Biology And Pathophysiology Of Cancer

1. Biology of Cancer Biology of Cancer
Pathophysiology of CancerPathophysiology of Cancer
Raul H. Morales-Borges, M.D., FICPS, FIACATHRaul H. Morales-Borges, M.D., FICPS, FIACATH
Ashford Institute of Hematology & OncologyAshford Institute of Hematology & Oncology

3. IntroductionIntroduction
Cancer is a leading cause of death and Cancer is a leading cause of death and
source of morbidity of adults in the source of morbidity of adults in the
Western world.Western world.
There are many causes including There are many causes including
environment, heredity, and behavior environment, heredity, and behavior
interactions.interactions.

4. IntroductionIntroduction
All malignant cells arise from a All malignant cells arise from a
transformation of a normal cell into an transformation of a normal cell into an
immortal cell which growth immortal cell which growth
uncontrolled.uncontrolled.
Such transformation occurs when the Such transformation occurs when the
genetic blueprint - the cell’s DNA - is genetic blueprint - the cell’s DNA - is
damaged or altered.damaged or altered.
Every cell contain a series of genetic Every cell contain a series of genetic
markers known as markers known as protooncogenes.protooncogenes.

5. IntroductionIntroduction
Tumor development is a multistep Tumor development is a multistep
process.process.
Molecular research is providing interesting Molecular research is providing interesting
new modalities of treatments.new modalities of treatments.
Management is multidisciplinary.Management is multidisciplinary.
Our goals should be prevention, early Our goals should be prevention, early
detection, and provide good quality of life. detection, and provide good quality of life.

6. 10/05/1110/05/11 66
Cancer Cancer
Cancer = Karkinoma, Crab (Cangrejo)Cancer = Karkinoma, Crab (Cangrejo)
Neoplasm = New Growth (Crecimiento Neoplasm = New Growth (Crecimiento
Nuevo)Nuevo)
Oncos = TumorOncos = Tumor

7. Definition from 1922Definition from 1922
It is a tissue overgrowth It is a tissue overgrowth
independently from the governing independently from the governing
laws of the body. laws of the body.

8. 10/05/1110/05/11 88
Caracteristicas de Tumor BenignoCaracteristicas de Tumor Benigno
Crecimiento lentoCrecimiento lento
Son bien diferenciadosSon bien diferenciados
Tienen una capsula bien definidaTienen una capsula bien definida
No invasion a otros tejidosNo invasion a otros tejidos
No metastasisNo metastasis

9. Ejemplos de tumores benignosEjemplos de tumores benignos
PapilomaPapiloma
AdenomaAdenoma
CystadenomaCystadenoma
NevusNevus
NeurofibromaNeurofibroma
LipomaLipoma
HemangiomaHemangioma
LinfangiomaLinfangioma
Fibromatosis Fibromatosis
(desmoide)(desmoide)
OsteomaOsteoma
CondromaCondroma
LeiomiomaLeiomioma
RhabdomiomaRhabdomioma
MeningiomaMeningioma

10. 10/05/1110/05/11 1010
Caracteristicas de Tumor MalignoCaracteristicas de Tumor Maligno
Proliferacion de celulas neoplasticas Proliferacion de celulas neoplasticas
No encapsuladosNo encapsulados
Pierden la diferenciacionPierden la diferenciacion
Estroma de soporteEstroma de soporte
Neovascularizacion (vasos sanguineo Neovascularizacion (vasos sanguineo
nuevos)nuevos)
Invasion y MetastasisInvasion y Metastasis

11. Ejemplos de tumores malignosEjemplos de tumores malignos
CarcinomaCarcinoma
AdenocarcinomaAdenocarcinoma
MelanomaMelanoma
SeminomaSeminoma
MielomaMieloma
LinfomaLinfoma
LeucemiasLeucemias
CondrosarcomaCondrosarcoma
NeuroblastomaNeuroblastoma
RetinoblastomaRetinoblastoma
Tumor de WilmTumor de Wilm
Tumor de EwingTumor de Ewing
MesoteliomaMesotelioma
SarcomaSarcoma
FibrosarcomaFibrosarcoma
AngiosarcomaAngiosarcoma

12. 10/05/1110/05/11 1212
Estadios de Tumores malignosEstadios de Tumores malignos
Depende del tamano del tumor, nodulos Depende del tamano del tumor, nodulos
linfaticos y metastasislinfaticos y metastasis
Estadio I – pequenoEstadio I – pequeno
Estadio II – algo mas grande, algunos Estadio II – algo mas grande, algunos
nodulosnodulos
Estadio III – invasion de estructuras vecinas, Estadio III – invasion de estructuras vecinas,
mas nodulosmas nodulos
Estadio IV - metastasisEstadio IV - metastasis

13. Carcinoma in situ (CIS)Carcinoma in situ (CIS)
Pre-invasive epithelial malignant tumors of Pre-invasive epithelial malignant tumors of
glandular or squamous cell origin.glandular or squamous cell origin.
Localized to the epithelium.Localized to the epithelium.
No broken local basement membrane.No broken local basement membrane.
No invasion of surrounded tissues.No invasion of surrounded tissues.
Seen in the cervix, beast, skin, oral cavity, Seen in the cervix, beast, skin, oral cavity,
esophagus, stomach, bronchus.esophagus, stomach, bronchus.

14. Cancer Cells: Cancer Cells:
TransformationTransformation
TransformationTransformation means the process by means the process by
which a cell becomes cancerous.which a cell becomes cancerous.
AutonomyAutonomy is when the cancer cell is is when the cancer cell is
independently from normal cellular independently from normal cellular
controls. Cancerous cells show controls. Cancerous cells show uninhibited uninhibited
growth. growth.
They are often They are often anchorage-independent anchorage-independent
(they divide even in a soft agar gel).(they divide even in a soft agar gel).
They are usually They are usually immortal. immortal.

15. Cancer Cells:Cancer Cells:
DifferentiationDifferentiation
Differentiation Differentiation refers to the process of refers to the process of
acquiring a specialized function and acquiring a specialized function and
organization.organization.
AnaplasiaAnaplasia is the absence of differentiation. is the absence of differentiation.
It is recognized by a loss of organization It is recognized by a loss of organization
and a marked increase in nuclear size, and a marked increase in nuclear size,
with evidence of ongoing proliferation. The with evidence of ongoing proliferation. The
cells are of variable size and shape cells are of variable size and shape
((pleomorphismpleomorphism).).

16. Cancer Stem CellsCancer Stem Cells
Two characteristics: Self-renew & Two characteristics: Self-renew &
Multipotent.Multipotent.
When a stem cell divides, each daughter When a stem cell divides, each daughter
cell has a choice:cell has a choice:
–It can either continue as a stem cell or go on It can either continue as a stem cell or go on
to become terminally differentiated, that is, to become terminally differentiated, that is,
completely matured (e.g., neuron, myocyte, completely matured (e.g., neuron, myocyte,
erythrocyte).erythrocyte).

17. 10/05/1110/05/11 1717
Grado de TumoresGrado de Tumores
Grado I – Bien diferenciadosGrado I – Bien diferenciados
Grado II – Moderadamente Grado II – Moderadamente
diferenciadosdiferenciados
Grado III – Pobremente diferenciadosGrado III – Pobremente diferenciados
Grado IV - AnaplasticosGrado IV - Anaplasticos

18. The Genetic Basis of CancerThe Genetic Basis of Cancer
Clonal selectionClonal selection: Cancer is a disease of : Cancer is a disease of
aging because the cells acquires a aging because the cells acquires a
number of genetic mutations over time number of genetic mutations over time
and the cells then may have a selective and the cells then may have a selective
advantage over its mutant neighbors advantage over its mutant neighbors
((Clonal proliferation or clonal expansionClonal proliferation or clonal expansion). ).

19. Malignant Cell Proliferation

20. Carcinogenesis

21. Molecular abnormalities in lung cancer
Commonly observed
genetic changes
Tobacco
carcinogen
Inappropriate response to external
signals
Loss of cell cycle control
Loss of apoptosis pathway
Loss of contact inhibition
Ability to metastasise
Angiogenesis
Immortality
Autocrine growth loops
Atypical alveolar
hyperplasia
Premalignant
adenomas
Lung cancer
Carcinoma
in situ
Dysplasia
Bronchial
metaplasia
Normal
epithelium

22. Sequential changes during lung cancer pathogenesis
Early Intermediate Late
Normal
epithelium
Hyperplasia Dysplasia CIS
Invasive
carcinoma
~80%
3p LOH/small telomeric deletions 3p LOH/contiguous deletions
~50%
Microsatellite alterations
~70%
9p21 LOH
~80%
Telomerase dysregulation Telomerase upregulation
~60%
myc overexpression
~80%
8p21-23 LOH
~40%
Neoangiogenesis
~40%
Loss of Fhit immunostaining
~70%
p53 LOH p53 mutations
~80%
Aneuploidy
~100%
Methylation
~30%
5q21 APC-MCC LOH
~20%
K-ras mutation
Hirsch et al 2001LOH, loss of heterozygosity

23. Oncogenes and Tumor-suppressor Oncogenes and Tumor-suppressor
genesgenes
Oncogenes are mutant genes that in their Oncogenes are mutant genes that in their
normal nonmutant state direct synthesis of normal nonmutant state direct synthesis of
proteins that positively regulate proteins that positively regulate
proliferation.proliferation.
Tumor-suppressor genes encode proteins Tumor-suppressor genes encode proteins
that in their normal state negatively that in their normal state negatively
regulate proliferation.regulate proliferation.

24. It’s an oncogene in a normal, It’s an oncogene in a normal,
nonmutant state.nonmutant state.
The protooncogenes serve to many The protooncogenes serve to many
basic functions to the normal cell basic functions to the normal cell
such as: growth, maturation and such as: growth, maturation and
proliferationproliferation
However, such protooncogenes can However, such protooncogenes can
be altered and become Oncogenesbe altered and become Oncogenes
Such Oncogenes confers certain Such Oncogenes confers certain
characteristic to the cell : characteristic to the cell :
uncontrolled growth, uncontrolled growth,
invasiveness and immortalityinvasiveness and immortality
PROTOONCOGENESPROTOONCOGENES

25. How does the change from How does the change from
protooncogenes to Oncogenes occur?protooncogenes to Oncogenes occur?
There are several There are several stepssteps toward the toward the
malignant transformation of a cellmalignant transformation of a cell
–Non-lethal genetic damage lies at the heart of Non-lethal genetic damage lies at the heart of
carcinogenesiscarcinogenesis
A genetic damage (A genetic damage (mutationmutation) may be acquired by ) may be acquired by
the action of environmental agents such as the action of environmental agents such as
chemicals, radiation or viruses, or it may be chemicals, radiation or viruses, or it may be
inheritedinherited

26. –Two classes of normal regulatory genes - the Two classes of normal regulatory genes - the
growth promoting protooncogenes and the growth promoting protooncogenes and the
growth inhibiting genes (growth inhibiting genes (antioncogenesantioncogenes) - are ) - are
the principal targets of genetic damagethe principal targets of genetic damage
–Carcinogenesis is a multistep processCarcinogenesis is a multistep process
at both the phenotypic and genetic at both the phenotypic and genetic
levellevel
–Every human cancer that has been analyzed Every human cancer that has been analyzed
reveals multiple genetic alterations involving reveals multiple genetic alterations involving
activation of several Oncogenes and activation of several Oncogenes and
inactivation of two or more antioncogenesinactivation of two or more antioncogenes

27. The genetic damage that activates The genetic damage that activates
Oncogenes may be subtle or large Oncogenes may be subtle or large
enough to be detected in a gross enough to be detected in a gross
chromosomal analysis: a karyotype chromosomal analysis: a karyotype
analysis.analysis.
In some cancers such alterations are In some cancers such alterations are
nonrandom and commonnonrandom and common
Specific alterations have been identified Specific alterations have been identified
for most leukemia's and lymphomasfor most leukemia's and lymphomas

28. The most common types of such The most common types of such
alterations are:alterations are:
– translocationstranslocations
– deletionsdeletions
– gene amplificationgene amplification
– point mutationspoint mutations

29. Point MutationsPoint Mutations
They are the most common events in They are the most common events in
small scale changes in DNA.small scale changes in DNA.
It’s an alteration of one or a few nucleotide It’s an alteration of one or a few nucleotide
base pairs.base pairs.
e.g., e.g., ras generas gene is associated with is associated with
pancreatic and colorectal cancer. pancreatic and colorectal cancer.

30. Chromosome TranslocationChromosome Translocation
It can cause excess and inappropriate It can cause excess and inappropriate
production of a proliferation factor (e.g., production of a proliferation factor (e.g.,
t(8;14) in Burkitt lymphomas) such as t(8;14) in Burkitt lymphomas) such as
MYC protein.MYC protein.
It can also lead to production of novel It can also lead to production of novel
proteins with growth promoting properties proteins with growth promoting properties
(e.g., t(9;22) in CML) such as BCR-ABL (e.g., t(9;22) in CML) such as BCR-ABL
protein. protein.

31. Gene AmplificationGene Amplification
Result of duplication of a small piece of a Result of duplication of a small piece of a
chromosome over and over again, so that chromosome over and over again, so that
instead of normal two copies of a gene, tens or instead of normal two copies of a gene, tens or
even hundreds of copies are present.even hundreds of copies are present.
Results in increased expression of an oncogene, Results in increased expression of an oncogene,
or in some cases, drug resistance genes.or in some cases, drug resistance genes.
E.g.: N-myc in Neuroblastoma & erb2 in Breast E.g.: N-myc in Neuroblastoma & erb2 in Breast
cancer.cancer.

32. Tumor-Suppressor genes Tumor-Suppressor genes
They are genes whose major function is to They are genes whose major function is to
negatively regulate cell growth and prevent negatively regulate cell growth and prevent
mutations.mutations.
Needs two (2) mutational events to contribute to Needs two (2) mutational events to contribute to
the cancer.the cancer.
Loss of function, acts in recessive fashion.Loss of function, acts in recessive fashion.
Inherited form is common and has a tissue Inherited form is common and has a tissue
preference.preference.
Examples: p53 (GBM, SCLC, BCA, CRC), Rb Examples: p53 (GBM, SCLC, BCA, CRC), Rb
(retinoblastoma), APC & MCC (CRC).(retinoblastoma), APC & MCC (CRC).

33. Loss of heterozygosityLoss of heterozygosity
Loss of a chromosome region in a tumor.Loss of a chromosome region in a tumor.
Unmasks inactivating mutations in Unmasks inactivating mutations in
recessive tumor suppression genes.recessive tumor suppression genes.
Also named as allelic loss.Also named as allelic loss.
Examples: LOH for 5q for sporadic Examples: LOH for 5q for sporadic
adenomas to carcinomas, Loss of the adenomas to carcinomas, Loss of the
13q14 chromosome region on one 13q14 chromosome region on one
chromosome for Rb.chromosome for Rb.

34. Gene SilencingGene Silencing
The epigenetic silencing is associated with The epigenetic silencing is associated with
methylation of both the DNA and methylation of both the DNA and
associated chromatin. So, no functional associated chromatin. So, no functional
protein will be produced.protein will be produced.

35. Holistic scheme of multistage carcinogenesis Holistic scheme of multistage carcinogenesis
with 3 types of control systemswith 3 types of control systems
Agonist induced
signal transduction
Cell cycle control
Fidelity of DNA
and Chromosome replication

36. In the near past, our understanding of In the near past, our understanding of
cellular function was rudimentarycellular function was rudimentary
Now, our knowledge of cells has Now, our knowledge of cells has
progressed to an understanding of many progressed to an understanding of many
complex interactions and networks:complex interactions and networks:
–extracellularextracellular
–intracellularintracellular
–intranuclearintranuclear

37. The genome project has amplified this The genome project has amplified this
capacity through numerous techniques, capacity through numerous techniques,
including the cluster array analysisincluding the cluster array analysis
Breast cancer cells are now classified in five Breast cancer cells are now classified in five
groupsgroups
–basal likebasal like- null cell- null cell
–erb2+ A & Berb2+ A & B
–normalnormal

38. Alterations in progrowth and Alterations in progrowth and
antigrowthantigrowth
Cancer cells have mutations that enable them to Cancer cells have mutations that enable them to
proliferate in the absence of external growth proliferate in the absence of external growth
signals. To achieve this, some caner cells signals. To achieve this, some caner cells
acquire the ability to secrete growth factors that acquire the ability to secrete growth factors that
stimulate their own growth (stimulate their own growth (Autocrine Autocrine
stimulation).stimulation).
Other have an Other have an increase in growth factor increase in growth factor
receptorsreceptors (EGFR), an (EGFR), an activating mutation in an activating mutation in an
intracellular signaling proteinintracellular signaling protein called called ras, an ras, an
antigrowth signaling antigrowth signaling such as such as Rb,Rb, and and a self- a self-
destruction mechanism destruction mechanism such as such as apoptosis (p53). apoptosis (p53).

39. AngiogenesisAngiogenesis
Neovascularization is a characteristic of Neovascularization is a characteristic of
cancer cells to provide their own new cancer cells to provide their own new
vessel supply. It’s secondary to purified vessel supply. It’s secondary to purified
angiogenic factors such as bFGF & angiogenic factors such as bFGF & VEGF.VEGF.
Vascular endothelial growth factor is Vascular endothelial growth factor is
angiogenic in vivo for endothelial cells.angiogenic in vivo for endothelial cells.
Basic fibroblast growth factor is mitogenic Basic fibroblast growth factor is mitogenic
for vascular endothelial cells and is for vascular endothelial cells and is
strongly angiogenic.strongly angiogenic.

40. Model of role of angiogenesis in Model of role of angiogenesis in
metastasismetastasis
Angiogenesis
Expansion of
Tumor cells
Microinvasion
Enter & Exit
Circulation
Limited growth in
Target Organ
Angiogenesis
Expansion into
detectable metastasis

41. TelomeresTelomeres
They are protective ends, or caps, on each They are protective ends, or caps, on each
chromosome and are placed and maintained by chromosome and are placed and maintained by
a specialized enzyme called a specialized enzyme called telomerasetelomerase. .
Telomerase is usually active only in germ cells in Telomerase is usually active only in germ cells in
ovaries and testes and in stem cells. ovaries and testes and in stem cells.
When the telomeres become critically small, the When the telomeres become critically small, the
chromosomes become unstable and fragment, chromosomes become unstable and fragment,
then the cells die. Cancer cells at critical activate then the cells die. Cancer cells at critical activate
telomerase to restore and maintain their telomerase to restore and maintain their
telomere to survive and divide. telomere to survive and divide.

42. Cyclin E*
Cell cycle and therapeutic targets
DNA
damage
or oxygen
deprivation
Cell suicide
(apoptosis)p53*
p21
Inactive
pRB
protein
External
signal that
inhibits cell
division
TGFb
Rb +
E2F
Early G
1
Late G
1 S G
2 M
Phases of cell cycle
p15*
p16*
p27
greenActivity that promotes cell division
pinkActivity that discourages cell division
*Mutation or deregulation of gene for this protein has
been found in human tumours
R
External
signal
that
promotes
cell
division
Cyclin E-
CDK2
complex
Proteins
involved in
DNA
synthesis
CDK2
DNA
synthesis
Cell
division
Cyclin B-
CDK1
complex
Cyclin A
CDK1
Cyclin B
Cyclin A-
CDK1
complex
Liberated
transcription
factors
Cyclin D-
CDK4/6
complex
CDK4/6
Cyclin D*

43. Prognostic and predictive factorsPrognostic and predictive factors
p53 statusp53 status
Other cell cycle components including p27, p15, p16, pRb, cyclin Other cell cycle components including p27, p15, p16, pRb, cyclin
and CDK and CDK
K-ras mutationsK-ras mutations
HER2/neu and epidermal growth factor receptor (EGFR)HER2/neu and epidermal growth factor receptor (EGFR)
Beta tubulinBeta tubulin
Expression of matrix metalloproteinase and inhibitorsExpression of matrix metalloproteinase and inhibitors
DNA topoisomerase IIDNA topoisomerase IIaa and II and IIbb
Single nucleotide polymorphism in myeloperoxidase gene Single nucleotide polymorphism in myeloperoxidase gene
reduces risk of lung cancerreduces risk of lung cancer
Heparin-binding growth factor pleiotrophinHeparin-binding growth factor pleiotrophin

44. Strategies for signalling inhibition
Tyrosine kinase
inhibitors (TKIs)
Immune
effector
cell
Anti-ligand
mAbs
Bispecific
Abs
Anti-receptor
mAbs
Ligand/toxin
conjugate
scFv/toxin
conjugates
Ligand-
genistein
conjugates
Intracellular
scFvs
Nucleus
Antisense
Inhibitors of
other signalling
molecules

45. DNA
Mode of action of EGFR inhibitors
Membrane
Extracellular
Intracellular
R
K
R
K EGFR-TKIEGFR-TKI
Signalling
Proliferation
Cell survival
(anti-apoptosis)
Growth factors
Chemotherapy/
radiotherapy sensitivity
Angiogenesis
Metastasis

R, epidermal growth factor receptor
EGF/TGFα
Antibody

46. Human Cancer & Family Genetics Human Cancer & Family Genetics
Germline mutations.Germline mutations.
Inheritance of a mutated gene that can Inheritance of a mutated gene that can
cause cancer.cause cancer.
Examples: Neuroblastoma, Wilm’s tumor, Examples: Neuroblastoma, Wilm’s tumor,
Neurofibromatosis, Breast Cancer, Neurofibromatosis, Breast Cancer,
Familial Polyposis coli or Adenomas of the Familial Polyposis coli or Adenomas of the
colon.colon.

47. Causas HereditariasCausas Hereditarias
Neurofibromatosis (Enfermedad de von Neurofibromatosis (Enfermedad de von
Reckinghausen) : Neurofibro-sarcomasReckinghausen) : Neurofibro-sarcomas
Sindrome de Gardner : Fibro-sarcomas desmoides del Sindrome de Gardner : Fibro-sarcomas desmoides del
mesenteriomesenterio
Retinoblastoma familiar : Osteo-sarcomasRetinoblastoma familiar : Osteo-sarcomas
Sindrome Familiar de Li-Fraumeni Sindrome Familiar de Li-Fraumeni
Sindrome de Stewart-Treves -AngiosarcomasSindrome de Stewart-Treves -Angiosarcomas
Hemocromatosis Hemocromatosis

48. 4848
Causas Geneticas de SarcomasCausas Geneticas de Sarcomas
Translocaciones: t(11;22), t(12;14), Translocaciones: t(11;22), t(12;14),
t(2;13), t(X;18), t(12;16)t(2;13), t(X;18), t(12;16)
Expesion de MDR 1Expesion de MDR 1
Mutaciones: genes p53, Rb Mutaciones: genes p53, Rb
Deleciones: 1p-, 3p-, 13q-Deleciones: 1p-, 3p-, 13q-
Proto-oncogenes: c-myc, N-myc, c-myb, Proto-oncogenes: c-myc, N-myc, c-myb,
c-mil/raf-1, c-fes, c-sisc-mil/raf-1, c-fes, c-sis
Pathologe 17(3):195-201, 1996 Diagnostic Molecular Pathology 5(2):98-106, 1996
Monographs in Pathology 38:65-128, 1996 American J of Pathology 150(6):1997-2007, 1997
Seminars in Oncology 24(5):515-525, 1997 J Cancer Research & Clinical Oncology 123(4):211-8, 1997

49. Inflammatory Conditions & Inflammatory Conditions &
CancerCancer
Reactive Oxygen Species
Increased COX2
Proliferation
Release of growth factors
Release of cytokines
Injury
Cancer

50. Chronic Inflammation & CancerChronic Inflammation & Cancer
Chronic Ulcerative Colitis : Colon CancerChronic Ulcerative Colitis : Colon Cancer
Chronic Hepatitis B or Hepatitis C : Liver CancerChronic Hepatitis B or Hepatitis C : Liver Cancer
COPD, Chronic asthma : Lung CancerCOPD, Chronic asthma : Lung Cancer
Chronic Cystitis : Bladder CancerChronic Cystitis : Bladder Cancer
Sjogren syndrome : LymphomaSjogren syndrome : Lymphoma
Chronic Thyroiditis : Lymphoma Chronic Thyroiditis : Lymphoma
Fibrocystic Breast Disease : Breast CancerFibrocystic Breast Disease : Breast Cancer
Benign Prostate Hyperplasia : Prostate CancerBenign Prostate Hyperplasia : Prostate Cancer

51. Histopathological Appearance of Benign Breast Disease (Hematoxylin and Eosin)
Hartmann, L. et al. N Engl J Med 2005;353:229-237
BENIGN BREAST DISEASES
(FIBROCYSTIC BREAST DISEASE)

52. Benign Breast Disease Benign Breast Disease
may not be so benignmay not be so benign
From Mayo Clinic Cancer CenterFrom Mayo Clinic Cancer Center
If developed before 40 y/o the risk of BCA If developed before 40 y/o the risk of BCA
can increase by can increase by 83%83% and if we add a and if we add a
strong family history the risk increases by strong family history the risk increases by
93%.93%.

53. Viral Infections & CancerViral Infections & Cancer
Ellerman in Denmark in 1908 and Rous in 1911: Ellerman in Denmark in 1908 and Rous in 1911:
Retrovirus and Avian leukemia & Avian sarcoma. Retrovirus and Avian leukemia & Avian sarcoma.
Hepatitis B & C viruses – Hepatocellular carcinomaHepatitis B & C viruses – Hepatocellular carcinoma
Herpes virus / Epstein-Barr – Burkitt lymphoma, Herpes virus / Epstein-Barr – Burkitt lymphoma,
nasopharyngeal carcinomanasopharyngeal carcinoma
KSHV / HHV-8 – Kaposi sarcomaKSHV / HHV-8 – Kaposi sarcoma
HPV – Cervical and anogenital carcinomaHPV – Cervical and anogenital carcinoma
Retrovirus Retrovirus
–HTLV-1 – Adult-T-cell leukemia/lymphomaHTLV-1 – Adult-T-cell leukemia/lymphoma
–HTLV-2 – Hairy- cell leukemia HTLV-2 – Hairy- cell leukemia
–HIV – Kaposi sarcoma HIV – Kaposi sarcoma

54. HEAD & NECK CANCERHEAD & NECK CANCER
Nasopharyngeal cancer Nasopharyngeal cancer
and Epstein-Barr virusand Epstein-Barr virus
Endemic in regions of Northern Africa and Endemic in regions of Northern Africa and
AsiaAsia
Etiology distinct from other head and Etiology distinct from other head and
neck cancers neck cancers
Epstein-Barr viral proteins detectable Epstein-Barr viral proteins detectable
in majority of nasopharyngeal tumorsin majority of nasopharyngeal tumors
Associated with frequent consumption Associated with frequent consumption
of salted fish or nitrosaminesof salted fish or nitrosamines
Stupp R, Vokes EE. Current Cancer Therapeutics. 3rd ed. 1998;165-166.

55. HPVHPV
>100 types identified
2
30–40 anogenital
2,3
–15–20 oncogenic*
,2,3
types,
including 16, 18, 31, 33, 35, 39,
45, 51, 52, 58
4
HPV 16 (54%) and HPV
18 (13%) account for the
majority of worldwide
cervical cancers.
5
–Nononcogenic
†
types include:
6, 11, 40, 42, 43, 44, 54
4
HPV 6 and 11 are most
often associated with
external genital warts.
3
1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076.
2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4.
Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527.
5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003:89;101–105.
Nonenveloped double-
stranded DNA virus
1
*High risk;
†
Low risk

56. 1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319–331. 2. Schiffman M, Castle PE. Arch Pathol Lab Med.
2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224.
Discovery of the Link Between Discovery of the Link Between
HPV and Cervical CancerHPV and Cervical Cancer
Body of information developed slowly based on advances
in cellular, molecular, and immunological diagnostic
technologies over the past 20 years
1
Epidemiological
case-control
studies
completed
1
HPV defined as
large, closely
related family
1
:
>100 types
2
;
30–40 anogenital
2,3
HPV genomes
found in cervical
carcinomas
1
HPV
viruses cloned
1
Mechanisms of
transformation
elucidated
(true “tumor virus”)
1
15–20 HPV types
classified as
oncogenic
2,3

57. Link Between HPV and Cervical Link Between HPV and Cervical
CancerCancer
99% of Cervical cancers and High-grade 99% of Cervical cancers and High-grade
cervical cancer precursor lesions cervical cancer precursor lesions
associated with HPVassociated with HPV
Risk for developing cervical cancer with Risk for developing cervical cancer with
HPV is 50-100x higher than without HPV HPV is 50-100x higher than without HPV
infectioninfection
Risk of High-grade precursor lesion with Risk of High-grade precursor lesion with
HPV is 300-foldHPV is 300-fold

58. Bacterial – Parasitic Infection & Cancer Bacterial – Parasitic Infection & Cancer
Helicobacter pylori – Gastric cancer, Helicobacter pylori – Gastric cancer,
MALTMALT
Opisthorchis viverrini – Cholangio-Opisthorchis viverrini – Cholangio-
carcinomacarcinoma
Schistosoma haematobium – Bladder Schistosoma haematobium – Bladder
carcinomacarcinoma

59. Environmental Factors & CancerEnvironmental Factors & Cancer
Carcinogens are agents Carcinogens are agents
that can cause cancer.that can cause cancer.
Xenobiotics are toxic, Xenobiotics are toxic,
mutagenic, and mutagenic, and
canrcinogenic chemicalscanrcinogenic chemicals
Important factors to be Important factors to be
considered are: time of considered are: time of
exposure, racial & gender exposure, racial & gender
disparities, human disparities, human
contamination & public contamination & public
health advocacyhealth advocacy
Tobacco smoke has Tobacco smoke has
polycyclic aromatic polycyclic aromatic
hydrocarbons, nitroso hydrocarbons, nitroso
compounds, compounds,
arylamines, benzo(a) arylamines, benzo(a)
pyrene metabolites, pyrene metabolites,
and benzene which and benzene which
are potent are potent
carcinogens.carcinogens.

60. Causas de SarcomasCausas de Sarcomas
Exposicion a RadioterapiaExposicion a Radioterapia
Pacientes inmunocomprometidosPacientes inmunocomprometidos
Exposicion a quimicos como hidro-carburos Exposicion a quimicos como hidro-carburos
policiclicos, cloruro de polivinil, asbestos, dioxina policiclicos, cloruro de polivinil, asbestos, dioxina
de los herbicidas.de los herbicidas.
Cicatrices de cirugias previas, quemaduras, dano e Cicatrices de cirugias previas, quemaduras, dano e
implantacion de cuerpo extranoimplantacion de cuerpo extrano
Hespes virus 8, HIV, HTLV-III, Rous Sarcoma virusHespes virus 8, HIV, HTLV-III, Rous Sarcoma virus
Tumores Benignos de huesos: condromas, displasia Tumores Benignos de huesos: condromas, displasia
fibrosa, Enfermedad de Paget del huesofibrosa, Enfermedad de Paget del hueso

61. Tobacco & Related CancersTobacco & Related Cancers
LungLung
Oral cavity, pharynx, larynx, nasal cavity, Oral cavity, pharynx, larynx, nasal cavity,
paranasal sinuses, esophagus & stomachparanasal sinuses, esophagus & stomach
Pancreas & LiverPancreas & Liver
Penis, kidney, bladderPenis, kidney, bladder
Cervix uteriCervix uteri
Myeloid leukemiaMyeloid leukemia

62. Radiation & CancerRadiation & Cancer
20 to 250 cGy for linear energy transfer 20 to 250 cGy for linear energy transfer
radiation, such as x-rays or gamma-rays is radiation, such as x-rays or gamma-rays is
the human cancer risk dose.the human cancer risk dose.
Radiation-induced gene mutations or Radiation-induced gene mutations or
chromosomal abnormalities that can be chromosomal abnormalities that can be
detected early (within 24 hours of radiation detected early (within 24 hours of radiation
exposure) are not solely responsible for exposure) are not solely responsible for
tumor development in normal human cells.tumor development in normal human cells.

63. Genomic instability & RadiationGenomic instability & Radiation
Mitotic failure
Cell death Chromosome alteration
Gene mutation
DNA damage
Ionizing radiation
Bystander
effect
&
Gap Junction
Intercellular
Communication

64. Ultraviolet radiation & Skin CancerUltraviolet radiation & Skin Cancer
It causes melanoma, basal cell carcinoma and It causes melanoma, basal cell carcinoma and
squamous cell carcinoma of the skin.squamous cell carcinoma of the skin.
The degree of damage depends on the intensity The degree of damage depends on the intensity
and wavelength content and the depth of and wavelength content and the depth of
penetration.penetration.
It induces release of tumor necrosis factor in the It induces release of tumor necrosis factor in the
epidermis.epidermis.
Inflammation is a critical component through Inflammation is a critical component through
hydrogen peroxide.hydrogen peroxide.
Activation of the mitogen-activated protein Activation of the mitogen-activated protein
kinase (MAPK) (eg. Melanoma) kinase (MAPK) (eg. Melanoma)

65. Multistep skin CarcinogenesisMultistep skin Carcinogenesis
Protein oxidation
Lipid peroxidation
Xenobiotics
Mutate
protooncogenes
Inflammation
ROS
Direct DNA
Damage
UVR
Oxidative
Stress

66. Alcohol ConsumptionAlcohol Consumption
Associated with cancer of the: oral cavity, Associated with cancer of the: oral cavity,
pharynx, hypopharynx, esophagus, liver, breast, pharynx, hypopharynx, esophagus, liver, breast,
colorectum.colorectum.
Mechanisms: effect of acetaldehyde, induction of Mechanisms: effect of acetaldehyde, induction of
cytochrome P-4502 E1 leading to the generation cytochrome P-4502 E1 leading to the generation
of ROS, increased procarcinogen activation, of ROS, increased procarcinogen activation,
modulation of cellular regeneration, nutritional modulation of cellular regeneration, nutritional
deficiency, altered mucosal integrity, enzyme deficiency, altered mucosal integrity, enzyme
and metabolic dysfunction, structural and metabolic dysfunction, structural
abnormalities. abnormalities.

67. Physical ActivityPhysical Activity
Related with breast and colon cancers.Related with breast and colon cancers.
Mechanisms: increases insulin and Mechanisms: increases insulin and
insulin-like growth factors, obesity, insulin-like growth factors, obesity,
decreasing free radical scavenger decreasing free radical scavenger
systems, inflammatory mediators, systems, inflammatory mediators,
increasing estrogen and androgens, increasing estrogen and androgens,
decreasing gut motility.decreasing gut motility.
Rx: for CRC we need 3.5 – 4 hours/week, Rx: for CRC we need 3.5 – 4 hours/week,
for BCA we need 30 – 60 minutes /day. for BCA we need 30 – 60 minutes /day.

68. Diet & ObesityDiet & Obesity
Important risk factors: low fiber and high fat diet, Important risk factors: low fiber and high fat diet,
obesity, alcohol consumption, contaminated obesity, alcohol consumption, contaminated
corn, peanuts and rice with aflatoxin, Chinese-corn, peanuts and rice with aflatoxin, Chinese-
style salted fish, hot beverages, grilled meat, red style salted fish, hot beverages, grilled meat, red
or processed food.or processed food.
Overweight and obesity are linked with cancer Overweight and obesity are linked with cancer
of: breast, colorectal, esophagus, gastric, liver, of: breast, colorectal, esophagus, gastric, liver,
gallbladder, pancreas, prostate, uterine, cervix, gallbladder, pancreas, prostate, uterine, cervix,
ovaries, non-Hodgkin’s lymphoma, multiple ovaries, non-Hodgkin’s lymphoma, multiple
myeloma, leukemia. myeloma, leukemia.

69. Biologic mechanisms of obesity Biologic mechanisms of obesity
and cancerand cancer
Free fatty acids,
TNF,
Resistin
Increased bioavailability of
Insulin-like growth factor-1
Increased WEIGHT
ADIPOSITY
Insulin resistant
Decreased liver synthesis, blood, and
tissue of insulin-like
growth factor binding protein 1 & 2
Decreased apoptosis &
Increased Cell proliferation
Tumor development

70. Obesity, hormones, and cancerObesity, hormones, and cancer
Aromatase &
17-B-Hydroxy
Steroid Dehydrogenase
Diffusion into target organs
Decreased apoptosis
Increased Proliferation
Loss of differentiation
Adipose tissue
Increased bioavailability of
Estradiol & testosterone
Reduced levels of
Sex Hormone Binding Globulin

71. Air PollutionAir Pollution
Indoor pollution is worse than outdoor Indoor pollution is worse than outdoor
pollution.pollution.
Indoor pollutants:Indoor pollutants:
–Environmental Tobacco SmokeEnvironmental Tobacco Smoke
–Radon gas (lung cancer)Radon gas (lung cancer)
–Inorganic Arsenic (bladder, skin, and lung Inorganic Arsenic (bladder, skin, and lung
cancers) cancers)

72. Electromagnetic fieldsElectromagnetic fields
It’s controversial, little evidence is It’s controversial, little evidence is
available. Further research is needed.available. Further research is needed.
Some association: Leukemia in children & Some association: Leukemia in children &
Brain Tumor in adults. Brain Tumor in adults.
EMR -> Thermal effect -> Protein EMR -> Thermal effect -> Protein
phosphorylation (?)phosphorylation (?)

73. Occupational CarcinogensOccupational Carcinogens
Asbestos: mesothelioma, lung cancerAsbestos: mesothelioma, lung cancer
Chromium, Nickel, Mustard gas: : lung cancerChromium, Nickel, Mustard gas: : lung cancer
Heterocyclic Amines: Colon Cancer Heterocyclic Amines: Colon Cancer
Dyes, Rubber, Paint, and Aromatic amines: Dyes, Rubber, Paint, and Aromatic amines:
Bladder cancerBladder cancer
Aflatoxin B, Vinyl chloride: Liver cancerAflatoxin B, Vinyl chloride: Liver cancer
Cadmium: Prostate cancer Cadmium: Prostate cancer
Benzol inhalation & leukemia in shoemakers, Benzol inhalation & leukemia in shoemakers,
rubber cement industry, explosives, and dyeing rubber cement industry, explosives, and dyeing
industry.industry.

74. Therapeutic drugs & CancerTherapeutic drugs & Cancer
Alkylating agents: melphalan, myleran – Alkylating agents: melphalan, myleran –
AMLAML
MOPP – AMLMOPP – AML
Immunosuppressants: azathioprine and Immunosuppressants: azathioprine and
cyclosporin – Lymphomacyclosporin – Lymphoma
Phenacetin – Renal & Bladder cancerPhenacetin – Renal & Bladder cancer
Hormones (estrogen, OCP’s, tamoxifen) – Hormones (estrogen, OCP’s, tamoxifen) –
Endometrial carcinoma Endometrial carcinoma

75. Tumor Spread, Invasion & Tumor Spread, Invasion &
Metastasis Metastasis
Direct Invasion (local)Direct Invasion (local)
–Cellular multiplication, mechanical pressure, release Cellular multiplication, mechanical pressure, release
of lytic enzymes, decreased cell to cell adhesion, of lytic enzymes, decreased cell to cell adhesion,
increased motility of cells, disruption of tumor-host increased motility of cells, disruption of tumor-host
microenvironmentmicroenvironment
Metastases to distant organs through lymphatic Metastases to distant organs through lymphatic
and blood systemand blood system
Metastases by way of implantation (tissue Metastases by way of implantation (tissue
spaces, body cavities, cerebrospinal spaces)spaces, body cavities, cerebrospinal spaces)

76. Tumor Invasion & MetastasisTumor Invasion & Metastasis
Anoikis: homelessness – cells detach from their Anoikis: homelessness – cells detach from their
matrix and undergo apoptosis.matrix and undergo apoptosis.
Lytic enzyems are: Matrix metallo-proteinases Lytic enzyems are: Matrix metallo-proteinases
such as type IV collagenase, Cysteine such as type IV collagenase, Cysteine
proteinases such as cathepsin b and D, and proteinases such as cathepsin b and D, and
Serine proteases such as urokinase-type Serine proteases such as urokinase-type
plasminogen activator.plasminogen activator.
Incresed expression of Twist expression causes Incresed expression of Twist expression causes
a loss of E-cadherin-mediated cell to cell a loss of E-cadherin-mediated cell to cell
adhesion.adhesion.
Three step theory of invasion: attachment, Three step theory of invasion: attachment,
degradation, and locomotion of the matrix. degradation, and locomotion of the matrix.

77. Clinical Manifestations of CancerClinical Manifestations of Cancer
(IL-1, TNF, IL-6, IFN)(IL-1, TNF, IL-6, IFN)
Pain is one of the main complaints. 25% of all Pain is one of the main complaints. 25% of all
cancer patients die with unrelieved pain.cancer patients die with unrelieved pain.
Fatigue is a second complaint.Fatigue is a second complaint.
Cachexia is from IL-6, IL-8, TNF.Cachexia is from IL-6, IL-8, TNF.
Anemia is secondary to TNF, IL-1, decreased Anemia is secondary to TNF, IL-1, decreased
EPO, impaired iron utilization, and chemo/radio.EPO, impaired iron utilization, and chemo/radio.
Nausea & Vomiting is usually 2ry to chemo.Nausea & Vomiting is usually 2ry to chemo.
Depression, anxiety, and delirium occurs in 50% Depression, anxiety, and delirium occurs in 50%
of patients.of patients.

78. Paraneoplastic SyndromesParaneoplastic Syndromes
Seen in 10% of cancer Seen in 10% of cancer
patients.patients.
Endocrine Manifestations:Endocrine Manifestations:
–Ectopic ACTH (Cushing’s): Ectopic ACTH (Cushing’s):
SCLC, Bronchial carcinoidSCLC, Bronchial carcinoid
–SIADH: Lung cancerSIADH: Lung cancer
–Hypercalcemia: Lung (Sq.), Hypercalcemia: Lung (Sq.),
Renal, Myeloma, ATCLL Renal, Myeloma, ATCLL
Hematologic Manifestations:Hematologic Manifestations:
–Polycythemia: Renal, Liver Polycythemia: Renal, Liver
–DVT/PE: Pancreas, LungDVT/PE: Pancreas, Lung
Gastrointestinal Gastrointestinal
Manifestations:Manifestations:
–Protein-losing enteropathyProtein-losing enteropathy
–Anorexia, CachexiaAnorexia, Cachexia
Renal Manifestations:Renal Manifestations:
–Membranous nephropathy: Membranous nephropathy:
stomach, lung, colon stomach, lung, colon
Cutaneous:Cutaneous:
–Acanthosis nigricans: GI Acanthosis nigricans: GI
cancer (Leser-Trelat) cancer (Leser-Trelat)
–Dermatomyositis: Breast & Dermatomyositis: Breast &
Bronchogenic ca.Bronchogenic ca.
Neurologic:Neurologic:
–Myasthenia: Bronchogenic ca.Myasthenia: Bronchogenic ca.
Rheumatologic:Rheumatologic:
–Hyperthtophic Hyperthtophic
osteoarthropathy: osteoarthropathy:
Bronchogenic ca. Bronchogenic ca.

79. Tumor markersTumor markers
(Biologic markers)(Biologic markers)
They are substances produced by cancer cells that are They are substances produced by cancer cells that are
found on tumor plasma membranes or in the blood, found on tumor plasma membranes or in the blood,
spinal fluid, or urine.spinal fluid, or urine.
AFP : Liver, Germ cell tumorsAFP : Liver, Germ cell tumors
B-HCG: Germ cell tumorsB-HCG: Germ cell tumors
CEA: Colon, Pancreas, Lung, breastCEA: Colon, Pancreas, Lung, breast
PSA: Prostate PSA: Prostate
CA19-9: Pancreas, Billiary treeCA19-9: Pancreas, Billiary tree
CA 125: OvarianCA 125: Ovarian
CA 15-3 or CA 27.29: BreastCA 15-3 or CA 27.29: Breast
B-2-microglobulin: Myeloma, LymphomaB-2-microglobulin: Myeloma, Lymphoma
Catecholamines: Pheochromocytoma Catecholamines: Pheochromocytoma

80. FDG-PET ScanningFDG-PET Scanning
FDG is a glucose analog that is taken up FDG is a glucose analog that is taken up
and trapped by tumor cells in most of and trapped by tumor cells in most of
patients with cancer. The positrons patients with cancer. The positrons
emitted by the F18 atom travel a short emitted by the F18 atom travel a short
distance before they encounter an distance before they encounter an
electron and undergo extinction with electron and undergo extinction with
emission of a pair of photons in opposite emission of a pair of photons in opposite
directions.directions.

81. Significance of FDG-PET scanSignificance of FDG-PET scan
Adds assessment to uncharacterized Adds assessment to uncharacterized
nodules and more accurately stages the nodules and more accurately stages the
tumor than CT.tumor than CT.
Intensity of uptake before tx is correlated Intensity of uptake before tx is correlated
with survival: high uptake = negative with survival: high uptake = negative
prognosis.prognosis.

82. More about PETMore about PET
It is a complement to CT in instances It is a complement to CT in instances
where CT has failed to detect distant where CT has failed to detect distant
metastatic disease, and advising biopsies metastatic disease, and advising biopsies
for LN’s > 1.0 cm on CT or positive on for LN’s > 1.0 cm on CT or positive on
FDG-PET. Biopsy is still advised for FDG-PET. Biopsy is still advised for
radio-graphically enlarged LN’s even if radio-graphically enlarged LN’s even if
FDG-PET scanning is negative. FDG-PET scanning is negative.

83. Cancer treatmentCancer treatment
Surgery is the goal standard.Surgery is the goal standard.
–Colorectal, Breast, Ovary, Lung, Thyroid, Skin, Uterus, Prostate Colorectal, Breast, Ovary, Lung, Thyroid, Skin, Uterus, Prostate
Chemotherapy: Lymphoma, Leukemia, Testicular, Chemotherapy: Lymphoma, Leukemia, Testicular,
Choriocarcinoma, Ovary, Breast Choriocarcinoma, Ovary, Breast
Radiation therapy: Breast, Uterus, Cervix, Lymphoma, Radiation therapy: Breast, Uterus, Cervix, Lymphoma,
LungLung
Hormonal therapy: Breast, Prostate, Endometrial, Hormonal therapy: Breast, Prostate, Endometrial,
AdrenalAdrenal
Immunotherapy: Melanoma, RCC, Leukemia Immunotherapy: Melanoma, RCC, Leukemia
Target therapy: Colon, Breast, Lung, RCC, Leukemia, Target therapy: Colon, Breast, Lung, RCC, Leukemia,
Lymphomas Lymphomas

84. Progress in OncologyProgress in Oncology
New diagnostic methodsNew diagnostic methods
Preventive MedicinePreventive Medicine
New Targeted and Personalized New Targeted and Personalized
Therapy Therapy
Palliative & Supportive CarePalliative & Supportive Care

85. THANK YOU !!!