06 Neoplasia.pptx

Dr.Abebaw A.MD
Pathology resident,HUCMHS
3/23/2022 1

 Definition & nomenclature
 benign & malignant neoplasms
 Epidemiology of cancer
 Carcinogenesis(molecular basis of cancer)
 Carcinogenic agents & their
cellular interactions
 Tumor immunity
 Clinical features of tumors
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 Neoplasia -the process of “ new growth“
 The new growth is a “neoplasm”.
 Neoplasia is the abnormal proliferation of cells in
a tissue or organ
 The term “ tumor” is now equated with
neoplasm.
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 The British oncologist Sir Rupert Willis defines
 “ Neoplasm as 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.”
 The abnormal mass is purposeless ,preys on the
host ,and is virtually autonomous
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Tumor.
Mass,lump,swelling.
- hemorrhage
- cyst
-aneurysm
Neoplasia/Neoplasm.
Cancer.
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- It results from heritable genetic alterations
that are passed down to the progeny of
tumor cells.
- autonomous (independent of physiologic
growth stimuli)
- dependant on the host for their nutrition and
blood supply.
- Fundamental to the origin of all neoplasms
is loss of responsiveness to normal growth
controls
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 Oncology (Greek “oncos”=tumor) is the study of
tumors or neoplasm.
 A medical professional who practices oncology is
an oncologist
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 All tumors have two basic components
1. Proliferating neoplastic cells - the
parenchyma
2. Supportive stroma - connective tissue and
blood vessels
 The stromal connective tissue provides the
framework for the parenchyma
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 scant stromal support - soft and fleshy.
 Abundant collagenous stroma-reffered to as
Desmoplasia.
 The nomenclature & biologic behavior of
tumors -based on parenchymal component.
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Neoplasms are named based upon two factors
 On the histologic type : mesenchymal &
epithelial
 On behavioral patterns : benign & malignant
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Benign
- localized
- it cannot spread to other sites
- amenable to local surgical removal
- the patient generally survives
 some defined as 'benign tumors' may still
produce negative health effects.
 a "mass effect"
 "functional" tumors of endocrine tissues
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Malignant
- collectively referred to as cancers
- derived from the Latin word for crab
- they adhere to any part that they seize on in
an obstinate manner, similar to a crab.
- invade and destroy adjacent structures
- spread to distant sites (metastasize) to cause
death.
- Red flag
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Benign
 1. kindly: having a kind
and gentle disposition
or appearance
 2. not life-threatening:
not a threat to life or
long-term health,
especially by being
noncancerous
 3. harmless: neutral or
harmless in its effect or
influence
 4. favorable: mild or
favorable in effect a
benign climate.
Malignant
 1. wanting to do
evil: full of hate and
showing a desire to
harm others
 2. harmful:
 3. likely to spread:
 4. likely to cause
death:
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 Benign tumor of mesenchymal cells are
designated by attaching the suffix – oma to
the cell of origin.
 Malignant tumor arising in mesenchymal
tissue are usually called sarcoma.
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 Benign Malignant
Connective tissue and derivatives
fibroblasts Fibroma Fibrosarcoma
adipose tissue Lipoma Liposarcoma
cartilage Chondroma Chondrosarcoma
Bone Osteoma Osteogenic sarcoma
 Endothelial and related tissues
Blood vessels Hemangioma Angiosarcoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Synovium Synovial sarcoma
Muscle
Smooth M Leiomyoma Leiomyosarcoma
Striated Rhabdomyoma Rhabdomyosarcoma
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 Benign epithelial tumors are variously
classified, based on their:
- cell of origin
- microscopic architecture &
- macroscopic pattern
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 Adenoma – The term applied for benign
epithelial neoplasm that form glandular
pattern as well as tumors derived from
glands not forming glandular pattern.
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 Papillomas- benign neoplasms producing
microscopically or macroscopically visible
finger like projection or warty projection
from epithelial surface
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- Benign tumors that form large cystic masses
are referred as cystadenoma.
- Some tumors produce papillary patterns that
protrude into cystic spaces are called
papillary cystadenoma
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Polyp:-
 When tumor produces macroscopically visible
projection above a mucosal surface
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- Malignant neoplasms of epithelial cell origin
are called carcinomas
- Squamous cell carcinoma denote a cancer in
which the tumor cells resemble stratified
squamous epithelium
- Adenocarcinoma denotes a lesion in which
the neoplastic epithelial cells grow in gland
patterns.
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- The parenchymal cells in a neoplasm, whether
benign or malignant, resemble each other.
- In some instances, however, the stem cell may
undergo divergent differentiation, creating so-
called mixed tumors. The best example is mixed
tumor of salivary gland origin.
- These tumors have obvious epithelial
components dispersed throughout an apparent
fibromyxoid stroma, sometimes harboring islands
of cartilage or bone.
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Teratoma
- contains mature or immature cells or tissues
representative of more than one germ-cell
layer and sometimes all three.
- Teratomas originate from totipotential cells
such as those normally present in the ovary
and testis and sometimes abnormally present
in sequestered midline embryonic rests.
- Such cells have the capacity to differentiate
into any of the cell types found in the adult
body (bone, muscle, fat, skin, tooth and
other tissues).
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- When all the component parts are well
differentiated, it is a benign (mature)
teratoma.
- Common pattern is an ovarian cystic
teratoma (dermoid cyst ) which
differentiates along ectodermal lines to
create cystic tumor lined by skin with hair,
sebaceous glands & tooth structures
- when less well differentiated, it is an
immature, potentially or overtly malignant
teratoma.
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 Malignancies of lymphoid tissue are called
lymphomas
 Malignant neoplasms of blood forming cells
are called leukemias
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-oma…………….Granuloma
Hamartoma
Atheroma
Teratoma
Choristoma
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-Oma……………….Yet malignant.
…….Hepatoma.
………Seminoma.
………Melanoma.
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Choristoma –
- an ectopic rest of normal tissue.
- For example a pancreatic nodular rest in the
mucosa of small bowel
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Hamartoma-
 A mass of disorganized but mature
specialized cells or tissue indigenous to the
particular site.
 Hamartoma in the lung may contain islands
of cartilage , blood vessels , bronchial –type
structures & lymphoid tissue .
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- Tumors can be distinguished on the basis of
 Differentiation and anaplasia
 Rate of growth
 Local invasion
 Metastasis
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A. Differentiation and anaplasia
- Differentiation refers to the extent to which
parenchymal cells resemble comparable
normal cells both morphologically and
functionally.
- well-differentiated tumors cells resemble
mature normal cells of tissue of origin.
- Poorly differentiated or undifferentiated
tumors have primitive appearing,
unspecialized cells.
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In general-
- benign neoplasms are well differentiated.
- Malignant neoplasms in contrast, range from
well differentiated, moderately
differentiated to poorly differentiated types.
- Malignant neoplasm composed of
undifferentiated cells are said to be
anaplastic, literally anaplasia means to form
backward.
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Morphologic changes which mark anaplasia
 Pleomorphism – both cells & nuclei show
variation in size & shape
 Abnormal nuclear morphology –
- abundant chromatin & are extremely dark
staining (hyperchromatic),
- high nuclear cytoplasmic ratio 1:1(normally
1:4 to 1:6)
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 The cell usually reveals large nucleoli with
high number and often abnormal mitoses(with
tripolar or quadripolar spindles)
 Loss of polarity-(disorderd growth)
 Tumor giant cells
 Necrosis
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B. Rate of growth
- The rate of growth of a tumor is determined
by three main factors :
1. The doubling time of tumor cells
2. The fraction of tumor cells that are in
replicative pool &
3. the rate at which cells are shed & lost in
the growing lesion.
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The doubling time of tumor cells
- It can be calculated that the transformed
cell (about 10 μm in diameter)must undergo
at least 30 population doubling to produce
109 cells (weighing 1gm) , which is the
smallest clinically detectable mass.
- Only 10 further doubling s are required to
produce a tumor weighing 1 kg
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The fraction of tumor cells in replicative pool
- The proportion of cells within the tumor
population that are in the proliferative pool
is referred as The growth fraction
- As tumors continue to grow , cells leave the
proliferative pool due to shedding, lack of
nutrients, apoptosis , by differentiating &
reversion to G0
- Thus, by the time the tumor is clinically
detectable , most cells are not in the
replicative pool
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 The growth fraction of tumor cells has
profound effect on their susceptibility to
cancer chemotherapy
 b/c most anticancer agents act on cells that
are in cycle.
 One strategy in treatment of tumors with low
growth fraction is to shift tumor cells from
G0 into cell cycle by debulking the tumor
with surgery or radiotherapy
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C. Local invasion
- Nearly all benign neoplasms grow as cohesive
expansile masses that remains localized to
their site of origin and do not have the
capacity to infiltrate , invade or metastasize
as malignant tumors.
- Benign -capsulated
- Hemangiomas and neurofibromas are
exceptions.
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 The growth of malignant neoplasms is
accompanied by progressive infiltration,
invasion and destruction of the surrounding
tissue.
 poorly demarcated from the surrounding
normal tissue
 Next to the development of metastasis,
invasiveness is the most reliable feature
that differentiates malignant from benign
neoplasms.
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70
Microscopic view of fibroadenoma of the breast seen in Figure 6-7. The fibrous capsule
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72
Microscopic view of breast carcinoma seen in Figure 6-9 illustrates the invasion of
breast stroma and fat by nests and cords of tumor cells (compare with previous
figure). Note the absence of a well-defined capsule.
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 Most carcinomas begin as localized growth
confined to the epithelium in which they
arise.
 As long as this early cancers do not penetrate
the basement membrane on which the
epithelium rests such tumors are called
carcinoma in-situ.
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D. Metastasis
- Metastasis are tumor implants discontinuous
with the primary tumor
- Metastasis unequivocally marks a tumor as
malignant because benign neoplasms don’t
metastasize
- The invasiveness of cancers permits them to
penetrate into blood vessels, lymphatics &
body cavities , providing the opportunity to
spread
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- With few exception, all cancers can
metastasize.
- The major exception are gliomas & basal cell
carcinomas of the skin.
- The more aggressive, the more rapidly
growing, & the larger the primary neoplasms
, the greater the likelihood that it will
metastasize
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Pathway of spread
 Seeding of body cavities & surfaces
(transcoelomic spread)
- It may occur whenever a malignant neoplasm
penetrates into a natural ‘open field’
- Most often involved is the peritoneal cavity but
other cavities - pleural, pericardial
subarachinoid & joint space may be affected
- It is often characteristic of ovarian carcinoma
- Sometimes mucus-secreting appendiceal
carcinomas fill the peritoneal cavity with
gelatinous neoplastic mass referred as
pseudomyxoma peritonei
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 Lymphatic spread
- Lymphatic route is the most common
pathway for the initial dissemination of
carcinomas
- The pattern of lymph node involvement
follows the natural routes of drainage.
Eg. carcinoma of breast usually arise in upper
outer quadrant disseminate first to the
axillary lymph nodes. Cancers of the inner
quadrant may drain to nodes within the chest
along the internal mammary arteries
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 Hematogenous spread
- It is typical for sarcoma but is also seen with
carcinoma
- Arteries are less readily penetrated than are
veins
- Liver & lung are most frequently involved in
hematogenous spread
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Characterstics Benign Malignant
Differentiation/anaplasi
a
Well differentiated;
structure may be typical
of tissue of origin
Some lack of differentiation
with anaplasia; structure is
often atypical
Rate of growth Usually progressive and
slow; may come to a
standstill or regress;
mitotic figures are rare
and normal
Erratic and may be slow to
rapid; mitotic figures may be
numerous and
abnormal
Local invasion Usually cohesive and
expansile well-
demarcated masses that
do not
invade or infiltrate
surrounding normal
tissues
Locally invasive, infiltrating
the surrounding normal
tissues; sometimes may be
seemingly cohesive and
expansile
Metastasis Absent Frequently present; the
larger and more
undifferentiated the
primary, the more
likely are metastases
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If cells LOOK BAD, they are probably going to BEHAVE BAD
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If cells LOOK GOOD, they are probably going to BEHAVE GOOD
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 Cancer epidemiology can contribute
substantially to knowledge about the origin
of cancer.
 Major insights into the causes of cancer can
be obtained by epidemiologic studies that
relate particular environmental, racial
(possibly hereditary), and cultural influences
to the occurrence of specific neoplasms.
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 The most common tumors in men are
prostate, lung & colorectal cancer .
 In women cancers of breast, lung colon &
rectum & cervix
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Geographic factors
 Specific differences in incidence rates of cancers are
seen worldwide.
For example
Stomach carcinoma - Japan
Lung cancer - USA
Skin cancer - New zeland & Australia
Liver cancer – Ethiopia
- It is believed that that most of these geographic
differences are the consequence of environmental
influences
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Environmental factors
- Environmental factors are the predominant
determinant of the most common sporadic
cancers.
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Asbestos----- lung cancer, mesothelioma
Vinyl chloride - Angiosarcoma of liver
Cigarette smoking----- lung cancer(90%), cancer of
mouth, pharynx, larynx, esophagus, pancreas & bladder
Alcohol abuse- Carcinoma of liver, cancer of oropharynx,
larynx & esophagus
Venereal infection (linked to age at first intercourse
and the number of sex partners )---Cervical carcinoma
Obesity
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 >55yrs.
 Children………..Hematopoietic.
-Neuroblastoma.
-Nephroblastoma.
-Retinoblastoma.
-Bone & skeletal muscle
cancers.
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Inherited cancer
syndromes
• Single mutant
genes
• Familial
retinoblastoma
Familial cancers
• Familial
clustering.
• Breast, colon.
Defective DNA
repair.
• Autosomal
recessive
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Nonhereditary (Acquired)predisposing
conditions
Precancerous conditions
These are non neoplastic conditions with well
defined association with cancer
 Regenerative, hyperplasic and dysplastic
proliferations are fertile soil for the origin of
malignant neoplasm.
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 Persistent regenerative cell replication (e.g.,
squamous cell carcinoma in the margins of a
chronic skin fistula or in a long-unhealed skin
wound; hepatocellular carcinoma in cirrhosis of
the liver)
 Hyperplastic and dysplastic proliferations (e.g.,
endometrial carcinoma in atypical endometrial
hyperplasia; bronchogenic carcinoma in the
dysplastic bronchial mucosa of habitual cigarette
smokers)
 Leukoplakia of the oral cavity, vulva, or penis
(e.g., increased risk of squamous cell carcinoma)
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Chronic inflammation & cancer
Helicobacter pylori gastitis - Gastric
carcinoma & lymphoma
Ulcerative colitis & crohn’s disease - Small &
large bowel carcinoma
Viral hepatatis – Hepatocellular carcinoma
Chronic pancreatitis- Pancreatic ca
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 most benign neoplasms do not become
malignant however, it can rarely constitute
preneoplastic conditions including
- Villous colonic adenoma - colonic cancer
- Carcinoma arising in pleomorphic adenoma
of salivary glands
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1) Non-lethal genetic damage lies at the
heart of carcinogenesis.
 Such genetic damage (mutation) may be
acquired by the action of environmental
agents such as chemicals, radiation or viruses
or it may be inherited in the germ line
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2) tumors are monoclonal
A tumor is formed by the clonal expansion of a
single precursor cell that has incurred the
genetic damage
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3) principal targets of genetic damage
 Four classes of normal regulatory genes
 growth-promoting proto-oncogenes,
 growth-inhibiting tumor suppressor genes,
 genes that regulate programmed cell death (i.e.,
apoptosis), and
 genes involved in DNA repair-
105
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 Carcinogenesis is a multistep process
both the phenotypic and genotypic levels.
- A malignant neoplasm has several phenotypic
attributes , such as excessive growth , local
invasion & the ability to metastasis.
- These characteristics are acquired in
stepwise fashion , a phenomena called tumor
progression
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 Self-sufficiency in growth signals
 Insensitivity to growth-inhibitory signals
 Evasion of apoptosis
 Defects in DNA repair
 Limitless replicative potential (i.e.,
overcoming cellular senescence)
 Sustained angiogenesis
 Ability to invade and metastasize
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1.Oncogenes that Promote Unregulated
Proliferation (Self-sufficiency in Growth
Signals)
 Proto-oncogenes: normal cellular genes
whose products promote cell proliferation
 Oncogenes: mutant versions of proto-
oncogenes that function autonomously
without a requirement for normal growth-
promoting signals
 Dominant
110
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 Oncogenes can promote uncontrolled cell
proliferation by several mechanisms:
 Stimulus-independent expression of growth
factor and its receptor, setting up an autocrine
loop of cell proliferation
 Mutations in genes encoding growth factor
receptors, leading to overexpression or
constitutive signaling
111
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 Mutations in genes encoding signaling molecules
 RAS is commonly mutated in human cancers;
normally flips between resting GDP-bound state
and active GTP-bound state; mutations block
hydrolysis of GTP to GDP
 Overproduction or unregulated activity of
transcription factors
 Translocation of MYC in some lymphomas leads
to overexpression and unregulated
expression of its target genes controlling cell
cycling and survival
112
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 Mutations that activate cyclin genes or inactivate
normal regulators of cyclins and cyclin-
dependent kinases
 Complexes of cyclins with cyclin-dependent
kinases (CDKs) drive the cell cycle by
phosphorylating various substrates;
 CDKs are controlled by inhibitors;
mutations in genes encoding cyclins,
CDKs, and CDK inhibitors result in
uncontrolled cell cycle progression.
 Such mutations are found in wide variety of
cancers including melanomas, brain, lung,
and pancreatic cancer.
113
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 Tumor suppressor genes encode proteins
that inhibit cellular proliferation by
regulating the cell cycle.
 Unlike oncogenes, both copies of the
gene must be lost for tumor development,
leading to loss of heterozygosity at the
gene locus.(recessive)
116
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 In cases with familial predisposition to
develop tumors, the affected individuals
inherit one defective (nonfunctional) copy of
a tumor suppressor gene and lose the second
one through somatic mutation.
 In sporadic cases both copies are lost
through somatic mutations.
117
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 2.1 RB Gene and Cell Cycle
 RB exerts antiproliferative effects by controlling
the G1-to-S transition of the cell cycle. In its active
form RB is hypophosphorylated and binds to E2F
transcription factor.
 This interaction prevents transcription of genes
like cyclin E that are needed for DNA replication,
and so the cells are arrested in G1.
 Growth factor signaling leads to cyclin D
expression, activation of the cyclin D-CDK4/6
complexes, inactivation of RB by phosphorylation,
and thus release of E2F.
119
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• Loss of cell cycle control is fundamental to
malignant transformation.
• Almost all cancers will have disabled the G1
checkpoint, by mutation of either RB or genes
that affect RB function, like cyclin D, CDK4,
and CDKIs.
• Many oncogenic DNA viruses, like HPV, encode
proteins (e.g., E7) that bind to RB and render it
nonfunctional.
120
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2.p53 Gene: Guardian of the Genome
 p53 protein acts as a critical gatekeeper
against neoplastic transformation (“guardian
of the genome”).
 p53 protein is activated by genes that sense
DNA damage !
 assists DNA repair by inducing genes for G1
arrest (p21) and DNA repair (GADD45) !
 If DNA repair is successful p53 allows cell
cycle to proceed (via MDM2) and if not
successful it then induces apoptosis (via
BAX).
122
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 Accumulation of neoplastic cells may result
not only from activation of growth-promoting
oncogenes or inactivation of growth-
suppressing tumor suppressor genes, but also
from mutations in the genes that regulate
apoptosis.
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 Apoptosis can be initiated through the
extrinsic or intrinsic pathways.
 Both pathways result in the activation of a
proteolytic cascade of caspases that destroys
the cell.
 Mitochondrial outer membrane
permeabilization is regulated by the balance
between pro-apoptotic (e.g., BAX, BAK) and
anti-apoptotic molecules (BCL2, BCL-XL).
125
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 Those who inherit mutations of DNA repair
proteins are at greatly increased risk of
developing cancer(sometimes called cancer
susceptibility genes)
- There are three types of defects in DNA
repair system
 Mismatch repair
 Nucleotide excision repair
 Recombination repair
Recessive
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i) Mismatch Repair Genes
 several genes have been identified which
correct mistakes of nucleotide pairing during
DNA replication,(esp G-T or A-C
mismatching); eg in human familial colon
cancer.
ii) Nucleotide Excision Repair Genes
 UV light causes cross-linking of pyrimidine
nucleotides (dimer formation) which results
in misreading during replication, unless
repaired by nucleotide excision repair (NER)
genes; eg skin cancers
3/23/2022 128

iii) Recombination Repair Genes
 double-strand DNA breaks (esp by radiation
or oxidation) repaired by homologous
recombination where the joining of the free
ends is mediated by a DNA-protein kinase; eg
human breast cancer
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- Most normal human cells have a capacity of
60 to 70 doublings. After this, the cells lose
the capacity to divide and enter a non
replicative senescence.
- This phenomenon has been ascribed to
progressive shortening of telomeres at the
ends of chromosomes.
- With each cell division, telomeres are
shortened, and beyond a certain point, loss
of telomeres leads to massive chromosomal
abnormalities and death
3/23/2022 130

- Tumor cells also must develop ways to avoid
cellular senescence; this is acquired by
activation of the enzyme telomerase, which
can maintain normal telomere length
3/23/2022 132

 tumors cannot grow larger than 1-2 mm
without vascularization to supply O2 and
nutrients.
 tumors stimulate the growth of host vessels
by a process called angiogenesis.
 angiogensis also stimulates tumor growth, via
growth factors (eg PDGF & IGF’s) and
provides the vasculature for metastasis.
 angiogenic factors may be produced by
tumor cells, supporting stromal cells or from
inflammatory cells infiltrating the tumor.
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- In contrast to normal vessels, tumor vessels
are disorganized, unstable and leaky.
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 Ability to invade tissues, a hallmark of
malignancy, occurs in four steps:
 loosening of cell-cell contacts,
 degradation of ECM,
 attachment to novel ECM components, and
 migration of tumor cells.
136
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 Cell-cell contacts are lost by the inactivation
of E-cadherin through a variety of pathways
 E-cadherin function is lost in almost all
epithelial cancers,
 either by mutational inactivation of E-cadherin
genes,
 by activation of β-catenin genes, or
 by inappropriate expression of the SNAIL and
TWIST transcription factors, which suppress E-
cadherin expression.
137
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Karyotypic (chromosomal) changes in tumors
- Two types of chromosomal rearrangment can
activate protooncogens –
- translocations & inversions . Translocations
are more common
3/23/2022 139

- Translocations can activate protooncogens
in two ways
 In lymphoid tumors, specific translocations
result in over expression of protooncogents
by removing them from their regulatory
elements
eg Burkitt lymphoma --- t(8:14) (q24;q32)
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Molecular basis of multistep carcinogenesis
- Most human cancers reveal multiple genetic
alterations involving activation of several
oncogens & loss of two or more tumor
suppressor genes .
-
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Tumor progression & Heterogeneity
- Over period of time, many tumors become more
aggressive & acquire greater malignant potential
– Tumor progression
- This biologic behavior is related to the
sequential appearance of subpopulations of cells
with phenotypic attributes such as
invasiveness, rate of growth , metastatic ability,
hormonal responsiveness & susceptibility to
antineoplastic drugs .
- Despite the fact that most malignant tumors are
monoclonal in origin , by the time they become
clinically detectable , their cells are extremely
heterogeneous .
3/23/2022 144

- A large number of agents cause genetic
damages and induce neoplastic
transformation of cells.
- They fall into three categories
 Chemical carcinogens
 Radiation carcinogenesis
 Oncogenic viruses & some other microbes
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A) Chemical carcinogenesis
- Chemical carcinogenic agents fall into
two categories
 Direct acting compounds – these don’t
require chemical transformation for
their carcinogenicity
 Indirect –acting compounds or
procarcinogens which require metabolic
conversion to produce ultimate
carcinogens capable of transforming
cells
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These include
 Direct-acting alkylating agents
- Therapeutic agents such as
cyclophosphamide used as anticancer
agents have been documented to induce
lymphoid neoplasms & leukemia
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 Polycyclic aromatic hydrocarbons
- These agents represent some of the most
potent carcinogens
Eg they are produced in the combustion of
tobacco & contribute to the causation of
lung & bladder cancer
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 Aromatic amines & Azo dyes
 Nitrosamines & amides
 Naturally occurring carcinogens
Eg Aflatoxin B1 is a potent hepatic
carcinogen , produced by some strains of
the fungus Aspergillus flavus that thrives
on improperly stored food
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Cancer induction steps:
 initiation
 promotion
 Initiation causes permanent DNA damage
(mutations)
 Promoters can induce tumors in initiated
cells, but they are non tumorogenic by
themselves
 The effects of promoters are reversible
 Initiation alone, however, is not sufficient for
tumor formation.
3/23/2022 151

Radiation carcinogenesis
Radiant energy whether in form of
 ultraviolet (UV) sun light or
 ionizing electromagnetic (X rays and
gamma (δ ) rays) and
 particulates (α, β, protons and neutrons)
 induce neoplasm
3/23/2022 153

 UV rays induce an increased incidence of
squamous cell carcinoma, basal cell
carcinoma and possibly malignant
melanoma of skin
 p53 and RAS are particularly prone to
mutation by UV light
3/23/2022 154

Microbial carcinogenesis
 Large groups of DNA and RNA viruses have
proved to be oncogenic and there is an
association between infections by the
bacterium Helicobacter Pylori and gastric
lymphoma
3/23/2022 155

i) DNA oncogenic viruses
This group includes
 Human Papilloma Virus (HPV)
 Epstein Barr Virus (EBV)
 Hepatitis B Virus (HBV)
3/23/2022 156

Human papilloma Virus (HPV)
 some forms of HPV cause benign
squamous papillomas(warts) (type 1,2,3,4,
7).
 It also implicated in the genesis of
squamous cell carcinomas of cervix and
anogenital region (types 16,18 and also
31,33,35,and 51 found in 85% SCC).
 It is also linked to the causation of oral
and laryngeal cancers.
3/23/2022 157

Epstein – Barr virus (EBV)
Member of the herpes family has been
implicated in the pathogenesis of four
tumors.
 The African form of Burkitt'slymphoma,
 B- cell lymphomas in immuno suppressed
individuals
 Some cases of Hodgkin’s disease
 Nasopharyngeal carcinoma
3/23/2022 159

Hepatitis B- virus (HBV)
 Strong epidemiologic association prevails
between HBV and hepatocellular carcinoma.
3/23/2022 160

RNA oncogenic viruses
 Only one retrovirus is firmly implicated in
the causation of cancer and it is Human T
cells leukemia/ lymphoma virus type 1
(HTLV-1).
 It is associated with a form of T-cell
leukemia /lymphoma.
 cause cancer by inserting themselves into
cellular DNA & inducing expression of
protooncogenes
3/23/2022 161

Helicobacter pylori
 There is an association between gastric
infections with Helicobacter pylori as a
cause of gastric carcinoma and lymphoma.
 The stronger link is with B cell lymphoma
of stomach.
 Treatment of H. pylori with antibiotics
results in regression of the lymphoma in
most cases.
3/23/2022 162

Helicobacter pylori
 The lymphoma arise from the mucosa
associated lymphoid tissues (MALT) hence,
they sometimes are called MALTomas.
 The lymphoid cells reside in the marginal
zones of lymphoid follicles and hence
alternatively
named as mantle zone lymphoma.
3/23/2022 163

Immune surveillance
 refer to recognition and destruction of
non-self tumor cells on their
appearance.
 cancers occur implies that immune
surveillance is imperfect.
3/23/2022 164

 Classification:
 tumor-specific antigens, which are
present only on tumor cells and not on
any normal cells, and
 tumor-associated antigens, which are
present on tumor cells and also on
some normal cells.
3/23/2022 165

 Cytotoxic t-lymphocytes
 Natural killer cells
 Macrophages
 Antibodies
3/23/2022 166

 Increased incidence in
immunocompromised hosts.
 Congenital IDs and AIDS – lymphomas
and other malignant tumors.
 So a tumor must have a mechanism to
escape the immune system.
3/23/2022 167

How?
 Selective outgrowth of antigen-negative variants -
immunogenic subclones may be eliminated.
 Loss or reduced expression of histocompatibility
molecules - Tumor cells may fail to express normal
levels of HLA class I.
 Immunosuppression - Many oncogenic agents (e.g.,
chemicals and ionizing radiation) suppress host
immune responses. Tumors or tumor products also
may be immunosuppressive.
3/23/2022 168

- Ultimately the importance of neoplasms lies
in their effects on patients.
- Although malignant tumors are of course
more threatening than benign tumors, any
tumor, even a benign one, may cause
morbidity and mortality
3/23/2022 170

Effects of tumor on host
Both benign and malignant neoplasms may cause
problems because of
1. Location and impingement on adjacent
structures
2. Functional activities such as hormone synthesis
3. Bleeding and secondary infection when they
ulcerate through adjacent natural surfaces
4. Initiation of acute symptoms caused by either
rupture or infarction
3/23/2022 171

Local and hormonal effects
- Location is crucial in both benign and
malignant tumors.
- A small (1-cm) pituitary adenoma can
compress and destroy the surrounding normal
gland and give rise to hypopituitarism
3/23/2022 172

 Benign neoplasms of endocrine origin may
produce manifestations by elaboration of
hormones.
 For example a benign B- cell adenoma of
pancreatic islets less than 1 cm in diameter
may produce sufficient insulin to cause fatal
hypoglycemia
3/23/2022 173

 Neoplasms in the gut (both benign and
malignant) may cause obstruction as they
enlarge
3/23/2022 174

Cancer cachexia
- Cachexia is a progressive loss of body fat and lean
body mass accompanied by profound weakness,
anorexia and anemia .
- The origin of cancer cachexia are obscure
 Reduced food intake has been related to
abnormalities in taste and central control of
appetite.
 In patients with cancer, calorie expenditure often
remains high and basal metabolic rate is increased
despite reduced food intake.
 TNF produced by macrophages and possibly by some
tumor cells is the mediator of the wasting syndrome
that accompanies cancer.
 Other cytokines such as IL-1 and IFN α synergize with
TNFα
3/23/2022 177

Paraneoplastic syndromes
- It is an aggregate of symptom complexes in
cancer - bearing patients that can not readily
be explained either by the local or distant
spread of the tumor or by the elaboration of
hormones indigenous to the tissue from
which the tumor arose.
- Paraneoplastic syndrome occurs in about 10%
of patients with malignant disease
3/23/2022 178

- It is important to recognize them for several
reasons:
 They may represent the earliest
manifestation of an occult neoplasm.
 In affected patients, they may represent
significant clinical problems and may even be
lethal.
 They may mimic metastatic disease and
confound treatment.
3/23/2022 179

- The endocrinopathies are frequently
encountered paraneoplastic syndromes.
- Because the cancer cells are not of
endocrine origin, the functional activity is
referred as ectopic hormone production .
3/23/2022 180

 Cushing syndrome is the most common
endocrinopathy .
 50% of the patients have carcinoma of lung
,chiefly the small cell type.
 it is caused by excessive production of
corticotropin or corticotropin like peptides
3/23/2022 181

 Hypercalcemia
- Overtly symptomatic hypercalcemia is most
often related to some form of cancer rather
than to hyperparathyroidism
- Two general processes are involved in cancer
associated hypercalcemia
 Osteolysis induced by cancer whether primary in
bone , such as multiple myeloma, or metastatic
to bone from any primary lesion
 hypercalcemia resulting from skeletal
metastases is not a paraneoplastic syndrome
 The production of calcemic humoral substances
by extraosseous neoplasms
3/23/2022 183

- Tumors most often associated hypercalcemia
are carcinomas of the breast, lung, kidney &
ovary.
- The most common lung neoplasm associated
with hypercalcemia is the squamous cell
bronchogenic carcinoma .
3/23/2022 184

Syndrome Mechanism Example
Cushing's Syndrome ACTH-like substance Lung (oat cell)
carcinoma
Hypercalcemia Parathormone-like
substance
Lung (squamous cell)
carcinoma
Hyponatremia Inappropriate ADH
secretion
Lung (oat cell)
carcinoma
Polycythemia Erythropoietin-like
substance
Renal cell carcinoma
Trousseau's
Syndrome
Hypercoagulable
state
Various carcinomas
Hypoglycemia Insulin-like substance Various carcinomas
and sarcomas
Carcinoid Syndrome -Serotonin
,bradykinin
Metastatic malignant
carcinoid tumors
3/23/2022 185

 Grading denotes the level of differentiation
whereas,
 staging expresses the extent of tumor spread
and forecast the clinical gravity of cancers
3/23/2022 186

 Grading of a cancer is based on the degree of
differentiation of tumor cells and the
number of mitoses within the tumor and
presumably correlates to aggressive
character of the neoplasm
 Cancers are classified into grades I to IV
with increasing anaplasia.
 Criteria for individual grades vary with each
form of neoplasm
3/23/2022 187

 The staging of cancers is based on the size of
primary lesions, its extent of spread to
regional lymph nodes and the presence or
absence of blood born metastases
3/23/2022 189

- TNM staging varies for each specific form of
cancer but there are general principles.
 With increasing size, the primary lesion is
characterized as T1 to T4.
 T0 is added to indicate an in - situ lesion.
 N0 for no nodal involvement whereas, N1 -N3
would denote involvement of an increasing
number and range of nodes
 Mo signifies no distant metastasis whereas M1 or
sometimes M2 indicates the presence of blood
born metastasis
3/23/2022 190

 staging has proved to be of greater clinical
value than grading
3/23/2022 191

 Histologic and cytologic methods
Several sampling approaches are available
1. Excision or biopsy
2. Fine needle aspiration
3. Cytologic smears
PAP smear
Fluid cytology
 Advanced techniques
Immunohistochemistry
Molecular diagnosis
Flow cytometry
Tumor markers
3/23/2022 192

 Excision or biopsy
- Biopsy is a tissue sample from a living person
to identify the disease.
- Biopsy can be either incisional or excisional
3/23/2022 193

 Fine-needle aspiration of tumors is another
approach that is widely used.
 This procedure is used most commonly with
readily palpable lesions affecting the breast,
thyroid, lymph nodes, and salivary glands.
 It is less invasive , more rapid , cheaper
than biopsy
3/23/2022 194

Cytologic (Papanicolaou) smears provide
another method for the detection of cancer.
The shed cells are evaluated for features of
anaplasia indicative of their origin from a
tumor .
3/23/2022 195

Tumour markers
- Tumour markers are biochemical indicators
of the presence of a tumor .
- They include cell surface antigens,
cytoplasmic proteins, enzymes and
hormones.
- Tumor markers can not be considered as
primary modalites for the diagnosis of cancer
and thus, act as supportive laboratory tests.
3/23/2022 199

Markers Associated Cancers
Hormones
Human chorionic gonadotropin Trophoblastic tumors,
nonseminomatous testicular
tumors
Calcitonin Medullary carcinoma of thyroid
Catecholamine and metabolites Pheochromocytoma and related
tumors
Ectopic hormones Paraneoplastic Syndromes
Oncofetal Antigens
a-Fetoprotein Liver cell cancer,
nonseminomatous germ cell
tumors of testis
Carcinoembryonic antigen Carcinomas of the colon,
pancreas, lung, stomach, and
heart
3/23/2022 200

Specific Proteins
Immunoglobulins Multiple myeloma and other
gammopathies
Mucins and Other Glycoproteins
CA-125 Ovarian cancer
3/23/2022 201

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