marka residents

1. NEOPLASIA
Dr. Hiba Al-Zghoul
Orthodontic resident

2. • Nomenclature
• Malignant vs. Benign
• Epidemiology
• Heredity and neoplasia
• Molecular basis of carcinogenesis
• Progression of malignancy

3. • “A neoplasm is an abnormal mass of
tissue the growth of which exceeds and is
uncoordinated with that of the normal
tissues and persists in the same
excessive manner after the cessation of
the stimuli which evoked the change”
-Willis
• Genetic changes
• Autonomous
• Clonal
Neoplasia

4. Nomenclature
Benign Tumors
• Suffix “oma” generally indicates a benign
tumor  usually for tumors of
mesenchymal origin
 Fibroma  fibroblastic cells
 Chondroma  cartilage
 Osteoma  osteoblasts

5. Nomenclature
Benign Tumors
• Classification based on:
a) Cells of origin
 Adenoma – derived from glands but not
necessarily reproducing glandular patterns
b) Microscopic architecture
 Cystadenoma – form large cystic masses
 Papilloma – produce papillary patterns that
protrude into cystic spaces
c) Macroscopic patterns
 Polyp – macroscopically visible projection above a
mucosal surface

6. Nomenclature
Benign Tumors
Teratomas
• Arise from totipotent cells
• Tumors that derive from more than
one germ cell layer  contain tissue
derived from ectoderm, endoderm,
and mesoderm
• Sites: ovaries, testes, anterior
mediastinum, and pineal gland

7. Tumor-like conditions
Hamartoma
• Non-neoplastic overgrowth of
disorganized tissue indigenous to a
particular site  disorganized but
mature specialized cells or tissues

8. Tumor-like conditions
Choristoma
• Non-neoplastic tissue in a foreign
location; ectopic rest of normal
tissues
• Examples: pancreatic tissue in the
stomach wall; gastric mucosa in
Meckel diverticulum

9. Nomenclature
MalignantTumors
1. Sarcoma - mesenchymal tissue
 Fibrosarcoma
 Liposarcoma
2. Carcinoma – epithelial cell origin
 Adenocarcinoma – glandular
 Squamous cell carcinoma

10. Hamartoma of the spleen. The hamartoma is the dark circular object on
the left that dominates the image. This is a cross-section, the growth being
about 9cm in diameter, while the spleen is actually about 11cm.

11. 1. Parenchyma
• Proliferating neoplastic cells
• Determine behavior and pathologic
consequences of tumor
• Serve as basis for nomenclature
2. Supportive stroma
• Connective tissue and blood vessels  due
to failure of production of anti-angiogenic
factors
• Provides the framework of the
parenchyma
Components of Benign & Malignant Tumors

12. • IN GENERAL, BENIGN TUMORS ARE WELL-
DIFFERENTIATED.
• MALIGNANT NEOPLASMS RANGE FROM
WELL-DIFFERENTIATED TO
UNDIFFERENTIATED
 Malignant neoplasms composed of
undifferentiated cells are said to be
ANAPLASTIC
Differentiation

13. (A) Normal smooth muscle. (B) Leiomyoma of the uterus. This benign, well-
differentiated tumor contains interlacing bundles of neoplastic smooth muscle
cells that are virtually identical in appearance to normal smooth muscle cells in
the myometrium.
A B

17. • Degree of differentiation of a neoplasm is
generally related to its behavior
 Poorly-differentiated neoplasms tend to
be more aggressive than well-
differentiated ones
Differentiation

18. • Lack of differentiation
• “to form backward”  reversion from a
high level of differentiation to a lower
level
Anaplasia

20. Morphologic Changes: Malignant Tumors
3. Mitoses
• Higher proliferative activity
• Atypical, bizarre mitotic figures
4. Loss of polarity
• Markedly disturbed orientation of
anaplastic cells
• Sheets or large masses of cells grow in a
disorganized manner

23. • Disordered growth
• Encountered principally in epithelia
• Changes include:
1. Loss in uniformity of individual cells with
loss of architectural orientation
2. Pleiomorphism
3. Hyperchromatic, abnormally large nuclei
4. Abundant mitotic figures that appear in
abnormal locations within the epithelium
Dysplasia

24. • If changes are marked and involve the entire
thickness of the epithelium but the lesion
remains confined to the normal tissue  pre-
invasive neoplasm  CARCINOMA-IN-SITU
• Often found adjacent to foci of invasive
carcinoma
• Does not necessarily progress to cancer but
may antedate the appearance of cancer
Dysplasia

25. .

26. Benign vs. Malignant Tumors
Characteristics Benign Malignant
Differentiation/
anaplasia
Well-differentiated; lack of differentiation with
anaplasia
Rate of growth progressive & slow Erratic (may be slow to rapid)
Local invasion Usually cohesive and well-
demarcated masses that do
not invade or infiltrate
surrounding normal tissues
Locally invasive, infiltrating
the surrounding normal
tissues; sometimes may be
seemingly cohesive
Metastasis Absent Frequently present
Histology Resembles cell of origin poorly differentiated
Few mitoses Many mitoses, abnormal
Normal or slight increase in
nuclear/cytoplasmic ratio
High nuclear/cytoplasmic
ratio
Cells are uniform throughout
the tumor
Cellular and nuclear
pleiomorphism

30. • Growth rate of tumors may be affected by
factors such as
• hormonal stimulation
• adequacy of blood supply
• Pressure constraints
Growth rate

31. Pathways of Spread
Lymphatic Spread
• Most common pathway for initial spread
of carcinomas
• Regional lymph nodes are the first line of
defense
• Nodal enlargement in proximity to a
cancer does not necessarily mean
dissemination of the primary lesion
• Pattern of LN involvement follows the
natural routes of lymphatic drainage

32. Pathways of Spread
Hematogenous Spread
• Typical of sarcomas but also seen with
carcinomas
• Arteries less readily penetrated as veins
the liver and lungs are the most
frequently involved secondary sites in
hematogenous dissemination.

33. Pathways of Spread
Direct Seeding of Body Cavities & Surfaces
• May occur whenever a malignant neoplasm
penetrates into a natural “open field” 
most often involves peritoneal cavity
 Serous cystadenocarcinoma of ovaries 
omentum
 Peripherally located lung CA  parietal
and visceral pleura
 Glioblastoma multiforme  CSF  brain
and spinal cord

35. Geographic and environmental factors
• Sun exposure
• Smoking
• Alcohol abuse: Cancers of oropharynx, larynx,
esophagus, pancreas, liver
• Body mass
Overweight increases the risk
• Environmental vs. racial factors
Japanese immigrants to USA
• Viral exposure
 HPV and cervical cancer
 HBV and liver cancer
 EBV and lymphoma

36. Predisposing factors for cancer
• Age: increased risk in persons older than 55 years
childhood: leukemias, CNS neoplasms
• Genetic predisposition: familial cancer syndromes
 Early onset
 Multiple or bilateral lesions
 Two or more relatives
• Non-hereditary predisposing factors:
Chronic inflammation
Precancerous conditions (squamous dysplasia,
leukoplakia)
Immune collapse

37. Less than 10% of cancer patients have
inherited mutations that predispose to
cancer.
Most of the geographic
differences are due to
environmental and cultural
factors rather than genetic
predisposition.

38. Categories of Genetic Predispositions to Cancer
Autosomal Dominant Cancer Syndromes
• Inheritance of a single mutant gene greatly
increases the risk of developing a tumor
• Inherited mutation usually a point mutation
occurring in a single allele of a tumor
suppressor gene
 Childhood retinoblastoma  RB tumor
suppressor gene
 Familial adenomatous polyposis 
adenomatous polyposis coli (APC) gene

39. Inherited Predisposition to Cancer
Inherited Cancer Syndromes (Autosomal Dominant)
Gene Inherited Predisposition
RB
p53
p161NK4A
APC
NF1, NF2
BRCA1, BRCA2
MEN-1, RET
MSH2, MLH1, MSH6
PATCH
Retinoblastoma
Li-Fraumeni Synd. (various tumors)
Melanoma
Familial adenomatous polyposis/colon
cancer
Neurofibromatosis 1 and 2
Breast and ovarian tumors
MEN-1, MEN-2
Hereditary nonpolyposis colon cancer
Nevoid basal cell carcinoma syndrome

40. Defective DNA Repair Syndromes
• Defects in DNA repair lead to DNA instability
• Generally autosomal recessive
• Includes:
1. Xeroderma pigmentosum
 Increased risk for developing skin
cancers due to UVL (produce
pyrimidine dimers)
 Includes basal cell CA, squamous cell
carcinoma

41. Defective DNA Repair Syndromes
• Includes:
2. Chromosome instability syndromes
 Chromosomes susceptible to damage
by ionizing radiation and drugs;
predisposition to cancer
 Includes: Fanconi anemia, ataxia
telangiectasia, Bloom syndrome

42. Defective DNA Repair Syndromes
• Includes:
3. Hereditary non-polypoid colon cancer
(HNPCC)
 most common cancer predisposition
syndrome  CA in colon, small
intestine, endometrium, ovary

43. Inherited Predisposition to Cancer
Familial Cancers
Familial clustering of cases, but role of inherited
predisposition not clear for each individual
Breast cancer
Ovarian cancer
Pancreatic cancer
Inherited Autosomal Recessive Syndromes of
Defective DNA Repair
Xeroderma pigmentosa
Ataxia-telangiectasia
Bloom syndrome
Fanconi anemia

44. Done with the
easy part !!!!!!!

45. Malignant transformation
• Self-sufficient in growth signals
• Insensitivity to growth inhibiting signals
• Evasion of apoptosis
• Defects in DNA repair : “spell checker”
• Limitless replicative potential: Telomerase
• Angiogenesis
• Invasive ability
• Metastatic ability

46. Principles
Non-lethal genetic damage lies at the heart of
carcinogenesis.
• May be acquired (environmental agents or
viruses) OR inherited in the germ line
• Environmental – exogenous agents or
endogenous products of cell metabolism

47. Principles
Four classes of regulatory genes are the principal
targets of genetic damage.
a) Protooncogenes
• Genes that code for proteins involved in
the control of cell growth (e.g. Growth
factors, growth factor receptors, signal
transducers)
• Mutant alleles dominant

48. Principles
Four classes of regulatory genes are the principal
targets of genetic damage.
b) Tumor suppressor genes
• Genes that produce products that inhibits
cell growth  control G1 to S phase of cell
cycle & nuclear transcription
• Recessive oncogenes

49. Principles
Four classes of regulatory genes are the principal
targets of genetic damage.
c) Apoptosis genes
• Regulate programmed cell death
• Example: BAX
 Activated by TP53 if DNA damage is
excessive
 BAX protein inactivates the BCL2 anti-
apoptosis gene
 Mutation of TP53  inactivate BAX
 no apoptosis

50. Principles
3. Four classes of regulatory genes are the
principal targets of genetic damage.
d) Genes involved in DNA repair
• Loss of activity  DNA instability 
somatic mutations in oncogenes or
tumor suppressor genes
• Both alleles must be inactivated

51. Self-sufficiency in growth signals
Role of Oncoproteins
1. Growth factors
• Most soluble growth factors made by
one cell type and act on a neighboring
cell to stimulate proliferation 
paracrine action
• Most cancer cells able to synthesize the
same growth factors to which they are
responsive in an autocrine loop
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52. Self-sufficiency in growth signals
Role of Oncoproteins
2. Growth factor receptors
• Normal transmembrane receptors:
transiently activated  followed by receptor
dimerization and tyrosine phosphorylation
• Oncogenic version: active without binding to
the growth factor  continuous mitogenic
signal to cell even in the absence of growth
factors in the environment

54. Self-sufficiency in growth signals
RAS Oncogone
• Point mutation of proto-oncogene the
single most common abnormality in
human tumors
• RAS proteins bind guanosine
nucleotides GTP and GDP

55. Self-sufficiency in growth signals
RAS Oncogone
Inactive RAS
GDP
Stimulation of
cells by growth
factors
Exchange of GDP
for GTP
Activated RAS
Stimulate mitogen-
activated protein
(MAP) kinase cascade
Flood nucleus with
signals for cell
proliferation
Hydrolysis of
GTP

56. Self-sufficiency in growth signals
RAS Oncogone
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57. ABL Oncogone
• ABL is a signal transduction molecule
The ABL proto-oncogene is activated by tyrosine kinase
• In chronic myelogenous leukemia and certain acute
leukemias, ABL gene is translocated from
chromosome 9 to chromosome 22, fuses with BCR
gene.
• The BCR-ABL causes a constitutive tyrosine kinase
activity
• Imatinib mesylate (Gleevec) is a BCR-ABL kinase
inhibitor
Self-sufficiency in growth signals

58. Self-sufficiency in growth signals
MYC Oncogone
• Transcription factor that is the most involved in
human tumors
• Induced when quiescent cells receive signal to
divide
• Activates several growth-promoting genes,
including cyclin dependent kinases CDKs
• Represses CDK inhibitors CDKIs
• Translocation  Burkitt’s lymphoma
• Amplification  carcinoma of breast, colon, lungs

60. Self-sufficiency in growth signals
B. Dysregulated activity of cyclins & CDKs
• Mutations that dysregulate activity of cyclins
and CDKs favor cell proliferation
• All cancers have genetic lesions that disable
the G1-S checkpoint

61. Insensitivity to growth inhibition
Tumor Suppressor Genes
• Apply breaks to cell proliferation 
prevent uncontrolled growth
• Recognize genotoxic stress  shut
down cell proliferation
• Expression in a normal cell  lead
to quiescence or permanent cell
cycle arrest (oncogene-induced
senescence)

62. Tumor Suppressor Genes: RB
• Exists in an active hypophosphorylated state
in quiescent cells and an inactive
hyperphosphorylated state in the G1/S cell
cycle transition
• Two mutations (hits) are required
Insensitivity to growth inhibition

63. Tumor Suppressor Genes: RB (retinoblastoma)
• Blocks E2F-mediated transcription
• Hypophosphorylated (active) RB  binds
to and inhibits E2F  no cyclin E
transcription  progression to S phase
inhibited
• Hyperphosphorylated (inactive) RB 
release of E2F  transcription of cyclin E
 DNA replication and progression
through cell cycle

65. Tumor Suppressor Genes: p53
• Most common target for genetic alterations
in human tumors
• Senses cellular stress, such as DNA
damage, shortened telomeres, and hypoxia
• Prevents malignant transformation by:
 Activation of quiescence
 Induction of senescence
 Triggering apoptosis

67. Evasion of apoptosis
Intrinsic Pathway
1. Cleavage and activation of BH3-only
protein BID by caspase 8
2. Permeabilization of mitochondrial
membrane
3. Release of cytochrome c
4. Binding of cytochrome c to APAF-1 
activation of caspase 9  cleavage and
activation of executioner caspases

68. Evasion of apoptosis
• Integrity of mitochondrial outer
membrane regulated by anti-apoptotic
proteins BCL2 & BCL-XL
• Pro-apoptotic proteins: BAX & BAK
• BH3-only proteins (BAD, BID, PUMA) 
regulate the balance between pro- and
anti-apoptotic proteins

69. Limitless replicative potential
• Most normal human cells with capacity of 60 – 70
doublings  after doublings, cell lose ability to
divide  become senescent  due to shortening
of telomeres at ends of chromosomes
• Short telomeres  recognized by DNA-repair
machinery  cell cycle arrest mediated by p53 and
RB
• 85% - 95% of cancers with up-regulation of enzyme
telomerase  lengthening of telomeres  no cell
cycle arrest or senescence

70. Sustained angiogenesis
• Solid tumors cannot enlarge beyond 1 to
2 mm in diameter unless they are
vascularized
• Cancer cells can stimulate:
1. Neoangiogenesis – new vessels from
previously existing capillaries
2. Vasculogenesis – endothelial cells
recruited from bone marrow

71. Sustained angiogenesis
• Tumor angiogenesis is controlled by a
balance between angiogenesis promoters
and inhibitors  involves proteases
secreted by tumor cells or inflammatory
cells
 Increased production of angiogenic
factors and/or loss of angiogenic
inhibitors
• Angiogenic switch controlled by physiologic
stimuli such as hypoxia

72. • Angiogenesis factors produced by tumor cells
include:
1. Vascular endothelial growth factor (VEGF)
2. Basic fibroblast growth factor (bFGF)
3. Angiopoietin (Ang)
Sustained angiogenesis

73. The metastatic
cascade.
Sequential steps
involved in the
hematogenous
spread of a tumor.

74. Ability to invade and metastasize
• Biologic hallmarks of malignant tumors
• Metastatic cascade divided into two phases:
1. Invasion of extracellular matrix
(basement membrane & interstitial
connective tissue)
2. Vascular dissemination, homing of tumor
cells, and colonization

75. Metabolic alterations in tumors
Warburg effect: Hypotheses
Growth advantage in the hypoxic tumor micro-
environment.
Hypoxia  stimulate angiogenesis and up-regulate
expression of enzymes for glycolysis
Mutations in oncogenes and tumor suppressors that
favor growth (e.g. RAS, p53, and PTEN)
• Alterations in signalling pathways in cancer
can also stimulate the uptake of glucose and
other nutrients  favor glycolysis

76. Thank you