9. Neoplasia 2 Flashcards
5 developments of cancer
- Normal
- Hyperplasia
- Mild dysplasia
- Carcinoma in situ
- Cancer – invasive
= malignant tumour
Giloma survival
• 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
Cancer - definition
• 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
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 in a different site of body
Metastasis - steps (general)
- 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
5 major steps in metastasis
- 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
3 broad Stages of metastasis
Invasion
Circulation
Colonisation
Invasion
• Invasion : primary tumour cells enter circulation
Circulation
• Circulation to the secondary site of tumour growth
Colonisation
• Colonisation : formation of secondary tumour
—> cells look for a specific conductive Environnement
• So they can grow
3 tissues in organs
- Epithelial cells
- Connective tissues
- Muscle cells
How do cells become invasive
—> 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
EMT = Epithelial to Mesenchymal Transition
—> under normal physiological circumstance – epithelial cells used to create mesenchymal tissue, mesenchymal tissue can help metastatic cells colonise.
3 steps of Tumor invasion
- Translocation of cells across extracellular matrix barriers
- Lysis of matrix protein by specific proteinases
• Punch holes through basal layer with enzymes - Cell migration
3 Components of invasion
a) Matrix degrading enzymes
b) Cell adhesion
c) Cell motility
a) Matrix degrading enzymes
—> 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
Matrix metalloproteinases (MMP)
- 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
2 types of Matrix metalloproteinases (MMP)
- Soluble and secreted groups; collagenase, gelatinase and stromelysins
- Membrane type (MT-MMP) group are anchored in the plasma membrane - sitting on the membrane
Regulation of MMP
- 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
TIMPs
• MMP activity is regulated by specific inhibitors, the tissue inhibitors of MMP (TIMPs). Binding TIMP to MMP is in a 1:1 stoichiometry.
MMP roles
• MMPs (matrix metalloproteinases) help the cancer cells to invade the ECM
Cell adhesion/ attachment
—> 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
Integrin
- 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
E‐cadherin and catenin complex
- Most important cell‐cell adhesion molecules
* Reduce expression of E‐cadherin and catenin increase the invasiveness of tumor cells
Cell motility/ migration is regulated by
- Small Rho GTPase family
2. Motility promoting factors – that regulate small rho gtpases
Cell crawling
• Cells must crawl – resynthesis cytoskeleton in the cell
Small Rho GTPase
- Regulated by other regulating proteins that can switch GTP –> GDP
- Many physiological processes require GTP
Regulated by protein phosphorylation via kinases
Motility promoting factors
- Hepatocyte growth factor/scattering factor
- Insulin‐like growth factor II
- Autotaxin
Improve cell movement
3 routes of metastasis
- Lymphatics
- Blood vessels
- Coelemic spaces
LYMPHATICS
- Spread to local and distant lymph nodes
- Frequent route of spread of carcinomas
- Can involve lymphatics of lung
VASCULAR SPREAD
- Spread through capillaries and veins to various organs.
* Common sites are lung, liver, bone and brain.
Intravasation
• Travel back of out blood to other locations to settle down
How is the blood a hostile environment
‐ Cells are normally anchorage‐dependent (anoikis)
‐ Shear forces tear cells apart
• Environment = mechanical forces can kill cells
Metastatic tropism
Where the cells travel during metastasis is normally random
But different preferences for different tumours
Dormant metastases
—> dormant = metastases that do nothing for many years
Eventually form macrometastasis
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
WHAT EFFECTS DO TUMOURS HAVE?
Depends on: • site of tumour • extent of local spread • site of metastasis • extent of metastatic
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.
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
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
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
SYSTEMIC EFFECTS OF NEOPLASMS – Neuromuscular
- Problems with balance.
- Sensory/sensorimotor neuropathies.
- Myopathy and myasthenia.
- Progressive multifocal leucoencephalopathy.
- Not due to metastasis to brain.
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
—> histogenic calasification of neoplasms
Connective tissues Haemopoietic Melanoma Germ cell Epithelail origin tumours – carcinoma
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
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
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.
3 specimens of tumour
Cytology
Biopsy
Surgery resection specimen
Cytology specimen
• Cytology = using cells, cells can be obtained without invasvie technique (brushings, needle aspiration, effusion, urine, EUS FNA…)
Lot of blue nuclei: malignant
Biopsy specimen
• Biopsy= tissue diagnosis (endoscopy, needle core biopsy, skin biopsy,…)
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….)
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
Sampling in cassettes
- Tissue is given fresh
2. Then put into cassettes
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
Special stains
• Collagen, elastic fibres, Iron deposits, Amyloidosis, Microorganisms
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…
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)
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
3 features of malignancy
- Architectural atypia
- Tumour necrosis – tumour outgrows blood supply
- Presence of mitosis
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
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
Staging of a carcinoma
Tnm
– T: tumour (size and depth of infiltration)
– N: lymph node status
– M: metastasis (presence or absence)
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)
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
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
Common sites of metastasis
Lung
Liver
Due to dual blood supply
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
Bladder tumour cystoscopy and Gross
- Epithehelial tumour - Most bladder tumours are papillary lesions
- Transitional epithelieum with papillar projections
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
Grading for prostatic adenocarcinoma
– prostatic adenocarcinoma: Gleason grading
Grading for breast adenocarcinoma
Bloom and Richardson system
Grading for kidney tumours
Fuhrman nuclear grading
Renal cell carcinoma
- Clear cytoplasm
* Alot of lipid and glycogen dissolved in tissue processing
Breast resection specimens – treatments
- Wide local excision
* Mastectomy
Molecular markers- hormone status in breast cancer
- ER assessment
- Predicts response to hormone therapy.
- Simple scoring systems are found to work best.
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
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
GIST – gastro intestinal strom tumour
- Arise from stroma of stomach
- Ultrasound guided endoscopy biopsy
- Specific antigen expressed by tissue – used to give diagnosis
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
Teratoma in tesis
- Malignant as there is some compartment
* Malignant tumour has all 3 TNM parts pressent
• Testicular tumours markers
Raised serum markers- HCG (Human chorionic gonadotropin) and AFP (alpha feto protein)
Surveillance – look t secretion of markers and measure them
High grade NHL
- A lot of cell and mitosis
* High grade lymphoma
2 classification of lymohoma
- Hodgkins
* Non hodgkins
Ewing’s sarcoma
- Molecular test can identify specific tranlsocation
* Looks like lymphoma tho
Hodgkins lymphoma
- Proliferation of atypical lymphoid cells- ‘Reed-Sternberg cells’
- Bi nuclear cell – mirror
Malignant melanoma – of skin surface
• Can arise from melanocytes at base of epidermis
Rhabdomyosarcoma
• Specific tumour of skeletal muscle tissue
