2. OVERVIEW
• History
• Nomenclature
• Benign vs Malignant
• Epidemiology
• Molecular basis
• Hallmarks of cancer
• Enablers of malignancy - Genomic instability, Inflammation
• Chemicals, Radiation and Microbes in carcinogenesis
• Clinical aspects – Local effects, Cachexia ,paraneoplastic syndromes
• Laboratory diagnosis – Methods with Tumor markers
• Grading and staging
3. NORMAL CELL DIVISION
• There are trillions of cells in our body
• Healthy cells are programmed to “know what to do and when to do it”.
4.
5.
6.
7.
8. WHAT IS CANCER
• Cancer is a general name for more than 100 different diseases
• The common point about all these different diseases is that a particular cell of the
body is growing out of control
• Cancer cells donot know “what to do, and when to do”
• This division uses up all the resources required by other cells of the body
9. CELCUS AND GALEN
• Celcus (25 BC) translated carcinos into latin – cancer
• Galen suggested the word oncos for swelling – Oncology thus was named
10. BIRTH OF MICROSCOPIC PATHOLOGY
• The 19th century modern microscope was invented and cancerous tissue could
be studied.
• Rudolf Virchow, often called the founder of cellular pathology, linked
microscopic findings with cancer types.
11. NOMENCLATURE
• Neoplasia means “new growth”
• Willis –
• A neoplasm is an abnormal mass of tissue,
• the growth of which exceeds and is uncoordinated with that of the normal tissues
• and persists in the same excessive manner after cessation of the stimuli which evoked the change
• Oncology (Greek oncos = tumor) is the study of tumors or neoplasms
• Benign Tumors - A tumor is said to be benign when its gross and microscopic appearances are
considered relatively innocent, implying that it will remain localized, will not spread to other sites, and
is amenable to local surgical removal
• Malignant tumors can invade and destroy adjacent structures and spread to distant sites
(metastasize) to cause death.
12.
13. MIXED TUMORS
• Pleomorphic adenoma - tumors contain epithelial components
scattered within a myxoid stroma that may contain islands of
cartilage or bone
• Teratoma - contains recognizable mature or immature cells
or tissues belonging to more than one germ cell layer (and
sometimes all three)
• Hamartomas - disorganized but benign masses composed
of cells indigenous to the involved site
• Choristoma – heterotopic rest of cells. For example, a small
nodule of well-developed and normally organized
pancreatic tissue may be found in the submucosa of the
stomach, duodenum, or small intestine
16. 1. DIFFERENTIATION
• Differentiation refers to the extent to which neoplastic parenchymal cells
resemble the corresponding normal
• Lack of resemblance to normal is called anaplasia
Well different
A
ia
n
ta
ep
dla
–sU
iasually benign
17. ANAPLASIA
• Pleomorphism - variation in size and shape of cells within the same tumor
• Large nuclei – N:C ratio is increased
• Hyperchromasia
• Loss of polarity
• Mitoses - atypical, bizarre mitotic figures
18. DYSPLASIA
• literally means “disordered growth”
• encountered principally in epithelium
• Show the above mentioned changes
• When changes involve whole epithelium without spread to dermis – carcinoma
in situ
19. II. LOCAL INVASION
• Benign tumors are surrounded by a capsule,
malignant tumors do not have capsule
• That means malignant tumors invade the
surrounding tissue
20. III. METASTASIS
Metastasis is defined by
the spread of a tumor to
sites that are physically
discontinuous with the
primary tumor
Pathways of spread
• Seeding into cavities – eg
peritoneal fluid, pleural
fluid, arachnoid space
• Lymphatic spread
• Hematogenous spread
30. • NON MODIFIABLE RISK FACTORS (GENETIC)
• Age - Most carcinomas occur in the later years of life (>55 years)
• Sex – Some cancers are common in males and some in females
34. IMMUNODEFICIENCY STATE
• AIDS DEFINING MALIGNANCIES
• Kaposci’s sarcoma
• Aggressive B cell Non Hodgkin lymphoma
• Cervical cancer
35. HEREDITY PREDISPOSES ONE TO EFFECTS OF
ENVIRONMENTAL CARCINOGENS !!!
• Inherited variations (polymorphisms) of enzymes that metabolize procarcinogens
to their active carcinogenic forms can influence cancer susceptibility.
• Of interest in this regard are genes that encode the cytochrome P-450 enzymes.
• A polymorphism confers an inherited susceptibility to lung cancers in cigarette
smokers.
37. MOLECULAR BASIS
• Molecular basis of cancer can be explained simpler by taking example of
colorectal cancer and the – Adenoma-carcinoma sequence as explained in the
following slide
• This is also known as MULTISTEP CARCINOGENESIS
38. Tumor suppressor genes take Second set of mutations
first hit - along with that known as driver mutation
ere are multiple mutations initiates carcinogenesis
donot seem to induce
inogenesis per se but with
the Once established, tumors evolve genetically
th during
that their outgrowth and progression under the
carc pressure of Darwinian selection (survival of
the timefa
it
ct
c
e
u
sm
t)u
. late and somehow
lead to cancer. They are
known as “passenger
mutations”
41. HALLMARKS OF CANCER
• All cancers display eight fundamental changes in cell physiology, which are
considered the hallmarks of cancer
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Altered cellular metabolism – Warburg phenomenon
4. Evasion of apoptosis
5. Limitless replicative potential (immortality) (stem cell like property)
6. Sustained angiogenesis
7. Ability to invade and metastasize
8. Ability to evade the host immune response
42. 1. SELF SUFFICIENCY IN GROWTH SIGNALS
• Genes that promote autonomous cell growth in cancer cells are called oncogenes,
and their unmutated cellular counter-parts are called proto-oncogenes.
• Oncogenes are created by mutations in proto-oncogenes and encode proteins
called oncoproteins that have the ability to promote cell growth in the absence of
normal growth-promoting signals.
• Cells expressing oncoproteins are thus freed from the normal checkpoints in a cell
cycle (G1S and G2M) and controls that limit growth, and as a result proliferate
excessively.
43. 1. SELF SUFFICIENCY IN GROWTH SIGNALS
(CONTD)
• Proto-oncogenes may encode growth factors, growth factor receptors, signal
transducers, transcription factors, or cell cycle components.
• A host of proto oncogenes with oncoproteins they express is given in the next
slide. It is impossible to remember all of them. As and when a tumor is studied,
its associated oncogene can be remembered. The following table is just for
information.
44.
45. II. INSENSITIVITY TO GROWTH INHIBITION
(INSENSITIVITY TO PRODUCTS OF TUMOR SUPPRESSOR
GENES)
• Whereas oncogenes drive the proliferation of cells, the products of most tumor
suppressor genes (such as RB and p53) apply brakes to cell proliferation, and
abnormalities in these genes lead to failure of growth inhibition.
• Let us consider the example of retinoblastomas (RB gene defect) first.
• Then we shall move to p53
47. “KNUDSON’S TWO HIT HYPOTHESIS”
• Approximately 40% of retinoblastomas are familial, with the predisposition to
develop the tumor being transmitted as an autosomal dominant trait. Carriers of
the retinoblastoma trait have a 10,000-fold increased risk of developing
retinoblastoma (often in both eyes) as compared to the general population.
• About 60% of retinoblastomas occur sporadically (virtually always in only one
eye).
• To explain these two patterns of occurrence of retinoblastoma, Knudson
proposed his now canonic “two-hit” hypothesis of oncogenesis.
48.
49. HOW DOES RB REGULATE THE CELL
CYCLE?
• RB, Governor of the Cell Cycle
• When hypophosphorylated, RB exerts antiproliferative effects by binding and
inhibiting E2F transcription factors that regulate genes required for cells to
pass through the G1-S phase cell cycle checkpoint.
• Normal growth factor signaling leads to RB hyperphosphorylation and
inactivation, thus promoting cell cycle progression.
• The antiproliferative effect of RB is abrogated in cancers through
a variety of mechanisms, including:
• Loss-of-function mutations affecting RB
• Gene amplifications of CDK4 and cyclin D genes
• Loss of cyclin-dependent kinase inhibitors (p16/INK4a)
• Viral oncoproteins that bind and inhibit RB (E7 protein of
HPV)
51. TP 53 - GUARDIAN
OF THE GENOME
• TP53, a tumor suppressor gene that regulates
cell cycle progression, DNA repair, cellular
senescence, and apoptosis, is the most
frequently mutated gene in human cancers.
• The majority of human cancers demonstrate
biallelic lossof-function mutations in TP53.
• Rare patients with Li- Fraumeni syndrome inherit one
defective copy of TP53 and have a very high
incidence of a wide variety of cancers.
• Like RB, p53 is inactivated by viral oncoproteins,
such as the E6 protein of HPV
52. III. WARBURG PHENOMENON
• Normal cells primarily produce energy through mitochondrial oxidative
phosphorylation.
• However, most cancer cells predominantly produce their energy through a high-rate
of glycolysis followed by lactic acid fermentation even in the presence of abundant
oxygen, this is called aerobic glycolysis, also termed the Warburg effect.
• Diagnostically the Warburg effect is the basis for the PET scan in which an injected
radioactive glucose analogue is detected at higher concentrations in malignant
cancers than in other tissues.
• Today, mutations in oncogenes and tumor suppressor genes are thought to be
responsible for malignant transformation, and the Warburg effect is considered to be
a result of these mutations rather than a cause.
53. IV. EVASION OF APOPTOSIS
• In the adult, cell death by apoptosis is a protective response to several pathologic conditions
that might contribute to malignancy if the cells remained viable.
• A cell with genomic injury can be induced to die, eliminating the chance that such a cell might
go on to give rise to a neoplasm.
• Apoptosis can be initiated through intrinsic or extrinsic pathways, both of which result in the
activation of a proteolytic cascade of caspases that destroys the cell.
• Abnormalities of both pathways are found in cancer cells, but lesions that incapacitate the
intrinsic (mitochondrial) pathway appear to be most common.
• In greater than 85% of follicular B-cell lymphomas, the anti-apoptotic gene BCL2 is
overexpressed due to a (14;18) translocation.
54. V. LIMITLESS REPLICATIVE POTENTIAL (STEM CELL
LIKE PROPERTY)
• All cancer cells are immortal, some cell lines established from cancers have now
been proliferating ceaselessly in laboratories for more than 60 years.
• This goes to show that at least some cells in all cancers must be stem cell–like;
these cells are sometimes referred to as cancer stem cells.
• These may arise through transformation of a normal stem cell or through
acquired genetic lesions that impart a stem like state on a more mature cell.
• Cancer cells acquire lesions that inactivate senescence signals and reactivate
telomerase, which act together to convey limitless replicative potential.
55.
56. VI. SUSTAINED ANGIOGENESIS
• Even if a solid tumor possesses all of the genetic aberrations that are required for malignant
transformation, it cannot enlarge beyond 1 to 2 mm in diameter unless it has the capacity to induce
angiogenesis.
• Growing cancers stimulate neoangiogenesis, during which vessels sprout from previously existing
capillaries.
• Relative lack of oxygen due to hypoxia stabilizes HIF1α, an oxygen-sensitive transcription factor
mentioned earlier, which then activates the transcription of the proangiogenic cytokines VEGF and
bFGF.
• These factors create an angiogenic gradient that stimulates the proliferation of endothelial cells and
guides the growth of new vessels toward the tumor.
• Neovascularization has a dual effect on tumor growth:
• perfusion supplies needed nutrients and oxygen, and
• newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors, such
as insulin-like growth factors (IGFs) and PDGF.
57. VII. INVASION AND METASTASIS
• Invasion and metastasis are the results of complex interactions between cancer
cells and normal stroma.
• The metastatic cascade is divided into two phases:
1. invasion of the extracellular matrix (ECM)
2. vascular dissemination, homing of tumor cells, and colonization.
58. VIII. ABILITY TO EVADE HOST IMMUNE RESPONSE
• Paul Ehrlich first conceived the idea that tumor cells can be recognized as
“foreign” and eliminated by the immune system.
• Subsequently, Lewis Thomas and Macfarlane Burnet formalized this concept by
coining the term immune surveillance, which implies that a normal function of the
immune system is to constantly “scan” the body for emerging malignant cells and
destroy them.
• This idea has been supported by many observations—the presence of
lymphocytic infiltrates (tumor specific T cells) around tumors.
59. VIII. ABILITY TO EVADE HOST IMMUNE RESPONSE
(CONTD)
• Tumor cells can be recognized by the immune system as non-self and destroyed.
• Antitumor activity is mediated by predominantly cell mediated mechanisms.
Other than that, NK cells and macrophages may also collaborate.
• Tumor antigens are presented on the cell surface by MHC class I molecules and are
recognized by CD8+ CTLs.
• The different classes of tumor antigens include products of mutated proto-
oncogenes, tumor suppressor genes, overexpressed or aberrantly expressed
proteins, tumor antigens produced by oncogenic viruses, oncofetal antigens,
altered glycolipids and glycoproteins, and cell type specific differentiation
antigens.
63. I. GENOMIC INSTABILITY (DEFECTS IN DNA REPAIR
SYSTEMS) AS ENABLER OF MALIGNANCY
• Persons with inherited mutations of genes involved in DNA repair systems are at greatly
increased risk for the development of cancer.
1. HNPCC syndrome - defects in the mismatch repair system, leading to development of
carcinomas of the colon.
2. Xeroderma pigmentosum - defect in the nucleotide excision repair pathway and are at
increased risk for the development of cancers of the skin exposed to UV light
3. Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia - defects in the homologous
recombination DNA repair system; characterized by hypersensitivity to DNA-damaging
agents, such as ionizing radiation.
4. Familial breast cancers – Mutated BRCA1 and BRCA2 which are involved in DNA repair.
64. II. CANCER ENABLING INFLAMMATION
• Infiltrating cancers provoke a chronic inflammatory reaction.
• Proposed cancer-enabling effects of inflammatory cells and resident stromal cells
include the following:
1. Release of factors that promote proliferation. Infiltrating leukocytes and activated
stromal cells have been shown to secrete a wide variety of growth factors, such as EGF,
and proteases that can liberate growth factors from the extracellular matrix (ECM).
2. Removal of growth suppressors. As mentioned, the growth of epithelial cells is
suppressed by cell-cell and cell-ECM interactions. Proteases released by inflammatory cells
can degrade the adhesion molecules that mediate these interactions, removing a barrier to
growth.
65. II. CANCER ENABLING INFLAMMATION (CONTD)
3. Enhanced resistance to cell death. Recall that detachment of epithelial cells from basement
membranes and from cell-cell interactions can lead to a particular form of cell death called anoikis. It
is suspected that tumor-associated macrophages may prevent anoikis by expressing adhesion
molecules such as integrins that promote direct physical interactions with tumor cells.
stimulate angiogenesis.
remodelling the ECM, while factors such as TNF and EGF may directly stimulate tumor cell motility.
4. Inducing angiogenesis. Inflammatory cells release numerous factors, including VEGF, which can
5. Activating invasion and metastasis. Proteases released from macrophages foster tissue invasion by
6. Evading immune destruction. A variety of soluble factors released by macrophages and other
stromal cells are believed to contribute to the immunosuppressive microenvironment of tumors,
including TGF-β and a number of other factors that either favour the recruitment of
immunosuppressive T regulatory cells or suppress the function of CD8+ cytotoxic T cells.
69. I. CHEMICAL
CARCINOGENS
• Direct-acting carcinogens require
no metabolic conversion to
become carcinogenic
• Indirectly acting agents require
metabolic conversion
70. II. RADIATION
CARCINOGENESIS
Ionizing radiation causes chromosome breakage, translocations, and, less
frequently, point mutations, leading to genetic damage and carcinogenesis.
UV rays induce the formation of pyrimidine dimers within DNA, leading to
mutations. Therefore, UV rays can give rise to squamous cell carcinomas and
melanomas of the skin. Individuals with defects in the repair of pyrimidine
dimers suffer from Xeroderma pigmentosa and are at particularly high risk.
Exposure to radiation during imaging procedures such as CT scans is linked to
a very small, but measurable, increase in cancer risk in children.
71. III. MICROBIAL CARCINOGENESIS
VIRAL / BACTERIAL
• HTLV-1
• A retrovirus that is endemic in Japan, the Caribbean, and parts of South America and
Africa that causes adult T-cell leukemia/lymphoma.
• HTLV-1 encodes the viral protein Tax, which turns on progrowth and pro-survival
signaling pathways (PI3K/AKT, NF-κB), leading to a polyclonal expansion of T cells.
• After a long latent period (decades), a small fraction of HTLV-1–infected individuals
develop adult T-cell leukemia/lymphoma, a CD4+ tumor that arises from an HTLV-1
infected cell, presumably due to acquisition of additional mutations in the host cell
genome.
72. III. MICROBIAL CARCINOGENESIS
VIRAL / BACTERIAL
• HPV
• An important cause of benign warts, cervical cancer, and oropharyngeal cancer
• Oncogenic types of HPV encode two viral oncoproteins, E6 and E7, that bind to Rb and
p53, respectively, with high affinity and neutralize their function.
• Development of cancer is associated with integration of HPV into the host genome
and additional mutations needed for acquisition of cancer hallmarks.
• HPV cancers can be prevented by vaccination against high-risk HPV types.
73. III. MICROBIAL CARCINOGENESIS
VIRAL / BACTERIAL
• EBV
• Ubiquitous herpesvirus implicated in the pathogenesis of Burkitt lymphomas, B-cell
lymphomas in patients with T-cell immunosuppression (HIV infection, transplant recipients),
and several other cancers.
• The EBV genome harbors several genes encoding proteins that trigger B cell signaling
pathways; in concert, these signals are potent inducers of B cell growth and transformation.
• In the absence of T-cell immunity, EBV-infected B cells can rapidly “grow out” as aggressive
B-cell tumors.
• In the presence of normal T-cell immunity, a small fraction of infected patients develop
EBV-positive B-cell tumors (Burkitt lymphoma, Hodgkin lymphoma) or carcinomas
(nasopharyngeal, gastric carcinoma).
74. III. MICROBIAL CARCINOGENESIS
VIRAL / BACTERIAL
• Hepatitis B virus and hepatitis C virus
• cause of between 70% and 85% of hepatocellular carcinomas worldwide.
• Oncogenic effects are multifactorial; dominant effect seems to be immunologically
mediated chronic inflammation, hepatocellular injury, and reparative hepatocyte
proliferation.
• HBx protein of HBV and the HCV core protein can activate signal transduction
pathways that also may contribute to carcinogenesis.
75. III. MICROBIAL CARCINOGENESIS
VIRAL / BACTERIAL
• H. pylori
• implicated in gastric adenocarcinoma and MALT lymphoma
• Pathogenesis of H. pylori-induced gastric cancers is multifactorial, including chronic
inflammation and reparative gastric cell proliferation.
• H. pylori pathogenicity genes, such as CagA, also may contribute by stimulating
growth factor pathways.
• Chronic H. pylori infection leads to polyclonal B-cell proliferations that may give rise to
a monoclonal B-cell tumor (MALT lymphoma) of the stomach as a result of
accumulation of mutations.
77. CLINICAL ASPECTS OF NEOPLASIA
• LOCAL AND HORMONAL EFFECTS
• CACHEXIA
• PARANEOPLASTIC SYNDROMES
78. I. LOCAL AND HORMONAL EFFECTS
1. Location is a critical determinant of the clinical effects of both benign and malignant tumors.
• Tumors may impinge upon vital tissues and impair their functions. A small (1 cm) pituitary adenoma,
although benign and possibly non functional, can compress and destroy the surrounding normal gland
and thus lead to serious hypopituitarism.
• Neoplasms in the gut, both benign and malignant, may cause obstruction as they enlarge.
• Melena (blood in the stool) and hematuria, for example, are characteristic of neoplasms of the gut and
urinary tract.
2. Benign and malignant neoplasms arising in endocrine glands can cause clinical problems by
producing hormones.
• A benign beta-cell adenoma of the pancreatic islets less than 1 cm in diameter may produce sufficient
insulin to cause fatal hypoglycemia.
79. II. CACHEXIA
• Individuals with cancer commonly suffer progressive loss of body fat and lean
body mass accompanied by profound weakness, anorexia, and anemia, referred
to as cachexia.
• TNFα (originally known as cachectin) is a leading suspect among several
mediators released from immune cells that may contribute to cachexia.
80. III. PARANEOPLASTIC SYNDROMES
• Some cancer-bearing individuals develop signs and symptoms that cannot readily be
explained by the anatomic distribution of the tumor or by the elaboration of
hormones indigenous to the tissue from which the tumor arose; these are known as
paraneoplastic syndromes. – list is given in next slide, brief discussion follows
• Some of them include
1. Endocrinopathies –
1. responsible cancers are not of endocrine origin and the secretory activity of such tumors is
referred to as ectopic hormone production.
2. Cushing’s syndrome is the prototype most commonly seen in small cell carcinoma of lung
3. Hypercalcemia –
1. due to production of calcemic humoral substances by extraosseous neoplasms, these substances
include PTHRP produced by cancers of breast, lung, kidneys and ovary.
2. Squamous cell carcinoma is most common lung carcinoma associated with hypercalcemia.
81. III. PARANEOPLASTIC SYNDROMES
4. Neuro myopathic syndromes – may take diverse forms such as peripheral
neuropathies or syndromes similar to myasthenia gravis. Cause is proposed to be
antibodies against tumor antigens cross reacting with normal neurons.
5. Acanthosis nigricans – gray black patches of thickened hyperkeratotic skin
6. Hypertrophic osteoarthropathies – characterised by periosteal new bone formation,
arthritis and clubbing of digits
7. Migratory thrombophlebitis – associated with deep seated cancers like that of
pancreas or lung
8. DIC – associated with APML or pancreatic adenocarcinoma
9. Non bacterial thrombotic endocarditis
84. LABORATORY DIAGNOSIS OF CANCER
1. CYTOLOGY
• FNAC
• EXFOLIATIVE CYTOLOGY – PAP SMEAR, BODY FLUIDS
2. HISTOLOGY
• H&E
3. IMMUNOHISTOCHEMISTRY
• identification of cell products or surface markers
4. FLOW CYTOMETRY
• identify cellular antigens expressed by “liquid” tumors, those that arise from blood-forming
tissues
85. LABORATORY DIAGNOSIS OF CANCER
5. MOLECULAR METHODS
• Until recently, molecular studies of tumors involved the analysis of individual genes.
• However, the past few years have seen the introduction of revolutionary technologies
that can rapidly sequence an entire genome;
• assess epigenetic modifications genome-wide (the epigenome);
• quantify all of the RNAs expressed in a cell population (the transcriptome);
• measure many proteins simultaneously (the proteome);
• and take a snapshot of all of the cell’s metabolites (the metabolome).
86. LABORATORY DIAGNOSIS OF CANCER
• BIOCHEMICAL METHODS – TUMOR MARKERS
• Biochemical assays for tumor-associated enzymes, hormones, and other tumor
markers in the blood
• they contribute to the detection of cancer and in some instances are useful in
determining the effectiveness of therapy or the appearance of a recurrence.
89. GRADING AND STAGING OF TUMORS
• Grading and staging are methods to
• quantify the probable clinical aggressiveness (grading) of a given neoplasm
• and its apparent extent and spread (staging) in the individual patient
• Grading –
• determined by cytologic appearance; based on the idea that behaviour and differentiation are related,
with poorly differentiated tumors having more aggressive behaviour
• Classified usually as Well , moderately and poorly differentiated
• Staging -
• determined by surgical exploration or imaging, is based on size, local and regional lymph node spread,
and distant metastases; of greater clinical value than grading
• The major staging system currently in use is the TNM staging - T for primary tumor, N for regional
lymph node involvement, and M for metastases
