ICS week 2 Flashcards
what are the characteristics of neoplastic cells in a tumour? what do they do/secrete? how can these secretions detect tumours?
- they reproduce (to a variable extent) the growth pattern and synthetic activity of the parent cell of origin
- may still synthesise and secrete cell products e.g. collagen, mucin or keratin, which may accumulate in the tumour where they are recognisable histologically
- cell products secreted into the blood can be used to monitor tumour growth and effects of therapy
what is the function of stroma in a tumour and what is it?
- connective tissue framework
- provides mechanical support, intercellular signalling and nutrition to the neoplastic cells
what is a desmoplastic reaction?
the process of stroma formation when it is particularly fibrous
what causes stroma formation?
- induction of connective tissue fibroblast proliferation by growth factors elaborated by tumour cells
what are cancer-associated fibroblasts? what do they do?
fibroblasts with slightly altered properties in a tumour
- secrete a matrix
- matrix gives mechanical support to neoplastic cells and has nutritive, intercellular signalling and enzyme-secreting properties
what do stromal myofibroblasts do in tumours?
- may be abundant, esp. in breast cancers
- their contractility is responsible for puckering and retraction of adjacent structures
what does growth of a tumour depend on? when does growth cease?
- its ability to induce blood vessels to perfuse it
- unless it’s permeated by a vascular supply, its growth is limited by the ability of nutrients to diffuse into it
- tumour ceases expanding when the nodule has a diameter of no more 1-2 mm
what can be used to treat inflammation?
- prostaglandin synthetase inhibiors (e.g. aspirin, ibuprofen)
- corticosteroids, NSAIDS, monoclonal antibodies: bind to DNA to upregulate inhibitors of inflammation, downregulate mediators of inflammation
what induces angiogenesis in tumours? what opposes this action?
vascular endothelial growth factor
- opposed by factors such as angiostatin and endostatin
what would suggest a host immune reaction to a tumour?
lymphocytic infiltrate of variable density
what is the gross appearance of a tumour on a surface?
can be described as sessile, polypoid, papillary, exophytic/fungating, ulcerated or annular
what are examples of the behaviour of a tumour correlating with its gross appearance?
- polypoid tumours are generally benign
- ulceration is associated with destructive invasive behaviour (key feature of malignancy)
how can ulcerated tumours be distinguished from non-neoplastic ulcers?
ulcerated tumours tend to have heaped-up irregular edges
what is a key characteristic feature of benign epithelial tumours?
- circumscription by a clearly defined border
- some malignant connective tissue tumours are also well circumscribed
why are tumours usually firmer than the surrounding tissue? what does this cause?
- stromal fibrosis
- causes a palpable lump in accessible sites
why are cut surfaces of malignant often variegated?
due to areas of necrosis, haemorrhage, fibrosis and degeneration
cut surfaces of which malignant tumours may seem uniformly bland?
- lymphomas
- seminomas
how do neoplasms differ histologically from their corresponding normal tissue?
- loss/reduction of differentiation
- loss/reduction of cellular cohesion
- nuclear enlargement, hyperchromasia and pleomorphism
- increased mitotic activity
what is the process of tumour angiogenesis?
- transformation of a single cell
- growth of an avascular tumour nodule with a diameter of 1-2 mm. limited by ability of nutrients to diffuse into it
- production of angiogenic factors stimulates proliferation and ingrowth of blood vessels; tumour growth is supported by perfusion
- the tumour eventually outgrows its blood supply and areas of necrosis appear, slowing growth
what are the different tumour shapes?
- sessile
- pedunculated polyp
- papillary
- exophytic/fungating
- ulcerated
- annular
which tumour shapes are more likely to be benign/malignant?
benign:
- sessile, polypoid and papillary
malignant:
- exophytic/fungating, ulcerated or annular
where are annular tumours common?
large bowel, often cause intestinal obstruction
how are tumours classified, and why is classification important?
- according to behaviour and histogenesis
- precise classification is important for planning effective treatment
what is behavioural classification?
divides tumours into benign and malignant
- main thing that distinguishes them is invasion
what are borderline tumours? what is an example?
defy precise behavioural classification because their histology is intermediate between that associated with benign and malignant tumours
- some ovarian tumours
what are characteristics of benign tumours?
- non-invasive and remain localised
- slow growth rate
- do not metastasise
- enveloped by a thin layer of compressed connective tissue (encapsulated)
what happens when a benign tumour arises in an epithelial or mucosal surface?
- tumour grows away from the surface because it cannot invade
- forms a polyp which can be pedunculated (stalked) or sessile (sitting on surface)
- non-invasive outward direction of growth creates an exophytic lesion
what is a pedunculated polyp?
stalked polyp
what is a sessile polyp?
polyp that sits on the surface
how is an exophytic lesion created?
by the non-invasive
outward growth of the benign tumour
what are benign tumours like histologically?
closely resemble parent cell or tissue, with only mild nuclear changes
why may benign tumours cause clinical problems? give examples for each reason
- pressure on adjacent tissues (e.g. benign meningeal tumour causing epilepsy)
- obstruction to the flow of fluid (e.g. benign epithelial tumour blocking a duct)
- production of a hormone (e.g. benign thyroid tumour causing thyrotoxicosis)
- transformation into a malignant neoplasm (e.g. adenomatous polyp progressing to an adenocarcinoma)
- anxiety
what are the characteristics of malignant tumours?
- invasive and capable of spreading directly or by metastasis
- rapid growth rate
- irregular margin (not circumscribed)
- variable histological resemblance to the parent tissue
what is metastasis?
- invade into and destroy adjacent tissues
- neoplastic cells penetrate walls of blood vessels and lymphatic channels and disseminate to other sites
what are metastases?
resulting secondary tumours that develop due to metastasis
what is carcinomatosis?
having widespread metastases
how is an endophytic tumour formed?
- malignant tumours on epithelial or mucosal surfaces may form a protrusion in early stages, but eventually invade to the underlying tissue
- formed by invasive inward direction of growth
what is the appearance of a malignant tumour?
- in solid organs, they tend to have irregular margins
- central necrosis due to inadequate perfusion
- atypical nuclear changes
- enlargement of nuclei
- darker staining (hyperchromasia)
- more variability in nuclear size, shape and chromatin clumping (pleomorphism)
what is hyperchromasia?
darker staining of nuclei
what is pleomorphism?
increased variability in nuclear size, shape and chromatin clumping
why are malignant tumours associated with a high morbidity and mortality rate?
- pressure on and destruction of adjacent tissue
- metastases
- blood loss from ulcerated surfaces
- obstruction of flow
- production of a hormone
- other paraneoplastic effects causing weight loss and debility
- anxiety and pain
why do malignant tumours have a heterogenous cut surface?
necrosis
what is the growth rate, mitoses and histological resemblance to normal tissue like in benign vs malignant tumours
- b: slow
- m: relatively rapid
- b: infrequent
- m: frequent and often atypical
- b: good
- m: variable, often poor
what is the nuclear morphology like in benign vs malignant tumours?
- b: near normal
- m: usually enlarged, hyperchromatic, irregular outline, multiple nucleoli and pleomorphic
what is the invasion, metastases and border like in benign vs malignant tumours?
- b: no
- m: yes
- b: never
- m: frequent
- b: often circumscribed or encapsulated
- m: often poorly defined or irregular
what is the necrosis, ulceration and direction of growth on skin or mucosal surfaces like in benign vs malignant tumours?
- b: rare
- m: common
- b: rare
- m: common on skin/mucosal surfaces
- b: often exophytic
- m: often endophytic
what is histogenesis? what is it determined by? what does it specify?
the specific cell or tissue of origin of an individual tumour
- determined by histopathological examination
- specifies the tumour type
what major categories of origin are there in histogenetic classification?
- epithelial cells (carcinomas)
- connective tissues (sarcomas)
- lymphoid and/or haemopoietic organs (lymphomas or leukemias)
where do carcinomas originate from?
epithelial cells
where do sarcomas originate from?
connective tissues
where do lymphomas or leukemias originate from?
lymphoid and/or haemopoietic organs
what is the behaviour, frequency and preferred route of metastasis like in carcinomas vs sarcomas?
c: malignant
s: malignant
c: common
s: relatively rare
c: lymph
s: blood
what is the in-situ phase and age group like in carcinomas vs sarcomas?
c: yes
s: no
c: usually over 50 years
s: usually under 50 years
what determines the tumour grade or degree of differentiation?
the extent to which the tumour resembles histologically its cell or tissue of origin
why is the degree of differentiation of malignant tumours clinically useful?
correlates strongly with patient survival (prognosis) and may indicate the most appropriate treatment
what is the difference between well-differentiated and poorly differentiated tumours?
- well-differentiated tumours more closely resemble the parent tissue than a poorly differentiated one
- moderately differentiated tumours are intermediate between the two extremes
- poorly differentiated tumours are more aggressive
what are anaplastic tumours?
tumours that are so poorly differentiated that they lack recognisable histogenetic features
what is the suffix for tumours?
-oma
what is the suffix for neoplastic disorders of blood cells?
-aemia
how are epithelial tumours named?
- histogenically according to their specific epithelial type
- behaviourally as benign or malignant
what can benign epithelial tumours be?
- papillomas
- adenomas
what is a papilloma?
benign tumour of non-glandular or non-secretory epithelium, e.g. transitional or stratified squamous epithelium
what is an adenoma?
benign tumour of glandular or secretory epithelium
what are the full names of benign epithelial tumours?
[name of specific epithelial cell type/glandular origin] [ papilloma/adenoma], e.g. squamous cell papilloma
what are malignant epithelial tumours called?
carcinoma
what are carcinomas of non-glandular epithelium called?
prefixed by name of the epithelial cell type
- e.g. squamous cell carcinoma
what are carcinomas of glandular epithelium called?
adenocarcinomas, then the name of the tissue of origin
- e.g. adenocarcinoma of the breast
what are epithelial tumours of squamous cell, transitional, basal cell and glandular type called in benign vs malignant tumours?
b: squamous cell papilloma
m: squamous cell carcinoma
b: transitional cell papilloma
m: transitional cell carcinoma
b: basal cell papilloma
m: basal cell carcinoma
b: adenoma (e.g. thyroid adenoma)
m: adenocarcinoma (e.g. adenocarcinoma of the breast)
what is a carcinoma in situ?
an epithelial neoplasm exhibiting all the cellular features associated with malignancy, which has not yet invaded through the epithelial BM which separates it from metastasis roues
what is dysplasia?
a phase which may preceed carcinoma in situ, where the epithelium shows disordered maturation with milder nuclear changes
what is intraepithelial neoplasia?
term used to encompass carcinoma in situ and dysplasia
what happens histologically to tissue undergoing dysplasia?
some loss of stratification; immature cells escape from basal cell layer
what happens histologically to tissue in carcinoma in situ?
total loss of stratification; immature cells throughout; basement membrane intact
what happens histologically to tissue in invasion?
erosion of basement membrane; tumour gains access to vascular channels; cells escape from tumour via lymphatics, leading to metastasis
what are mesenchymal tumours of smooth muscle, striated muscle, adipose tissue and blood vessels called when benign vs malignant?
b: leiomyoma
m: leiomyosarcoma
b: rhabdomyoma
m: rhabdomyosarcoma
b: lipoma
m: liposarcoma
b: angioma
m: angiosarcoma
what are mesenchymal tumours of bone, cartilage, mesothelium and synovium called when benign vs malignant?
b: osteoma
m: osteosarcoma
b: chondroma
m: chondrosarcoma
b: benign mesothelioma
m: malignant mesothelioma
b: synovioma
m: synovial sarcoma
how are connective tissue and other mesenchymal tumours named?
according to their cell of origin and behavioural classification
what is a lipoma?
benign tumour of the lipocytes of adipose tissue
what is a rhabdomyoma?
benign tumour of striated muscle
what is a leiomyoma?
benign tumour of smooth muscle cells
what is a chondroma?
benign tumour of cartilage
what is a osteoma?
benign tumour of bone
what is an angioma?
benign vascular tumour
what is a liposarcoma?
malignant tumour of lipocytes
what is a rhabdomyosarcoma?
malignant tumour of striated muscle
what is a leiomyosarcoma?
malignant tumour of smooth muscle
what is a chondrosarcoma?
malignant tumour of cartilage
what is an osteosarcoma?
malignant tumour of bone
what is an angiosarcoma?
malignant vascular tumour
what is Burkitt’s lymphoma?
a B cell lymphoma associated with the Epstein-Barr virus and malaria and endemic in certain parts of Africa
what is Ewing’s sarcoma?
a malignant tumour of bone of uncertain histogenesis
what is Hodgkin’s lymphoma?
a malignant lymphoma characterised by the presence of Reed-Sternberg cells
what is Kaposi’s sarcoma?
a malignant neoplasm derived from vascular endothelium, no commonly associated with AIDS and human herpesvirus-8 infection
what is a teratoma?
a neoplasm of germ cell origin that forms cells representing all three germ cell layers of the embryo: ectoderm, mesoderm and endoderm
what are teratomas like in their benign form?
- often easily recognised
- tumour may contain teeth and hair and on histology, respiratory epithelium, cartilage, muscle, neural tissue, etc
what are teratomas like in their malignant form?
the representatives of ectoderm, mesoderm and endoderm may appear more mature and can be less easily identifiable
where do teratomas occur most often? why may this be?
- occur most often in the gonads, where germ cells are abundant
- in germ cells, genetic information is in its least repressed state and is capable of programming divergent lines of differentiation
what are ovarian teratomas usually like?
benign and cystic
what are testicular teratomas usually like?
almost always malignant and solid
where are extragonadal sites for teratomas?
mediastinum and sacrococcygeal region
what are embryonal tumours?
types of tumour that occur in the very young
- usually under 5 years old
- tumours bear histological resemblance to the embryonic form of the organ they arise in
what are examples of embryonal tumours?
- retinoblastoma
- nephroblastoma
- neuroblastoma
- hepatoblastoma
what is retinoblastoma?
embryonal tumour that arises in the eye
- inherited predisposition
what is a nephroblastoma?
embryonal tumour that arises in the kidney
- Wilms’ tumour
what is a neuroblastoma?
embryonal tumour that arises in the adrenal medulla or nerve ganglia
- may mature into a harmless benign ganglioneuroma
what is a hepatoblastoma?
embryonal tumour that arises in the liver
what are mixed tumours?
show a characteristic combination of cell types
what are examples of mixed tumours?
- mixed parotid tumour (pleomorphic salivary adenoma): glands embedded in a cartilagenous or mucinous matrix derived from myoepithelial cells of the gland
- fibroadenoma of the breast: lobular tumour consisting of epithelium-lined glands or clefts in a loose fibrous tissue matrix
what are endocrine tumours?
derived from peptide hormone secreting cells scattered diffusely in various epithelial tissues
- many are functionally active, and excessive secretion of their products may be harmful
what are the names of endocrine tumours producing a specific peptide hormone?
name of the hormone together with the suffix ‘-oma’
what is an insulinoma? what does it cause?
- insulin-producing tumour originating from beta cells of the islets of Langerhans
- causes episodic hypoglycaemia
what is a gastrinoma? what does it cause?
- gastrin secreting tumour
- causes Zollinger-Ellison syndrome with extensive peptic ulceration
what is a medullary carcinoma of the thyroid gland?
calcitonin-producing tumour of the thyroid gland
what are phaeochromocytomas of the adrenal medulla?
secrete adrenaline and noradrenaline, which causes paroxysmal hypertension
what are carcinoid tumours?
endocrine tumours of the gut and respiratory tract that do not produce any known peptide hormone or a mixture of peptide hormones
what is multiple endocrine neoplasia syndrome?
familial predisposition to develop endocrine tumours
what is the commonest site of carcinoid tumours?
appendix
where do carcinoids often metastasise to
mesenteric lymph nodes and the liver
what is carcinoid syndrome? what is it caused by?
- extensive metastasis of carcinoid tumours
- tachycardia, sweating, skin flushing, anxiety, diarrhoea)
- due to excessive production of 5-hydroxytryptamine and prostaglandins
what is a hamartoma?
a tumour-like legion, the growth of which is coordinated with the individual
- lacks autonomy of a true neoplasm
what is the behaviour and cell types of hamartomas?
- always benign
- usually consist of two or more mature cell types normally found in the original organ
what is an example of a hamartoma? what does this consist of? what may also be considered as hamartomas?
- lung: usually a mixture of cartilage and bronchial-type epithelium
- pigmented naevi or moles
what is the clinical importance of hamartomas?
- may be mistaken for malignant neoplasms e.g. on a chest Xray
- sometimes assoicated with clinical syndromes, e.g. tuberous sclerosis
what is a cyst?
a fluid-filled space lined by epithelium
what are types of cyst? give examples for each
- neoplastic (e.g. cystadenoma, cystadenocarcinoma, cystic teratoma)
- congenital (e.g branchial and thyroglossal cysts) due to embyrological defects
- parasitic (e.g. hyatid cysts due to Echinococcus granulosus)
- retention (e.g. epidermoid and pilar cysts of the skin)
- implantation (e.g. due to surgical or accidental implantation of epidermis)
what is a general feature of neoplastic cells?
relatively or absolutely autonomous, unresponsive to extracellular growth control, showing self-sufficiency in growth signalling and evading apoptosis
in what way are neoplastic cells unstable? in what is this reflected?
- they are genomically unstable; leads to formation of many clones with divergent properties within one tumour
- reflected in histology, which may show a heterogenous growth pattern, some areas more differentiated than others
what is the aberrant proliferation and cellular immortalisation of neoplastic cells enabled by?
- autocrine growth stimulation: abnormal expression of genes (oncogenes) encoding growth factors, their receptors, intracellular signalling proteins or transcription factors; inactivation of tumour suppressor genes
- reduced apoptosis: abnormal expression of apoptosis-inhibiting genes
- telomerase: present in germ cells and stem cells. prevents telomeric shortening
what is the nuclear DNA like in neoplastic cells?
abnormal; total amount is much higher than normal cells.
- evident in nuclear hyperchromasia
- there may be increase in exact multiples of the diploid state, or inexact multiples
what is polyploidy?
increase in amount of DNA is exact multiples of the diploid state
what is aneuploidy?
presence of inexact multiples of the diploid state of DNA after chromosome losses and gains
what are aneuploidy and polyploidy associated with in neoplastic cells? what is this called?
- increased tumour aggressiveness and pleomorphism
- chromosomal instability
what is the abnormality of DNA levels associated with on a chromosomal level?
karyotypic abnormalities
- presence of additional (whole or part) chromosomes and chromosomal translocations and rearrangements
what is an example of an association of a karyotypic abnormality with a specific tumour?
association of the Philadelphia chromosome, t(9;22) with chronic myeloid leukemia
what is mitotic and apoptotic activity like in malignant tumours?
- more mitotic activity
- grossly abnormal mitotic figures, showing tripolar and other arrangements etc
how can cellular proliferation be estimated?
- mitosis counting
- DNA measurements
- determination of the frequency of expression of cell cycle associated protiens
- rate of cell loss through necrosis or apoptosis
how is cellular proliferation related to prognosis?
higher frequencies of cellular proliferation associated with a worse prognosis
what are metabolic abnormalities in tumour cells?
- deregulated energetics with a tendency towards anaerobic glycolysis
- no metabolic abnormalities specific to neoplastic process
what is the surface/adhesion of tumour cells like?
- abnormal surface
- less cohesive, may be due to reduced specialised intercellular junctions
- loss of adhesiveness enables metastasis
what is gene derepression in tumour cells?
- in normal cells, there is repression of genes, and only those required are selectively expressed
- derepression of uneccessary genes leads to inappropriate synthesis of unexpected substances
- some genes that are normally active may become repressed
what are the major types of tumour product?
- substances appropriate to the cell of origin
- substances inappropriate or unexpected for their cell of origin
- fetal reversion substances
- substances required for growth and invasion
what are the markers for a myeloma?
- monoclonal immunoglobulin
- Bence Jones protein
- in blood
- immunoglobulin light chain (kappa or lambda) in urine
what is a marker for hepatocellular carcinoma?
- alpha-fetoprotein (AFP)
- also associated with testicular teratoma
what is a marker for gastrointestinal adenocarcinomas?
- carcinoembryonic antigen (CEA)
- false positives occur in some non-neoplastic conditions
what is a marker for neuroendocrine tumours?
- peptide hormones
what is a marker of phaeochromocytoma?
- vanillyl mandelic acid (VMA)
- metabolite of catecholamines in urine
what is a marker for carcinoids?
5-Hydroxyindoleacetic acid (5-HIAA)
- metabolite of 5-HT in urine
what is a marker for choriocarcinomas?
hCG
- in blood or urine
what are markers for malignant teratomas?
AFP and hCG
- in blood
- in blood or urine
what is carcinogenesis?
the process that results in the transformation of normal cells to neoplastic cells by causing permanent genetic alterations
what does clonal mean?
single-cell origin; neoplasms
what is a carcinogen? what is their site of action?
an environmental agent participating in the causation of tumours
- site of action is the DNA; this makes them mutagenic
what is the multistep carcinogenesis hypothesis?
more than one carcinogen is needed for complete neoplastic transformation of a cell, and it may occur in several discrete steps
what is the ‘hit-and-run’ nature of carcinogens?
once established, neoplastic behaviour doesn’t require continued presence of the carcinogen
- evidence of specific causative agents usually not found in eventual tumours
how much of cancer risk is due to environmental agents?
85%
- still influence of inherited factors
what is a latent interval?
time interval between exposure to a carcinogen and appearance of signs and symptoms leading to diagnosis of tumour
what can carcinogens be identified from?
- epidemiological studies
- assessment of occupational risks
- direct accidental exposure
- carcinogenic effects in laboratory animals
- transforming effects on cell cultures
- mutagenicity testing in bacteria
what types of tests are employed for carcinogenic or mutagenic activity?
- bacterial cultures for mutagenicity testing (Ames test)
- cell and tissue cultures in which growth-transforming effects are sought
- lab animals where tumour incidence is monitored
what are the main classes of carcinogenic agent?
- chemicals
- viruses
- ionising and non-ionising radiation
- exogenous hormones
- bacteria, fungi and parasites
- micellaneous agents
what are procarcinogens?
- some agents act directly, needing no metabolic conversion
- others (procarcinogens) require metabolic conversion into active carcinogens
what are examples of chemical carcinogens?
- polycyclic aromatic hydro carbons - aromatic amines - nitrosamines - azo dyes - alkylating agents - other organic chemicals
what is the metabolic pathway for conversion of polycyclic aromatic hydrocarbons into active ultimate carcinogens?
- local conversion by mixed function oxygenases
what is the metabolic pathway for conversion of aromatic amines into active ultimate carcinogens?
- hydroxylation and conjugation in the liver
- deconjugation in the kidney
- travel/settle to the bladder
what is the metabolic pathway for conversion of nitrates and nitrites into active ultimate carcinogens?
- travel through the stomach
- conversion to nitrosamines by intestinal bacteria
- settle in gut/liver/stomach
where may enzymes for conversion of procarcinogens be and how does this affect where the tumour forms?
- enzyme may be ubiquitous within tissues; tumour occurs at site of contact or entry
- other enzymes are confined to certain organs, and thus induce tumours remote to the site of entry
- some carcinogens are synthesised in the body from components in the diet
what are features of polycyclic aromatic hydrocarbons?
- procarcinogens; effect is at site of contact because enzymes (mixed function oxidases) are ubiquitous in human tissues and readily induced in susceptible individuals
- if substance is absorbed into the body, there may be risk of cancer at sites remote from point of initial contact
what is the tumour most commonly associated with polycyclic aromatic hydrocarbons?
- carcinoma of the lung
- more common in smokers than non-smokers
- risk parallels the quantity of tobacco consumed
what does tobacco smoke contain?
- many candidates for carcinogenic activity
- e.g. 3,4-benzpyrene
- when chewed, there is an increased risk of carcinoma of the mouth
what are features of aromatic amines as carcinogens? how is it metabolised?
- procarcinogen; conversion by hydroxylation in the liver into the active carcinogenic metabolite, 1-hydroxy-2-naphthylamine
- carcinogenic effect in liver is masked immediately by conjugation with glucuronic acid in the liver
- bladder cancer results due to the conjugated metabolite being excreted in the urine and deconjugated in the urinary tract by glucuronidase, exposing the urothelium to the active carcinogen, 1-hydroxy-2-naphthylamine
what is the active carcinogenic metabolite of aromatic amines?
1-hydroxy-2-naphthylamine
what are the uses of nitrosamines?
- fertilisers; they are washed by rain into rivers and underground water tables where they can contaminate drinking water
- nitrates and nitrites are used as food additives
what is the association of nitrosamines and carcinogenesis?
- ultimate proof of a causal relationship with humans is lacking, there is epidemiological evidence linking carcinomas of the GI tract to ingestion of nitrosamines and dietary nitrates and nitrites
- potent carcinogens in laboratory animals
how are nitrosamines metabolised?
- procarcinogens
- metabolised by commensal bacteria within the gut
- converted to carcinogenic nitrosamines by combination with secondary amines and amides
what are azo gyes?
derivatives of aromatic amines
what is an example of an azo dye? what cancers is it associated with?
- dimethylaminoazobenzene (butter yellow), food dye: liver cancer in animals
- 2-acetylaminofluorene: bladder and liver cancer in animals
what is the action of alkylating agents?
- alkylation is involved in the metabolism of many carcinogens
- bind directly to DNA
what cancer are alkylating agents associated with? what is an example of one?
- cyclophosphamide
- leukemia
- small risk in humans
what is an example of other organic chemicals as a carcinogen, what tumour is it associated with and what is it used in?
- vinyl chloride; used in PVC manufacture
- liver angiosarcoma
what human tumours have a viral aetiology?
- carcinoma of the cervix (HPV)
- Burkitt’s lymphoma (Epstein-Barr virus)
- nasopharyngeal carcinoma (Epstein-Barr virus)
- hepatocellular carcinoma (hepatitis B and C viruses)
- T-cell leukaemia/lymphoma in Japan and the Caribbean (RNA retrovirus)
what are the usual effects of human papillomavirus?
- many subtypes
- causes common wart (squamous cell papilloma)
- the lesion occurs most commonly on the hand, which enables transmission between individuals
- virus is abundant in abnormal cells of the lesion
what causes anogenital and cervical warts?
low-risk HPV types
what causes the common wart (squamous cell papilloma)?
- benign
- spontaneously regressing
- HPV 6 or 11
what causes precursor, CIN and cancer of the cervix?
- high risk types HPV 16 and 18
what is Epstein-Barr virus?
- first discovered in cell cultures from Burkitt’s lymphoma (B-cell lymphoma endemic in certain regions of Africa, occurring only sporadically elsewhere)
- not the only cause of Burkitt’s lymphoma
- malaria may be a cofactor for Burkitt’s lymphoma
- causes nasopharyngeal carcinoma in the Far East
how can UV light act as a carcinogen? what can protect against it?
- skin cancer more common on parts of body exposed to sunlight
- UVB more than UVA
- melanin can act as a protective agent
what types of cancer are associated with UV light exposure?
- most types of skin cancer
- malignant melanoma and basal cell carcinoma
- increased risk in patients with Xeroderma pigmentosum; numerous skin cancers occur due to DNA damage by skin cells
what tumours are hepatitis B and C viruses associated with?
hepatocellular carcinoma; strong association
what tumours is human herpesvirus-8 associated with?
- Kaposi’s sarcoma
- primary effusion lymphoma
- explains association between sexually acquired AIDS and Kaposi’s sarcoma
what tumour is associated with human T-cell lymphotropic virus-1? where is it endemic?
- adult T-cell leukemia/lymphoma
- endemic in Southern Japan and Caribbean basin
what are examples of hormones acting as carcinogens?
- exogenous oestrogens can be shown to promote formation of mammary and endometrial carcinomas
- weak association between breast carcinoma and oral contraceptives containing oestrogens
- androgenic and anabolic steroids induce hepatocellular tumours
- oestrogenic steroids may make pre-existing lesions abnormally vascular
give an example of bacteria acting as a carcinogen
- helicobacter pylori causes gastritis and peptic ulceration
- strongly implicated in the pathogenesis of gastric MALT lymphomas
- initially, the lesions are dependent on continuing presence of H. pylori, but eventually become fully autonomous
- H. pylori is associated with gastric adenocarcinoma
what are mycotoxins?
toxic substances produced by fungi
what are examples of fungi acting as carcinogens?
- aflatoxins produced by Aspergillus flavus are among the most potent carcinogens
- especially aflatoxin B1
- linked to high incidence of hepatocellular carcinoma in certain parts of Africa
what are examples of parasites acting as carcinogens?
- Schistosoma haematobium is implicated with bladder cancer formation (esp. in Egypt)
- liver flukes Opisthorachis viverrini and Clonorchis sinensis (dwell in bile ducts where they induce an inflammatory reaction and epithelial hyperplasia) are associated with adenocarcinoma of the bile ducts (cholangiocarcinoma), esp. in Far East
what lesions does inhalation of asbestos fibres lead to?
- asbestosis
- pleural plaques
- malignant mesothelioma
- carcinoma of the lung
where can mesothelioma occur? what is it associated with?
- exceptionally rare in absence of asbestos exposure
- pleura is the most frequent site
- strong association for peritoneal mesothelioma
what are host factors that influence the cancer risk?
- race
- diet
- constitutional factors
- premalignant lesions and conditions
- transplacental exposure
why is oral cancer common in India and South-East Asia?
- not due to race
- due to tobaccco/betel nut chewing and reverse smoking
what is an example of the effect of race on cancer?
- cancer of the stomach is uncommon in Africa
- incidence in North American blacks of African descent is higher than the white population
what are dietary factors that increase cancer risk?
- positive correlation between high dietary fat, red or processed meat with colorectal cancers
- alcohol is a risk factor for breast and oesophageal cancer
what is a dietary factor that may be protective against cancer risk? how does it do this?
- dietary fibre
- promotes more rapid intestinal transit; any carcinogens in the bowel contents remain in contact with the mucosa for a shorter time
what tumour is multiple endocrine neoplasia associated with? why?
- endocrine tumours
- several types (MEN I, II, III) are attributed to MEN1 gene on chromosome 11 and to RET gene (MEN II and III) on chromosome 10 (AD)
what tumour is xeroderma pigmentosum associated with? why?
- skin tumours
- unrepaired UV-induced DNA lesions
- due to deficiency of DNA nucleotide excision repair enzymes
- due to autosomal recessive inheritance of one of the XP genes
what tumours is familial adenomatous polyposis coli associated with? why?
- colorectal adenomas and adenocarcinomas
- cancer preceded by > 100 adenomatous polyps
- inherited mutant APC gene on chromosome 5 (AD)
what tumours is hereditary non-polyposis colorectal cancer or Lynch syndrome associated with? why?
- colorectal carcinoma and others
- mutated genes (MLH1 on chromosome 3 or MSH2 on chromosome 2) involved in DNA mismatch repair (AD)
what tumours is von Hippel-Lindau syndrome associated with? why?
- renal cell carcinoma, cerebellar haemangioblastoma, phaeochromocytoma
- AD inheritance of mutant VHL gene on chromosome 3
what tumours is Li-Fraumeni syndrome associated with? why?
- breast carcinoma, soft-tissue sarcomas, leukemia, brain tumours
- AD inheritance of mutant p53 gene on chromosome 17
what tumour is retinoblastoma syndrome associated with? why?
- retinoblastoma
- AD inheritance of mutant RB1 gene on chromosome 13
what tumours is familial breast carcinoma associated with? why?
- breast carcinoma
- ovarian carcinoma
- prostatic carcinoma (males)
- AD inheritance of mutated BRCA1 gene on chromosome 17 or BRCA2 gene on chromosome 13
what tumour is fanconi anaemia associated with? why?
- leukemia, other tumours
- bone marrow failure
- congenital effects
- AR inheritance of a FANC gene with deficiency of the FA DNA repair pathway
how does incidence of cancer change with age?
increases with age
how can the effect on incidence of cancer by increasing age be explained?
- cumulative risk of exposure to carcinogens
- long latent interval
- accumulating mutations may make ageing cell more sensitive to carcinogenic effects
- incipient tumours developing in young people may be eliminated by a defence system, and this may be lost with age
how much more common is breast cancer in women?
200 times
why is breast cancer more common in women than in men?
- greater mammary epithelial volume
- promoting effects of oestrogens
- more common in women who are nulliparous and those who experienced early menarche/late menopause
what is a premalignant lesion?
an identifiable local abnormality associated with an increased risk of a malignant tumour developing at that site
what are examples of premalignant lesions?
- adenomatous polyps of the colon and rectum
- epithelial dysplasias in various sites, esp. in the cervix
what is a premalignant condition?
one that is associated with an increased risk of malignant tumours
what are examples of premalignant conditions?
- chronic UC: increased risk of colorectal cancer
- congenital abnormalities can predispose to cancer
- undescended testis is more prone to neoplasms
- in hepatic cirrhosis, there’s an increased risk of hepatocellular carcinoma
what is an example of a transplacental carcinogenesis?
administration of the carcinogen, diethylstilbestrol, to the mother and the carcinogenic effect only being exhibted only in the child as vaginal clear cell adenocarcinoma
what is the latency part of carcinogenesis?
- tumours result from clonal proliferation of single cells, which takes time to grow into a nodule of cells large enough to cause signs and symptoms
- change from a normal cell into a growing and potentially fatal neoplasm has multiple genetic events
what is initiation in carcinogenesis?
where a carcinogen induces the genetic alterations that give the transformed cell its neoplastic potential
what is promotion in carcinogenesis?
stimulation of clonal proliferation of the initiated transformed cell
what is progression in carcinogenesis?
process culminating in malignant behaviour characterised by invasion and its consequences
what is an example of the sequence of initiation, promotion and progression in carcinogenesis?
- initiator: methylcholanthrene. acts as a mutagen to induce mutations in relevant genes. these are initiated cells.
- a promotor e.g. croton oil stimulates proliferation of initiated cells to form a benign tumour (papilloma)
- progression: further genetic and epigenetic changes leads to progression to invasive malignancy (carcinoma)
how does an adenocarcinoma develop?
- a single epithelial cell within a mucosal gland becomes transformed into a tumour cell by carcinogenic events
- abnormal cell proliferates to produce a clone of cells populating one gland (monocryptal adenoma)
- further proliferation forms a benign, non-invasive adenoma (adenomatous polyp) protruding from the mucosal surface
- transformed cells become malignant due to genetic/epigenetic changes
- malignant cells invade blood vessels and lymphatics and metastasise
what is the chromosomal abnormality in Burkitt’s lymphoma? what does this lead to?
- translocation of c-myc oncogene (chromosome 8) to immunoglobulin gene locus (chromosome 14)
- results in aberrant expression of c-myc oncogenes in B cells, driving proliferation
what is the chromosomal abnormality in chronic myeloid leukaemia? what does this lead to?
- translocation involving chromosomes 9 (c-abl) and 22 (bcr) (Philadelphia chromosome)
- results in fusion of c-abl and bcr to form a chimaeric gene; bcr-abl fusion protein has tyrosine kinase activity
what is the chromosomal abnormality in follicle centre cell lymphoma? what does this lead to?
- translocation involving chromosomes 14 (Ig locus) and 18 (bcl-2)
- results in aberrant expression of bcl-2 oncogene, inhibiting apoptosis
what is the chromosomal abnormality in Ewing’s tumour and peripheral neuroectodermal tumour? what does this lead to?
- translocation involving chromosomes 11 (fli-1) and 22 (ews)
- EWS-FLI-1 fusion protein expressed. distinguishes tumours from neuroblastoma
what genetic alterations are required to transform a normal cell into a neoplastic cell?
- expression of telomerase, to avoid replicative senescence resulting from telomeric shortening with each cell division
- loss or inactivation of both copies of a tumour suppressor gene, to remove inhibitory control of cellular replication
- activation or abnormal expression of oncogenes, to self-stimulate cell proliferation
what does telomerase do? how does it affect telomeres and cells?
- telomerase expression confers immortalisation on the cells
- cells lacking telomerase (most cells, except stem/germ cells) have limited replicative ability
- chromosomal telomeres shorten each time a cell divides
- eventually telomeres become so short that there is loss of repetitive telomeric sequences at the ends of chromosomes, triggering cellular senescence and death
which normal cells do have telomerase?
stem cells and germ cells
what does maintenance of genomic integrity involve? what occurs if these processes fail?
- involves genes and their products that sense and repair DNA damage
- failure leads to genomic instability which leads to neoplastic transformation
what are two major patterns of genomic instability?
- chromosomal instability (e.g. Fanconi anaemia) causing chromosome breaks
- microsatellite instability (e.g. hereditary non-polyposis colorectal cancer) due to defective DNA mismatch repair
what are the key steps in neoplastic transformation?
- normal cell -> immortalisation due to telomerase expression
- removal of growth inhibition by inactivation of tumour suppressor gene function (e.g. p53, pRB)
- autocrine growth stimulation by oncogene activation e.g. Ras
- neoplastic transformation
what is the two hit hypothesis? how does this apply to sporadic tumours?
- first hit is the inheritance of a mutant (defective) allele of a tumour suppressor gene, the other allele being normal (wild type) and expressing sufficient suppressive effect
- second hit is the acquired mutational loss of function of the normal allele, depriving the cell of suppressive effect of the tumour suppressive gene
- in sporadic tumours, both hits are required
how are tumour suppressor genes further categorised according to their mechanism of function?
- caretaker genes: maintain the integrity of the genome by repairing DNA damage
- gatekeeper genes: inhibit the proliferation or promote the death of cells with damaged DNA
what are caretaker genes?
- type of tumour suppressor genes
- maintain the integrity of the genome by repairing DNA damage
what are gatekeeper genes?
- type of tumour suppressor genes
- inhibit the proliferation or promote the death of cells with damaged DNA
what was the first inhibitory tumour suppressor gene to be well characterised? what is it associated with?
- RB1 gene
- retinoblastomas
what are retinoblastomas? where do they occur? what are their characteristics?
- malignant tumours derived from the retina
- occur almost always in children
- may be hereditary, occur bilaterally and in siblings
- may be sporadic, occurring unilaterally and without familial associations
what is the genetic component of retinoblastomas?
- some with hereditary retinoblastomas show a germline deletion on chromosome 13 (location of RB1)
- only one further mutational loss of the other gene in any target retinal cell is needed for a tumour to develop
- sporadic retinoblastoma cases have two normal chromosomes 13 and require two mutations or losses of RB1 in the same cell before the tumour can develop
what is p53? where is it located?
- tumour suppressor gene
- short arm of chromosome 17
- gene most frequently mutated and extensively studied in human cancer
what are the normal functions of p53 protein?
- enable repair of damaged DNA before S phase in the cell cycle by arresting the cell cycle in G1 until it’s repaired
- enabling apoptotic cell death if there is extensive DNA damage
what are examples of gatekeeper genes?
p53, RB1, APC
what is the function and tumour susceptibility of p53?
- transcriptions factor that responds to DNA damage
- Li-Fraumeni syndrome
- also mutated in 50% of cancers
what is the function and tumour susceptibility of RB1?
- transcription regulator; controls cell cycle G1/S checkpoint
- familial retinoblastoma
- often mutated in other human cancers
what is the function and tumour susceptibility of APC?
- regulates beta-catenin function in Wnt pathway
- familial adenomatous polyposis coli
- often mutated in sporadic colorectal cancers
what are examples of caretaker genes?
- BRCA1/2
- MSH2
- MLH1
- FANC genes
- XP genes
what is the function and tumour susceptibility of BRCA1?
- DNA repair; d/s breaks
- breast and ovarian cancer
- rarely mutated in sporadic breast cancers
what is the function and tumour susceptibility of BRCA2?
- DNA repair; d/s breaks
- breast, prostate and pancreatic cancer
- homozygous mutation associated with Fanconi anaemia
what is the function and tumour susceptibility of MSH2 and MLH1?
- DNA repair; mismatch repair pathway
- hereditary non-polyposis colorectal cancer or Lynch syndrome
- defective mismatch repair permits mismatch mutations and tumour formation
what is the function and tumour susceptibility of FANC genes?
- DNA repair; Fanconi anaemia repair pathway
- Fanconi anaemia
- defective Fanconi anaemia DNA repair pathway permits cross-link mutations and tumour formation
what is the function and tumour susceptibility of XP genes?
- DNA repair; nucleotide excision repair pathway
- Xeroderma pigmentosum
- defective nucleotide excision repair pathway permits UV-mutations and tumour formation
what happens to p53 levels in cells with DNA damage? what does this prevent?
increase until either the damage is repaired or the cell undergoes apoptosis
- prevents propagation of possibly mutated genes
by which mechanisms can p53 lose its normal function?
- non-sense mutations or missense mutations
- complexes of normal p53 and mutant p53 inactivating/subverting the function of the normal protein
- binding of normal p53 protein to proteins encoded by oncogenic DNA viruses
what is a consequence of altered p53 function?
undergo mitotic replication rather than apoptotic death
what is the genetic component of Li-Fraumeni syndrome?
- inherited predisposition to a wide range of tumours
- at birth they are heterozygous for the defective gene
- eventually the normal allele is lost or mutated, enabling neoplastic transformation
what is loss of heterozygosity?
normal allele is lost or mutated
what are oncogenes?
genes driving the neoplastic behaviour of cells
what are oncogenic RNA retroviruses?
RNA viruses that can transfer their genome/parts of it to the genome of cells they infect
what enzyme do retroviruses contain? what does it do?
- reverse transcriptase
- enables viral RNA to be reverse transcribed into complementary DNA, which is incorporated into the cell’s genome
what genes do oncogenic viruses contain?
viral oncogenes
how can proto-oncogenes be necessary for life?
- transcription of proto-oncogenes is tightly controlled
- present in genome of even primitive protozoa and metazoa
- cellular oncogenes are needed for tissue growth and differentiation, esp. in embryogenesis and healing
- when activated, they contribute towards tumour growth
what is transfection?
normal or partially transformed cell cultures can be fully transformed by addition of DNA bearing oncogenes
what is transduction?
oncodenic retroviruses can transform cells by transferring oncogenes from another cell
how can oncogenes be classified?
into 5 groups according to the function of the oncoprotein
what are the five classifications of oncogenes?
give examples for each
- growth factors (e.g. sis coding for PDGF)
- receptors for growth factors (e.g. erbB coding for EGF receptor)
- signalling mediator with tyrosine kinase activity (e.g. src)
- signalling mediator with nucleotide binding activity (e.g. ras and GTP) disrupting intracellular signalling
- nuclear binding transcription factor oncoproteins involved in regulation of cellular proliferation (e.g. myc)
what can oncogenes be activated by?
- mutation: leading to an oncoprotein altered so it is excessively active
- excessive production of a normal oncoprotein: due to gene amplification, enhanced transcription or reduced degradation
what can increased expression of oncogenes be detected by?
- presence of more than one oncoprotein within or on cells
- increased production of mRNA transcripts of the oncogene
- increased numbers of copies of the oncogene in the genome
what is the genetic mechanism of inherited retinoblastoma? what does it produce?
- inherited germline mutation or absence of one of the paired RB1 genes
- mutation or loss of RB1 gene in any retinal cell
- bilateral retinoblastoma
what is the genetic mechanism of sporadic retinoblastoma? what does it produce?
- normally paired RB1 genes
- mutation or loss of one RB1 gene
- mutation or loss of other RB1 gene in same cell or its daughter cells
- unilateral retinoblastoma
what are the mechanisms of oncogene activation?
- translocation of an oncogene from an untranscribed site to a position adjacent to an actively transcribed gene
- point mutation where the substitution of a single base in the oncogene is translated into an amino acid substitution of a single base in the oncoprotein, causing it be hyperactive
- amplification by insertion of multiple copies of the oncogene. leads to cellular proliferation
- insertional mutagenesis: insertion of promoter/enhancer sequences of a retrovirus, leading to proximity of an oncogene to a promoter, which activates its expression
what is an example of translocation in activating oncogenes?
- simplified chromosomal translocation in Burkitt’s lymphoma, where the c-myc oncogene is translocated from chromosme 8 to 14l where it’s placed adjacent to an immunoglobulin gene, and is then transcribed in the B lymphocytes
what is an example of point mutations activating oncogenes?
codon 12 in the ras oncogene
- signalling mediator with nucleotide binding activity
- results in a gene product with increased or inappropriate activity
what is an example of amplification activating oncogenes?
N-myc in neuroblastoma
how is the Philadelphia chromosome formed? what does this express?
- translocation of the c-abl gene from chromosome 9 to 22,
- expression of a bcr-abl fusion protein in chronic myeloid leukaemia
what can cause aberrant or autocrine stimulation of growth? what can this lead to?
- when expressed in inappropriate circumstances, a cell can become autonomous and proliferate without external signals
- oncoproteins may transmit growth signals within the cell or convert growth signalling into changes in gene expression, triggering cell division
what causes epigenetic contribution?
results from aberrant expression of normally repressed non-mutated genes or repression of normally active genes
what are mechanisms for epigenetic contribution to tumour growth?
- gene silencing by hypermethylation of promotor DNA sequences
- gene up- or down- regulation due to histone modifications (methylation, acetylation, phosphorylation)
- interference of gene transcription by microRNA (short sequences of inhibitory RNA) with increased miRNA leading to more degradation of mRNA and reduced expression
- copy number changes to enhancer and silencer DNA sequences alter control of gene expression
what is the function and discovery of the sis oncogene?
- simian sarcoma virus
- growth factor (PDGF)
what is the function and discovery of the erb-B oncogene?
- avian erythroblastosis virus
- receptor (EGF)
what is the function and discovery of the src oncogene?
- rous sarcoma virus
- intracellular signalling (protein-tyrosine kinase)
what is the function and discovery of the abl oncogene?
- abelson mouse leukaemia virus
- intracellular signalling (protein-tyrosine kinase)
what is the function and discovery of the ras oncogene?
- rat sarcoma cirus
- intracellular signalling (GTP-binding, binary switch)
what is the function and discovery of the erk oncogene?
- extracellular-signal-regulated kinase
- intracellular signalling (serine-threonine kinase)
what is the function and discovery of the myc oncogene?
- avian myelocytomatosis virus
- transcription factor (driving proliferation, regulating apoptosis)
what is the epithelial-mesenchymal transition?
in epithelial neoplasms, invasion and metastasis require the acquisition of motile and migratory properties normally associated with cells of mesenchymal lineage
what are factors influencing tumour invasion?
- decreased cellular adhesion
- secretion of proteolytic enzymes
- abnormal or increased cellular motility
how do adhesion factors affect invasion of tumours?
- altered expression of adhesion molecules (e.g. E-cadherin) allows decreased cell-cell adhesion in carcinomas
- integrin receptors are dispersed around the tumour cell to allow altered tumour cell-matrix adhesion
what is motility like in normal cells?
- more motile than normal
- show loss of normal mechanism that arrests or reverses normal cellular migration (contact inhibition of migration)
what are one of the most important proteinases in neoplastic invasion?
matrix metalloproteinases
what are matrix metalloproteinases secreted by? what is their function?
- secreted by malignant neoplastic cells
- digest surrounding connective tissues
what are the three major families of matrix metalloproteinases? what do they each digest?
- interstitial collagenases: degrade types I, II and III collagen
- gelatinases: degrade type IV collagen and gelatin
- stromelysins: degrade type IV collagen and proteoglycans
what are matrix metalloproteinases counteracted by?
tissue inhibitors of metalloproteinases (TIMPs)
- net effect determined by the balance
what tissues offer least resistance to tumour growth?
- perineural spaces and vascular lumina
- invasion often occurs here
what tissues offer most resistance to neoplastic invasion?
- cartilage
- fibrocartilage of intervertebral discs
how can invasion be recognised in epithelial tumours?
- basement membrane is a clear line of demarcation between tissue boundaries
how can invasion be recognised in connective tissue tumours?
- less easy to recognise
- unless there is clear evidence of vascular or lymphatic permeation; other histological features are assessed for prognosis
what is invasion within epithelium called? what is it named after?
- pagetoid infiltration
- named after Paget’s disease of the nipple, which is due to infiltration of the epidermis of the nipple by tumour cells from a ductal carcinoma in the breast
what is pagetoid infiltration?
invasion within epithelium
what is metastasis?
process whereby malignant tumours spread from their site of origin (primary tumour) to form other tumours at distant sites (secondary tumours)
what is carcinomatosis?
extensive metastatic disease
what are the steps involved in the metastatic sequence?
- detachment of tumour cells from their neighbours
- invasion of the surrounding connective tissue to reach conduits for metastasis
- intravasation into the lumen of the vessels
- evasion of host defence mechanisms
- adherence to endothelium at a remote location
- extravasation of the cells from the vessel lumen into the surrounding tissue
on reaching the site of metastasis, there is recapitulation of the events required for primary tumour growth
what are possible mediators of the detachment process of metastasis? what are its consequences?
- loss of surface adhesion molecules
- migration of individual cells enabled
what are possible mediators of the invasion process of metastasis? what are its consequences?
- metalloproteinases
- upregulation of integrin expression
- down-regulation of tissue inhibitors of metalloproteinases
- erosion of tissue boundaries
what are possible mediators of the intravasation process of metastasis? what are its consequences?
- metalloproteinases
- down-regulation of tissue inhibitors of metalloproteinases
- access to vascular routes of dissemination
what are possible mediators of the evasion of host defences process of metastasis? what are its consequences?
- reduced expression of MHC class I antigen
- shedding of ICAM-1 blocks T-cell receptor
- survival against host defences
what are possible mediators of the adherence process of metastasis? what are its consequences?
- binding of CD44 to endothelial ligand
- arrest of movement by adhesion to endothelium
what are possible mediators of the extravasation process of metastasis? what are its consequences?
- integrins
- Laminin receptor
- colonisation of site of metastasis
what are the routes of metastasis?
- haematogenous (by blood stream): to form secondary tumours in organs perfused by blood that’s drained from a tumour
- lymphatic: to form secondary tumours in the regional lymph nodes
- transcoelomic: in pleural, pericardial and peritoneal cavities where there is a neoplastic effusion
what route of metastasis do carcinomas prefer?
lymphatic spread
what route of metastasis do sarcomas prefer?
haematogenous spread
what organs are commonly affected by haematogenous metastases? what are the tumours like?
- liver, lung, bone, brain
- bone is favoured by haematogenous metastases by 5 carcinomas: lung, breast, kidney, thyroid and prostate
- metastases are frequently multiple, and primary tumours are usually solitary
- solid tumours rarely metastasise to skeletal muscle or spleen
what are the effects of lymphatic metastases?
- tumour cells reach the lymph node through the afferent lymphatic channel
- tumour cells settle and grow in the periphery of the node, extending to replace
- lymph nodes are usually firmer and larger, and groups may be matted together by tumour tissue and connective tissue reaction to it
- may cause oedema
where does transcoelomic metastasis occur? what is the fluid like?
- peritoneal, pleural and pericardial cavities - leads to effusion of fluid into the cavity
- fluid is rich in protein and may contain fibrin, and neoplastic cells
- cytological examination of the aspirated fluid is important in diagnosing the cause of effusions
- tumour cells often grow as nodules on the mesothelial surface of the cavity
how do tumours exert local effects?
through compression and displacement of adjacent tissues and, if malignant, through their destruction by invasion
what are examples of tumour type-specific effects?
- thryotoxicosis may result from a thyroid adenoma
- Cushing’s syndrome may result from an adrenocortical adenoma
- hyperparathyroidism may result from a parathyroid adenoma
what are paraneoplastic syndromes? give an example
metabolic consequences of a tumour may be unexpected or inappropriate
- e.g. small cell carcinomas of the lung often secrete ACTH or ADH
what is cachexia?
- catabolic clinical state of a cancer patient with severe weight loss and debility
- mediated by tumour-derived humoral factors that interfere with protein metabolism
- can occur early
how do non-specific metabolic effects affect weight?
- disseminated malignant tumours are associated with profound weight loss despite adequate nutrition
- weight loss could be due to interference with nutrition due to oesophageal obstruction, severe pain, depression, etc
what is the Wharburg Effect?
- cancers producing energy by high rate of glycolysis with fermentation of lactic acid, whereas normal cells have a low rate of glycolysis with oxphos
how can the Wharburg Effect be used clinically?
to image tumours by PET using 2-18F-2-deoxyglucose (FDG) as the Wharburg Effect increases FDG uptake by tumours
what are examples of non-specific tumour effects?
- neuropathies and myopathies are associated with presence of malignant neoplasms, esp. with lung carcinoma
- venous thrombosis is associated with mucus-producing adenocarcinomas, esp. pancreas
- glomerular injury can result from deposition of immune complexes provoked by tumour antigen
what is a patient’s treatment guided by?
- tumour type
- grade/degree of differentiation
- stage or extent of spread
what is done to determine tumour type?
- cellular appearances and its relationship to the surrounding structures from which a direct origin may be evident
- subclassification if variants with different behaviours exist
- genetic analysis or immunohistology may be used
what are the features contributing to the assessment of tumour grade?
- mitotic activity
- nuclear size, hyperchromasia and pleomorphism
- degree of resemblance to the normal tissue
what is the stage of a tumour?
the extent of spread
how is tumour stage determined?
histopathological examination of the resected tumour and by clinical assessment of the patient, e.g. by imaging
when was the Duke system devised? who by, and what for?
- 1930
- Cuthbert Dukes
- colorectal cancers
what are the Dukes categories?
Dukes’ A: invasion into, but not through, the bowel muscular wall
Dukes’ B: invasion through the bowel muscular wall but without lymph node metastases
Dukes’ C: involvement of the local lymph nodes
Dukes’ D: hepatic metastases present
what is the TNM system? what are its stages?
T: primary tumour, suffixed by a number indicating tumour size/local anatomical extent, varying according to organ
N: lymph node status, suffixed by a number denoting the number of lymph nodes containing metastases
M: anatomical extent of distant metastases
what is tumour dormancy?
minute deposits can evade detection by the most sophisticated imaging techniques, and remain dormant before their regrowth causes signs and symptoms
what is innate immunity?
instinctive, non-specific, does not depend on lymphocytes, present from birth
what is adaptive immunity?
- specific acquired/learned immunity
- requires lymphocytes and antibodies
what are innate and adaptive immunity made of?
cells and soluble factors (humoral)
what categories do leukocytes have?
- lymphocytes
- phagocytes
- auxillary cells
what are types of lymphocyte?
- B cell
- T cell
- large granular lymphocyte
what are types of phagocyte?
- mononuclear phagocyte
- neutrophil
- eosinophil
what are types of auxillary cells?
- basophil
- mast cell
- platelets
what are examples of soluble mediators?
- antibodies
- cytokines
- complement
- inflammatory mediators
- interferons
what are antibodies produced by?
B lymphocytes
what are cytokines produced by?
- T lymphocytes, large granular lymphocytes and mononuclear phagocytes
- tissue cells
what are complements produced by?
mononuclear phagocytes
what are inflammatory mediators produced by?
basophils, mast cells and platelets
what do tissue cells produce?
interferons and cytokines
what does the multipotent haematopoietic stem cell (haemocytoblast) produce in haematopoiesis?
- common myeloid progenitor cells
- common lymphoid progenitor cells
what mediates the differentiation of haemocytoblasts into common myeloid progenitor cells?
- IL-f, IL-3, IL-6, GM-CSF, SCF
what can common myeloid progenitor cells differentiate into?
- megakaryocytes
- erythrocytes
- myeloblasts
what mediates the differentiation of common myeloid progenitor cells into megakaryocytes?
SCF, TPO, IL-3, GM-CSF
what mediates the differentiation of common myeloid progenitor cells into erythrocytes?
SCF, Epo, IL-3, GM-CSF
what mediates the differentiation of common myeloid progenitor cells into myeloblasts?
GM-CSF
what do megakaryocytes produce?
thrombocytes
what can myeloblasts differentiate into?
- basophils
- neutrophils
- eosinophils
- monocytes
what mediates the differentiation of myeloblasts into basophils and neutrophils?
SCF, G-CSF, GM-CSF, IL-3, IL-6
what mediates the differentiation of myeloblasts into eosinophils?
IL-3, IL-5, GM-CSF
what mediates the differentiation of myeloblasts into monocytes?
SCF, M-CSF, GM-CSF, IL-3, IL-6
what can a common lymphoid progenitor cell differentiate into? what is this mediated by?
- small lymphocyte
FLT-3 ligand, TNF-a, TGF-b1, IL-2, IL-7, IL-12, SDF-1
what can small lymphocytes differentiate into?
B and T lymphocytes
- B in the bone marrow and T in the thymus
what mediates the differentiation of small lymphocytes into T lymphocytes?
IL-1, IL-2, IL-4, IL-6, IL-7
what cells are classed as polymorphonuclear leukocytes?
- neutrophils
- eosinophils
- basophils
what cells are classed as mononulear leukocytes?
- monocytes
- T cells
- B clels
what do monocytes differentiate into?
macrophages in tissue
what are the types of T lymphocytes?
- T regulator lymphocytes
- T helper lymphocytes (CD4) (Th1 and Th2)
- Cytotoxic T lymphocytes (CD8)
what do B lymphocytes differentiate into?
plasma cells
what are complement substances?
- soluble factors
- group of ~20 serum proteins secreted by the liver that need to be activated to be functional
- are activated only as part of the immune system through 3 pathways
what are the modes of action of complement substances?
- direct lysis
- attract more leukocytes to the site of infection
- coat invading organisms
what are antibodies?
- heavy globular plasma proteins that bind specifically to antigens
what is an example of an antibody?
immunoglobulins
what are immunoglobulins?
- soluble glycoproteins
- secreted
- bound to B cells as part of B-cell antigen receptor
what are the classes of Ig’s?
IgG (IgG1-4) IgA (IgA1 and 2) IgM IgD IgE
what are the regions/sites in IgG?
- Fab
- Fc
- light chains: kappa and lamda (212 residues)
- heavy chain (450 residues)
- variable region
- hinge region
what proteins are the light chains made up of in IgG?
V(L), C(L)
V(H), C(H)1
what proteins is the heavy chain in IgG made up of?
C(H)2, C(H)3
what is the most predominant Ig in human serum? what is its proportion?
IgG: 70-75%
what is the structure of IgM?
- pentamer, formation requires J chain
- same light chains and proteins as IgG
- C(H)4 also present
what is the function of IgM? where is it found?
- mainly primary immune response, initial contact with antigens
- found in blood, too big to cross endothelium
what is the monomeric form of IgM? what is its function?
mIgM
- antigen-specific receptor on B cells
what is the proportion of IgM in serum?
10%
what is the proportion of IgA in serum?
15%
what is the structure of IgA?
- in humans, 80% of serum IgA is a monomer (most animals have it as a dimer)
what is the predominant Ig in mucous secretions?
- e.g. saliva, colostrum, milk, bronchiolar and genitourinary secretions
- secretory IgA (sIgA)
what is the structure of sIgA?
dimer
- held together with a J chain and a secretory component
what is the proportion of IgD in serum?
1%
what is the structure of IgD?
- light chains
- carbohydrate units
- hinge region
- tailpieces
what is mIgD?
transmembrane monomeric form of IgD, present on mature B cells
what is the proportion of IgE in serum?
~0.05%
what is the function of IgE?
- associated with hypersensitivity allergic response and defence against parasitic infections
- basophils and mast cells express an IgE-specific receptor that has high affinity for IgE; they are continually saturated with it
- binding Ag triggers release of histamine by basophils and mast cells
what is the structure of IgE?
- light chains
- same proteins as IgG, with added C4
- Fc portion
- carbohydrate unit
what is the function of an antibody? what is the process of binding?
- acts as an adapter that links a microbe to a phagocyte
- the antigen has an epitope which binds to the antigen-binding site on the antibody’s Fab region
- the antibody’s Fc region binds to the Fc receptor and the phagocyte
what are cytokines? give examples
proteins secreted by immune and non-immune cells
- interferons
- interleukins
- colony stimulating factors
- tumour necrosis factors
what are interferons? give examples
type of cytokine that induce a state of antiviral resistance in uninfected cells and limit the spread of viral infection
- IFN alpha and beta: produced by virus infected cells
- IFN gamma: released by activated Th1 cells
what are interleukins? give examples
- produced by over 30 types of cells
- can be proinflammatory (IL-1) or anti-inflammatory (IL-10)
- can cause cells to divide, differentiate and secrete factors
what is the function of colony stimulating factors?
involved in directing division and differentiation of bone marrow stem cells
what is the function of tumour necrosis factors?
- e.g. TNF alpha and beta
- mediate inflammation and cytotoxic reactions
what are chemokines?
group of ~40 proteins that direct movement of leukocytes and other cells from the bloodstream into the tissues or lymph organs, by binding to specific receptors on cells
what are examples of chemokines?
CXCL
CCL
CX3CL
XCL
what does CXCL (chemokine) affect?
mainly neutrophils
what does CCL (chemokine) affect?
monocytes, lymphocytes, eosinophils, basophils
what does CX3CL (chemokine) affect?
mainly T lymphocytes and natural killer cells
what does XCL (chemokine) affect?
mainly T lymphocytes
what are characteristics of innate (non-specific) immunity?
- first line of defence
- provides barrier to antigen
- instinctive
- present from birth
- slow response
- no memory
- doesn’t depend on lymphocytes
what are characteristics of adaptive (specific) immunity?
- response is specific to antigen
- learnt behaviour
- memory to specific antigen
- quicker response
what is innate immunity composed of?
- physical and chemical barriers
- phagocytic cells (neutrophils and macrophages)
- blood proteins (complement, acute phase)
what are examples of physical barriers to infection in the skin/eyes?
- lysozyme in tears and other secretions
- skin: physical barrier, fatty acids, commensals
what are examples of physical barriers in the respiratory system?
- removal of particles by rapid passage of air over turbinate bones
- mucus and cilia in the bronchi
- commensals
what are examples of physical barriers in the GI/GU systems?
- gut: acid, rapid pH change from stomach to intestines, commensals in the intestines
- flushing of urinary tract
- low pH and commensals of the vagina
what happens when physical barriers are breached?
tissue damage (trauma) or infection
what is the response to a breach in physical barriers?
- coagulation
- acute inflammation
- kill pathogens, neutralise toxins, limit pathogen spread
- phagocytosis
- proliferation of cells to repair damage
- remove blood clot and remodel extracellular matrix
- re-establish normal structure/function of tissue
what is inflammation?
a series of reactions that bring cells and molecules of the immune system to sites of infection or damage
what are hallmarks of inflammation?
- increased blood supply
- increased vascular permeability
- increased leukocyte transendothelial migration (extravasation)
what are sensing microbes?
blood: monocytes, neutrophils
tissues: macrophages, dendritic cells
what are sensing receptors?
PRRs on cells (pattern recognition receptors)
PAMPs on microbes (pathogen-associated molecular patterns)
what do TLRs do?
recognise PAMPs expressed by microbes
what are complements?
group of ~20 serum proteins that need to be activated to be functional
what are the activation pathways for complement activation?
- classical: antigen-antibody complexes (adaptive)
- alternative: complement binds to microbe
- lectin: activated by mannose binding lectin which is bound to the microbe
what are functions of complement?
- lysis of bacteria/microbes directly (MAC)
- chemotaxis (C3a and C5a)
- opsonisation (C3b)
what happens in extravasation by neutrophils? what mediates steps?
- CD15 receptor on neutrophil binds to E-selectin on endothelium
- chemokine receptor on neutrophil is affected by chemokines on endothelium
- integrin (CD18/CD11b) on neutrophil binds to adhesion molecules (ICAM-1) on the endothelium
- CD31/PCAM-1 enables movement through the endothelium into the tissue
- bug in the tissue is releasing TNFa throughout
what are the steps in phagocytosis?
- binding
- engulfment
- phagosome formation
- phagolysosome formation
- membrane disruption/fusion
- secretion/antigen presentation
what is involved in a bacterium binding to a phagocyte?
C3b receptors bind to FcR, CR, MR receptors
what happens in phagosome formation? what mediates this?
- acidification
- cytotoxic molecules
- proteolysis
- FA/11 (macrosialin, CD68)
what is secreted from the phagocyte?
H2O2, NO, TNFa etc
what are the two mechanisims of microbial killing present in neutrophils and macrophages?
O2 dependent and O2 independent
what is involved in O2 dependent mechanisms of microbial killing in neutrophils and macrophages?
Reactive Oxygen Intermediates (ROI)
- superoxides are converted to hydrogen peroxide then .OH (free radical)
- NO causes vasodilation, increases extravasation and is anti-microbial
what is involved in O2 independent mechanisms of microbial killing in neutrophils and macrophages?
- enzymes (e.g. lysozymes)
- proteins (e.g. defensins, TNF)
- pH
why do we need adaptive immunity?
- microbes evade innate immunity (proteases, decoy proteins etc)
- intracellular viruses and bacteria hide from innate immunity
- need memory to
what deals with intracellular and extracellular microbes?
intracellular: T/cell mediated
extracellular: humoral (Ab)/B cells
what are primary lymphoid organs?
- thymus (T cells)
- bone marrow (B cells)
- bone marrow (APC/dendritic cells/macrophages/B cells)
what are secondary lymphoid organs?
- spleen
- lymph nodes
- MALT
what are antigen presenting cells?
- macrophages
- dendritic cells
- B cells
why does cell-mediated immunity require intimate cell to cell contact?
- to control Ab responses via contact with B cells
- to directly recognise and kill viral infected cells
what does cell-mediated immunity require?
- MHC
- intrinsic/endogenous (intracellular) antigens
- extrinsic/exogenous antigens
what do T lymphocytes respond to?
do not respond to soluble antigens, only intracellular presented antigens
what is the outcome of T cell selection?
T cells that recognise self are killed in the foetal thymus as they mature
what do T cell receptors recognise? what is the process?
- foreign antigens in association with the MHC
- MHC molecule presents peptide from the infected cell
- antigen peptide is bound to the MHC molecule
- T cell receptor recognises MHC and peptide
what is the structure of T cell receptors?
- heterodimers: 90% are ab, 10% gd
- V alpha or gamma + V beta or delta
- C alpha or gamma + C beta or delta
what is the function of the MHC?
- displays peptides from self or non-self proteins (e.g. degraded microbial proteins on the cell surface - invasion alert)
what is the MHC coded by? what are the differences between MHC I and II?
- Human Leukocyte Antigen genes
- MHC I: coded by HLA (A, B and C genes) - glycoproteins on all nucleated cells (graft rejection)
- MHC II: coded by HLA (DP, DQ and DR genes) - glycoproteins only on APC
what is MHC III?
codes for secreted proteins (complement)
what is the structure of MHC class I?
alpha 1, 2 and 3
beta2m
8-10 aa peptide
on all nucleated cells
what is the structure of MHC class II?
alpha 1 and 2
beta 1 and 2
13-24 aa peptide
just on APC
what is the MHC class, T cell and function of intrinsic antigens?
intracellular e.g. virus
- MHC class I
- Tc (CD8)
- kill infected cell with intracellular pathogen
what is the MHC class, T cell and function of extrinsic antigens?
extracellular e.g. phagocytosis
- MHC class II
- Th (CD4)
- help B cells make antibodies for extracellular pathogen, can help directly kill
what co-stimulatory molecules are involved in T cell activation?
CD28 on T cell binds to CD80/CD86 on APC
- required for full T cell activation
what happens in T cell activation? what does this lead to?
IL-2 is secreted by and binds to IL-2R on T cells (autocrine)
leads to differentiation, division, effector functions, memory
what happens to CD3 in T cell activation?
phosphorylated. connects both TCR on T cells
what is the role of CD4 and CD8 in T cell activation?
binds MHC to Lck tyrosine kinase in the T cell; activates several events and leads to phosphorylation of CD3
what is a naive T cell?
alpha-beta T cell
what can naive T cells differentiate into?
CD4 and CD8 T cells
what can CD4 T cells differentiate into?
TH1 and TH2 cells
what is the differentiation of CD4 into TH1 cells mediated by?
IL-12hi
what is the differentiation of CD4 into TH2 cells mediated by?
IL-12lo
what is the function of CD8 T cells?
kill intracellular pathogens directly
what is the function of TH2 cells? what is this mediated by?
- antibody production
- activate eosinophils and mast cells
- helminth infections and allergy
- induce B cellls to make IgE, promotes release of inflammatory mediators
- IL-4, IL-5, IL-6, IL-10 and IL-13
what is the function of TH1 cells? what is this mediated by?
- helps kill intracellular pathogen
- activates macrophages which leads to inflammation
- promotes production of cytotoxic T cells
- induce B cells to make IgG antibodies
- IL-2, IFN-gamma, TNF beta
what causes the formation of a cytosolic T cell/Tc/CD8/CTL cell to form?
CD8 naive cell + MHC I/peptide = Tc/CTL
what actions does a cytosolic T cell perform?
- inflammatory cell recruitment (mediated
by chemokines, TNF, GM-CSF) - macrophage activation (mediated by IFNgamma), leading to intracellular killing
how does the cytosolic T cell affect infected host cells directly?
forms proteolytic granules and releases perforins and granulysin
- perforin leads to apoptosis
- granulysin leads to killing of the pathogen
how are Th1 (CD4) cells activated?
- APC presents Ag with MHC II to a naive CD4 T cell
- stimulation with high levels of IL-12 activates them to CD4 Th1 cells
what happens to activated CD4 Th1 cells?
- travel to secondary lymphoid tissue
- clonal expansion (proliferation)
- Th1 cell recognises Ag on infected cells with MHC II via CD4 TCR
- uses CD40L/CD40
- Th1 secretes IFNgamma and stops virus spread by apoptosis, and activates macrophages
what happens to B cells that recognise self?
killed in bone marrow
what is expressed on B cells?
membrane bound Ig (mIgM or mIgD)
how do B cells present Ag to T cells?
- Ag binds to mIgM/D and is phagocytosed
- peptide displayed on surface with MHC II
- TCR of naive Th (CD4) binds to MHC II
what connects naive Th (CD4) cells and B cells?
CD28 - CD80/CD86
CD40L - CD40
LFA-1 - ICAM-1/ICAM-3
CD2 - LFA-3
how do naive CD4+ T cells become primed?
- APC phagocytoses Ag (extrinsic) and presents it to naive CD4+ T cells via MHC II
- naive T cells turn into primed Th2 cells
what is the action of primed Th2 cells on B cells?
- Th2 cells bind to B cells that are presenting Ag (via MHC II)
- Ag captured by B cell using mIgR
- Th2 cell secretes cytokines (IL-4, IL-5, IL-10 and IL-13)
how do the cytokines secreted by Th2 cells affect B cells?
- causes B cells to divide (clonal explansion); this happens in the lymph nodes
- differentiate into plasma cells (antibody forming cells/AFC) and memory B cells (Bm)
what are secondary lymphoid organs and tissues?
- Waldeyer’s ring (tonsils and adenoids)
- bronchus associated lymphoid tissue
- spleen
- lymphoid nodules
- Peyer’s patches
- urogenital lymphoid tissue
what do plasma cells do after being produced?
secrete antibodies of same specificity but are generally IgM - later turn into IgG but still have same specificity to the same antigen (class switching)
what is class switching?
antibodies that have the same specificity, switch to a different type but keep the same specificity to the same antigen
what can specific secreted antibodies do?
- neutralise toxin by binding to it
- increase opsonisation/phagocytosis
- activate complement
what is the antibody role in antigen recognition? how does structure reflect this?
- Fab regions; variable in sequence
- bind specific antigens specifically
what is the antibody role in antigen elimination? how does its structure reflect this?
- Fc region; constant in sequence
- binds to complement, Fc receptors on phagocytes, NK cells, etc
what are variable regions in antibodies? how can they behave?
- bind antigens
- differ between antibodies with different specificities
- encoded by separate exon
- multiple V region exons in the genome can recombine and mutate during B cell differentiation to give different antibody specificities
what are constant regions in antibodies?
same for antibodies of a given H chain class or L chain type
what are the weights of light and heavy chains?
light: 25kD
heavy: 50kD
how do antibody classes differ between eachother?
- amino acid sequence of their heavy chains
- functions
what are the general functions of IgG?
- main class in serum and tissues
- important in secondary/memory responses
- crosses placenta
what are the general functions of IgM?
- important in primary responses
what are the general functions of IgA?
- in serum and secretions
- protects mucosal surfaces
what are the general functions of IgE?
- present at very low levels
- involved in allergy, response to parasitic infections
what is involved in antibody specific binding/multivalency?
- Fab
- neutralize e.g. toxins (IgG, IgA)
- immobilise motile microbes (IgM)
- prevent binding to, and infection of, host cells
- form complexes
what is involved in antibodies enhancing innate mechanisms?
- Fc
- activate complement (IgG, IgM)
- bind Fc receptors on phagocytes (IgG, IgA) to enhance phagocytosis, on mast cells (IgE) to release inflammatory mediators, and on NK cells (IgG) to enhance killing of infected cells
how are antibodies investigated in research, diagnostics and therapy?
- identify and label molecules in complex mixtures
- serotype pathogens
- identifying cell types
- humanized antibodies are used in therapy
what is OKT3’s specificity and indication?
- CD3
- transplant rejection
what is Campath’s specificity and indication?
- CD52
- chronic lymphocytic leukaemia
what is Herceptin’s specificity and indication?
- Her-2
- breast cancer
what is Remicade’s specificity and indication?
- TNF alpha
- Crohn’s disease, rheumatoid arthritis
what is CroFab’s specificity and indication?
- snake venom
- rattle snake antidote
what is Synagis’s specificity and indication?
- RSV
- respiratory syncitial virus
what is the function of T helper cells (CD4+)?
- help B cells make antibody
- activate macrophages and NK cells
- help development of cytotoxic T cells
what is the function of T regulatory cells (CD4+)?
- suppress immune responses
what is the structure of the TCR?
- very similar to Fab arm of an antibody
- V alpha and beta
- C alpha and beta
- multiple V region exons in the genome can recombine during T cell differentiation to give different TCR specificities
what is the difference between the antigens that B and T cells recognise?
- B cells recognise soluble, free, native antigens
- T cells recognise cell-associated, processed antigen
where are the HLA genes located?
chromosome 6
how polymorphic are HLA genes?
- most polymorphic proteins in humans
- many different alleles at each gene locus
- e.g more than 1400 alleles of HLA-B locus
how is the virus processed in virus infected cells in CD4 targeted cells?
- viral proteins are broken down in the cytosol
- peptides are transported to the endoplasmic reticulum, bind to MHC I and are displayed on the cell surface
how is the foreign material processed in APC?
- foreign material is internalised and broken down
- peptides bind to MHC II in endosomes, and displayed on the cell surface
what is the cell source and role of IL-1?
- macrophages, endothelial and epithelial cells
- induces inflammation, fever activation of leukocytes
what is the cell source and role of IL-2?
- T cells
- stimulates T, B and NK cell growth
what is the cell source and role of IL-4?
- Th2 cells, mast cells
- induces IgE production, promotes Th2 differentiation
what is the cell source and role of IL-8?
- macrophages, endothelium, fibroblasts, keratinocytes
- induces neutrophil chemotaxis
what is the cell source and role of IL-10?
- monocytes, Th2 cells
- down-regulates Th1 cytokines, MHC II expression
what is the cell source and role of Interferon gamma?
- Th1 cells, NK cells
- activates macrophages and NK cells, increases MHC II expression
what is the cell source and role of TNF alpha?
- T cells, macrophages and NK cells
- activates neutrophils and endothelial cells, induces cachexia
what cytokines do Th1 cells produce?
IL-2, gamma-interferon, TNF beta
what cytokines do Th2 cells produce?
IL-4, IL-5, IL-6, IL-10 and IL-13
what cytokines do T regulator cells produce?
IL-10, TGF beta
what is the hygiene hypothesis? who/when produced it?
- Dr David Strachan, 1989
- insufficient exposure to certain types of infection skews Th1/Th2 balance towards Th2
- negative correlation between helminth infections and allergic disease
what is the counter regulation hypothesis?
- infection protects against allergy by promoting IL-10 and TGF beta production
- increased T regulator cells
- decreased Th1 and Th2
what is the percentage of breast cancer in the UK?
31% of all cancers, 80% of these affecting women aged over 50
what is the commonest cause of death among women aged 35-55?
breast cancer
how many new cases of breast cancer are there per year in the UK? what is an individual woman’s risk?
- reports in 2008 showed there are 48034 new cases each year
- 99% of new cases occur in women
- in high risk areas, there is a 1 in 8 chance of developing it
what are the risk factors for breast cancer?
- female sex; risk increases with age
- long intervals between menarche and menopause
- older age at first full-term pregnancy
- obesity and high-fat diet
- radiation
- family history of breast cancer
- geographic factors
- benign breast disease
- mammographic density
what factors lead to altered/increased growth of breast epithelium?
- family history
- atypical hyperplasia
- radiation
- unopposed oestrogens (by obesity and long duration between menopause and menarche)
how do female sex and age affect breast cancer risk?
- only 1% of breast cancers occur in men, so being female is an important risk factor
- increasing age: up to 50 years, the rate of increase is steep, then it slows down
- the incidence of breast cancer increases into old age
how does age at menarche and menopause affect breast cancer risk?
- higher risk of breast cancer in women with an early age at menarche
- women whose natural menopause occurs before 45 years have only half the breast cancer risk of those whose menopause occurs after 55 years
how does age at first full-term pregnancy affect breast cancer risk?
- nulliparous women have an increased risk of developing breast cancer
- in parous women, protection is related to early age for the first full-term pregnancy
- if first birth is delayed to mid or late thirties, the risk is greater than a nulliparous woman
how does weight and diet affect breast cancer risk?
- little/no increased risk for women of above-average weight but below 50 years
- women aged 60 or over with higher weight have increased risk
- high-fat diet may be a factor
how does radiation affect breast cancer risk?
women treated for Hodgkin’s disease by mantle radiation are at increased risk and now undergo surveillance
how does family history affect breast cancer risk?
- women with a first degree relative had breast cancer have double the risk compared to women with no family history
- risk increased if the relative was under 50 when developing breast cancer or if many first degree relatives are affected
- 85% of people who develop breast cancer don’t have a family history
what percentage of breast cancers are due to inherited gene mutations?
5-8%
what are the most common mutations leading to breast cancer? where are they located? what lifetime risk percentage are they associated with?
- BRCA1 gene on Chr 17q (65%)
- BRCA2 gene on Chr 13q (45%)
which other inherited cancer syndromes increase risk of breast cancer?
- mutation in p53 gene in Li-Fraumeni syndrome
- PTEN germline mutations in Cowden’s syndrome
- mutations in the CKEK2 gene
how does gene mutation contribute to familial breast cancer risk?
- increase it very significantly, but account for only 25% of familial risk
- most of the inherited risk of breast cancer is due to inheriting many different genetic variants, each with a weak association with risk (polygenic model of susceptibility)
what is the role of SNPs in breast cancer risk?
- single nucleotide polymorphisms have been associated with increased risk
- FGFR2 gene is the strongest
how does geographic variation affect breast cancer risk?
- variation between rates in different countries
- highest rates are in North America, north-west Europe, Australia and New Zealand
- lowest rates are in South-East Asia and Africa
- age at menarche, first pregnancy and menopasue and post-menopausal weight affect this
- difference between high and low incidence countries is accounted for by a surplus of oestrogen positive breast cancer
what is mammographic density?
- amount of white area in the breast seen on mammography
- reflects the relative amount of fibroglandular tissue in contrast to adipose tissue, which appears black on mammography
how does mammographic density affect breast cancer risk?
- independant risk factor
- women with >75% dense breast tissue have four to fivefold risk of breast cancer compared to those with <10% dense tissue
- twin studies suggest that the level of breast density is inherited, but modifiable by age, pregnancy and exogenous hormones
- mechanism unknown
how do hormones affect breast cancer risk?
- overexposure to oestrogens and underexposure to progesterones is important
- fat cells can synthesise oestrogens
- pregnancy causes high concentrations of progesterones/prolactin
- repeated surges of oestrogen from menstruation has a stimulatory effect on breast epithelium
how do oral contraceptives and HRT affect breast cancer risk?
- slightly increased risk for current/recent users of oral contraceptives
- no long-term increase
- combined oestrogen and progesterone HRT increase the relative risk twofold, and is greater the longer the treatment
- risk decreases with cessation
- oestrogen-only preparations have lower risk
how do hormone receptors affect breast cancer risk?
- oestrogen interacts with a nuclear receptor; interaction with DNA forms differentiation- and proliferation-associated factors
- oestrogen receptors can be detected in about 75% of breast cancers
- progesterone receptor present in ~50% of tumours
how can viruses affect breast cancer risk?
- in mice, a tumourigenic virus is transmitted via milk (Bittner factor)
- no similar agent found for human breast cancer
what is the process of hormone-responsive breast epithelium?
- hormones pass from the blood stream and interact either with membrane receptors (prolactin) or nuclear receptors (oestrogen)
- hormone-receptor interactions activate DNA response elements
- leads to production of differentiation and proliferation factors
what type of cancer are breast cancers?
adenocarcinomas: derived from epithelial cells of the ducts or glands
what are the types of non-invasive carcinoma? what does it mean?
- means that malignant cells are confined to either the ducts or the acini of hte lobules, with no evidence of penetration of the tumour cells through the basement membrane into the fibrous tissue
- ductal and lobular carcinoma in situ
where/when/how much does ductal carcinoma in situ occur?
- occurs in pre and postmenopausal women, in 40-60 year age group
- can be found in surgical biopsies or by mammography screening due to calcification
- 5% of breast carcinomas present clinically, and 20% of cases in screening
what is the macroscopic/gross appearance of ductal carcinoma in situ?
- can present as a palpable mass, esp. if extensive and associated with fibrosis
- if larger ducts are involved, presentation can be as nipple discharge, or as Paget’s disease
- can be 10-100 mm in length
- usually unifocal, confined to one quadrant of the breast
- bilateral disease is uncommon
- macroscopic appearances depend on the architecture
- creamy nectrotic material may exude from cut surface
what is the histological appearance/change in ductal carcinoma in situ?
- changes occur in small and medium sized ducts, and in large ones for older women
- varying cytoplasmic and nuclear pleomorphism in ductal cells
- frequent and abnormal mitotic figures
- can be classified into high-grade and non-high-grade lesions
what are the patterns of DCIS?
- solid: ducts completely filled with cells
- comedo: central necrosis, which may calcify and be detectable on mammogram
- cribriform: numerous gland-like structures within the sheets of cells
what is the presentation and incidence of lobular carcinoma in situ?
- does not present as a palpable lump and is found in biopsies removed for other reasons
- often multi-focal within one breast and frequently bilateral
- 1/4 to 1/3 of all patients with LCIS who are treated by biopsy alone will develop an invasive carcinoma; can occur in either or both breasts, may be a long time interval
what is an invasive breast carcinoma?
cells have broken through the basement membrane around the breast structure where they have arisen
- spread into surrounding tissue
what are the histological types of invasive breast carcinoma and their relative incidence for palpable tumours?
- infiltrating ductal of no special type (75%)
- infiltrating lobular (10%)
- mucinous (3%)
- tubular (2%)
- medullary (3%)
- papillary (2%)
- others (5%)
what is the gross/macroscopic appearance of invasive carcinomas?
- 10-80mm in diameter or more, depending on whether detected by mammography or presenting clinically
- firm on palpation and may show tethering to the overlying skin or underlying muscle
- skin may show peau d’orange: dimpling due to lymphatic permeation
- nipple may be retracted due to tethering and contraction of the intramammary ligaments
what does the macroscopic appearance of the tumour depend on? what terms can this give rise to?
amount or type of stroma within the carcinoma
- scirrhous
- medullary (or encephaloid)
- mucinous (or colloid)
what does scirrhous mean?
- implies that there is a prominent fibrous tissue reaction, usually in the central part of the tumour
- leads to carcinoma having a dense white appearance
- grates when cut
- yellow streaks may be there due to presence of elastic tissue in the tumour
- carcinomas with a prominent stromal reaction have irregular edges, extending into the adjacent fat or other structures
what are the characteristics of medullary tumours?
- very cellular with little stroma
- edges of the carcinoma are more rounded and discrete than scirrhous tumours
- necrosis is common
- when palpated, tumours feel much softer
what are the characteristics of mucinous carcinomas?
- predominance of mucin, or jelly like material within them
- well defined edge
what are the most common infiltrating breast carcinomas?
infiltrating ductal carcinomas of no specifal type (75%)
what is the macroscopic appearance of infiltrating ductal carcinomas?
scirrhous consistency
what is the histological appearance of infiltrating ductal carcinomas?
- tumour cells are arranged in groups, cords and gland-like structures
- marked variation seen in different carcinomas even though they are the same type
- size of solid cell groups is variable
- DCIS often present
- amount of stroma between tumour cells is variable
- elastosis around ducts or within the stroma is common in scirrhous tumours
how is the degree of differentiation/grade of the tumour based on for breast tumours?
- extent to which it resembles non-tumourous breast
- whether cells are in gland-like pattern or solid sheets
- degree of nuclear pleomorphism
- number of mitotic figures present
what are grade III breast tumours composed of?
- sheets of pleomorphic, non differentiated sheets
- many mitotic figures
what is the incidence/people affected of infiltrating lobular carcinomas?
- usually occurs in premenopausal women
- 10% of invasive breast carcinomas in the UK
- incidence varies in other parts of th eworld
what are the features of infiltrating lobular carcinomas?
- often diffuse and poorly defined
- may be multifocal
what are the histological characteristics of infiltrating lobular carcinomas?
- cells are small and uniform and dispersed singly, or in columns one cell wide
- dense stroma
- elastosis can be present
- cells infiltrate around pre-existing breast ducts and acini, rather than destroying them
- cells may appear signet ring in shape due to accumulation of mucin
- cells lack E-cadherin
what is the incidence of mucinous carcinomas?
- usually in postmenopausal women
- 2-3% of invasive carcinomas
what are the macroscopic characteristics of mucinous carcinomas?
- well circumscribed
- soft, grey, gelatinous cut surface
- no dense stroma
- round edges
- don’t cause retraction of the nipple or tethering of the skin
what are the histological features of mucinous carcinomas? what is the survival rate like?
- composed of small nests and cords of tumour cells
- little pleomorphism
- embedded in large amounts of mucin
- survival is better than in invasive ductal/lobular carinomas
what are the features and incidence of tubular carcinomas?
- small lesions
- less than 10mm diameter
- firm, gritty tumours
- irregular outline
- 1-2% of invasive carcinomas presenting systematically and 20% of screen-detected tumours
what are the histological features of tubular carcinomas? what is the survival rate like?
- composed of well formed tubular structures
- cells show little pleomorphism or mitotic activity
- good survival
what is the incidence and features of medullary carcinomas?
- incidence is difficult to assess because not all the criteria for diagnosis have been adhered to
- range from very rare to 5%
- usually in postmenopausal women
- circumscribed and often large
what are the histologcial features of medullary carcinomas?
- large tracts of confluent cells with little stroma in between them
- marked nuclear pleomorphism
- frequent mitotic figures
- never evidence of gland formation
- poorly differentiated
- around the islands of tumour cells there is prominent lymphocytic infiltrate (predom. T cells) with macrophages
what is the survival rate of medullary carcinomas? what may this be due to?
- significantly better 10 year survival than women with invasive duct carcinomas
- despite aggressive cytological features
- may be due to lymphocytic and macrophage infiltrate
what is the incidence of papillary carcinomas?
- rare
- occur in post-menopausal women
what are the features of papillary carcinomas?
- usually circumscribed
- can be focally necrotic
- little stromal reaction
- tumours in the form of papillary structures
- areas of intraductal papillary growth
what is the molecular classification of breast cancer?
- heterogenous disease
- molecular classification based on biological characteristics of tumours
- six core intrinsic subtypes, differing in incidence, prognosis and response to treatment
what are Luminal A tumours?
- high level expression of ER
- associated with good prognosis
what are Luminal B tumours?
- lower-level expression of ER
- often positive for Her2
- poorer prognosis than Luminal A tumours
what is the Her2-enriched subgroup?
- predominantly Her2 overexpressing
- poor prognosis
what are characteristics of basal-like and claudin-low groups of tumours?
- poor prognosis
- lack of targeted treatment
- often negative for ER, PR, and Her2
- basal-like group expressing proteins characteristic of normal basal or myoepithelial cells
- claudin-low group has low expression of set of the clauding cell adhesion molecules
what is the triple negative phenotype?
- being negative for ER, PR and Her2
what is the normal-like group of tumours?
- clusters closely with normal breast samples on gene array
- poorly characterised subtype
what are the groups in the molecular classification of breast cancer?
- Luminal A
- Luminal B
- Her-2 enriched
- basal-like
- claudin-low
- normal
when was Paget’s disease first described?
by Sir James Paget in 1874
what are clinical features of Paget’s disease of the nipple? why is recognition important?
- roughening, reddening and slight ulceration of the nipple
- associated with an underlying DCIS or invasive carcinoma, mainly in the subareolar region
what is the incidence of Paget’s disease of the nipple? what is it associated with?
- with 2% of all breast carcinoma
- associated with higher frequency of multicentric breast carcinomas
what are the histological characteristics of Paget’s disease?
within the epidermis of the nipple, large pale-staining malignant cells are present, they cause the clinical changes
what are the pathways of breast carcinoma spread?
- direct (local)
- lymphatic
- haematogenous
where can breast carcinoma spread to via direct spreading?
- underlying muscles and overlying skin (detected via ulceration/tethering)
- axillary lymph node
- supraclavicular lymph node
where can breast carcinoma spread to via lymphatics?
- spread to skin lymphatic channels leads to peau d’orange
- axillary lymph nodes are commonest initial site of metastasis via lymphatics
- intramammary, supraclavicular and tracheobronchial lymph nodes
what is peau d’orange?
dimpling due to lymphatic permeation
where can breast carcinomas spread to via the blood?
- lund
- bone
- opposite breast
- brain
- liver
can can extensive infiltration of cancer of the bone marrow cause? what can destruction of bone marrow cause?
- leucoerythroblastic anaemia
- destruction of bone can result in hypercalcaemia, with renal complications
what are the prognostic factors for breast carcinomas?
- type of carcinoma
- histological grade
- stage
- oestrogen receptors
- Her-2
- prognostic gene signature
what does the presence of oestrogen receptors within a carcinoma indicate? what treatments can be used?
- indicates that the tumour cells have a higher degree of functional differentiation
- women whose tumours are oestrogen receptor-positive have better survival figures than those who are negative
- more likely to benefit from tamoxifen, an oestrogen receptor antagonist, and aromatase inhibitors
what is tamoxifen?
oestrogen receptor antagonist
how can Her-2 act as a prognostic factor for breast carcinoma?
c-erbB-2/HER-2 is altered in ~20% of invasive breast carcinomas
- amplification of gnee with overexpression of the membrane related protein
- poor prognosis
- trastuzumab developed as a treatment
what is a treatment for carcinomas with altered Her-2?
- trastuzumab (Herceptin)
- humanised monoclonal antibody
- used as an adjuvant treatment and to treat women with metastatic disease
what are gene signatures?
patterns of gene expression that can predict prognosis
what is one of the most extensively validated prognostic gene signatures?
- 70-gene signature
- marketed as Mammaprint
- derived by comparing tumours from women free of metastatic disease at 5 years and those that had developed metastasis
what increases risk of breast carcinomas in men?
- affects about 1%
- rare in young men
- increased risk with Klinefelter’s syndrome and for carriers of BRCA2
how do breast carcinomas present in men?
- lump
- nipple discharge/retraction
- Paget’s disease is commoner in men, probably due to small size of male breast
- DCIS and all types of invasive carcinoma can occur, but LCIS has not been reported
