tumour pathology Flashcards
what is dysplasia?
pre-malignant change
earliest change in the process of malignancy that can be visualised.
in epithelium
Key features:
1→ Disorganisation of cells
– Increased nuclear size
– Increased mitotic activity
– Abnormal mitoses
2→ Grading of dysplasia
– High grade - higher risk = shorter time of progression to cancer
– Low grade - lower risk = longer time of progression to cancer
3→ No invasion - but it can progress to cancer.
what is a tumor/ neoplasm? how are they classified?
abnormal growing mass of tissue.
Characteristics:
- uncoordinated growth with surrounding tissue
- continuation of growth after removal of stimuli
- irreversible change
classified by:
tissue of origin
- epithelium & connective tissue (mesenchyme) & Blood cells
- Lymphoid tissue & Melanocytes & Neural tissue & Germ cells (ovary/testis)
bein/malignant
what is cancer?
pathological condition characterised by the ability to invade into adjacent tissue and to metastasise and grow at other sites within the body
it is a malignant tumor.
how to name tumours in epithelium:
benign tissue end in - oma
malignant tissue end in - carcinoma
how to name tumours in connective tissue:
e.g. Osteo & Lipo & Fibro
benign tissue -oma e.g. osteoma
malignant tissue - sarcoma e.g. osteosarcoma
how to name tumours in blood:
No benign tumours in blood cells
malignant tissue - Leukaemia
hwo to name lymphoid tissue tumours:
No benign tumours in lymphoid tissue
malignant tissue - lymphoma
how to name tumours in melanocytes (melanin):
benign tissue - Naevus
malignant tissue - Melanoma
how to name tumours in Neural Tissue Tumours:
most common
CNS → e.g. Astrocytoma
PNS → e.g. Schwannoma
how to name tumours in germ cells:
Teratomas
composed of various tissues & develop in ovary/testis
- Ovarian teratomas usually → benign
- Testicular teratomas sually → malignant
Benign vs Malignant Tumours
What are the differences?
Benign:
* Non-invasive growth pattern
* Usually encapsulated
* No invasion
* No metastases
* Cells similar to normal
* Benign tumours are “well-differentiated”
* Function similar to normal tissue
* Rarely cause death
Malignant:
* Invasive growth pattern
* No capsule or capsule breached by tumour cells
* Cells abnormal
* Cancers often “poorly differentiated”
* Loss of normal function
* Spread of cancer
* Frequently cause death
what are properties of cancer cells?
Loss of tumour suppressor genes:
- Adenomatous polyposis (APC)
- Retinoblastoma (Rb)
- BRCA1
Gain of function of oncogenes:
- B-raf
- Cyclin D1
- ErbB2
- c-Myc
- K-ras, N-ras
Altered cellular function
Abnormal morphology → histopathological diagnosis
Capable of independent growth but no single feature is unique to cancer cells
Tumour biomarkers
what are tumour suppressor genes and oncogenes?
Tumour suppressor genes (anti-oncogenes)
- genes that regulate cell growth.
Oncogenes
- genes that have the potential to cause cancer, they are expressed at high levels.
what are tumour biomarkers?
biological molecules that suggest the presence of cancer in a patient
can characterise known tumours.
1– Onco-fetal proteins
2– Oncogenes
3– Growth factors and receptors
4– Immune checkpoint inhibitors
how is cell function altered in cancer?
Loss of cell-to-cell adhesion
Altered cell-to-matrix adhesion
Production of tumour-related proteins
– Tumour biomarkers
what are clinical uses of tumour biomarkers?
- Alpha-fetoprotein
– Teratoma of testes
– Hepatocellular carcinoma - Carcino-embryonic antigen (CEA)
– Establish diagnosis of Colorectal cancer - Oestrogen receptor
– Breast cancer (prevent breast cancer by inhibiting osterogen) - Prostate specific antigen
– Diagnosis of Prostate cancer
what are is the clinical usefulness of predictive tumour biomarkers?
Kras (oncogene) → drugs affect Kras pathway in Colorectal cancer
BRAF → drugs affect Braf pathway
EGFR → drugs affect EGFR pathway
PD-L1 → immune checkpoint marker
Her2 → levels determine which patient needs herceptin therapy
what is tumour growth maintenanced by?
balance between cell growth and cell death.
Angiogenesis & Apoptosis
what is tumour angiogenesis?
new blood vessel formation by tumours to sustain growth.
It also provides route for release of tumour cells into circulation.
The more blood vessels in a tumour = poorer prognosis (outcome)
what are the modes of spread of cancer?
Local spread - moving into nearby normal tissue
Lymphatic spread - tumor spread via lymphatic vessels
Blood spread - tumor spread via blood vessels
Trans-coelomic spread - dissemination of malignant tumors throughout the surfaces and organs of the abdominal and pelvic cavity covered by peritoneum
what are the steps in cell cycel?
interphase
- the cell grows and accumulates nutrients needed for mitosis;
the cell is synthesizing RNA, producing protein and growing in size
- G1
- S
- G2
mitosis - phase during which the cell splits itself into two distinct cells
cytokinesis - new cell is completely divided
what is G1/S transition?
a rate-limiting step in the cell cycle (aka restriction point)
cells that progress through this point are committed to enter S phase
what are check points?
Several checkpoints are used to control and regulate the Cell Cycle
→ They prevent progression into the next phase if the requirements have not been met.
i.e. to ensure that damaged or incomplete DNA is not passed on to daughter cells.
G1 checkpoint
- Inadequate nutrient supply
- external stimulus lacking
- Abnormal cell size
- DNA damage detected
G2
- abnormal cell size
- dna damage detected
S
- dna not replicated
M
-Chromosome misalignment
what factors regulate the cell cylcle?
External factors
- hormones
- growth factors
- cytokines
Intrinsic factors
→ critical checkpoints e.g. {{c1::G1 restriction point}}
what are two key classes of regulatory molecules determine a cells progress through the cell cycle?
cyclins → regulatory subunits that have no catalytic activity
* accumulate and get destroyed as cycle progresses
cyclin-dependent kinases (CDKs) → activated by the regulatory sub-unit cyclins
- The active enzyme complex = CDK/cyclin complex
what is the role of Cyclins and Cyclin-dependent kinases (CDKs) in the Cell Cycle?
Cyclin + CDK → Cyclin/CDK complex
Different CDK/cyclin complexes operate at sequential stages of the cycle
- Active CDK/cyclin complexes phosphorylate target proteins
- Phosphorylation results in activation/inactivation of target proteins
Substrates regulate events in the next cycle phase
what are cell cycle inhibitors? give examples:
molecules that slow or stop cell cycle progression through various mechanisms.
e.g.
CDK inhibitors → bind to cyclin/CDK complexes
INK4A gene family → bind to CDK4 and arrests the cell cycle in G1 phase
CIP/KIP gene family → halt cell cycle in G1 phase by inactivating cyclin-CDK complexes
What’s the role of the Retinoblastoma gene in regulating the cell cycle?
encodes 110 kDa phosphoprotein (pRb) expressed in almost every human cell
function:
prevents excessive cell growth
inhibits cell cycle progression until a cell is ready to divide.
When the cell is ready to divide, Rb is phosphorylated to pRb.
hypophosphorylated Rb → active state
→ inhibits cell cycle progression i.e. cells remain in G1 phase
Phosphorylated Rb → inactive state → inactivation of Rb
what is carcinogenesis?
failure of cell cycle control, when the balance between proliferation and apoptosis is disrupted.
more than one mutation is necessary
- Uncontrolled proliferation of cells forms tumours
Factors that affect it:
Environmental factors
- chemicals
- Radiation
- Oncogenic viruses
e.g. HPV - genital, anal, throat
Hepatitis B - liver
EBV- lymphoma
Inherited factors
Two frequently disrupted regulatory pathways:
1- The cyclin D-pRb-E2F pathway
2- p53 pathway
what is the role of p53?
p53 activates when DNA damage is detected
halts the cell cycle at the G1/S or G2/M checkpoint.
This pause allows DNA repair mechanisms to fix the damage, preventing the propagation of mutations.
cancers are dysregulated at G1-S checkpoint
The following are normally anti-oncogenes,
but they are mutated in the majority of cancers:
- cyclin D - CDK4 - p16 - Rb
- Cells with mutated p53 proliferate and form malignant neoplasms
what is proto oncogene?
a normal gene which, when altered by mutation, becomes an oncogene
They are normal genes coding for normal growth regulating proteins
– Growth factors
– Growth factor receptors
– Signal transduction
growth factor receptor - EGF
HER2 - protoncogene
activates due to amplification
breast, ovary. lung, stomach
