Neoplasia

Question 1

define neoplasm/neoplasia

Answer 1

An abnormal growth of cells that
persists after the initial stimulus is removed”.

For malignant neoplasms the definition needs extending: “an abnormal growth
of cells that persists after the initial stimulus is removed AND invades surrounding tissue with potential to spread to distant
sites”

Question 2

what do tumour, cancer, dyspalsia, neoplasm mean

Answer 2

A tumour is any clinically detectable lump or swelling.

A neoplasm is just one type of tumour.

A cancer is any malignant neoplasm.

Dysplasia is a pre-neoplastic alteration in
which cells show disordered tissue organisation. It is not neoplastic because the change is reversible. it becomes malignant when it invades other tissues, such as past the basal layer of epilthelium

Question 3

what is a metastatis

Answer 3

A metastasis is a malignant neoplasm that has spread
from its original site to a new non-contiguous site. The original location is the primary site and the place to which it has spread is a secondary site.

Question 4

beningn vs malginant neoplasms

Answer 4

beningn are limited to site of growth

A benign neoplasm has cells that closely
resemble the parent tissue, i.e. they are well differentiated.

malignant have the ability to metastatise

Malignant neoplasms range from well to poorly differentiated - the more poorly differentiated the worse the grade and the worse the outlook

Question 5

what 4 things will you see in a neoplastic group of cells that have a worsening level of diffrentation

note: this also applies to areas of dysplasia - as it is pre neoplastic

Answer 5

pleomorphism - varying size and shape of cell

hypercrhomasia - increased nuclear staining

mitotic figures present

increased nuclear/cytoplasmic ratio

Question 6

what is the key difference between dysplasia and malignancy

Answer 6

dysplasia is a reversible state, malignancy is not

Question 7

to what extent is cancer intrinsic vs extrinsic and inherited vs envriomental

Answer 7

studies on Japanese migrants imply that cancer is about 85% environmental and 15% familial genetic traits

intrisic factors are age, gender, genetics

extrinsic factors are enviroment and lifesytle - smoking, obesity, lack of exercise, alcohol

Question 8

are neoplasms monocolonal ? what does this mean ?

Answer 8

neoplasms are monoclonal -they all originated from a single founding cell.

this fits the initiation and promotion concept

Question 9

outline the basics of naming cancers

get the key ones, skin, blood, lymph not the random specific ones for now

Answer 9

Benign neoplasms ends in –oma.

Malignant ones end in – carcinoma if it is an epithelial malignant neoplasm, which
constitute 90% malignant tumours, or –sarcoma if it is a stromal malignant neoplasm.

Carcinomas can be in-situ (no invasion
through epithelial basement membrane) or invasive (penetrated through basement membrane).

Leukaemia is a malignant neoplasm of blood-forming cells arising in the bone marrow

lymphomas are malignant neoplasms of lymphocytes, mainly affecting lymph nodes.

Myeloma is a malignant neoplasm of
plasma cells.

Germ cell neoplasms arise from pluripotent cells,
mainly in the testis or ovary.

Neuroendocrine tumours arise
from cells distributed throughout the body.

Some neoplasms are called “-blastomas”, which occur mainly in children and are formed from immature precursor cells, e.g. nephroblastoma.

Question 10

how does a malignant neoplasm metastasie

Answer 10

For malignant cells to get from a primary site to a secondary site they

must:
(1) grow and invade at the primary site;
(2) enter a transport system and lodge at a secondary site;
(3) grow at the secondary site to form a new tumour (colonisation).

At all points the cells must evade destruction by immune cells.

this requires a set of alterations

Question 11

what alterations does a malignant neoplasm need to metastasie

and what is an EMT

Answer 11

Invasion into surrounding tissue by carcinoma cells requires: altered adhesion - Altered adhesion between malignant cells involves a reduction in E-cadherin and Integrin expression.

stromal proteolysis - The cells must degrade basement membrane and stroma to invade. This involves altered expression of proteases, notably matrix metalloproteinases (MMPs).

motility - Altered motility involves changes in the actin cytoskeleton.

Together, these three changes
create a carcinoma cell phenotype that sometimes appears more like a mesenchymal cell than an epithelial cell, hence this is called epithelial-to-mesenchymal transition (EMT)

Question 12

explain the concept of a nice and seed and soil

Answer 12

Malignant cells take advantage of nearby non-neoplastic cells, which together form a
cancer niche. These normal cells provide some growth factors and proteases.

The “seed and soil” phenomenon, which may explain the seemingly unpredictable distribution of blood-borne metastases, is due to interactions between malignant cells and the local tumour environment (i.e. the niche) at the secondary site - ie why tumor may grow well at some sites

Question 13

what are the mechanisms of spread of neoplasms
3 ways

how and where will neoplasms spread ?

Answer 13

Malignant cells can reach distant sites by entering:

(1) blood vessels via capillaries and venules;
(2) lymphatic vessels;
(3) fluid in body cavities (pleura, peritoneal, pericardial and brain ventricles), which is known as transcoelomic spread

For lymphatic metastasis this is very predictably to draining lymph nodes.

For transcoelomic spread this is predictably to other areas in the coelomic space or to adjacent organs.

For blood-borne metastasis this is sometimes (but not always) to the next capillary bed that the cells encounter - so most commonly the lungs and liver but can also spread to bone and brain

Question 14

what neoplasms commonly spread to bone

Answer 14

The neoplasms that most frequently spread to

bone are breast, bronchus, kidney, thyroid and prostate.

Question 15

what is different about how carcinomas and sarcomas spread ?

Answer 15

carcinomas typically spread first to draining lymph nodes and then to blood-borne distant
sites

sarcomas tend to spread via the blood stream

Question 16

why do rates of metastaises for different cancers differ, give examples

Answer 16

Some malignant neoplasms are more aggressive and metastasise very early in their course, e.g. small cell bronchial carcinoma.

Others almost never metastasise, e.g. basal cell carcinoma of the skin.

Question 17

outline the local and systemic effects that neoplasms can have genrally

Answer 17

the local effects of primary and secondary neoplasms are due to

(1) direct invasion and destruction of normal tissue;
(2) ulceration at a surface leading to bleeding / possible infection;
(3) compression of adjacent structures
(4) blocking tubes and orifices

SYSTEMIC EFFECTS OF NEOPLASMS:
Increasing tumour burden leads to a parasitic effect on the host.
Together with secreted
factors such as cytokines this contributes to reduced appetite and weight loss (cachexia), malaise,

immunosuppression and thrombosis also occur

Benign neoplasms of endocrine glands are well differentiated so typically produce hormones, e.g. a thyroid adenoma produces thyroxine.

Malignant tumours sometimes also produce
hormones; e.g. bronchial small cell carcinoma can produce ACTH or ADH

Miscellaneous systemic effects include neuropathies affecting the brain and peripheral nerves,

skin problems such as pruritis and myotosis.

Question 18

what does carcinogenesis mean ?

Answer 18

the causes of cancer and the reasons that caused them

Question 19

outline causes of carinogenesis and what that are categorised into

what are cigarettes

Answer 19

we have chemicals - often considered mutagens hence initiators and also promoters sometimes

ames test shows that initiators are mutagens

radiation such as UV to skin and x rays/gamma rays
these are initiators. they cause damage and mutations, they also generate free radicals, which causes further damage

cigarette smoke is considered a complete caringnogen which mean sit is both an initiator and a promoter

infections are also cacinogenic

Question 20

what is a pro carcinogen ?

Answer 20

something that is not a carcinogen until it is converted to a carcinogen in the liver by cytochrome p450 enzymes

Question 21

outline how and what infections are cacinogenic

Answer 21

Human Papilloma virus (HPV), which is strongly linked to cervical carcinoma, is a direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB protein function respectively, both of which are important in cell proliferation.

In contrast, Hepatitis B and C viruses are indirect carcinogens that cause chronic liver cell injury and regeneration. and hence promote mutations

Question 22

what role do proto-oncogenes and tumour supressor genes play in cancer formation ?

what are the third set of genes involoved

Answer 22

Genes that inhibit neoplastic growth are known as tumour suppressor genes Because they act
like brakes on tumour growth, both alleles must be inactivated, which explains why they need two hits, i.e. one for each allele.

In contrast, genes that enhance neoplastic growth are known oncogenes and are abnormally activated versions of normal genes called proto-oncogenes.
Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth.

think two person bike analogy

the third set of genes involved are called caretaker genes - involve protecting from mismatch repair, neucleotide excision repair and DNA double strand breaks - when inactivated they lead to genetic instability

Question 23

what is progression ?

Answer 23

occurs after promotion

Most malignant tumours require alterations affecting a
combination of multiple TS genes and proto-oncogenes.

a general principle of step-wise
accumulation of mutations in malignant neoplasms. This steady accumulation of multiple mutations is called cancer progression.

Question 24

what are the six hallmarks of cancer and the enabling factor ?

Answer 24

1. cell immortalisation
2. resistance to apoptosis
3. self sufficient growth signals
4. resistance to growth stop signals
5. sustained ability to induce new blood vessels (angiogenesis)
6. the ability to invade and
   produce metastases.

enabling factor - genetic instability

Question 25

draw a model of cancer pathogenisis and descirbe it

add hallmarks, ect

include all details from the lecture

Answer 25

check against neopalsia 3

Question 26

what factors should be considered when thinking about tumour outcome

Answer 26

age, gender, health, tumours site and type and grade, the treatments we have available

Question 27

outline the general idea of tumour staging system

what examples do you need to have an idea about ? - do not know the details of this - just the general idea

Answer 27

TNM staging system

T refers to the size of the primary tumour and is typically expressed as T1 through to T4

N describes the extent of regional node metastasis via LYMPHATICS, for example N0 to N3.

M denotes the extent of distant metastatic spread via the BLOOD e.g. M0 or M1.

the T, N and M status are then converted into a stage from I to IV.
stage I is early local disease and stage II is advanced local disease (i.e. N0, M0), stage III is regional metastasis (i.e. any T, N1 or
more, M0) and stage IV is advanced disease with distant metastasis (i.e. any T, any N and M1).

ann arbour - Lymphoma has its own special system called Ann Arbor staging. In brief, stage I indicates lymphoma in a single node region, stage II
indicates two separate regions on one side of the diaphragm, stage III indicates spread to both sides of the diaphragm, and stage IV indicates diffuse or disseminated involvement of one or more extra-lymphatic organs such as bone marrow or lung.
Staging is a powerful predictor of survival.

Dukes staging has been used for colorectal carcinoma (Dukes’ A: Invasion into but not through
the bowel, Dukes’ B: Invasion through the bowel wall, Dukes’ C: Involvement of lymph nodes, Dukes’ D: Distant metastases)

Question 28

what does tumour grade describe ?

give one example

Answer 28

the level of differentiation - well differentiated tissue still looks like source tissue, is a low grade and has good survival

the more disorganised a tissue look the higher the grade and the worse the outlook

Typically, G1 is well-differentiated, G2 is
moderately differentiated, G3 is poorly differentiated and G4 is undifferentiated or anaplastic.

For example, breast carcinoma uses the modified BloomRichardson system, which assesses tubule formation, nuclear variation
and number of mitoses

Question 29

outline the general treatment principles for cancer treatment and key definitions

Answer 29

Cancer can be treated by surgery, radiotherapy, chemotherapy, hormone therapy and treatment targeted to specific molecular alterations. Therapy that targets the immune system has recently shown enormous promise.

Surgery is the mainstay of treatment for most cancers

Adjuvant treatment is given after surgical removal of a primary tumour to eliminate subclinical disease - micrometastasies.

Neoadjuvant treatment is given to reduce the size of a primary tumour prior to surgical excision.

Question 30

outline the principles of radiotherapy, chemotherapy and hormone therapy

broad scope here not the deets

Answer 30

RADIATION THERAPY KILLS PROLIFERATING CELLS BY TRIGGERING APOPTOSIS OR INTERFERING WITH MITOSIS:
Radiotherapy is focused on the tumour with shielding of surrounding healthy tissue. It is given in fractionated doses to minimise normal tissue .
This is because high dosage causes either direct or free-radical induced DNA damage that is detected by the cell cycle check-points, triggering apoptosis. Double-stranded DNA breakages cause damaged
chromosomes that prevent M phase from completing correctly.

CHEMOTHERAPY DRUGS AFFECT PROLIFERATING CELLS IN VARIOUS WAYS:
Antimetabolites mimic normal substrates involved in DNA replication, e.g. Fluorouracil.
Alkylating and platinum-based drugs, e.g. cisplatin, cross-link the two strands of the DNA helix.
Antibiotics act in several different ways
Plant-derived drugs

HORMONE THERAPY IS RELATIVELY NON-TOXIC TREATMENT FOR CERTAIN MALIGNANT TUMOURS: Selective oestrogen receptor modulators (SERMs), such as tamoxifen, bind to oestrogen receptors, preventing oestrogen from binding. only for specific tumours

Question 31

using breast cancer as an exapmle highlight the potential for immune therapy treatments - give some drugs as an example and what they do

Answer 31

ONCOGENES CAN BE TARGETED BY CANCER THERAPY:

Identifying cancer-specific alterations such as oncogene mutations provides an opportunity to target drugs specifically at cancer cells.

Two early examples were Trastuzumab (Herceptin) and Imatinib (Gleevec). A quarter of breast cancers have gross over-expression of the HER-2 gene and Herceptin can block Her-2 signalling.

New potential targeted therapies continue to emerge.
The cancer immunity cycle highlights points where immune treatments can be used. Examples include nivolumab and ipilimumab, which block immune checkpoints.

Question 32

how do we monitor the tumour burden

get two exapmles hint - hepatocellular carcinoma and testicular cancer

Answer 32

Various substances are released by cancer cells into the
circulation (also urine and faeces).

in general they are most useful for monitoring tumour burden during treatment and follow up.

Tumour markers include hormones (e.g. human chorionic gonadotrophin released by testicular tumours), ‘oncofetal’ antigens (e.g. alpha fetoprotein released by hepatocellar carcinoma), and mucins/glycoproteins (e.g. CA-125 released by
ovarian cancer)

Question 33

outline the cancer screening pros and cons

Answer 33

Cancer screening attempts to detect
cancers as early as possible when the chance of cure is highest.

However screening can have problems such as lead time bias, length bias and over diagnosis.

ie diagnosising a cancer that will not become malignant during the pateints lifetime, so is pointless to treat