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Y1 TP2 Pathological Processes (topic 3 Onwards) > 9. Neoplasia 2 > Flashcards

9. Neoplasia 2 Flashcards

1
Q

5 developments of cancer

A
  1. Normal
    1. Hyperplasia
    2. Mild dysplasia
    3. Carcinoma in situ
    4. Cancer – invasive
      = malignant tumour
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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
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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

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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

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5
Q

Metastasis - steps (general)

A
  1. Carinoma in situ – cells on basement membrane that have lost control of cell cycle
    1. Invasive carcinoma – break through basement membrane
    2. Transport through circulation
    3. Extraversion – cells leave circulatory system
    4. Form micrometastasis - tiny clusters of tumour cells that settle and wait
    5. Colonization to form macrometastasis
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6
Q

5 major steps in metastasis

A
  1. Invasion and infiltration of surrounding normal host ‘ tissue with penetration of small lymphatic or vascular channels;
  2. Release of neoplastic cells, either or single cells or small clumps, into the circulation;
  3. Survival in the circulation;
  4. Arrest in the capillary beds of distant organs;
  5. Penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells
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7
Q

3 broad Stages of metastasis

A

Invasion
Circulation
Colonisation

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8
Q

Invasion

A

• Invasion : primary tumour cells enter circulation

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9
Q

Circulation

A

• Circulation to the secondary site of tumour growth

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10
Q

Colonisation

A

• Colonisation : formation of secondary tumour

—> cells look for a specific conductive Environnement
• So they can grow

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11
Q

3 tissues in organs

A
  • Epithelial cells
    • Connective tissues
    • Muscle cells
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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

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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.

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14
Q

3 steps of Tumor invasion

A
  1. Translocation of cells across extracellular matrix barriers
  2. Lysis of matrix protein by specific proteinases
    • Punch holes through basal layer with enzymes
  3. Cell migration
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15
Q

3 Components of invasion

A

a) Matrix degrading enzymes
b) Cell adhesion
c) Cell motility

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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

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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
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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
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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
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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.

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21
Q

MMP roles

A

• MMPs (matrix metalloproteinases) help the cancer cells to invade the ECM

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22
Q

Cell adhesion/ attachment

A

—> detacth cells from other cells and from basal laminar by destroying the connections below

  1. Integrin: cell‐matrix adhesion – anchor cell to basement membrane
  2. E‐cadherin/catenin adhesion complex: cell‐ cell adhesion – cell to ceel connection
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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
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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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25
Q

Cell motility/ migration is regulated by

A
  1. Small Rho GTPase family

2. Motility promoting factors – that regulate small rho gtpases

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26
Q

Cell crawling

A

• Cells must crawl – resynthesis cytoskeleton in the cell

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27
Q

Small Rho GTPase

A
  • 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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28
Q

Motility promoting factors

A
  • Hepatocyte growth factor/scattering factor
  • Insulin‐like growth factor II
  • Autotaxin

Improve cell movement

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29
Q

3 routes of metastasis

A
  • Lymphatics
  • Blood vessels
  • Coelemic spaces
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30
Q

LYMPHATICS

A
  • Spread to local and distant lymph nodes
    • Frequent route of spread of carcinomas
    • Can involve lymphatics of lung
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31
Q

VASCULAR SPREAD

A
  • Spread through capillaries and veins to various organs.

* Common sites are lung, liver, bone and brain.

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32
Q

Intravasation

A

• Travel back of out blood to other locations to settle down

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33
Q

How is the blood a hostile environment

A

‐ Cells are normally anchorage‐dependent (anoikis)
‐ Shear forces tear cells apart
• Environment = mechanical forces can kill cells

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34
Q

Metastatic tropism

A

Where the cells travel during metastasis is normally random

But different preferences for different tumours

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35
Q

Dormant metastases

A

—> dormant = metastases that do nothing for many years

Eventually form macrometastasis

36
Q

WHY DON’T ALL MALIGNANT CELLS METASTASISE?

A

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
37
Q

WHAT EFFECTS DO TUMOURS HAVE?

A 
Depends on: 
	• site of tumour 
	• extent of local spread 
	• site of metastasis 
	• extent of metastatic
38
Q

LOCAL EFFECTS OF NEOPLASMS- BENIGN

A

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.
39
Q

LOCAL EFFECTS OF NEOPLASMS- MALIGNANT

A
  • 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
Q

SYSTEMIC EFFECTS OF NEOPLASMS - Haematological

A

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

41
Q

SYSTEMIC EFFECTS OF NEOPLASMS Endocrine

A

• 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

42
Q

SYSTEMIC EFFECTS OF NEOPLASMS – Neuromuscular

A
  • Problems with balance.
    • Sensory/sensorimotor neuropathies.
    • Myopathy and myasthenia.
    • Progressive multifocal leucoencephalopathy.
    • Not due to metastasis to brain.
43
Q

WHY DO NEOPLASMS KILL PEOPLE?

A
  • Local effect e.g. brain, perforation, haemorrhage Benign or malignant
    • Replacement of essential body organs Malignant

Many combined effects of tumour can kill patient

44
Q

—> histogenic calasification of neoplasms

A 
Connective tissues 
Haemopoietic 
Melanoma
Germ cell 
Epithelail origin tumours – carcinoma
45
Q

Classification of tumours

A
  • Oma = tumour (bening or malignant)
    • Carcinoma = epithelial malignancy
    • Sarcoma = connective tissue malignancy
    • Aemia = maliognancy of bone marrow derived cells (exceptions e.g. anaemia
46
Q

Treatment for malignant neoplasia

A

• 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

47
Q

How do we approach treatment of tumours

A

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.

48
Q

3 specimens of tumour

A

Cytology
Biopsy
Surgery resection specimen

49
Q

Cytology specimen

A

• Cytology = using cells, cells can be obtained without invasvie technique (brushings, needle aspiration, effusion, urine, EUS FNA…)

Lot of blue nuclei: malignant

50
Q

Biopsy specimen

A

• Biopsy= tissue diagnosis (endoscopy, needle core biopsy, skin biopsy,…)

51
Q

Surgical resection specimen

A

• Surgical resection specimen = used if patient is defo going to have surgical treatment (lobe of liver, lung, segment of bowel, kidney, prostate….)

52
Q

Frozen sections

A

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

53
Q

Sampling in cassettes

A
  1. Tissue is given fresh

2. Then put into cassettes

54
Q

Samples of fresh tissue - technique

A

• 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

55
Q

Special stains

A

• Collagen, elastic fibres, Iron deposits, Amyloidosis, Microorganisms

56
Q

Immunohistochemistry – common nowadays

A
  • 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…
57
Q

Molecular pathology (gene mutation analysis; FISH; detection of specific translocations)

A

• 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
Q

Colon polyps

A
  • 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

59
Q

3 features of malignancy

A
  • Architectural atypia
    • Tumour necrosis – tumour outgrows blood supply
    • Presence of mitosis
60
Q

Grading tumours

A

• 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

61
Q

Staging of tumour

A
  • Spread of tumour
    • How has tumour has spread
  • Staging depends on the type and the location of the tumour
  • Most commonly used is TNM
62
Q

Staging of a carcinoma

Tnm

A

– T: tumour (size and depth of infiltration)
– N: lymph node status
– M: metastasis (presence or absence)

63
Q

T - staging

A
  • 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)
64
Q

N- staging TNM staging

A
  • 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

65
Q

M - staging

A
  • 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
Q

Common sites of metastasis

A

Lung
Liver

Due to dual blood supply

67
Q

Prognostic features to comment on histology

A
  • Extra mural vascular invasion in GI tumours
  • Distance to serosal surface in GI tumours
  • Distance to radial margin in rectal and oesophageal tumours
68
Q

Bladder tumour cystoscopy and Gross

A
  • Epithehelial tumour - Most bladder tumours are papillary lesions
    • Transitional epithelieum with papillar projections
69
Q

Prostate cancer date ition

A

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

70
Q

Grading for prostatic adenocarcinoma

A

– prostatic adenocarcinoma: Gleason grading

71
Q

Grading for breast adenocarcinoma

A

Bloom and Richardson system

72
Q

Grading for kidney tumours

A

Fuhrman nuclear grading

73
Q

Renal cell carcinoma

A
  • Clear cytoplasm

* Alot of lipid and glycogen dissolved in tissue processing

74
Q

Breast resection specimens – treatments

A
  • Wide local excision

* Mastectomy

75
Q

Molecular markers- hormone status in breast cancer

A
  • ER assessment
  • Predicts response to hormone therapy.
  • Simple scoring systems are found to work best.
76
Q

Molecular markers Her-2/neu

A
  • 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
77
Q

Benign mesenchymal/connective tissue neoplasm

A

• 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

78
Q

GIST – gastro intestinal strom tumour

A
  • Arise from stroma of stomach
    • Ultrasound guided endoscopy biopsy
    • Specific antigen expressed by tissue – used to give diagnosis
    • Mutation = deletion of gene
79
Q

Osteosarcoma

A

• 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

80
Q

Teratoma in tesis

A
  • Malignant as there is some compartment

* Malignant tumour has all 3 TNM parts pressent

81
Q

• Testicular tumours markers

A

Raised serum markers- HCG (Human chorionic gonadotropin) and AFP (alpha feto protein)
Surveillance – look t secretion of markers and measure them

82
Q

High grade NHL

A
  • A lot of cell and mitosis

* High grade lymphoma

83
Q

2 classification of lymohoma

A
  • Hodgkins

* Non hodgkins

84
Q

Ewing’s sarcoma

A
  • Molecular test can identify specific tranlsocation

* Looks like lymphoma tho

85
Q

Hodgkins lymphoma

A
  • Proliferation of atypical lymphoid cells- ‘Reed-Sternberg cells’
    • Bi nuclear cell – mirror
86
Q

Malignant melanoma – of skin surface

A

• Can arise from melanocytes at base of epidermis

87
Q

Rhabdomyosarcoma

A

• Specific tumour of skeletal muscle tissue

Y1 TP2 Pathological Processes (topic 3 Onwards) (9 decks)

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