9. Neoplasia 2 Flashcards
(87 cards)
1
Q
5 developments of cancer
A
- Normal
- Hyperplasia
- Mild dysplasia
- Carcinoma in situ
- Cancer – invasive
= malignant tumour
2
Q
Giloma survival
A
• Severity of changes determines chances of survival in patient
Cells go from full differentiate state ---> embryonic stage of de differentiated cells • Cells that are fully differentiate = better chance of survival
3
Q
Cancer - definition
A
• Cancer defines as a population of cells that have lost their normal controls of growth and differentiation and are proliferating without check. - lost control of cell cycle
4
Q
Metastasis
A
• 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 in a different site of body
5
Q
Metastasis - steps (general)
A
- Carinoma in situ – cells on basement membrane that have lost control of cell cycle
- Invasive carcinoma – break through basement membrane
- Transport through circulation
- Extraversion – cells leave circulatory system
- Form micrometastasis - tiny clusters of tumour cells that settle and wait
- Colonization to form macrometastasis
6
Q
5 major steps in metastasis
A
- Invasion and infiltration of surrounding normal host ‘ tissue with penetration of small lymphatic or vascular channels;
- Release of neoplastic cells, either or single cells or small clumps, into the circulation;
- Survival in the circulation;
- Arrest in the capillary beds of distant organs;
- Penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells
7
Q
3 broad Stages of metastasis
A
Invasion
Circulation
Colonisation
8
Q
Invasion
A
• Invasion : primary tumour cells enter circulation
9
Q
Circulation
A
• Circulation to the secondary site of tumour growth
10
Q
Colonisation
A
• Colonisation : formation of secondary tumour
—> cells look for a specific conductive Environnement
• So they can grow
11
Q
3 tissues in organs
A
- Epithelial cells
- Connective tissues
- Muscle cells
12
Q
How do cells become invasive
A
—> must pass through basal laminar and connective tissue
• Cancer cells need to change their epithelial properties, to lose their adhesion and to penetrate through potent physical barriers
○ Cells need to acquire abilities through mutations to become invasive
13
Q
EMT = Epithelial to Mesenchymal Transition
A
—> under normal physiological circumstance – epithelial cells used to create mesenchymal tissue, mesenchymal tissue can help metastatic cells colonise.
14
Q
3 steps of Tumor invasion
A
- Translocation of cells across extracellular matrix barriers
- Lysis of matrix protein by specific proteinases
• Punch holes through basal layer with enzymes - Cell migration
15
Q
3 Components of invasion
A
a) Matrix degrading enzymes
b) Cell adhesion
c) Cell motility
16
Q
a) Matrix degrading enzymes
A
—> can be used to help penetrate – punch holes in the basal membrane
- Required for a controlled degradation of components of the extracellular matrix (ECM)
- The proteases involved in this process are classified into serine‐, cysteine‐, aspartyl‐, and metalloproteinase. - need metal ions for function
• These can cleave proteins- break proteins in basal layer
17
Q
Matrix metalloproteinases (MMP)
A
- 20 members, subdivided into 4 groups, based on their structural characteristics and substrate specificities
- A zinc ion in the active centre of the protease is required for their catalytic activities
18
Q
2 types of Matrix metalloproteinases (MMP)
A
- Soluble and secreted groups; collagenase, gelatinase and stromelysins
- Membrane type (MT-MMP) group are anchored in the plasma membrane - sitting on the membrane
19
Q
Regulation of MMP
A
- MMP is controlled by an increased expression on a transcriptional level.
- MMPs are calcium-dependent proteases, which are synthesized as a inactive proenzymes and are activated by the cleavage of a propeptide.
- MMP activity is regulated by specific inhibitors, the tissue inhibitors of MMP (TIMPs). Binding TIMP to MMP is in a 1:1 stoichiometry.
- MMP2 and MMP9, which cleave type IV collagen the major constituent of basement membrane, are believed to be of special importance
20
Q
TIMPs
A
• MMP activity is regulated by specific inhibitors, the tissue inhibitors of MMP (TIMPs). Binding TIMP to MMP is in a 1:1 stoichiometry.
21
Q
MMP roles
A
• MMPs (matrix metalloproteinases) help the cancer cells to invade the ECM
22
Q
Cell adhesion/ attachment
A
—> detacth cells from other cells and from basal laminar by destroying the connections below
- Integrin: cell‐matrix adhesion – anchor cell to basement membrane
- E‐cadherin/catenin adhesion complex: cell‐ cell adhesion – cell to ceel connection
23
Q
Integrin
A
- Heterodimeric transmembrane receptors consists of alpha and beta subunits
- Function to provide interactions between cells and macromolecules in the ECM (basement membrane)
- Integrin can affect the transcription of MMP genes
24
Q
E‐cadherin and catenin complex
A
- Most important cell‐cell adhesion molecules
* Reduce expression of E‐cadherin and catenin increase the invasiveness of tumor cells
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Cell motility/ migration is regulated by
1. Small Rho GTPase family
| 2. Motility promoting factors – that regulate small rho gtpases
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Cell crawling
• Cells must crawl – resynthesis cytoskeleton in the cell
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Small Rho GTPase
* Regulated by other regulating proteins that can switch GTP --> GDP
* Many physiological processes require GTP
Regulated by protein phosphorylation via kinases
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Motility promoting factors
* Hepatocyte growth factor/scattering factor
* Insulin‐like growth factor II
* Autotaxin
Improve cell movement
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3 routes of metastasis
* Lymphatics
* Blood vessels
* Coelemic spaces
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LYMPHATICS
* Spread to local and distant lymph nodes
* Frequent route of spread of carcinomas
* Can involve lymphatics of lung
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VASCULAR SPREAD
* Spread through capillaries and veins to various organs.
| * Common sites are lung, liver, bone and brain.
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Intravasation
• Travel back of out blood to other locations to settle down
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How is the blood a hostile environment
‐ Cells are normally anchorage‐dependent (anoikis)
‐ Shear forces tear cells apart
• Environment = mechanical forces can kill cells
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Metastatic tropism
Where the cells travel during metastasis is normally random
| But different preferences for different tumours
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Dormant metastases
---> dormant = metastases that do nothing for many years
| Eventually form macrometastasis
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WHY DON’T ALL MALIGNANT CELLS METASTASISE?
Cells may invade and circulate.
• May get to distant site but environment may not be appropriate for growth of those cells.
• Incorrect receptors
• Metabolic factors
• Failure of angiogenesis “Seed and Soil
Low probability that the cell will have all these mutations and can still survive to metastasise
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WHAT EFFECTS DO TUMOURS HAVE?
```
Depends on:
• site of tumour
• extent of local spread
• site of metastasis
• extent of metastatic
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LOCAL EFFECTS OF NEOPLASMS- BENIGN
Cause compression
‐ pressure atrophy
‐ altered function eg. pituitary
* In a hollow viscus cause partial or complete obstruction.
* Ulceration of surface mucosa.
* Space occupying lesion – brain.
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LOCAL EFFECTS OF NEOPLASMS- MALIGNANT
* Tend to destroy surrounding tissue.
* In a hollow viscus cause partial or complete obstruction, constriction.
* Ulceration.
* Infiltration around and into nerves, blood vessels, lymphatics.
* Space occupying lesion ‐ brain
40
SYSTEMIC EFFECTS OF NEOPLASMS - Haematological
Anaemia
– due to ulceration (benign and malignant ) or internal bleeding
– infiltration of bone marrow (leukaemia, metastasis)
– haemolysis
Low white cell and platelets
– infiltration of bone marrow, treatment
Thrombosis
– carcinoma of pancreas
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SYSTEMIC EFFECTS OF NEOPLASMS Endocrine
• Excessive secretion of hormones
‐ benign and malignant neoplasms of endocrine glands e.g.parathyroid hormone, corticosteroid
• Ectopic hormone secretion
‐ ACTH by small cell carcinoma of bronchus
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SYSTEMIC EFFECTS OF NEOPLASMS – Neuromuscular
* Problems with balance.
* Sensory/sensorimotor neuropathies.
* Myopathy and myasthenia.
* Progressive multifocal leucoencephalopathy.
* Not due to metastasis to brain.
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WHY DO NEOPLASMS KILL PEOPLE?
* Local effect e.g. brain, perforation, haemorrhage Benign or malignant
* Replacement of essential body organs Malignant
Many combined effects of tumour can kill patient
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---> histogenic calasification of neoplasms
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Connective tissues
Haemopoietic
Melanoma
Germ cell
Epithelail origin tumours – carcinoma
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Classification of tumours
* Oma = tumour (bening or malignant)
* Carcinoma = epithelial malignancy
* Sarcoma = connective tissue malignancy
* Aemia = maliognancy of bone marrow derived cells (exceptions e.g. anaemia
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Treatment for malignant neoplasia
• NOT always surgery
Example treatments
• Tumours treated with chemotherapy onlyLYMPHOMA
• Tumours treated with chemotherapy prior to surgery- some sarcomas and carcinomas
• Tumours treated with surgery and then chemotherapy- testicular tumours and others
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How do we approach treatment of tumours
Multidisciplinary Approach in cancer management
Each MDM team will discuss each individual cancers
• Team approach- involving surgeons, pathologists, radiologistsand oncologists.
• Also cancer nurse specialists(CNS)
• Pathologists role- tissue diagnosis pre-treatment
• After surgery- final stage and prognostic markers.
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3 specimens of tumour
Cytology
Biopsy
Surgery resection specimen
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Cytology specimen
• Cytology = using cells, cells can be obtained without invasvie technique (brushings, needle aspiration, effusion, urine, EUS FNA…)
Lot of blue nuclei: malignant
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Biopsy specimen
• Biopsy= tissue diagnosis (endoscopy, needle core biopsy, skin biopsy,…)
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Surgical resection specimen
• Surgical resection specimen = used if patient is defo going to have surgical treatment (lobe of liver, lung, segment of bowel, kidney, prostate….)
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Frozen sections
Operation on a localised surface – remove some tissue to dtermine if it is cancerous tumour to then decide on surgery
• Fresh tissue frozen at minus 20 degrees
• Sections cut in a cryostat
• Rapid staining and mounting Delay: as quick as possible, from 10 min after receipt in the Department
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Sampling in cassettes
1. Tissue is given fresh
| 2. Then put into cassettes
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Samples of fresh tissue - technique
• Fixation of tissue
• Gross description and sampling
• Processing
– Dehydration
– Embedding in paraffin wax
• Embedded in molten wax
• Then cooled down
• Becomes like a chunk block than can be cut into sections using a microtome
• Thin sections floated in water grpah - collected on glass slide
• Sample on glass slide is stained with haemotoxylin and eosin
• Add cover slip to glass slide
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Special stains
• Collagen, elastic fibres, Iron deposits, Amyloidosis, Microorganisms
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Immunohistochemistry – common nowadays
* A method of detecting the presence of specific proteins in cells or tissues.
* An antibody with colour for each antigen is added to sample. (epithelial, lymphoid, B cells, T cells, Smooth muscle, skeletal muscle…
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Molecular pathology (gene mutation analysis; FISH; detection of specific translocations)
• to support the diagnosis (specific translocations in sarcomas (myxoid liposarcomas, synovial sarcoma, Ewing’s tumour,…)or to predict response to targeted drugs (KIT in GIST; EGFR2 in breast adenocarcinoma; RAS in colorectal adenocarcinomas)
58
Colon polyps
* Familial adenomatous polyposis (FAP)
* Inherited mutation of APC gene (tumour suppressor gene)
* Truncated APC gene product - loss of gene function = cancer
Raised regions = polyps, patient develops thousands of polyps and one can become cancer
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3 features of malignancy
* Architectural atypia
* Tumour necrosis – tumour outgrows blood supply
* Presence of mitosis
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Grading tumours
• Most commonly used is based of the degree of resemblance to the tissue of origin
– well-differentiated
– moderately differentiated
– poorly differentiated
– anaplastic = completely differenitated compared to origin tumour
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Staging of tumour
* Spread of tumour
* How has tumour has spread
* Staging depends on the type and the location of the tumour
* Most commonly used is TNM
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Staging of a carcinoma
Tnm
– T: tumour (size and depth of infiltration)
– N: lymph node status
– M: metastasis (presence or absence)
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T - staging
* pT Primary tumour
* pTX Primary tumour cannot be assessed
* pT0 No evidence of primary tumour
* pT1 Tumour invades submucosa
* pT2 Tumour invades muscularis propria
* pT3 Tumour invades through muscularis propria into subserosa or non-peritonealised pericolic
* or perirectal tissues
* pT4 Tumour directly invades other organs (pT4a) and/or involves the visceral peritoneum
* (pT4b)
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N- staging TNM staging
* pN Regional lymph nodes
* pNX Regional lymph nodes cannot be assessed
* pN0 No regional lymph node metastasis
* pN1 Metastasis in 1 to 3 regional lymph nodes
* pN2 Metastasis in 4 or more regional lymph nodes
Depends on how many lymph nodes are involved
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M - staging
* For distal deposits, usually not present in the main resection specimen but eventually biopsied at the time of surgery (liver, peritoneum,..)
* pM Distant metastasis
* pMX Distant metastasis cannot be assessed
* pM0 No distant metastasis
* pM1 Distant metastasis
66
Common sites of metastasis
Lung
Liver
Due to dual blood supply
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Prognostic features to comment on histology
* Extra mural vascular invasion in GI tumours
* Distance to serosal surface in GI tumours
* Distance to radial margin in rectal and oesophageal tumours
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Bladder tumour cystoscopy and Gross
* Epithehelial tumour - Most bladder tumours are papillary lesions
* Transitional epithelieum with papillar projections
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Prostate cancer date ition
As prostate tumour is not visible clinically or radioactively – so use prostate specific antigen level
• Raised psa can indicate postate cancer
• Can't see prostate on biopsy – go through rectum instead
Take 6 biopsies
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Grading for prostatic adenocarcinoma
– prostatic adenocarcinoma: Gleason grading
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Grading for breast adenocarcinoma
Bloom and Richardson system
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Grading for kidney tumours
Fuhrman nuclear grading
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Renal cell carcinoma
* Clear cytoplasm
| * Alot of lipid and glycogen dissolved in tissue processing
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Breast resection specimens – treatments
* Wide local excision
| * Mastectomy
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Molecular markers- hormone status in breast cancer
* ER assessment
* Predicts response to hormone therapy.
* Simple scoring systems are found to work best.
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Molecular markers Her-2/neu
* Human Epidermal Growth Factor Receptor 2.
* 185 Kd transmembrane cell surface tyrosine kinase receptor,
* gene on chromosome 17 amplified in 20% cancers
* Gene amplification associated with poor prognosis
* Also used to select patients for Herceptin therapy
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Benign mesenchymal/connective tissue neoplasm
• Lipoma = benign fatty tumour, looks like fat on surface
• Liposarcoma = if lipids, fat are around abdomen – retroperitoneum
○ If MDM2 gene is amplified from here tumour is malignant
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GIST – gastro intestinal strom tumour
* Arise from stroma of stomach
* Ultrasound guided endoscopy biopsy
* Specific antigen expressed by tissue – used to give diagnosis
• Mutation = deletion of gene
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Osteosarcoma
• Bone cancer e.g. here in lower end of femur
Diagnosis made on biopsy
Chemotherapy
Prosthetic replacement treatment – remove part of bone with tumour
Necros – response to treatment
Look at margins of tumour to determine treatment
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Teratoma in tesis
* Malignant as there is some compartment
| * Malignant tumour has all 3 TNM parts pressent
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• Testicular tumours markers
Raised serum markers- HCG (Human chorionic gonadotropin) and AFP (alpha feto protein)
Surveillance – look t secretion of markers and measure them
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High grade NHL
* A lot of cell and mitosis
| * High grade lymphoma
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2 classification of lymohoma
* Hodgkins
| * Non hodgkins
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Ewing’s sarcoma
* Molecular test can identify specific tranlsocation
| * Looks like lymphoma tho
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Hodgkins lymphoma
* Proliferation of atypical lymphoid cells- ‘Reed-Sternberg cells’
* Bi nuclear cell – mirror
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Malignant melanoma – of skin surface
• Can arise from melanocytes at base of epidermis
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Rhabdomyosarcoma
• Specific tumour of skeletal muscle tissue
