanx
(often associated with clubbing of
nail)
Nonbacterial
thrombotic
endocarditis
Mucus-secreting pancreaticMucus-secreting pancreatic
and colorectal carcinomasand colorectal carcinomas
Sterile vegetations on mitral valve
Seborrheic keratosis Stomach carcinomaStomach carcinoma
Sudden appearance of
numerouspigmenled seborrheic
keratoses (Lescr-Trdlat sign)
Superficial migratory
thrombophlebitis
Pancreatic carcinomaPancreatic carcinoma
Release of procoagulants
(Trousseau's sign)
Nephrotic syndrome
Lung, breast, stomachLung, breast, stomach
carcinomascarcinomas
Diffuse membranous
glomerulopathy

88. DISORDER ASSOCIATED CANCER ECTOPIC HORMONE
Cushing syndrome
Small cell carcinoma of lung,
medullary carcinoma of thyroid
ACTH (adrenocorticotropic
hormone)
Gynecomastia Choriocarcinoma (testis)
hCG (human chorionic
gonadotropin)
Hypercalcemia
Renal cell carcinoma, primary
squamous cell carcinoma of lung,
breast carcinoma. Malignant
lymphomas (contain 1α-hydroxylase)
PTH-relaled protein
(parathyroid hormone)
Calcitriol (vilamin D)
Hypocalcemia Medullary carcinoma of thyroid Calcitonin
Hypoglycemia Hepatocellular carcinoma Insulin-like factor
Hyponatremia Small cell carcinoma of lung Antidiuretic hormone
Secondary
polycythemia
Renal cell and hepatocellular
carcinomas
Erythropoietin

89. Nerve and Muscle SyndromesNerve and Muscle Syndromes
Pathogenesis: Nerve cells and/or muscle fibers are destroyed by autoimmune processes and
by tumor-induced apoptosis. The most important forms are as follows:
• — Myasthenia gravis occurs in patients with thymus tumors (thymomas).
• — Limbic encephalopathy occurs in patients with small cell bronchogenic carcinoma.
• — Degeneration of the cerebellar cortex occurs in patients with small cell bronchogenic
carcinoma, breast cancer, or ovarian carcinoma.
Vascular and Hematologic ChangesVascular and Hematologic Changes
• — Hemolysis: The tumor synthesizes cytotoxic substances and/or autoreactive antibodies,
damaging the bone marrow and leading to hemolytic anemia. This occurs in patients with
leukemias or Hodgkin’s
• disease’s lymphoma.
• — Erythrocyte proliferation: The tumor synthesizes substances that stimulate erythropoiesis
(erythropoietin), leading to polyglobulism (an overabundance of erythrocytes). This occurs
in patients with renal cell carcinoma.
• — Leukocyte proliferation: The tumor synthesizes substances that stimulate myelopoiesis,
leading to a leukemoid reaction. This occurs in patients with stomach cancer or large cell
bronchogenic carcinoma.
• — Macroscopic coagulopathy: The tumor synthesizes thromboplastic substances that lead
to thrombosis. This occurs in patients with pancreatic or adenoid carcinomas.
• — Disseminated intravascular coagulation: The tumor synthesizes thromboplastic and
fibrinolytic substances that consume the clotting factors. This occurs in patients with
leukemias.
• Note: Coagulopathy is characterized by thromboticNote: Coagulopathy is characterized by thrombotic vascular occlusion (primarily invascular occlusion (primarily in
the lung), whereasthe lung), whereas disseminated intravascular coagulation is characterizeddisseminated intravascular coagulation is characterized by hyalinby hyalin
microthrombi (primarily in the microvasculaturemicrothrombi (primarily in the microvasculature of the lung).of the lung).

90. Dermatologic DisordersDermatologic Disorders
 —— Acanthosis nigricansAcanthosis nigricans manifests itself asmanifests itself as thickening ofthickening of
the skin with clearly discerniblethe skin with clearly discernible papillary lines,papillary lines,
hyperpigmentation, andhyperpigmentation, and wart-like papillomas.wart-like papillomas. It occurs inIt occurs in
patients with stomach cancer or squamouspatients with stomach cancer or squamous cell bronchogeniccell bronchogenic
carcinoma.carcinoma. (А)(А)
 —— Bazex’s syndromeBazex’s syndrome (paraneoplastic acrokeratosis)(paraneoplastic acrokeratosis)
manifests itself as reddish purple plaquesmanifests itself as reddish purple plaques of calcification onof calcification on
the hands, feet,the hands, feet, nose, and ears.nose, and ears. It occurs in patients withIt occurs in patients with
carcinoma of the tonguecarcinoma of the tongue or tonsils.or tonsils. ((BB))
 —— Erythema gyratum repensErythema gyratum repens is a rare skin rashis a rare skin rash resemblingresembling
zebra stripes that changes daily.zebra stripes that changes daily. It occurs in patients withIt occurs in patients with
various carcinomas.various carcinomas. ((C, D)C, D)
 —— Hypertrichosis lanuginosaHypertrichosis lanuginosa is a rare manifestationis a rare manifestation
involving excessive growth of theinvolving excessive growth of the head and body hair.head and body hair. ItIt
occurs in patients with various carcinomas.occurs in patients with various carcinomas. (Е,(Е, F)F)
А
B
C
D
F
E

91. 7 warning signs of7 warning signs of
cancercancer
 CC change in bowel or bladder habitchange in bowel or bladder habit
 AA a sore that doesn’t heala sore that doesn’t heal
 UU unusual bleeding or dischargeunusual bleeding or discharge
 TT thickening or lumpthickening or lump
 II indigestionindigestion
 OO obvious change in wart or moleobvious change in wart or mole
 NN nagging cough or hoarsenessnagging cough or hoarseness

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93. THANK YOU !