NEOPLASM

BY- CHUIMEE
SAPNA
ADIL
“ ‘Neoplasia' 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 

R A WILLIS

DEFINITION
NEO = NEW
PLASIA = GROWTH
TUMOR = SWELLING ?
TUMOR = NEOPLASM
DIFFRENCE
BETWEEN
NEOPLASIA &
HYPERPLASIA
?
NOMENCLATURE

Tumor has 2 components :

 Parenchyma (made up of neoplastic cells)
 Connective tissue stroma (made up of supporting structures mainly
connective tissue and blood vessels)

 Parenchyma determines the behaviour & consequence of tumor

 Stroma provides blood supply to the neoplastic cells, it also provides a
framework on which neoplastic cells can grow
NOMENCLATURE

On the basis of clinical course :

 BENIGN
 MALIGNANT (CANCER)

On the basis of tissue of origin :

 Epithelial
 mesenchymal
BENIGN

 Named by tissue of origin with attached suffix – oma (more applicable to benign tumors of
mesenchymal origin)

Benign tumors of mesenchymal origin :

• Fibroma( benign tumor of fibroblast)
• Osteoma (benign tumor of osteoblast)
• chondroma (benign tumor of cartilage)

 Not all endings (– oma) are benign tumors

 Example : hematoma, granuloma, lymphoma, hamartoma
BENIGN

Benign tumors of epithelial origin :

 Adenoma is a benign tumor of epithelial tissue with glandular origin, glandular
characteristics, or both
 Papilloma is a benign epithelial tumor growing exophytically (outwardly projecting) in
finger-like projections
 Cystadenoma is a type of benign tumor that develops from ovarian tissue
 Polyp is macroscopically visible benign tumor, it has finger like projections beyond the
mucosal surface & into the lumen
MALIGNANT

 Malignant tumor of mesenchymal origin :

 Prefix (origin)+ suffix (sarcoma)

 Example :
• Fibrosarcoma (malignant tumor of fibroblast)
• Chondrosarcoma (malignant tumor of bone/ cartilage)
MALIGNANT

 Malignant tumor of epithelial origin :

 Prefix (origin)+ suffix (carcinoma)

 Example :
• Adenocarcinoma
• Squamous cell carcinoma
MIXED TUMOR

 Tumors derived from a single germ cell layer that differentiates into more than one cell
type.
Example :
 Pleomorphic adenoma of salivary gland is a mixed tumor
 Parotid gland is the commonest site
 Characterized by an admixture of polygonal  epithelial and spindle-
shaped myoepithelial elements in a variable background stroma that may be mucoid,
myxoid, cartilaginous or hyaline
TERATOMA

 Made of a variety of parenchymal cell types that derive from more than one germ cell
layer formed by totipotent cells that are able to form ectoderm, endoderm & mesoderm

Commonest site :
 Ovaries, testis, anterior mediastinum, pineal gland
CLASSIFICATION

 Based on cell of origin : Epithelial & Mesenchymal

 Based on behavior of tumor : Benign & Malignant
 Based on appearance of the tumor
Based on degree of differentiation
How do benign & malignant tumors differ?

 Differentiation & anaplasia

 Rate of growth
 Presence of capsule
 Local invasion
 Distant metastases
1. Differentiation

 This indicates the degree of resemblance of the tumor cell to its cell of origin,
functionally & morphologically.

Example:
Cells of a lipoma may look exactly like normal fat cells.
LIPOMA LIPOSARCOMA
Features of differentiation include :

 Epithelial cells :
- formation of glands
- formation of keratin
- formation of secretion
 Connective tissue cells :
- formation of osteoid
- presence of lipoblasts
- Striations in tumors of skeletal muscle
 When a tumor cell loses its differentiation it gradually gains features of DYSPLASIA

 It is a process of gradual loss of differentiation

 It is an abnormal growth which may precede malignancy

 Complete loss of differentiation  ANAPLASIA

Cytological Features of Dysplasia

 Increased nuclear size

 Increased N/C ratio
 Variation in nuclear & cell size : PLEOMORPHISM
 Loss of differentiating features
 Increased nuclear DNA content : HYPERCHROMATISM
 Nucleoli :Prominent, sometimes multiple
 Mitotic figures : Increased
 Abnormal mitoses: may be present
 Loss of polarity : in an epithelial surface
Severe Dysplasia/ Anaplasia
Intraepithelial Neoplasia

Dysplasia involving an epithelial surface

 Low grade & High grade
 High grade dysplasia, limited by epithelial basement membrane  CARCINOMA IN
SITU

 Not all dysplasias progress to higher grade or carcinoma in situ.

 Not all carcinoma in situ progress to invasive CA
 Some cases of dysplasia can regress
Intraepithelial Neoplasia
2. Rate of growth

 Rate of growth usually correlates with level of differentiation

 May be rapid in some benign tumors
 Some tumors may shrink in size
 Some malignant tumors may outgrow their blood supply
Some tumor growths are semi controlled :
HORMONE DEPENDENT :
 This is through presence of receptors on surface
- Breast CA
- Thyroid CA
- Prostatic CA
 Local invasion & Encapsulation .3

 Benign tumors frequently have a capsule

 Malignant tumors progressively invade & destroy surrounding tissue example
-Breast cancer infiltrating skin
-Basal cell carcinoma face infiltrating nerve

*Second most important feature distinguishing malignant tumors

4. Metastasis

 Spread of malignant tumors to distant sites not contiguous with the main tumor
 Most important in diagnosing malignancy
 All tumors can potentially metastasize except BASAL CELL CARCINOMA
 Metastasis is often proportionate to the size and differentiation of the primary tumor
Routes of metastases :
 Lymphatics
 Blood vessels
 Seeding within body cavities / Transcoelomic Spread
1- Lymphatic Spread :

 More characteristic in Carcinoma

 Spread follows the anatomical route of drainage unless skip
“metastases” e.g.
 Breast cancer in left upper quadrant  Left axillary L.N.
 In medial quadrant  internal mammary chain 
supraclavicular & infraclavicular
 Lung Ca - Peribronchial  tracheobronchial LNs  hilar LNs
IMPORTANT IN SURGICAL RESECTION

 Sentinel Lymph Node :

 First lymph node in the pathway of a primary tumor
 Usually outlined by dye

 Not all enlarged L.N.s indicate metastases

Example : Reactive hyperplasia
Histiocytic infiltrate in sinuses
2- Hematogenous spread :

 Usually venous first following anatomical drainage : Lung & Liver

 More characteristic of Sarcoma, but may in occur in later stages of
carcinoma
 Certain carcinomas invade veins early
 RENAL Carcinoma  renal vein IVC
 Hepatocellular Carcinoma Portal &Hepatic v.
3- Transcoelomic spread :

Within peritoneal or pleural cavity e.g.:

 CA of upper lobe of lung to lower lobe
 CA of stomach to ovary
 CA of ovary tends to spread widely through peritoneal
surface
 CA of colon across peritoneum to S.I. & colon
Summary

BENIGN MALIGNANT
 Well-differentiated  Anaplastic
 Low mitotic index  High mitotic index
 Slow Growth  Rapid growth
 With capsule  Infiltrative growth without capsule
 No invasion  Invasion
 No metastases  Metastases
MOLECULAR BASIS OF
CANCER
Basic Principles:

 Cancer arises from nonlethal genetic damage which can be transmitted to cell progeny.
Most tumors initially develop as monoclonal, arising from a single mutated cell.

Three kinds of genes are targets for carcinogenic transformation:

 1) proto-oncogenes promote cell growth and require the alteration of only one allele to
create out of control cellular growth (dominant gene)
 2) tumor suppressor genes inhibit cell growth and require the alteration of both alleles to
affect cell growth (recessive oncogenes), DNA repair genes are similar
 3) genes that regulate apoptosis may be dominant or recessive but influence the ability of
the cell to target itself for destruction following cell damage
 Tumor progression refers to the ability of transformed cells to acquire further abnormal
characteristics over time, independent of tumor size. These include ability to invade,
metastatic spread, further anaplasia. It is believed that these characteristics are acquired
through mutations within the tumor leading to subgroups of cells with varying
characteristics. At the time of diagnosis, most tumors are heterogenous and have multiple
cell lines present. The absence of p53 in many human tumors may contribute to the
increased instability of DNA in tumorus.
ONCOGENES

Proto-oncogenes are normal cellular genes that regulate cell growth, division, and
differentiation. Oncogenes are cancer-causing genes derived from proto-oncogenes
by mutation, retroviral transduction, gene amplification, or dislocations. Oncogenes
occur as transformations of genes that normally regulate expression of growth
factors and receptors, signal transducing proteins, nuclear transcriptions factors, and
cyclins and their associated proteins.
Classes
of
Oncogenes
Methods of Activation of Oncogenes:

1. Point mutations: typical of ras proteins

2. Chromosomal rearrangements: translocation may associate a growth factor or receptor with

an actively transcribed area, or result in the formation of an active hybrid protein. For
example Philadelphia chromosome c-abl-bcr has hybrid activity

3. Gene Amplification: duplication, multiplication of DNA sequences in the genome.

Associated with N-myc In neuroblastoma and c-erb 2 in breast cancer.
 Loss of 5q
Mutation and loss of
Normal Adenomatous Polyposis Coli
epithelium (APC) gene.

Hyperproliferative
epithelium DNA hypomethylation

Mutation of ras genes

Tumour
Early
adenoma

progression Intermediate
adenoma
Loss of 18q
Loss of Deleted in Colorectal Carcinoma
(DCC) gene

Dysplastic Loss of 17p

adenoma Mutation and loss ofTP53
gene

Carcinoma

“Other alterations”

Metastases
Carcinogens/process of carcinogenesis

 Carcinogens are agents that have the ability to initiate the formation of cancer. They are
divided into 4 groups:
 Chemical Carcinogens
 Physical Agents
 Ionizing Radiation
 Oncogenic Viruses
 It is useful to remember that 80 - 90% of all cancers may be related to environmental
 agents including diets, lifestyles, and viruses.
 Several environmental agents often act together (co-carcinogenesis).
Chemical carcinogenesis

 It was Sir Percival Pott in 1775 who associated the increased incidence of scrotal skin cancer to
chronic exposure to soot in chimney sweepers. Over the succeeding 2 centures hundreds of chemicals
have been shown to transform cells in culture and to cause tumours in experimental animals and in
humans exposed to them. These chemicals are known as carcinogens and the process by which they
cause tumours. Or cancer is called carcinogenesis. Nature has protected cells from these harmful
agents (think of some of these protectors). Therefore, if one Or a group of agents are to produce a
neoplasm they have to damage more than one gene. Thus, the Neoplastic transformation is a
progressive process involving multiple “hits” or genetic changes.
 Alterations in DNA cause changes in one or both of the following types of genes:
 Proto-oncogenes
 Tumor suppressor genes
Chemical
carcinogenesis
Ultraviolet Light

 Strong epidemiologic relationship to squamous cell, basal cell, and melano-carcinoma in

fair skinned people.
 Causes formation of pyrimidine dimers in the DNA leading to mutations.
 Activation of T-suppressor cells facilitates emergence of tumor clones.
 Individuals with defects in the enzymes that mediate DNA excision-repair are especially
susceptible.
Ionizing Radiation

 Ionizing radiation includes: X-rays, gamma rays, as well as particulate radiation; alpha,
beta, positrons, protons, neutrons and primary cosmic radiation. All forms are
carcinogenic with special sensitivity in:
 Bone Marrow: Acute leukemia occurs before other radiation-induced neoplasia (Seven year
mean latent period in atomic bomb survivors).
 Thyroid: Carcinoma occurs in 9 % of those exposed during infancy or childhood.
 Lung: Increased frequency of lung cancer in miners exposed to Radon gas (an alpha particle
emitter).
Viral Carcinogenesis

 A large number of RNA and DNA viruses have been implicated in the causation of a variety of cancers in
animals and humans some important ones are listed below.
 Human papiloma virus (HPV). There are more than 70 types of these DNA viruses. HPV types 16, 18 and
31 are associated with precancerous and invasive squamous cancer of the cervix.
 Epstein-Barr Virus (EBV) is a member of the Herpes family. It is associated with 4 types of human
cancers:
1. African Burkitt lymphoma
2. B-cell Lymphoma (particularly in immunosuppressed individuals)
3. Hodgkin lymphoma
4. Nasopharyngeal carcinoma
 Hepatitis B virus is associated with increased risk of developing hepatocellular carcinoma
 RNA viruses like Human T-Cell Leukemia Virus Type 1 (HTLV) is associated with some forms of T-Cell
leukemia/Lymphoma.
Cancer Invasion

 What really distinguishes benign tumours from malignant cancers is the ability of cancer
to invade and matastasise.

 Malignant Neoplasms grow by progressive infiltration, invasion, destruction, and

penetration of the surrounding tissue do not develop capsules
 This is why surgeons do Wide Excisions
 For a cancer cell to invade it has to:
 Detachment from other tumor cells.
 Adhesion to the extracellular matrix.
 Proteolytic degradation of the extracellular matrix.
 Motility and migration into the extracellular matrix.
 This process requires a number of genes to be activated. The extracellular matrix is a thick environment rich in
collagen, glycoproteins and proteiglycans. Cells have to detach from the tumour mass and they can do that by
reducing the cell-cell adhesion molecules on their surface (like E-Cadherins and others). They then have to adhere
to proteins in the extracellular matrix by producing molecules on the surface called Integrins. Cells then can move
towards rich sources of growth factors in a process called chemotaxis. But there are still a lot of tightly packed
molecules and polymers in the Extracellular matrix so the cancer cell also secret proteolytic molecules called
(matrix metallo-proteases, serine and cysteine proteases to degrade the extracellular matrix). This process also
release some growth factors hidden in the extracellular matrix.
 Cell-Extracellular matrix adhesion molecules involved in invasion and metastasis
 Integrins: A family comprising many heterodimeric cell-surface molecules that mediate
cell adhesion to different extracellular matrix molecules.
 Laminin receptors
 CD44: Mediates tumor cell attachment to hyaluronate.
Cancer
Invasion
Cancer metastasis

 Metastasis is defined as the development of secondary implants discontinuous with the

 primary Malignant neoplasm and possibly in remote tissues. Once metastases are detected
a cure becomes difficult if not impossible. Also, patients survival dramatically drops if
metastases are present.
 Cancers spread by three ways:
1. Direct spread into natural cavities. Such as peritoneum, pleura, etc
2. Lymphatic spread (via lymphatic vessels)
3. Haematogenous spread (via veins)
Cancer
metastasis

Adhesion to endothelial cells

Tumour cells express E-Selectins
Molecules that bind to
Sialyl-Lewis X on endothelial cells
 Facts about metastasis

 Direct spread
 Cancer of the Colon invades the peri-colonic fat and breaks free into the peritoneal cavity
 Cancer of the Ovary is another big peritoneal spreader
 Cancer involvement of cavities tends to produce haemorrhagic effusion, adhesions
 Lymphatic Spread
 More typical of carcinomas rather than sarcomas (hematogenous)e.g Breast, stomach, Papillary thyroid carcinoma
 Cancer cells travel in lymphatics and reach regional lymph nodes. They get arrested, die or grow or travel to other
nodes
 Regional Lymph nodes draining the cancer area are first involved
 It is the rationale for lymph node dissection in many Carcinomas. The lymph nodes in the specimen are enlarged
and firm.
 Hematogenous Spread
 Sarcomas predominate but Carcinomas also use this rout
 Arteries are rarely invaded
 Veins are the route of hematogenous spread
 Liver and Lungs are the usual endpoints of hematogenous spread, but remember that metastases can also
metastasise.
 Portal flow to liver and vena caval flow to lungs
 Renal Cell Ca has a propensity to invade the renal vein and hepatocellular cancer has a tendency to penetrate
portal and hepatic radicles.
 The distribution of metastases follow the anatomical distribution. Thus, breast cancer in the upper-outer
quadrant is likely to metastasise to the axillary lymph nodes, while a upper-inner breast cancer (medial) tends to
metastasise to supraclavicular lymphnodes. Colon cancer tends to metastasise to Liver while cancers of the lower
rectum tends to metastasise to the lung.
Cancer grading and staging

 Grading and staging tumours are important because of their clinical relevance and so that
different clinicians know how to standardise, plan and organise patients ‘ treatment.
 Grading is based on the degree of differentiation and the number of mitosis within a tumour.
 Cancers are classified as grades I to IV with increasing metaplasia. In general, Higher-grade
tumours are more aggressive than lower grade tumours. It is important to note that within the
same tumour some cells have different grades and this is because of tumour progression. Thus
tumour grade could change as the tumour grows.
 Staging is based on the anatomic extent of the tumour.
 In 1932 Cuthbert Dukes described a system for staging rectal cancer. The staging system
associated the clinical-pathological behaviour of rectal tumours with prognosis (Figure 5).
When the tumour is confined entirely within the wall of the bowel (Dukes’ A) more than 90
% of patients can be cured by surgery alone. Penetration through the muscularis propria
(Dukes’ B) worsens the prognosis, and when there is metastasis to the lymph nodes (Dukes’
C) the outlook deteriorates further so that two-thirds of the affected patients die of the disease
within five years. When distant metastases to the liver are present (Dukes' D) most patients
will die by the end of the first year (Dukes, 1932).
 Currently, two of staging are used: the TNM (Tumour, Node, Metastases) and the American
Joint Committee (AJC) systems. Both systems use the primary tumour size, extent of
invasion and number of Lymph nods involved with the tumour and the presence or absence of
distant metastases as factors relevant to prognosis.
Primary tumor (T)
T0 No evidence of primary tumor
T1 Tumor <5 cm
T2 Tumor >5 cm

Lymph nodes (N)

N0 No regional metastasis
N1 Regional node metastasis
Distant metastasis (M)
M0 No distinct metastasis
M1 Distant metastasis

Histopathalogic grading (G)

G1 Well differentiated (low grade)
G2 Moderately differentiated (intermediate grade)
G3 Poorly differentiated (high grade)
G4 Undifferentiated

Stage
IA G1 T1 N0 M0
IB G1 T2 N0 M0
IIA G2 T1 N0 M0
IIB G2 T2 N0 M0
IIIA G3 T1 N0 M0
G4 T1 N0 M0
IIIB G3 T2 N0 M0
G4 T2 N0 M0
IVA Any G Any T N1 M0
IVB Any G Any T Any N M1
CANCER DIAGNOSIS
General Outline :

 History & clinical examination

 Radiographic techniques

i- X ray
ii- CT scan
iii- MRI
iv- Ultrasound
 Laboratory tests : general & specialized
1-Morphological Methods :

1- Cytological methods :
 Study of cells :
- Smear
- FNA, Brush, Fluid tapping…etc
Papanicolaou stain (PAP) often used.
False(+), False (-)
- A negative report does not exclude
malignancy, repeat
- Advise biopsy, even if (+ )
2- Histological methods :

 Biopsy of tissue:
Needle & core biopsy , Endoscopic Biopsy, or open surgical biopsy
 Frozen Section (Rapid technique)
 Paraffin Section ( 36-48 hrs. or longer )
 H&E, Special histochemical stains e.g.
( PAS, CONGO RED, PERL’s stains) or by
IMMUNOHISTOCHEMICAL Methods
3- Immunocytochemistry
 Staining by use of monoclonal AB directed against various components in cell may help
in diagnosis of undifferentiated cancers or help in identifying source of a metastatic
tumor. e.g.
 Cytokeratin Carcinoma
Common leukocyte antigenLymphoma S 100 Neural tissue, melanocytic lesions
Desmin, Vimentin  Sarcoma
4-Electron microscopy :

 For recognition of desmosomes , or neurosecretory granules….etc

5- Flow Cytometry :

 For measuring DNA content , detecting diploid versus aneuploid tumors….etc.

 Correlates with rate of growth & prognosis
 Useful in the diagnosis & classification of Lymphoma & Leukemia
2- Biochemical Assays :

 Used to identify tumor associated enzymes, hormones , antigens … etc

 These are useful as markers for diagnosis of a tumor OR for assessing the progress of a known
tumor
Tumor markers represent biochemical indicators of the presence of a tumor.
 Their uses are to :
I - Confirm diagnosis.
II -Determine the response to treatment .
III - Detect early relapse.
 Present in serum or urine.
 Many are present in normal & tumor tissue, so they are not very specific but their level is
important.
 Types of Tumor Markers

1- Hormones :
 Human Chorionic Gonadotrophic Hormone
( HCG)
Elevated levels are seen in Pregnancy
& Gestational Trophoblastic Disease
 Calcitonin useful in diagnosis of some
thyroid carcinomas
 Ectopic hormones in paraneoplastic S.not used
 2- Oncofetal Antigens :

 Carcinoembryonic Antigen ( CEA ) :

in fetal tissue & some malignancies –
Colorectal CA & Pancreatic CA


Alpha Fetoprotein (AFP) :
Cirrhosis : Elevated
Hepatocellular carcinoma : Extremely high
 3- Isoenzymes :

 Prostatic Acid Phosphatase ( PAP )

 levels seen in Metastatic prostatic CA

Useful in : * Staging prostatic CA
* Assessment of prognosis
* Response to therapy.
4- Specific Proteins :

 Immunoglobulins secreted in Multiple Myeloma

 Prostate -specific antigen ( PSA ) :
Present in epithelium of prostatic ducts.
*  Prostatic hyperplasia &
*  in Prostatic CA
* Level correlates with Stage of CA
5- Several mucins
 MUC-1 in breast CA
 CA-125 in ovarian CA
 CA-19-9 in pancreatic & hepatobiliary CA
3- Molecular Diagnosis :

 Methods used include :

 PCR (Polymerase Chain Reaction)
 FISH (Fluorescent In Situ Hybridization)
 Used to detect gene rearrangement,
translocations, amplifications…etc
 BCR-ABL Chronic Myeloid Leukemia
 Monoclonal proliferation of B or T cells
 13q 14 deletion in Retinoblastoma….
 For prognosis : gene amplification
 HER- 2 NEU in breast carcinoma
 N-MYC in neuroblastoma
 Detection of residual disease in
chronic myeloid leukemia (BCR-ABL)
 Detection of genes of hereditary
cancer e.g BRCA-1 in breast cancer