Neoplasia

Dr D S O’Briain

April 2008

Neoplasm

• 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 (Willis 1952)

Cancer vocabulary

• Neoplasia (G): neo—new; plasia—growth• Tumor (L): swelling• Oncos (G): mass, bulk (oncology)• Cancer (L): crab• Karcinos (G): crab (carcinoma)• -oma (G, L): tumour• Sarx, sarcos (G): flesh• Metastasis (pl -es): meta—change; stasis—standing• Adena (G): gland (adeno-)• Squama (L): skin scale (squamous)

Cellular dysplasia

• Nuclear size enlarged, variable

• Chromatin increased, variable

• Nucleolus enlarged, malformed

• Mitoses increased, abnormal

• Nucleus/Cytoplasm increased ratio

Differentiation

Resembles adult tissue in

• Cell morphology

• Architecture

• Function

Benign vs malignant neoplasms

Property Benign Malignant

Differentiation Well

(like normal)

Well—poor, anaplasia

Growth Slow,

rare mitoses

Varies, mitoses rare—frequent

Local invasion None (expansile)

Expansile— infiltrative

Metastasis Absent Absent—present

Growth and proliferation

Cell proliferation/growth,

Regeneration (repair)

Hyperplasia

Tumour

Purposeful Purposeless

Physiological stimuli ? Stimuli

Feedback control Reduced/absent feedback control

Reversible Irreversible

Beneficial deleterious

Grading and staging of tumours

Grade:• cytological differentiation, mitotic rate, grade I-IV • Well, moderately, poorly differentiated• Low, intermediate, high grade lymphoma

Stage:• Size of primary tumour, extent of spread• TNM (tumour, node, metastasis)• Stage I-IV (lymphoma, carcinoma; criteria defined for

each form of neoplasm)

Major tumour categories

Tissue Benign Malignant

Epithelial Adenoma, papilloma Carcinoma

Connective Tissue -oma Sarcoma

Neuroectodermal Schwannoma Glioma, melanoma

Haemopoietic — Lymphoma, leukaemia

Germinal tissue Teratoma Embryonal carcinoma

Epithelial tumoursBenign: • papillomas, adenomas (polyp), tubulovillous

Malignant: stroma (desmoplasia), scirrhous (hard), encephaloid, medullary (soft)

• Adenocarcinoma; mucinous, papillary, cystadenocarcinoma (renal, hepatic)

• Squamous (contains keratin pearls, prickles) carcinoma• Basal cell, transitional cell, clear cell carcinomas• Endocrine (carcinoid, islet cell tumour, small cell carcinoma)

Connective tissue neoplasms

Leiomyoma Leiomyosarcoma

Rhabdomyoma Rhabdomyosarcoma

Lipoma Liposarcoma

Fibroma Fibrosarcoma

Chondroma Chondrosarcoma

Osteoma Osteosarcoma

Synovioma Synovial sarcoma

Angioma Angiosarcoma

Neuroectodermal tumours

Central• Glial: astrocytoma, oligodendroglioma,

ependyoma• Neural: medulloblastoma, neuroblastoma,

ganglioneuroma, meningomaPeripheral• Schwannoma, Neurofibroma, • Naevus, Melanoma

Leukaemia and lymphoma

Lymphoma: solid tumours of lymphoid tissueLeukaemia: blood and bone marrow involvement (some overlap between lymphoma and leukaemia types)

Lymphoma: (low, high grade, B and T cell)• Hodgkin lymphoma, • non- Hodgkin lymphoma Leukaemia: • acute myeloid, acute lymphoid• Chronic myeloid, chronic lymphoid

Germinal tumours

• Teratoma:

Benign: mature, cystic

Malignant: malignant, embryonal carcinoma, choriocarcinoma

• Seminoma, germinoma

• Sex cord stromal tumours

• Placenta: hydatidiform mole, choriocarcinoma

Mixed tumour

Not germinal tumours

• adenosquamous carcinoma,

• fibroadenoma, carcinosarcoma, mixed mullerian tumour

• pleomorphic adenoma

• paediatric blastomas

• metaplastic tumours

• collision tumours

Effects of cancer

• Damage or obstruct critical structures (location)

• Infiltrates nerves—pain

• Functioning activity (hormones)

• Bleeding

• Ulcerate—infected

• Infarct

• Cachexia and paraneoplastic effects

Spread of Cancer• Expansion—compression of surrounding tissue—formation of

(pseudo)capsule• Local invasion (infiltrative)

Follows line of least resistanceDamages surrounding tissueAlters function of tissueMakes excision difficultCauses pain (nerve invasion)

• Lymphatic spread: permeates lymphatics, metastasizes to node• Haematogenous spread: anatomical (portal/systemic) retrograde,

venous• Intracavity: meningeal, serosal cavities• Recurrence: residual tumour, second primary

Site of metastases

Anatomic factors• Sarcoma ˛ lung ˛ general circulation• Carcinoma ˛local lymph nodes ˛ lung, bone, brain• GI primary ˛ liver• Prostate, breast ˛ local venous plexus• Ovary ˛ peritoneumHumoral factors (homing, soil)• Local; preferential adhesion, preferential growth, local

diffusion of attractants (migratory directors)

Metastases—metastatic cascade

• 70% of newly diagnosed cancers have metastases• Millions of tumour cells circulate daily• Less than 0.01% initiate colonies

1. Adhere to endothelium: fibrin platelets, clotting factors, receptors basement membrane

2. Dissolve basement membrane: proteases, collagenases IV, cathepsins

3. Locomotion: initiation (random), directed by autocrine and host growth factors

Paraneoplastic effects

• Endocrinopathies: Cushings syndrome, hyponatremia (SIADH), hypercalcemia, hyperthyroidism, hypoglycemia

• Neuromuscular: cerebellar ataxia, Eaton Lambert syndrome

• Skin disorders: acanthosis nigricans, dermatomyositis

• Blood/vascular: venous thrombosis, DIC, marantic endocarditis, cytopenias, cythemias

• Kidney: renal failure, nephrotic syndrome

• Extermities: digital clubbing, hypertrophic osteoarthropathy

Tumour markers

Class Type Tumour

Antibodies Protein M band Myeloma, lymphoma

Antigens (oncofetal) Carcinoembryonic antigen Colon Ca, others

Alpha-fetoprotein Germ cell tumour, liver Ca

Prostate specific antigen Prostate carcinoma

Hormones HCG Germ cell

Calcitonin Medullary carcinoma thyroid

Ectopic ACTH, ADH Lung Ca, others

Enzymes Acid phosphatase Prostate Ca

Cancer incidenceTwo-thirds of cancer occurs in 5 sites (for each sex)

Rates vary geographically and with time

Because of different survival rates, these incidence figures do not correspond to cancer deaths by site

Other prominent sites: cervix, ovary, stomach, oesophagus, pancreas, kidney,skin

Females (%)• Breast 26

• Colorectal 15

• Lung 10

• Endometrium 9

• Leuk/lymphoma 8

Males (%)• Lung 22

• Prostate 18

• Colorectum 14

• Leuk/lymphoma 8

• Bladder 7

Cancer incidence—secular changes

Increasing• Lung• Pancreas• (Cervix, ovary,

leukaemia)

Decreasing• Stomach• Endometrium• Liver• Colorectal (females)

Cancer deaths (per 100000) geographic variation

Tumour High incidence

Rate Low incidence

Rate

Colorectal Hungary 36 Mexico 5

Lung Hungary 84m/22f Mexico 17m/7f

Ireland 38m/18f

Breast Ireland 26f China 6f

Cervix Zimbabwe 43f Australia 3f

Stomach China 33m/15f USA 4m/2f

Prostate Norway 28 China 1

Oesophagus China 22m/10f Greece 1m/0.4f

Cancer incidenceMortality by age group

Age Relative incidence Tumour

0-15 1.0 Leukaemia, CNS

(bone, soft tissue, kidney)

15-34 2.5 Leukaemia, CNS, breast, lymphoma (testis, uterus, skin)

35-54 25 Lung, breast, colorectal (uterus, ovary, CNS, pancreas, leukaemia)

55-74 75 Lung, colorectal, breast, prostate

(pancreas, ovary, stomach, uterus)

75+ 50 Colorectal, lung, prostate, breast

(pancreas, bladder, uterus)

Cancer in Ireland—rank among 50 countries (age adjusted death rates per 100 000 population (2002)

Site Female

Rank Incidence

Male

Rank incidence

All sites 6 124 18 168

Breast 3 26

Liver 42 2 42 3

Colorectal 12 14 5 24

Oesophagus 8 4 11 8

Lung 8 18 27 38

Prostate 14 20

Stomach 34 5 38 9

Uterus 40 2

What is meant by cancer cure?

• Optimal result: remission of disease, absence of relapse, good quality of life, normal life expectance, death from another cause

In practical terms cure is expressed by:• Mean survival (average duration of survival—for all patients, or by

stage)• 1 year (or 5 year, 10 year) survival—for all or by stage• Actuarial correction (correct for age related mortality) Kaplan Meyer

curveOther parameters: disease free survival, quality of life, disease or therapy

related morbidity, death from other causes• Spontaneous remission, miracles

Cancer therapycurative—palliative

Surgery Conservative—radical

Debulking, limb sparing, organ transplant

Radiotherapy External, implant

nuclides

Chemotherapy Single agent—combination

Induction—maintenance

Other forms Immunotherapy, novel forms, alternative therapy

5-year survival (all stages)

• <20% group: liver (3%), pancreas (3%), oesophagus (6%), lung (13%), stomach (16%)

• 20-40% group: brain (22%), myeloma (24%), leukaemia (34%), ovary (37%)

• 50% group: colorectal, kidney, oral cavity/pharynx, non-Hodgkin lymphoma

• 75% group: breast, prostate, cervix, larynx, Hodgkin lympoma, bladder, melanoma, endometrium, (testis, thyroid)

Cancer screening

Consider Whole population or age/sex groups, high risk groups, family groups, individuals, role of education

Cervix Papanicolou smears

Colon Occult blood, colonoscopy

Breast Self examination, mammography

Melanoma Skin observation

Stomach endoscopy

Cell cycle

G0 ˛ G1 ˛ S ˛ G2 ˛ M ˛ G0

˛ Terminal differentiation

˛ Apoptosis

Rate of proliferation(rate of entry to cycle)x (duration in cycle)x(cell loss)

Assume a 10 um cell

30 doublings 109 cells—1 g

40 doublings 1012 —I Kg

Clonality

• A population of cells may represent the progeny of one (monoclonal) or many (polyclonal) stem cells

• Markers such as G6PD (in female heterozygotes), kappa or lambda light chains, or specific B or T cell receptor rearrangements are found in a proportion of cells in a polyclonal population but in all the cells in a monoclonal population

• Monoclonality implies a neoplastic proliferation

Cancer; a disease caused by alteration of a cell’s genes

Gene categories

• Proliferation

• Suppressor

• Apoptosis control

• DNA repair

Proto-oncogenes

Cell growth and proliferation involve:

• External factors (first messengers) which bind receptor—transmembrane signal conduction

• Signal is transmitted to nucleus by second messenger

• DNA transcription begins, leading to cell division

Proto-oncogene products are involved in all of these reactions

Activation of proto-oncogenes

• Proto-oncogenes are part of the normal genome and under normal control

• When activated they are termed c-onc (they have introns and exons)

• Identical or similar genes occur in viruses (v-onc) these have only exons

• Gene function altered by: Point mutation, Chromosome translocations, Gene amplification, Deletions, Altered expression: eg methylation

Retrovirus

3 types of oncogenic retrovirus1) acute transforming

2) slow transforming

3) human T cell leukaemia virus

Oncogenic DNA viruses

Produce transforming proteins—

Human papilloma virus (HPV): about 40 types skin warts (benign), condylomas (venereal warts, benign) verrucous

carcinoma, carcinoma of cervix, penis

Herpes virus• Epstein Barr virus: infectious mononucleosis, Burkitt lymphoma, Hodgkin

lymphoma, nasopharyngeal carcinoma HHV8: kaposi sarcoma

Tumour suppressor genesRetinoblastoma gene (13q14) suppresses tumour formation.

P53 (17q13)—the guardian of the genome• It senses DNA damage and slows the cycle to allow repair;

• if repair fails it induces apoptosis

Apoptosis genes

• Loss of apoptosis leads to cell accumulation

• Bcl-2 anti-apoptosis

• Bax pro-apoptosis

DNA repair genes

These repair errors in DNA transcription

• Hereditary non-polyposis colon carcer (usully right colon tumours)

• (important in these rare disorders: xeroderma pigmentosum, Bloom’s syndrome, ataxia telangiectasia, Fanconi anaemia

Cancer aetiological factors

• Smoking

• Diet

• Environment

• Hormonal agents

• Age

Canceraetiological factors

Observed factors

• Smoking

• Diet

• Environment

• Hormonal status/gender

• Age

• Genetic

Aetiology

• Chemical

• Radiation

• Virus

• Genetic– Oncogenes

Cancer—chemical inductionPott—scrotal carcinoma in sweeps

coal tar—skin cancer

Polycyclic aromatic hydrocarbons

Benzpyrene

Heterocyclic hydrocarbons Aflatoxin

Aromatic amines Azo dyes

Nitrosamines

Metals Ni, Pb, Cd, Co, Ba

Physical carcinogenesis

• Radiation– UV light 290-320 nm

• Asbestos, a fibrous silicate: mesothelioma, lung carcinoma

Radiation and cancerNeoplasm AssociationThyroid Thymic radiation, atom bomb

Leukaemia Atom bomb, radiologists, Rx ankylosing spondylosis

Breast Atom bomb, radiotherapy, mammography

Skin Radiologists

Liver Thorium dioxide

Lung Uranium miners

Bone Radium dial painters

Controversy Low level radiation, paternal radiation, radon gas