Learning Outcomes

At the end of the lecture the students should be able to:

 explain dysplasia.
 explain the carcinogens.
 explain the differences between benign and malignant tumours.
 describe the spread of cancer
 describe the effects of tumour on the host
 discuss the diagnosis of tumour.
 Dysplasia

 Disordered growth – Loss in individual cell uniformity &

architecture orientation
 Site - surface epithelial cells - skin, cervix & breast
 Found adjacent to cancer
  Risk of cancer (premalignant conditions)
 Pathological hyperplasia & epithelial metaplasia can
progress to dysplasia
• Human papilloma virus type 16  cervical dysplasia
• Ultraviolet light. Squamous cell dysplasia, skin
Features of Dysplasia
 Cellular & nuclear pleomorphism (variation in size & shape)
• Large hyperchromatic nucleus
• Nucleus : Cytoplasm (normal 1:4 or 1:6)
• Numerous mitoses with normal mitotic spindles
 Loss of maturation
Mild & moderate dysplasia → Reversible

Carcinoma in situ
• Full thickness dysplasia
• Dysplastic cells do not penetrate basement membrane

Invasive cancer
Cancer cells penetrate basement membrane
 Neoplasia

• An abnormal mass of tissue, the growth of which exceeds &

is uncoordinated with that of normal tissues & persists in
the same excessive manner after cessation of the stimuli
which evoked the change (British oncologist Willis)

• A disorder of cell growth caused by a series of acquired mutation

in a single cell & its clonal progeny  autonomous excessive
proliferation - independent of physiologic growth signals
• Tumors have two basic components:
1) Neoplastic cells - the tumor parenchyma
2) Reactive stroma - connective tissue, blood vessels
& cells of immune system
Classification

Benign tumours
Well-circumscribed tumour, localized & do not spread to other organs;
remove by local surgery
suffix: ‘oma’

Malignant tumours - ill-defined tumour, can invade & destroy adjacent

tissues & spread to distant organs (metastasize) to cause death
Epithelial cell origin: carcinoma
Mesenchymal origin: sarcoma
Malignant tumours: suffix: ‘oma’: melanoma, lymphoma
 Tumour of Origin Benign Malignant
Composed of One Parenchymal cell Type (Simple Tumour)
Tumours of Epithelial Origin
Stratified squamous Squamous cell papilloma Squamous cell carcinoma
Basal cell of skin & adnexa Basal cell carcinoma
Epithelial lining of glands & ducts Adenoma Adenocarcinoma
Papilloma Papillary carcinoma
Cystadenoma Cystadenocarcinoma
Respiratory passage Bronchial adenoma Bronchogenic carcinoma
Renal epithelium Renal tubular adenoma Renal cell carcinoma
Liver cell Hepatic adenoma Hepatocellular carcinoma
Urinary tract epithelium Transitional cell papilloma Transitional cell carcinoma
(Transitional cell)
Placental epithelium Hydatidiform mole Choriocarcinoam
Testicular epithelium (Germ cell) Seminoma
Melanocytes Nevus Melanoma
 Tumours of Origin Benign Malignant
Tumour of Mesenchymal Origin
Connective Tissue & Derivatives Fibroma Fibrosarcoma
Lipoma Liposarcoma
Chondroma Chondrosarcoma
Osteoma Osteogenic sarcoma
Leiomyoma Leiomyosarcoma
Rhabdomyoma Rhabdomyosarcoma
Vessels & Surface Coverings
Blood vessels Hemangioma Angiosarcoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Mesothelium Mesothelioma
Brain coverings Meningioma Invasive meningioma
Blood Cells & Related Cells
Hematopoietic cells Leukaemia
Lymphoid tissue Lymphoma
Tumour of Origin Benign Malignant
More than one neoplastic cell type (Mixed tumors), usually derived from one germ cell layer
Salivary gland Pleomorphic adenoma Malignant mixed tumour
(Mixed tumour of salivary gland origin) of salivary gland origin
Breast Fibroadenoma
More than one neoplastic cell type derived from more than one germ cell layer—teratogenous
(Compound Tumour)
Totipotential cells in Mature teratoma, Dermoid cyst Immature teratoma,
gonads or embryonic rests Teratocarcinoma
 Characteristics of Benign & Malignant Tumours
1. Differentiation & Anaplasia
2. Rate of growth
3. Mode of growth
4. Spread of tumour. Local invasion & Metastasis
1. Differentiation and Anaplasia

Differentiation. Extent of neoplastic cells resemble the corresponding

normal cell both morphologically & functionally

 Well differentiated tumour: resembles normal cell; rare mitosis

 Benign tumours: well differentiated.
 Malignant tumours: from well differentiated to poorly differentiated
Poorly differentiated - Lack of differentiation – Anaplasia

Features of Anaplasia (Hallmark of malignancy)

1) Cellular & nuclear pleomorphism
2) Large hyperchromatic nucleus
3) Nucleus:Cytoplasm (1:1)
4) Abnormal large nucleoli
5) Numerous atypical mitoses (triopolar, quadripolar or multipolar spindles)
6) Tumour giant cell
7) Loss of polarity (orientation)
2. Rate of Growth

Growth & spread of tumour depend on stroma

Benign tumour
Slow growth rate - Slow expanding grow
 compress adjacent fibrous tissue (pressure atrophy)
 form fibrous Capsule
• Separate from adjacent normal tissue
• Creates well-defined cleavage plane
• Discrete, readily palpable, moveable (non-fixed) tumour
& easily excisable by surgery
Malignant tumour

• Variable growth rate

• Growth rate correlates with degree of differentiation of malignant tumor.
• Anaplastic (high-grade) cancers have an increased growth rate
• Low-grade cancers have a slow growth rate.

• Growing tumor cells require blood supply

• Rapid growth  insufficient blood supply  central ischemic necrosis
3. Mode of growth
Benign tumour.
• Well circumscribed tumour; localized to tissue of origin
 Local surgical removal  generally survive
• No infiltration, invasion nor metastasis
Malignant tumour
• Poorly demarcated from adjacent normal tissue
• Infiltration, invasion & destruction to adjacent tissue
• Spread to distant organs (metastasize) to cause death
• Difficult surgical resection - Tumour + wide margin of adjacent normal
tissue
• Local Invasion is the most reliable feature that differentiates cancers from
benign tumors.
• Some tissues resist invasion. E.g., mature cartilage, elastic tissue of arteries

• All malignant tumors require O2 and nutrients to survive

• Stimulates angiogenesis within the tumor and its metastatic sites
Spread of Malignant Tumour

• Local invasion & distant metastasis - Hallmark of malignancy

Metastasis

• Cancer spreads to distant sites from its tissue of origin

where it grows independently & discontinuously with
primary tumour
 All cancer can metastasize except: basal cell carcinoma
Pathways of metastasis
1. Blood spread
2. Lymphatic spread
3. Direct seeding of body cavities & surfaces
4. Iatrogenic spread: spread of tumour cells on surgical instruments
1) Blood spread
• Common pathway for spread of sarcoma
• Vein > Artery (thicker wall)

• Common sites: liver, lungs, brain & bone,

adrenal glands

• Malignant cells enter

 the portal vein metastasize to the liver
 the vena cava metastasize to the lungs

• Rarely sites of secondary deposits:

skeletal muscle & spleen
2) Lymphatic spread

• Regional lymph nodes are the first line of defense against the spread of
carcinomas.
• E.g., breast cancer  axillary lymph node
• Tumour emboli  afferent lymphatic vessel  enter the sinuses of the
regional lymph nodes  invade the parenchymal tissue of the lymph node
 invade efferent lymphatics vessel  the thoracic duct  the systemic
circulation
• Skip metastasis: Bypassed local regional lymph nodes due to:
– Venous-lymphatic anastomoses
– Inflammation or radiation obliterate lymphatic channels
• Enlarged lymph node due to:
 Spread & growth of cancer cells
 Reactive hyperplasia (tumor-specific immune response)
 3) Seeding of Body Cavities & Surfaces
Cancer cells exfoliate from surface of organ

Spread across body cavity: pleura , pericardial,
peritoneal, subarachnoid & joint spaces

Seed on surface of body cavities & organs
Eg. Carcinoma ovary or appendix spread to
peritoneum  Ascites
 Epidemiology of Cancer
Age

 Cancer incidence increases with age

 Old age (common): Colorectal, lung, and prostate cancer
• Accumulation of somatic mutation
• Host immune response
 Infancy & children: acute leukemia, neuroblastoma
Acquired Predisposing Conditions
1. Chronic inflammation
• Asbestosis, silicosis - lung cancer, mesothelioma
• Chronic pancreatitis - pancreas cancer
• Chronic cholecystitis - gallbladder cancer
• Reflux oesophagitis & Barret oesophagus - oesophagus cancer
• Chronic gastritis/ulcer - adenocarcinoma stomach, lymphoma
• Chronic hepatitis - hepatocellular carcinoma
• Chronic cervicitis - cervix cancer
• Chronic cystitis - bladder cancer

2. Precancerous conditions
Pathological hyperplasia, metaplasia, dysplasia

3. Immunodeficiency state: T-cell immunodeficiency

Environmental Factors

1) Infection
• Human T-cell leukemia virus-type1 - adult T-cell leukemia/lymphoma
• Human papillomavirus - cancer (cervix & oropharynx)
• Epstein-Barr virus - lymphoma, cancer (stomach, nasopharynx)
• Hepatitis B & C virus - Hepatocellular carcinoma
• Helicobacter pylori - Gastric adenocarcinoma, lymphoma

2) Smoking - cancer
(mouth, pharynx, larynx, lung, oesophagus, pancreas, bladder)

3) Alcohol - cancer (oropharynx, larynx, esophagus), hepatocellular carcinoma

• Smoking & Alcohol -the risk of upper airways & GI tract

 Environmental Factors Cont.

4) Diet

5) Obesity - Body weight  risk of cancer

6) Reproductive history
• Prolonged oestrogen exposure: risk of cancer (breast & endometrium)
7) Environmental carcinogens

 Radiation - ionizing radiation, UV rays, x-rays

 Leukaemia, cancer (thyroid, breast, colon, lung)
 skin (squamous cell carcinoma, melanoma)
 Occupational cancer
• Arsenic -cancer (lung, skin)
• Asbestos - cancer (lung, oesophagus, stomach, colon), mesothelioma
• Benzene - acute myeloid leukaemia
• Beryllium, chromium, radon & its decay products - lung cancer
• Cadmium - prostate cancer
• Nickel - cancer (lung, oropharynx)
• Vinyl chloride - hepatic angiosarcoma
Chemical Carcinogens

Initiator  permanent DNA damage (mutation)

 Initiation alone is not sufficient for cancer formation

Promoter induces cancer arise from initiated cells

 Non-tumorigenic by themselves

Direct-acting carcinogens do not require metabolic conversion to become

carcinogen - anticancer drugs (cyclophosphamide, chlorambucil,
nitrosoureas, & others)

Indirect-acting carcinogens (Procarcinogens) require metabolic conversion to

become active carcinogen - aflatoxinB1, griseofulvin, betel nuts, nitrosamine &
amides, vinyl chloride, nickel, chromium, insecticides, fungicides
 Carcinogenesis

Mutation of normal regulatory genes

• Growth-promoting proto-oncogenes: Her2/neu
• Growth-inhibiting tumour suppressor genes: BRCA1 & 2, p53
• Genes that regulate apoptosis
• Genes involved in DNA repair
 Clinical Aspects of Neoplasia / Effects of Tumour on the Host

Local & Hormonal Effects

1) Tumour compress adjacent tissue  impair function

• Pituitary adenoma / carcinoma compress normal pituitary gland
 hypopituitarism
• Leiomyoma uterus  menorrhagia, infertility, abortion, urinary frequency

2) Tumour (benign tumour or well-differentiated carcinoma)

of endocrine gland  secrete hormones
• Adenoma thyroid  hyperthyroidism
• Adenoma pancreas (Insulinoma)  hypoglycaemia
 Local & Hormonal Effects Cont.

Cancer arise within or spread to endocrine gland  destroy the gland

 endocrine insufficiency

Nonendocrine tumour produce hormones or hormone like substance

 Paraneoplastic syndrome

Erosive & destructive growth of cancer on surface (skin, mucosa of GIT)

 ulcer, secondary infections & bleeding
Tumour in GIT
 Benign
• Polyp  obstruction
 Malignant.
• Polypoid & infiltrative: Obstruction (vomiting, abdominal distension,
visible peristalsis, constipation)
• Ulcerative: Bleeding (haemetemesis, melena), infection
Cancer Cachexia. Progressive loss of body fat & lean
body mass (muscle) with profound weakness,
muscle wasting, anorexia & anemia.
Associated with
• Basal metabolic rate
• Systemic inflammation -  acute phase proteins
Paraneoplastic Syndrome
• Some cancer patients develop signs & symptoms that cannot readily
be explained by:
 Site of the tumor
 Production of hormones indigenous to tissue from which tumor
arise
• Occur in about 10% of cancer patients
• The earliest manifestation of occult neoplasm
• Can cause significant clinical problems & may be lethal
• May mimic metastatic disease & confound treatment
Endocrinopathy (Ectopic hormones)
• Cushing syndrome (ACTH) - Lung cancer
• Hypoglycemia (Insulin) - Liver cancer
• Hypercalcemia (PTH) - Cancer (breast,
lung, kidney & ovary)
 Nerve & Muscle syndrome
• Myasthenia - lung cancer
• Disorders of CNS & PNS (Peripheral neuropathy,
cortical cerebellar degeneration) - Breast cancer

Skin
 Acanthosis nigricans (gray-black patches
of thickened, hyperkeratotic skin with
velvety appearance) -
lung, stomach, uterus cancer
 Dermatomyositis: Lung & breast cancer
Bone, cartilage & soft tissue changes –
Hypertrophic osteoarthropathy: Lung cancer
 Periosteal new bone formation, primarily at
the distal ends of long bones, metatarsals,
metacarpals & proximal phalanges
 Arthritis of adjacent joints
 Clubbing of digits
Vascular & Haematologic Changes
 Nonbacterial thrombotic endocarditis: mucin-secreting adenocarcinoma
 Migratory thrombophlebitis (Trousseau sign): pancreas & lung cancer
 Disseminated intravascular coagulation: Acute promyelocytic leukemia,
prostate cancer
II. Spread of Cancer.
Local infiltration, invasion &
destruction to adjacent tissue
e.g., Breast cancer skin invasion
 Ulcer  Infection
Lung
Cough
Haemoptysis
Dyspnoea

Brain
Headache
Convulsion
Liver. Jaundice, hepatomegaly
Bone. Pain, fracture
Vertebral column – cancer thyroid & prostate
Staging has greater clinical value than grading

Staging based on Grading based on Histological Dx

Size of primary tumour Well differentaiated
Spread to regional lymph node Moderately differentaiated
+/- Metastasis Poorly differentaiated
 Laboratory Diagnosis of Tumours

1) Histologic Diagnosis
2) Cytologic Diagnosis
3) Immunohistochemistry
4) Blood film & Bone marrow examination
5) Tumour markers
6) Molecular diagnosis

Clinical data are invaluable for pathologic diagnosis

 Radiation  skin changes ~ cancer
 Healing fracture ~ osteosarcoma
1) Histological Diagnosis

 Specimen must be
adequate, representative &
properly preserved

 No area of haemorrhage
& necrosis

 Routine: Haematoxylin &

Eosin stain - Cancer cells
show features of anaplasia
2) Cytological Diagnosis

Cancer cells. less cohesive & shed into fluid or secretion

Fine needle aspiration of tumour

• Palpable organs: Breast, Thyroid
• Deep structures, using image guidance (USG):
liver, pancreas
• Natural body secretions:
urine (prostate, bladder), sputum(lung)

Cytologic smear - Papanicolaou smear: cervix cancer

3) Blood film & Bone marrow examination
Diagnosis of leukaemia & lymphoma
4) Immunhistochemistry

• Use specific antibody to detect cell products or surface markers

• Classify undifferentiated cancer (Diagnosis)
 Cytokeratin (+) Undifferentiated carcinoma & (-) Large cell lymphoma
• Detect the molecules that have prognostic or therapeutic significance
 Breast cancer: Estrogen receptor(+) Good prognosis & response to
hormonal Rx
 Her2/neu (+) : Ab block Her2/neu receptor
• Determine the site of origin of metastatic tumors
 Prostatic specific antigen (+): cancer prostate
5) Tumour Marker

Tumour associated enzymes, hormones, & other tumour markers in blood

 cannot be used for definite Dx of cancer

To determine effectiveness of therapy & appearance of recurrent

 Carcinoembryonic antigen - colon, stomach, pancreas cancer
 -fetoprotein - hepatocellular carcinoma
 Prostatic specific antigen - prostate cancer
 Human chorionic gonadotropin - testicular tumors
 CA-125 - ovarian tumors
6) Molecular Diagnosis

1) Diagnosis of cancer: BCR-ABL: leukaemia

2) Prognosis of cancer: HER-2/NEU: poor prognosis
3) Detection of minimal residual disease: BCR-ABL: leukaemia
4) Diagnosis of hereditary predisposition to cancer: BRCA-1 & BRCA-2
in Breast cancer
5) Guiding therapy with oncoprotein-directed drugs