Lecture prepared for Undergraduate MBBS students

1. Neoplasia
Dr. Umme Kulsum Munmun
Assistant Professor
Department of Pathology
Cumilla Medical College

2. Definition of Neoplasm
 A neoplasm is an abnormal mass of tissue, the growyh of
which exceeds and is uncoordinated with that of the normal
surrounding tissue and persists in the same excessive
manner even after cessation of stimuli which evoked the
change

3.  At the molecular level, neoplasm is disorder of growth
regulatory genes ( the activation of growth regulatory genes
and inactivation of tumour suppressor genes)
 It develops in a multistep fashion
 Different neoplasms, even of the same histologic type, may
show different genetic changes

4.  The causative mutations give the neoplastic cells a survival
and growth advantage, resulting in excessive proliferation
that is independent of physiologic growth signals
(autonomous)

5.  In the modern era, “A neoplasm can be defined as a
disorder of cell growth that is triggered by a series of
acquired mutations affecting a single cell and its clonal
progeny.”

6. Structural Characteristics
 The gross appearance of tumour is varied
 May be polypoid, papillary, nodular, lobulated, cystic,
fungating and ulcerated etc

7.  Two basic components of tumours—
• Parenchyma – made up of proliferating neoplastic cells, largely
determines the biologic behaviors of the tumour. The
classification, nomenclature and histological diagnosis are also
made according to the parenchymal cells
• Supporting stroma – made up of connective tissue, blood
vessels and lymphatics

10. Biological Behavior
 Benign
 Malignant

11. Nomenclature
 Neoplasms are named according to a binomial system
according to
the histogenic origin of the parenchymal
component and
the biologic behavior
Benign tumours - ‘~oma’ eg. Lipoma, fibroma
Malignant tumours – ‘~ carcinoma’ , ‘~sarcoma’ eg.
Adenocarcinoma, liposarcoma

14. More than one neoplastic cell type, mixed
tumour, usually derived from one germ layer
Tissue of origin Benign Malignant
Salivary gland Pleomorphic
adenoma
Malignant mixed
tumor of salivary
gland origin
Renal anlage Wilms tumour

15. More than one neoplastic cell type, derived
from more than one germ layer- teratogenous
Tissue of origin Benign Malignant
Totipotential cells in
gonads or in
embryonic rests
Mature teratoma Immature teratoma

16.  Adenoma – benign epithelial neoplasms producing gland
patterns – derived from glands but not necessarily exhibiting
gland patterns

17.  Papillomas – Benign epithelial neoplasms, growing on any
surface, – Produce microscopic or macroscopic finger-like fronds

18.  Polyp – a mass that projects above a mucosal surface, as in the
gut, to form a macroscopically visible structure

19.  Cystadenomas – hollow cystic masses; typically they are seen in
the ovary

20. Adenoma vs Adenocarcinoma

21. Lipoma

22. Tumours with Aberrant differentiation (Not true neoplasm)
 A hamartoma is composed of tissues that are normally present
in the organ in which the tumor arises
– Eg: a hamartoma of the lung consists of disorganized mass of
bronchial epithelium and cartilage that may become so large that
it presents as a lung mass. Its growth is coordinated with that of
the lung itself
 A choristoma resembles a hamartoma but contains tissues that
are not normally present in its site of origin
– Eg: A orderly mass of pancreatic acini and ducts in
the wall of the stomach is properly called a choristoma.

23. Cartilage choristoma in liver

24.  Pluripotent cells can mature into several different cell types
 Neoplasms of pluripotent or precursor cells are generally
called Embryomas or Blastomas
 Example:
- Retinoblastoma (occular growth)
- Neuroblastoma (common in adrenal gland)
- Nephroblatoma (renal tumour)
- Hepatolastoma (hepatic growth)
- Acute lymphoblastic lymphoma (hematological
malignancy)

25.  All blastomas are childhood tumors
 All blastomas are malignant tumors
 Except:
– Chondroblastoma
– Osteoblastoma
– Pulmonary blastoma

26. Benign vs Malignant Features
Features Benign Malignant
Rate of growth Progressive but
slow. Mitoses
few and normal
Variable. Mitoses
more frequent
and may be
abnormal
Differentiation Well
differentiated
Well differentiated to
various degrees of
anaplasia
Capsule Common Less common
Local invasion
Metastasis
Cohesive growth.
Capsule & BM
not breached
Absent
Poorly cohesive
and infiltrative
May occur

27. Differentiation and Anaplasia
 ‘Differentiation’ denotes to the degree to which a neoplastic
cell resembles the normal mature cells of the tissue both
morphologically and functionally
 Benign tumours are usually well differentiated. They
resemble closely their normal counterpart
 Malignant tumours on the other hand, show variable degree
of differentiation

28.  Malignant tumours that are composed of undifferentiated cells
are said to be anaplastic, that means no morphological
resemblance to normal tissue
 ‘Anaplasia’ denotes to the lack of differentiation

29. ANAPLASIA
 Pleomorphism and anisonucleosis
Size
shape
 Abnormal nuclear morphology
Hyperchromasia
High nuclear cytoplasmic ratio (upto 1:1)
Chromatin clumping
Prominent nucleoli
Irregular nuclear membrane
 Abnormal mitoses tripolar, quadripolar and multipolar spindles
 Loss of polarity

31. Characteristics of a single
malignant cell
 Abormal size – usually larger than normal
 Large nuclei
 Small cytoplasm
 Altered nuclear: cytoplasm ratio (1:1)
 Hyperchromatic nuclei / coarse chromatin
 Chromatin clumping
 Irregular nuclear membrane
 Multiple nuclei
 Prominent nucleoli
 Bizarre (tri-, quadri- or multipolar) mitotic spindle

32. Features of Malignant Tumors
 Cellular features
 Local invasion
 Malignant: expand, invade and infiltrate the surrounding
tissue (basement membrane)
Whereas Benign tumours expand and push aside without
invading, infiltrating surrounding capsule or
basement membrane
 Metastasis
Unequivocal sign of malignancy

34. Dysplasia
 Literally means abnormal growth, the term implies disordered
growth of epithelim
 In dysplasia some but not all of the features of
malignancy are present
 Dysplastic cells may show a degree of pleomorphism,
hyperchromasia, increased mitosis and loss of architectural
orientation or polarity
 Dysplasia may develop into malignancy
Uterine cervix
Colon polyps
 Graded as low-grade or high-grade
 Dysplasia may NOT develop into malignancy

38. Tumours grading
 Grading is based on
(1) the degree of anaplasia
(2) number of mitoses
 • Grade-I : Well-differentiated (less than 25% anaplastic
cells)
 • Grade-II : Moderately-differentiated (25-50% anaplastic
cells)
 • Grade-III : Moderately-differentiated (50-75% anaplastic
cells)
 • Grade-IV : Poorly-differentiated or anaplastic (more than
75% anaplastic cells)

39.  Criteria for grading vary in different types of tumour

40. Tumours staging
 International TNM system is commonly used for solid
tumours– T: Tumour (size of primary tumour), N: Nodes
(local/ regional node involvement), M: Metastases (distant
metastases)
 T0 No evidence of tumour Tis Carcinoma in situ T1-4
Progressive increase in tumour size

41.  NX Regional lymph nodes can’t be assessed
 N0 Regional lymph nodes not involved
 N1-4 Progressive increase in number of local/ regional
lymph nodes involved
 M0 No evidence of distant metastases
 MX distant metastases can’t be assessed
 M1-3 Increasing involvement of distant metastases

43. Natural History Of Malignant
Tumors
 Malignant change in the target cell, referred to as
transformation
 Growth of the transformed cells
 Local invasion
 Distant metastases

44. METASTASIS
 Metastasis is the process by which a tumor cell leaves the
primary tumor, travels to a distant site via the circulatory
system, and establishes a secondary tumor
 Routes of Metastasis: Mainly 3 types
 Through the circulatory (blood) system (hematogenous)
:Common route for sarcomas but certain carcinomas also
frequently metastasiseby this mode.
 •Ex: liver, lungs, brain, bones, kidney and adrenals

45.  Through the lymphatic system : commonly carcinoma
 Through the body wall into the abdominal and chest
cavities (transcoelomic)
 eg. Pseudomyxoma peritonei , Cruckenberg tumour of
ovary

46. Metastasis

48. Locally malignant tumours
 Groups of malignant tumours that spread only locally by
direct infiltration but rarely metastasize
 Examples:
- Basal cell carcinoma of skin
- Osteoclastoma/ giant cell tumour of bone
- Adamantinoma of jaw
- Carcinoid tumour
- Astrocytoma of brain
- Craniopharyngioma in pituitary fossa

49. Molecular basis of cancer
 Non- lethal genetic damage (mutation) lies at the heart of
carcinogenesis (initiation and transformation)
 Clonal expansion of a single progenitor cell that incurred the
genetic damage
 Carcinogenesis results from the accumulation of complementary
mutations in a stepwise fashion over time (progression)

50. Normal growth regulatory genes
 Three normal regulatory genes
- Growth promoting proto-oncogenes
- Growth inhibiting tumour suppressor genes
- Apoptosis regulatory genes
- Apoptosis inducer
- Apoptosis suppressors
 4th – DNA repair genes

51. Normal Cell Growth
 Proto-oncogene product leads to cell growth with external
stimuli
 This growth stimuli should be balanced by the products of
tumour suppressor genes
 Any mutated genes will either be repaired by DNA repair
genes (maintains genomic integrity) or killed by products of
apoptosis regulatory genes

52. Principles of carcinogenesis
 Cancer is caused by alteration or mutations in genetic code
 Induced in somatic cells by
- carcinogenic chemicals
- radiation
- some viruses
 Herediary/ germline mutations
5-10 %

53. Principles of carcinogenesis
 Neoplastic transformation is a progressive process involving
multiple hits or genetic damages
 Mutation affects one or more of the following genes
Proto-oncogenes
Tumour suppressor genes
Genes that regulate apoptosis
DNA repair genes
 Approximately 90- 90% of all cancers are sporadic
 5-10% are inherited

54.  Proto-oncogenes  
uncontrolled growth
 Tumour suppressor genes 
 Uncontrolled growth
 DNA repair genes 
 unable to recognize and repair non lethal genetic
damage  Mutator phenotype/ Genomic instability
Gain of function mutation
Loss of function mutation
Loss of function mutation

57.  Driver mutations :
Mutations that contribute to the development of the
malignant phenotype are reffered to as ‘driver mutations’.
 Passenger mutations:
Mutations that have no phenotypic consequence, are called
‘passenger mutations’
 The first driver mutation that starts a cell on the path to
malignancy is termed ‘initiating mutation’

58.  Initiated cell acquires a number of additional driver mutations ,
each of which contributes to the development of cancer
 Mutation in DNA repair genes is a common early step on the road
to malignancy , it leads to genomic instability
 By the time a cell acquires all of the driver mutations needed for
malignant behavior, it may bear hundreds or even thousands of
additional mutations (tumour progression, diagnosis)

60. Cellular and molecular
hallmarks of cancer
 All cancers display eight fundamental changes in cell
physiology , which are considered the hallmarks of cancer

61. Hallmarks
 Self – sufficiency in growth signals
 Insensitivity to growth inhibitory signals
 Altered cellular metabolism
 Evasion of apoptosis
 Limitless replicative potential (immortality)
 Sustained angiogenesis
 Ability to invade and metastasize
 Ability to evade the host immune response

62.  Germline mutations are changes to your DNA that you
inherit from the egg and sperm cells during conception.
 Somatic mutations are changes to your DNA that happen
after conception to cells other than the egg and sperm.
Mutations can lead to genetic conditions
and familial cancer syndromes.

64. Proteins involved in normal cellular
growth :
 Growth factors
 Growth factor receptors
 Proteins involved in signal transduction
 Nuclear regulatory proteins
 Cell cycle regulators

68. Carcinogenic agents
 1) Chemical carcinogens
 2) Radiation
 3) Infectious Pathogens

69. CHEMICAL CARCINOGENS:
INITIATORS
DIRECT
 β-Propiolactone
 Dimeth. sulfate
 Diepoxybutane
 Anticancer drugs
(cyclophosphamide,
chlorambucil, nitrosoureas,
and others)
 Acylating Agents
 1-Acetyl-imidazole
 Dimethylcarbamyl chloride
PROCARCINOGNS
 Polycyclic and Heterocyclic
Aromatic Hydrocarbons
 Aromatic Amines, Amides, Azo
Dyes
 Natural Plant and Microbial
Products
 Aflatoxin B1 Hepatomas
 Griseofulvin Antifungal
 Cycasin from cycads
 Safrole from sassafras
 Betel nuts Oral SCC

70. CHEMICAL CARCINOGENS:
INITIATORS
OTHERS
 Nitrosamine and amides (tar, nitrites)
 Vinyl chloride angiosarcoma in Kentucky
 Nickel
 Chromium
 Insecticides
 Fungicides
 PolyChlorinated Biphenyls (PCBs)

71. CHEMICAL CARCINOGENS:
PROMOTERS
 HORMONES
 PHORBOL ESTERS (TPA), activate kinase C
 PHENOLS
 DRUGS, many

72. RADIATION CARCINOGENS
UV:BCC, SCC, MM
IONIZING:
 alpha, beta, gamma ray, X-ray
 Hematopoetic and Thyroid (90%/15yrs) tumors in
fallout victims
 Solid tumors either less susceptible or require a longer
latency period than LEUK/LYMPH
 BCCs in Therapeutic Radiation

73. VIRAL CARCINOGENESIS
 HPV SCC
 EBV Burkitt Lymphoma, NPC, Hodgkin lymphoma
 HBV Hepatocellular Carcinoma (Hepatoma)
 HTLV1 T-Cell Malignancies
 KSHV Kaposi Sarcoma (HHV-8)

74. H. pylori CARCINOGENESIS
 Gastric lymphomas (i.e., M.A.L.T.-omas)
 Gastric CARCINOMAS

75. HOST DEFENSES
 IMMUNE SURVEILLENCE CONCEPT
 CD8+ T-Cells
 NK cells
 MACROPHAGES
 ANTIBODIES

77. How do tumor cells
escape immune surveillance?
 Mutation, like microbes, like “evolution”
↓ MHC molecules on tumor cell surface
 Lack of CO-stimulation molecules, e.g., (CD28, ICOS),
not just Ag-Ab recognition
 Immunosuppressive agents
 Antigen masking
 Apoptosis of cytotoxic T-Cells (CD8)

78. Effects of TUMOR on the HOST
 Location anatomic ENCROACHMENT
 HORMONE production
 Bleeding, Infection
 ACUTE symptoms, e.g., rupture, infarction
 METASTASES

79. CACHEXIA
Individuals with cancer commonly suffer progressive loss
of body fat and lean body mass accompanied by profound
weakness, anorexia and anaemia referred to as cancer
cachexia.
 TNF α
 IL-6 by tumor cells
 PIF (Proteolysis Inducing Factor) by tumor cells

80. PARA-Neoplastic 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 –
paraneoplastic syndromes

81. PARA-Neoplastic Syndromes
 May be the earliest manifestation of an occult neoplasm
 Can cause significant clinical problems and may even be
lethal
 May mimic metastatic disease and therefore confound
treatment

82. ENDOCRINE

83.  Nerve/Muscle, e.g., myasthenia w. lung ca.
 Skin: e.g., acanthosis nigricans, dermatomyositis
 Bone/Joint/Soft tissue: HPOA (Hypertrophic Pulmonary
OsteoArthropathy)
 Vascular: Trousseau, Endocarditis
 Hematologic: Anemias
 Renal: e.g., Nephrotic Syndrome

84. LAB DIAGNOSIS
 CYTOLOGY: (exfoliative)
 CYTOLOGY: (FNA, Fine Needle Aspirate)
 BIOPSY (gold standard)

85. IMMUNOHISTOCHEMISTRY
 Categorization of undifferentiated tumors
 Leukemias/Lymphomas
 Site of origin
 Receptors, e.g., ER, PR

86.  Flow cytometry
 FISH –fluorescent in situ hybridization
 DNA micro-arrays

87. Tumor markers
 Biochemical assays
 Not definitive diagnosis of cancer
 Caontribute to the detection of cancer
 Useful in determining the effectiveness of therapy
 Or the appearance of a recurrence

89. THANK YOU

90. TUMOR MARKERS
 HORMONES: (Paraneoplastic Syndromes)
 “ONCO”FETAL: AFP, CEA
 ISOENZYMES: PAP, NSE
 PROTEINS: PSA, PSMA (“M” = “membrane”)
 GLYCOPROTEINS: CA-125, CA-195, CA-153
 MOLECULAR: p53, RAS
 NOTE: These SAME substances which can be measured in
the blood, also can be stained by immunochemical methods
in tissue