Esa 2 Mod 4 - Neoplasm

Front 1

Define invasion.

Back 1

Invasion is the ability of cells to break through the basement membrane and then spread through the stroma. The cells either carry out direct invasion into surrounding tissue or into lymphatic/vascular channels. It is characteristic of malignant cells.

Front 2

Describe the mechanisms facilitating invasion and metastasis.

Back 2

1. Altered cell-cell interactions – no longer as many cadherins in between cells and catenins within cells, bound to the actin cytoskeleton. This causes loss of polarity of cell, nucleus no longer in correct position.
2. Altered cell – cell stromal interactions – integrins are cell surface glycoproteins, attached to basement membrane.
3. Altered enzyme synthesis – malignant cells release GFs which activate fibroblasts in stroma to secrete proteases – matrix metalloproteinases which bind to the malignant cells and modify the stroma, allowing the cells to invade. MMP 1 – breaks down type 1 collagen, MMP 2 & 9 – breaks down type 4 collagen.
4. Movement of tumour cells is helped by thymocin and hepatocyte growth factor
5. Cells then spread to distant sites via lymphatics, blood vessels and coelomic spaces and metastasise at sites which are suitable for their growth – ie correct receptors, allows angiogenesis and correct metabolic factors.

Front 3

Define metastasis.

Back 3

Metastasis is the spread of a malignant tumour to a distant organ via lymphatics, blood vessels and cavities. A metastasis is a secondary tumour and the site of origin of a tumour is the primary.

Front 4

Why can malignant cells metastasise to any organ?

Back 4

Malignant cells are selective as to where they grow.
They are selective due to :
• Incorrect receptors
• Metabolic factors
• Failure of angiogenesis  formation of blood vessels. Growth factors produced by cancer cells e.g. VEGF, can aid invasion. Angiogenic inhibitors try and stop this.

Front 5

Describe the routes of spread of malignant cells.

Back 5

Routes: Lymphatics, blood vessels, coelemic spaces (pleural cavity, peritoneal cavity)
Lymphatics
Spread to local and distant lymph nodes, frequent spread of carcinomas, can involve lymphatics of lung. Usually involved with breast and melanoma.
Vascular spread
Spread though capillaries and veins to various organs, common sites are lung, liver, bone and brain.

Front 6

List the common sites of origin of metastasis in the lung and why is the lung a common site of metastasis?

Back 6

Metastases in the lung are very common due to the fact they travel via the blood from primary tumours and blood passes twice through the lungs – pulmonary and systemic circulations.
- Sarcomas e.g. osteosarcoma
- carcinomas e.g. breast, stomach, large intestine
- kidney (cannon ball)
- testis eg malignant teratoma

Front 7

list the common sites of origin of metastasis in the liver.

Back 7

Liver
Common site for
- carcinomas of large intestine (linked to hepatic portal)
- bronchial carcinoma,
- Breast carcinoma.

Front 8

List the common sites of orgin of metasises of bones

Back 8

Bone – particular tumours love killing bone
Metastasis from these sites via blood vessels can cause destruction to bone and therefore increase serum calcium concentration.
- bronchial carcinoma
- breast carcinoma
- thyroid carcinoma
- Renal carcinoma.
Can cause production of dense bone: prostate

Front 9

List the sites of origin of metastases of the Brain.

Back 9

Can cause a wide range of symptoms - problems within the brain and the meninges and act as a space occupying lesion ( SOL)
- bronchial carcinoma
- breast carcinoma,
- testicular carcinoma
- malignant melanoma. Pneumonic: Bridget Bordeaux teased men.
Metastases spread via vascular system.

Front 10

What determines the effects of a tumour?

Back 10

In certain sites a small tumour can have devastating effects. Adversely people can survive a long time with very extensive metastatic spread. The extent of injury depends on:
- Site of primary tumour
- Extent of local spread
- Site of metastasis
- Extent of metastatic spread
- functional effects eg neuroendocrine function

Front 11

Describe the local effects of benign neoplasms.

Back 11

DON’T INVADE!
- Cause compression
 pressure atrophy – due to compression of blood vessels
 altered function eg pituitary glands – less hormone secretion
- In a hollow viscus ( organ that is not completely solid – lumen eg small/ large intestine, stomach, oesophagus) cause partial or complete obstruction by COMPRESSION of lumen.
- Ulceration of surface mucosa and bleeding – not as common as malignant.
- Space occupying lesion - brain

Front 12

Describe the local effects of malignant neoplasms

Back 12

INVADE
- Tend to destroy surrounding tissue.
- In a hollow viscus cause partial or complete obstruction and constriction by growing around lumen.
- Ulceration occurs.
- Infiltration around and into nerves, blood vessels and lymphatics.
- Space occupying lesion - brain

Front 13

Describe the Systemic effects of neoplasms

Back 13

Haematological
- anaemia – due to ulceration, infiltration of bone marrow, haemolysis
- Low white cell and platelets - infiltration of bone marrow, treatment
- Thrombosis – carcinoma of pancreas – trousseaus sign: blood clots in portal vessels break off to form DVT
Endocrine
- Excessive secretion of hormones- neoplasms of endocrine glands eg parathyroid glands –PTH- hypercalcaemia, adrenal glands: cortisol- cushings, pituitary gland: GH- acromegaly.
- Ectopic hormone secretion – ACTH, by small cell carcinoma of bronchus, parathyroid related hormone ( does everything EXCEPT activate C1 hydroxylase to convert 25 hydroxyvitamin d into calcitriol)
- Carcinoid syndrome – epithelial cells – well differentiated neuro-endocrine tumour – 5-HT- serotonin: flushing of skin and diarrhoea
Skin:
- Increased pigmentation – gastic, malignant melanoma
- Herpes zoster (shingles)– lymphoma, immunosuppressant drugs – chemotherapy
- Pruritis (itching) – Jaundice ( pancreas adenocarcinoma), hodgkin’s lymphoma.
- Dermatomyositis – rash of shawl like distribution - Bronchial carcinoma
Neuromuscular
- Sensory/sensorimotor neuropathies
- Myopathy and Myasthenia gravis
- Progressive multifocal leucoencephalopathy – viral, inflammation of white mater of brain at several locations
- May mimic metastasis to brain
- Problems with balance.
Largely unknown:
- Cachexia – severe weight loss and debility
- Malaise – weary
- Pyrexia – fever.

Front 14

WHY DO NEOPLASMS KILL PEOPLE?

Back 14

Local effects – raised intracranial pressure, perforation, haemorrhage
Systemic effects – replacement of essential body organs by neoplasm – bone marrow, lung tissue, liver, brain.

Front 15

What are the different forms of anaemia and how are they caused.

Back 15

Microcytic anaemia – small RBCs – ion deficiency – haemorrhage – neoplasms
Normocytic anaemia – decreased production of RBCs – leukaemia
Macrocytic anaemia – large RBCs – vitamin B12 and folate deficiency – seen in alcoholics as poor diet and in malabsorbtion – colon carcinomas

Front 16

Define catchexia.

Back 16

Catchexia is severe loss of weight, muscle atrophy, fatigue and loss of appetite in an individual that is not trying to lose weight. The loss of body mass cannot be reversed nutrionaly. Catchexia is a symptom of cancer, end stage, HIV, chronic obstructive pulmonary disease, congestive heart failure, metabolic acidosis, autoimmune diseases and drug addictions.

catchexia is mediated by tumour derived humeral factors that interfere with protein metabolism eg TNF

Front 17

Which altered gene is linked to famililal adenomatous polyposis.

Back 17

The alteration is in gene APC on chromosome 5 q 21 which codes for adenomatous polyposis coli a tumour suppressor protein.
Adenocarcinomas, polyps, occur throughout the colon and predispose patient to colonrectal cancer.
The alteration occurs in the germline of one of the patient’s parents.

Front 18

Which altered genes is linked to hereditary non-polyposis colon cancer HNPCC?

Back 18

HNPCC is associated with inherited mutations in DNA mismatch repair genes causing a microsatellite repeat replication error to go unrepaired. The replication error results in frameshift mutation that inactivates or alters tumour suppressor genes so that cancers can develop eg colon, ovarian and endometrium.
HNPCC is associated with right ascending mucinous adenocarcinomas through colon. NO POLYPS.
Microsatellites are repeated sequences of DNA. Microsatellite instability is where repeats or deletions go unrepaired resulting in longer or shorter microsatellites.
HNPCC is also called lynch syndrome.

Front 19

Which altered gene is linked to Li Fraumeni syndrome?

Back 19

Li fraumeni syndrome is linked to germline mutations in the p53 gene which codes for the tumour suppressor protein p53 involved in cell arrest, DNA repair and if failure of that apoptosis.
The mutation causes several types of cancer including breast cancer, brain cancer, acute leukaemia, soft tissue sarcoma and osteosarcoma.

Front 20

Which altered gene is linked to familial breast/ovarian cancer?

Back 20

The genes involved with familial breast/ovarian cancer are the mutated BRCA 1 and 2 genes, tumour suppressor genes. The mutation can cause breast cancer in men as well as in women.

Front 21

Which altered gene is linked to familial retinoblastoma?

Back 21

Retinoblastoma is a tumour of the retina in children and can be bilateral and in teenagers can cause osteosarcoma.
The mutated gene is the tumour suppressor gene, retinoblastoma which codes for a protein that decides whether a cell enters the next phase in the cell cycle eg at G1 checkpoint. To be activated cyclin dependent kinases phosphorylate the protein.

Front 22

Describe the functions of oncogenes and tumour suppressor genes and the changes which occur in neoplasia.

Back 22

proto-oncogenes code for proteins which regulate cell growth eg signal transductors, transcription factors, growth factor receptors. Oncogenes are the mutated form of proto-oncogenes and increase the production of these proteins thus pre-disposing to cancer. Oncogenes are dominant, gain-in-function mutations.
Tumour suppressor genes code for proteins which inhibit cell growth by causing cell arrest, DNA repair and if DNA repair fails apoptosis. Mutated tumour suppressor genes are inactivated and so genes are not activated. They are recessive, loss in function mutations that follow the 2 hit hypotheses. In order for mutation to take full effect both alleles must be mutated.

Front 23

Describe the role of certain oncogenes.

Back 23

C myc: is a transcription factor which binds to DNA to stimulate transcription. Amplified number of c myc in neuroblastoma and breast cancer. In burkitt’s lymphoma translocation of chromosome 8 to 14 causes inappropriate transcription, and then is Epstein barr virus causes further mutations leading to cancer.
Ras: is a signal transductor and so when mutated continuously stimulates cell without the activation of growth factors. This mutation is found in colon and lung cancer.
Her 2: is a growth factor receptor and so in mutated form over expression of the receptor is seen in neuroblastomas and in breast cancer. Herceptine is a drug which is given to treat breast cancer by binding to HER 2 and preventing activation leading to proliferation.

Front 24

Describe the role of certain tumour suppressor genes.

Back 24

Retinoblastoma is found in G1 checkpoint ( RESTRICTION POINT) where the cell in the cell cycle is arrested and the DNA is checked for mutations before being allowed to enter S phase. If the DNA is mutated it is either repaired and then retinoblastoma is activated by cyclin dependent kinases which phosphorylate it and allows the cell to continue in the cell cycle. If the DNA is not repaired then it enters apoptosis.
P53 gene codes for a protein which binds to and modulates expression of genes important for cell cycle arrest, DNA repair and apoptosis.
- Radiation, free radicals, chemicals cause DNA damage -> increased p53 protein -> cell cycle inhibitor increased -> growth arrest -> DNA repair or apoptosis.
If homozygous for mutated rb or p53 then DNA damage is unrepaired and mutations become fixed. A clonal expansion of monoclonal mutated cells -> extra mutations – no longer clonal, sub clonal -> DNA is unstable.

Front 25

Describe the stages of carcinogenesis.

Back 25

Carcinogenesis is not just an alteration to one gene but an accumulation of alterations and many factors are involved. This is why a long time elapses between exposure to stimulus and appearance of clinical cancer.
1. Initiation: exposure to initiator ( carcinogenic agent) causes genetic abnormality which is not itself sufficient to cause abnormal growth. However, it makes cell more susceptible to developing neoplasia if later exposed to promoting agents as it is permanently genetically altered.
2. Promotion: prolonged exposure of initiated cell to promoting agents induces cell proliferation and leads to secondary genetic abnormalities in key genes regulating cell growth eg oncogenes
Promoting agents have NO effect on normal cell, only initiated cell. Transient exposure of promoter will have no effect, must be prolonged to allow adequate proliferation to cause secondary abnormality.
3. Progression: proliferation continues and increases number of mutated cells forming a monoclonal expansion. Eventually further mutations arise producing sub-clone.
4. Development of neoplasm.

Front 26

Describe the types of cancer caused by radiation disasters – Hiroshima and Chernobyl.

Back 26

Hiroshima – survivors of atomic bombs dropped, suffered from leukaemia and solid tumours eg breast, colon, thyroid and lung 17 years after exposure. Leukaemia arose first because haemopoetic cells are labile and so have a high proliferative rate compared to stabile cells.
Chernobyl – radiation caused thyroid cancers due to mutated ret oncogenes.

Front 27

Describe 2 situations where radiation was used for treatment in non neoplastic conditions and the results of this.

Back 27

Radiation of the neck in children suffering from thymic asthma caused thyroid carcinoma.
Radiation of spine in ankylosing spondilitis ( fused vertebrae) caused damage to bone marrow leading to leukaemia.

Front 28

Describe why radiologists used to get cancer and why.

Back 28

Radiologists used to test X RAYS ( ionising radiation) on back of hand resulting in squamous cell carcinoma.

Front 29

Describe the differences in squamous cell carcinoma, basal cell carcinoma and malignant melanoma.

Back 29

Squamous cell carcinoma – proliferation of superficial squamous cells causing pink appearance in slides, keratin produced, more dangerous as metastasis. Thickness of carcinoma is important – thick is bad, thin is okay.
Basal cell carcinoma – proliferation of bottom layer of epidermal – basal cells causing ulceration and mainly local spread and very rarely metastasise. The appearance in histiological slides is blue.
Malignant melanoma – proliferation of melanocytes found in basal layer of epidermis as well as surrounding hair follicles. The tumour will show brown pigment – moles. Metastasise anywhere!!! Bad diagnosis – if basement membrane is penetrated.

Front 30

What is the result in prolonged UV radiation? Who is more susceptible to it?

Back 30

Malignant melanoma or basal cell carcinoma
Occupational factors eg agricultural workers more at risk
Increased incidence due to use of sun beds and more trips abroad.
Retinitis pigmentosa - increased risk to cancer from UV radiation due to failure of DNA repair - inherited susceptibility

Front 31

Describe how chemical carcinogens interact with DNA and how and where they act.

Back 31

Carcinogens may cause specific base damage or single strand breaks. The damage may be repaired imperfectly.
Some chemicals act directly while others need to be converted to an active form.
If the enzyme for conversion to active form is found everywhere, then tumours occur at site of entry but if enzymes are confined in certain organs the tumours will occur there.

Front 32

Describe the effects of polycyclic hydrocarbons.

Back 32

The most important polycyclic hydrocarbon is 3,4 benzypyrene that is produced in combustion of tobacco and fossil fuels. It is converted to active form by hydroxylation and causes lung cancer, bladder cancer and skin cancer. It inactivate p53- tumour suppressor gene.
In the past chimney sweeps developed scrotal cancer as the soot went down their trousers – occupational risk.

Front 33

Name types of lung cancer.

Back 33

Small cell carcinoma – release of ACTH
non small cell carcinoma
-> adenocarcinoma
-> squamous cell carcinoma
-> large cell carcinoma

Front 34

Describe the effects of aromatic amines.

Back 34

The most common aromatic amine which is a carcinogen is beta napthylamine. Beta napthylamine is hydroxylated in the liver to 1 hydroxy 2 napthylamine and then conjugated with glucuronic acid (non-toxic). However the non toxic form is then deconjugated to active form in the urinary tract by urinary glucuronidase.
Occupational risk – found in rubber and dye workers and increases risk of bladder cancer.

Front 35

Describe the effects of nitrosamines? How have the effects been proved?

Back 35

Animal experiments have proved that conversion of dietary nitrates/nitrites to nitrosamines by gut bacteria leads to GI cancer.

Front 36

Describe an alkylating agent.

Back 36

Nitrogen mustard binds directly to DNA.

Front 37

Which virus causes burkitt’s lymphoma?

Back 37

Epstein barr virus which is a member of herpes virus.
Malaria is believed to activate the EB virus.
Burkits lymphoma is associated with the reciprocal translocation of the c myc gene at chromosome 8 q 24 to chromosome 14

Front 38

Which virus and toxin causes liver cell carcinoma?

Back 38

Hepatocellular carcinoma.
Hepatitis B – viral DNA integrates into host cell and causes liver cell injury an regenerative hyperplasia with increased risk of genetic changes. It also disrupts normal growth control.
Aspergillus is yeast which is breathed in and causes bronchopulmonary allergic aspergillosis, narrowing of airways, and can invade cavities from primary tb or bronchictasis producing an aspergiloma ( fungal ball). It releases alfratoxins which can cause acute hepatic necrosis resulting in later cirrhosis and or hepatocullular carcinoma

Front 39

Which virus is associated with cervical carcinoma?

Back 39

Human papilloma virus eg 16 and 18 are high risk HPV and associated with cervical cancer. HPV genes disrupt normal cell cycle and extend life span of genital epithelial cells so more likely for mutation to occur.

Front 40

What does asbestos do?

Back 40

Asbestos can cause malignant mesothelioma – cancer of pleura and lung cancer

Front 41

What can cause bladder cancer?

Back 41

Schistosoma a fluke flatworm can cause bladder carcinoma. This is due to male and female adult worms in permanent copulation in the superior, inferior mesenteric veins or venous plexus, constantly producing eggs. These eggs are excreted in faeces and urine and eventually cause fibrosis of the bladder which can cause cancer. Other causes include occupational hazards such as working in rubber and dye factories.

Front 42

How can hormomes cause cancer, give an example.

Back 42

Long exposure of oestrogen eg early period and late menopause also if you haven’t had children or breast fed can increase risk of breast carcinoma.

Front 43

What can helicobacter pylori cause?

Back 43

Chronic gastritis which can lead to gastric cancer.
Lymphoma

Front 44

Give some medical conditions conditions which can lead to cancer.

Back 44

Ulcerative colitis -> colorectal carcinoma, DNA damage and microsatelitie instability leading to inactivation of tumour suppressor genes -> bleeding and ulceration are symptoms of UC and cancer so masks symptoms of cancer
Cirrhosis – present in 90% of hepatocellular carcinoma, cirrhosis can be caused by hepatitis/ alcohol/ drugs.
Adenoma of colon/rectum -> adenocarcinoma
Hashimoto’s thyroiditis – associated with non-hodgkin’s lymphoma
Chronic atrophic gastritis – triggered by helicobacter pylori – increased risk of gastric adenocarcinoma.

Front 45

Describe geographical variations in the incidence of malignant tumours.

Back 45

Burkitt’s lymphoma is mainly seen in Africa – Epstein bar virus activated by malaria.
Gastric cancer is mainly seen in japan due to low fibre diet - high fibre is protective!!
Breast cancer risk is increased in women who do not have children, or do not breast feed, or have early period or late menopause – long exposure to oestrogen.

Front 46

describe the symptoms associated with pancreatic cancer.

Back 46

Pancreatic cancer can cause jaundice ( conjugated bilirubin - urobilogen) if it is a cancer of the head of the pancreas ( 90% are) as it obstructs the common bile duct as the major pancreatic duct and common bile duct enter into the 2nd part of the duodenum at the duodenal papilla - ampulla of vater.
Pancreatic cancers cause thrombosis - trousseau sign - blood clots in portal vessels or deep veins.
Can cause diabetes melitis
Steatorrhea - if pancreatic enzymes are not released.
May be of the exocrine or endocrine.
endocrine release hormones.

Front 47

What is carcinoid tumour?

Back 47

Carcinoid syndrome - epithelial cells - well differentiated neuro-endocrine tumour which releases 5HT (serotonin)

Front 48

What causes bladder cancer?

Back 48

Schistosoma - a parasite
working in rubber or dye factories - aromatic amines present eg beta naphylamine.
Beta naphylamine is hydroxylated in the liver to 1 hydroxy 2 naphylamine and then conjugated with glucuronic acid. It is deconjugated in the urinary tract by urinary glucuronidase.

Front 49

What does a small cell carcinoma secrete?

Back 49

ACTH

Front 50

What is c-myc?

Back 50

C-myc codes for a transcription factor that binds to DNA in promoter sequence, upstream from ORF, triggering transcription.
C-myc is a proto-oncogene which when mutated becomes an over expressed oncogene, causing increased transcription.
It is found in burkitt's lymphoma translocated from 8 q 24 to chromosome 14 caused by epstein barr virus.
It is also present in neuroblastomas and breast carcinomas

Front 51

What is a neuroblastoma?

Back 51

A neuroblastoma is a neuro-endocrine tumour

Front 52

What is ras?

Back 52

Ras is a proto-oncogene coding for signal transductors. When mutated the oncogene produces signal transductors without stimulation from growth factors.
Ras mutations are seen in colon and liver cancer.

Front 53

What is HER-2?

Back 53

HER-2 is a gene coding for growth receptors. The mutated oncogene over expresses HER- 2. They are found in breast cancers and can be treated by herceptin. They are also found in neuroblastomas.

Front 54

Describe intrinsic factors increasing risk of carcinogenesis.

Back 54

Intrinsic factors:
- Inherited susceptibility
- Age – cumulative exposure to carcinogens, increased chance of mutations with age
- Immune status
- Hormones – longer oestrogen exposure ( early period or late menopause), not having children or not breast feeding

Inheritance
Inherited conditions which predispose to the development of tumours – relate to DNA repair.
Inherited susceptibility to development of a tumour or a group of tumours due to alteration of one or more genes.

Front 55

Describe extrinsic factors increasing risk of carcinogensis.

Back 55

Extrinsic factors:
- Radiation
- Chemicals
- parasites and viruse

Front 56

Give examples of inherited susceptibility to the development of tumours due to defects in DNA repair mechanisms.

Back 56

- retinitis (xeroderma) pigmentosa
- ataxia telangiectasia
- fanconi's anaemia

Front 57

What is retinits pigmentosa?

Back 57

Retinitis (xeroderma) pigmentosa is an inherited susceptibility to malignant melanomas and basal cell carcinomas as when exposed to UV rays they don’t repair aswell after UV damage.

Front 58

What is ataxia telangiectasia?

Back 58

Ataxia telangiectasia a neurodegenerative disease which is an inherited susceptibility to lymphomas. Ataxia = poor co-ordination and telangiectasia = small dilated blood vessels. It is caused by defective response to radiation damage which increases susceptibility to lymphoid malignancies. Sufferers usually die before 20 years old.

Front 59

What is fanconi's anaemia?

Back 59

Fanconi’s anaemia is a genetic defect in DNA repair protiens resulting in most patients having acute myelogenous leukaemia. It also causes bone marrow hypofunction - results in impaired ability to make RBCs ( anaemia). Predisposition to cancer.