Neoplasia Flashcards
Define neoplasia
abnormal growth of cells that persists after the initial stimulus is removed, irreversible
Define dysplasia
pre-neoplastic alteration in which cells show disordered tissue organisation.
It is not neoplastic = reversible - also represents altered differentiation.
Mild, moderate and severe dysplasia indicates worsening differentiation
Define tumour
clinically detectable lump/swelling
Define cancer
any malignant neoplasm
Define metastasis
malignant neoplasm that has spread from its original site to a new non-contiguous site
original location is the primary site and the place to which it has spread is a secondary site
Define anaplasia
Cells with no resemblance to any tissue
When a benign/malignant tissue is described as well differentiated, what does that mean?
Tissue that closely resembles the parent tissue
Define pleomorphism
increasing variation in size and shape of cells and nuclei
Define progression
The process of a neoplasm emerging from a monoclonal population, characterised by the accumulation of yet more mutations
Describe and compare benign and malignant tumours
Benign = confined to origin, pushing outer margin, rarely dangerous, do not metastasise.
Malignant = potential to metastasise, irregular outer margin/shape, may show areas of necrosis and ulceration (if on a surface)
What are the microscopic characteristics of neoplasms showing varying degrees of differentiation?
With worsening diff individual cells = increasing nuclear size and nuclear to cytoplasmic ratio,
increased nuclear staining (hyperchromasia),
more mitotic figures and increasing variation in size and shape of cells and nuclei
Define grade
Clinicians use the term grade to indicate differentiation, high grade being poorly differentiated
Distinguish between in-situ and invasive malignancy
In-situ = no invasion through epithelial basement membrane
Invasive = penetrated through basement membrane
What 3 factors enable a neoplasms to come about?
Initiators, mutations, promotors
Describe clonality of neoplasms
combination of initiators/promoters = expanded, monoclonal population of mutant cells.
Chemicals, infections, radiation = initiators but can also act as promoters.
Mutations can be inherited
What is lyonisation?
In early female embryogenesis one allele is randomly inactivated in each cell
What are proto-oncogenes?
Play normal role in cell signally for cell growth – when they change/mutate they remain always switched on
What are tumour suppressor genes?
Recessive (have to inactivate both alleles)
normally oppose/suppress neoplasm formation,
inhibiting cell cycle,
become inactive in cancer
What does the suffix –oma mean?
Benign neoplasm
Define carcinoma
Epithelial malignant neoplasm
Define sarcoma
Stromal malignant neoplasm
Define blastomas?
Formed from immature precursor cells
Where is squamous carcinoma found?
Squamous epithelial = skin larynx, oesophagus
What is adenocarcinoma?
Epithelial neoplasm of the glands
What is malignant melanoma?
Neoplasm of melanocytes or cells that devel from melanocytes
What is a teratoma?
Tumour composed of tissues not normally present – germ cell origin forms cell representing all 3 germ cell layer
What is Hodgkin’s lymphoma?
Type of lymphoma – with the presence of multinucleatedReed–Sternberg cells(RS cells) in lymph nodes
What does adenoma refer to?
Glandular
What is a papilloma?
Benign epithelial tumour growing exophytically (outwardly projecting)
Where is transitional cell carcinoma found?
transitional epithelial = bladder, ureters
What is a benign mesenchymal tumour?
Connective tissue neoplasm
What is a glioma?
Benign connective tissue neoplasm – in the brain/spine
Lymphomas
malignant neoplasms of lymphocytes, mainly affecting lymph nodes
What is a germ cell neoplasm?
arise from pluripotent cells, mainly in the testis or ovary
What is leukaemia?
neoplasm of blood-forming cells arising in the bone marrow
What is a myeloma?
Malignant neoplasm of plasma cells
What is a neuroendocrine tumours?
Arise from hormone secreting cells distributed throughout the body
Define invasion
Property of malignant neoplastic cells enabling them to infiltrate normal tissues and enter blood vessels/lymphatics
Outline the process that leads to metastasis
Grow/invade at primary site,
Enter a transport system and lodge at a secondary site,
Grow at the secondary site to form a new tumour (colonisation)
Invasion involves what 3 important alterations?
Altered adhesion, stromal proteolysis and motility
Explain epithelial-to-mesenchymal transition
Altered adhesion, stromal proteolysis and motility
= create a carcinoma cell phenotype that sometimes appears more like a mesenchymal cell than an epithelial cell
How is adhesion altered in carcinoma cells?
reduction in E-cadherin expression, changes in Integrin expression
How is stromal proteolysis altered in neoplasia?
cells must degrade basement membrane and stroma to invade
= altered expression of proteases, notably matrix metalloproteinases (MMPs)
How is motility altered in carcinoma cells?
changes in the actin cytoskeleton.
Signalling through integrins is important and occurs via small G proteins such as members of Rho family.
Describe the routes of metastases
Lymphatic,
blood: via capillaries and venules,
transcoelomic: fluid in body cavities (pleura, peritoneal, pericardial and brain ventricles)
What is a micrometastases?
Surviving microscopic deposits that fail to grow - apparently disease-free person may harbour many micrometastases, a phenomenon known as tumour dormancy
Outline what determines the site of metastases
1) where the regional drainage of blood (first capillary bed)/lymph (lymph node)/coelomic (elsewhere in coelomic space) fluid drain to.
2) seed and soil = interactions between malignant cells and local tumour environment (niche)
How do carcinoma spread vs sarcomas?
C = lymph. S = blood
List the common sites of blood-borne metastases
Lung, bone, liver, brain
List the neoplasms that most frequently spread to bone
Breast, bronchus, kidney, thyroid, prostate
How can the effects of a neoplasm be broken down?
Local = Primary neo, secondary neo.
Systemic = burden, hormones, miscellaneous
What is a paraneoplastic syndrome?
The systemic effects a neoplasm has on the body
Which neoplasms commonly cause osteolytic lesions?
Osteosarcoma of the knee, breast/kidney/lung cancer metastasis
which neoplasms commonly cause sclerotic lesions?
Prostate adenocarcinoma
Describe the local effects of benign/malignant neoplasms
1) Direct invasion/destruction of normal tissue.
2) Ulceration at surface = bleeding.
3) Compression of adjacent structures.
4) Blocking tubes/orifices
Describe the systemic effects of neoplasms
1) Endocrine: hormone prod by endocrine tumour, ectopic hormone prod.
2) Haematological: anaemia, thrombosis, DIC.
3) Neurological.
4) Dermatological.
5) General: cachexia, malaise, immunosuppression, fever, finger clubbing, hypercalcaemia, pruritis, myositis
Discuss colorectal carinoma
predisposing = diet, obesity, smoking, lack of physical activity
pres = blood in the stool, a change in bowel movements, weight loss, lethargy
macroscopic = tumor growing outward
microscopic = irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma
staging = TNM
marker = over express cyclooxygenase-2 (COX-2) enzyme
screening = fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy
What is the presentation and appearance of osteosarcoma?
pres = bones pain
macroscopic = tumour on the bone
microscopic = neoplastic osteoblast
What is the presentation and appearance of ovarian teratoma?
pres = pain/pressure in pelvis, irregular periods
macroscopic = contain hair, sebum, teeth
microscopic =tissue of all three germ layers
What is the presentation of chronic lymphocytic leukaemia?
pres = enlarged lymph nodes , lethargy, breathless, hepatosplenomegaly
What is the presentation and appearance of uterine leiomyoma?
Benign tumours from overgrowth of SM and CT in the uterus
pres = excessive menstrual bleeding (menorrhagia), anemia, infertility
macroscopic = multiple tumours
microscopic = spindle cells
What is the most frequent cancer in men/women?
prostate/breast
What are the 2 most common oesophagal tumours?
squamous cell carcinoma
adenocarcinoma
What is an exophytic tumour?
grows out from the surface
common in benign neoplasms, indicated non-invasive
What is a papillary tumour?
finger like projections
What is a polypoid tumour?
exophytic mass often on a stalk
What is a sessile tumour?
raised by flat
What is an annular tumour?
encircling like a ring
What is an endophytic tumour
invasion into surrounding tissue, irregular tumour margin
When is tumour necrosis seen?
when the tumour grows rapidly and out-strips its blood supply
usually a feature of malignant tumours
What is a lipoma?
benign neoplasm of adipose tissue
What is kaposi’s sarcoma?
vascular neoplasm caused by human herpes virus 8 (HHV8)
usually in HIV +ve
What does carcinogenesis mean?
causes of cancer
Explain the multifactorial nature of neoplasia pathogenesis
Intrinsic = hereditary, age, gender, hormonal
extrinsic = environment, behaviour, lifestyle
Explain how migration studies illustrate the relative contribution of intrinsic and extrinsic factors
Japanese-USA migration studies show 85% cancer risk extrinsic
Outline extrinsic carcinogenic agents and their mechanisms of action
Chemicals = polycyclic hydrocarbons, aromatic amines, e.g., 2-naphylamine, nitrosamines
Radiation = UV and ionising
Infections = HPV, Epstein Barr virus, hep B/C, HIV, Helicobacter pylori, parasites
What are pro-carcinogens?
Chems converted to carcinogens by CP450
How is HIV carcinogenic?
acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur
How is HPV carcinogenic?
direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and RB protein function respectively, both of which are important in cell proliferation.
How is hepatitis carcinogenic?
indirect carcinogens that cause chronic liver cell injury and regeneration
The functions of proto-oncogenes
Abnormally activated versions of normal genes that enhance neoplastic growth
What is a tumour suppressor gene?
Inhibit neoplastic growth
Both alleles inactivated in neoplasia
What is the role of RAS?
Proto-oncogene
Encodes G protein that pushes cell past cell restriction point
What is the role of c-myc?
Transcription factors
What is the role of c-erbB-2 (HER-2)?
Growth factor receptor
What is the role of RB protein?
Major cell-cycle checkpoint = inhibit free entry in
Inactivation in both alleles in neoplasia
What is the role of p53?
Role in inducing apoptosis
What are caretaker genes?
Genes that maintain genetic stability
What is the inheritance of Hereditary non-polyposis colon cancer syndrome?
Autosomal dominant
germline mutation affects one of several DNA mismatch repair genes
What is the inheritance of Familial breast cancer?
Associated with BRCA1 BRCA2 genes that are important for repairing dsDNA breaks
Mutations can be found in sporadic malignant neoplasms
What is the inheritance Retinoblastoma and the two hit hypothesis?
Dominant
2 hit hypo = first hit was delivered through the germline and affected all cells in the body. The second hit was a somatic mutation
In contrast, sporadic retinoblastoma has no germline mutation and so requires both hits to be somatic mutations and to occur in the same cell
What is the inheritance of Xeroderma pigmentosum?
Autosomal recessive
Mutation in one of the 7 genes that affect DNA nucleotide excision repair
= very sensitive to UV damage = skin cancer at young age
What are the 3 stages in carcinogensis?
Initiation
Promotion
Progression
Outline initiation
= mutagens
Outline promotion
Cause prolonged proliferation
Outline progression including the adenoma-carcinoma sequence
= accum of multiple mutations
illustrated by colon carcinoma, which usually starts as a colonic adenoma, from which arises a carcinoma
What are the 6 hallmarks of cancer?
1) self-sufficiency in growth signals;
2) resistance to growth stop signals;
3) no limit on the number of times a cell can divide (cell immortalisation);
4) sustained ability to induce new blood vessels (angiogenesis);
5) resistance to apoptosis;
6) the ability to invade and produce metastases
What is genetic instability?
When chromosome segregation during mitosis is abnormal in malignant cells
How is asbestos exposure related to the devel of tumours?
Rock can be ground down to for fibers
Used for buildings
Fibers can crumble = carcinogenic = lodge in lung = mesothelioma
Why does the dye industry have linked to the devel of malignancies?
Exposure to 2-napthylamine = carcinogen
Show long delay between exposure and malignant neoplasm onset
Showed risk depends on carcinogen dosage
What are the conditions associated with an increased risk of malignancy?
UC
Cirrhosis
Hashimotos thyroiditis
Chronic atrophic gastritis
What is the leading cause of cancer-related death?
Lung 22%
What is the commonest type of cancer in adults?
Breast, prostate, lung, colon/rectum = carcinomas = 53%
What is the commonest type of cancer in children?
<14 = leukaemia, CNS, lymphomas
Describe what is meant by tumour stage and understand its significance
TNM staging translated into I, II, III, IV
Standardised across the world
Understand the principals of TNM staging
T = size of primary tumour (T1-4) N = nodes mets (N0-3) M = metastatic spread (M0-1)
Outline the Ann Arbor
Staging for lymphoma
I = single node
II = 2 separate regions on one side of diaphragm
III = spread both ides of diaphragm
IV = diffuse involvement of one or more extra-lymphatic organs such as bone marrow/lung
What is the Dukes’ staging systems
Staging for colorectal carcinoma A = not through bowel B = invasion through bowel wall C = involve lymph nodes D = distant mets
Describe what is meant by tumour grade and understand its significance
Used for squamous cell carcinoma and colorectal carcinoma
G1 = well-diff G2 = moderately diff G3 = poorly diff G4 = undiff/anaplastic
Briefly outline the Bloom Richardson grading system for breast carcinoma
Assesses tubule formation, nuclear variation, number of mitoses
Describe the principles behind surgery as a treatments for cancer
Surgery = aim to de-bulk tumour
Describe the principle of radiotherapy as a treatment for cancer
x-rays or other types of ionising radiation to kill rapidly dividing cells.
Ds-DNA breaks cause damaged chromosomes preventing M phase from completing. Given in fractionated doses
Describe Chemo as a treatment for cancer
antimetabolites = mimics normal substrates in DNA replication
alkylating = cross link DNA, lead to apoptosis
Abx = inhib DNA topoisomerase needed for DNA synthesis
plant-derived = blocks microtubules assembly and mitotic spindle formation
Describe hormone therapy as a treatment for cancer
preventing oestrogen binding in breast cancer, blocking androgens binding in prostate cancer
Describe targeted molecular therapies as a treatment for cancer
drugs that block immune checkpoints, targeting chromosomal translocations
What is adjuvant treatment?
Why used: given after surgical removal of primary tumour to eliminate subclinical disease
Clinical disease free but on the premise they have micro-mets
What is neoadjuvant treatment?
why used: given to reduce size of primary tumour prior to surgical excision
In-operable to operable
Describe the use of tumour markers in diagnosis and monitoring of disease
Useful for monitoring tumour burden
Hormones = human chorionic gonadotropin (HCG)
Oncofetal antigens = carcinoembryonic antigen (CEA), alpha fetoprotein (AFP)
Specific proteins = prostate specific antigen (PSA)
Mucins and glycoproteins = cancer antigen 125 (CA 125)
Describe UK cancer screening programs
Aim = detect as early as possible when the chance of cure is highest
Problems = lead time bias, length bias (how long it takes for a growth to present), over diagnosis picking up benign but believing they are malignant)
E.g. Cervix, breast, colorectal
