Neoplasia Flashcards
What is a carcinoma? How do they spread? Give some examples.
Malignant epithelial neoplasm
Spread via lymphatics
Lung, breast, prostate, colon, pancreas, ovaries
How did the G6PDH enzyme help establish that neoplasms are monoclonal?
G6PDH is an X-linked gene, and can be found as heat-sensitive alleles or heat-insensitive alleles
In females, one X chromosome is inactivated (lyonised), so in normal polyclonal cells from females there will be a mixture of heat-sensitive and heat-insensitive cells
However in neoplasms, all cells are either heat-sensitive or heat-insensitive (therefore neoplasms are monoclonal - derived from a common cell precursor)
What is a sarcoma? How does it spread? Give some examples.
Malignant neoplasm of mesenchyme
Spreads via bloodstream
e.g. lipoma, chondrosarcoma, osteosarcoma, leiomyosarcoma (smooth muscle)
What are the differences between benign and malignant tumours?
BENIGN:
- enlarges but does not invade/destroy surrounding tissue
- does not metastasise
- defined perimeter
MALIGNANT:
- invades and destroys surrounding tissue
- metastasises to secondary sites
What is the difference between in situ and invasive neoplasms?
IN SITU = neoplasm has not invaded the epithelial basement membrane
INVASIVE = neoplasm has invaded the epithelial basement membrane
What is tumour burden?
Total mass of tumour tissue in an individual with cancer
How does a neoplasm invade and metastasise?
- Grow and invade the primary site
- Enter a transport system
- Colonise and grow at the secondary site
INVASION =
- Adhesion: reduction in E-cadherin expression between malignant cells; altered integrin expression alters adhesion between malignant cells and the stroma
- Stromal proteolysis: altered production of matrix mellanoproteinases allows degradation of the basement membrane
- Motility: changes in actin cytoskeleton
- Signalling: integrins act through G-proteins e.g. Rho proteins
What routes can neoplasms spread by?
Lymphatic system
Bloodstream
Transcoelomic spread (via fluid in body cavities e.g. pleura, peritoneum, pericardium )
What is a cancer niche?
Combination of malignant neoplasms and the surrounding normal tissue
The normal cells provide growth factors and proteases for the malignant cells
What determines the site of secondary tumours?
- the regional drainage of blood, lymph, and coelomic fluid e.g. metastases tend to form at the next capillary bed, including the lungs and liver
- “seed and soil” = idea that different types of cancer require different conditions (or niches) to grow, and therefore may spread in seemingly unpredictable ways
What are the most common sites of metastases?
Brain Liver Lung (all blood in body passes through at some point + space & air available for the growth of metastases) (high blood supply) \+ kidney, breast, colon, prostate, bone
What are the most common tumours which metastasise to the bones?
BLTKP: (breast,lung, thyroid, kidney, prostate)
What are the local effects of neoplasms?
- direct invasion and destruction of normal tissue
- ulceration -> bleeding
- compression of adjacent structures
- blocking tubes and orifices
What are the systemic effects of neoplasms?
(paraneoplastic syndromes)
Cachexia (reduced appetite & weight loss)
Malaise
Fever
Immunosuppression (direct destruction of bone marrow)
Thrombosis (RBC aggregation)
Hormone production:
+ thyroxine (benign thyroid adenoma)
+ ACTH/ADH (malignant bronchial small cell carcinoma)
+ PTHrp (bronchial small squamous carcinoma)
Neuropathies Pruritis (itching) Abnormal pigmentation Fever Myositis
What is the difference in appearance between primary and secondary tumours?
PRIMARY = one tumour which enlarges
SECONDARY = many seedings of small tumours
What is the most common type of brain primary neoplasm?
Gliomas
- astrocytomas (most common; worst grade = glioblastoma)
- ependymoma
- mixed/oligodendroglial
+ meningioma, craniopharyngioma
What is the response of lymph nodes to infection in the body?
Follicles enlarge and become germinal centres in response to the detection of infection (become active lymph nodes)
Describe the pathology of carcinoid tumours. What is carcinoid syndrome?
Neuroendocrine neoplams which produce hormones e.g. 5HT (-> diarrhoea), kallikrein (-> flushing)
Midgut tumours e.g. enteric chromaffin cells
Growth factors and cytokines produced cause an inflammatory response -> fibrosis -> partial obstruction of intestine
CARCINOID SYNDROME = constellation of symptoms (diarrhoea, flushing, bronchoconstriction, fibrosis of heart valves, abdominal cramping, peripheral oedema)
Why do neoplasms of the head of the pancreas cause jaundice? Why can this cause a DVT?
Compresses common bile duct (which runs through the head of the pancreas before entering the duodenum)
Bilirubin cannot be transported out of the liver/backflow of bile
Coagulation system activated -> DVT
What are the three ways that jaundice may occur?
PRE-HEPATIC = e.g. haemolytic anaemias, hereditary spherocytosis
HEPATIC = e.g. liver cancer obstructing ciliary branches
POST-HEPATIC = e.g. obstructed gallbladder
Define carcinogensis.
Causes of cancer (in particular carcinomas)
Give some examples of intrinsic and extrinsic risk factors for cancer.
INTRINSIC:
- hereditary
- age
- gender (effects of oestrogen)
EXTRINSIC:
- radiation
- chemicals
- infection
- lifestyle
What are the three things that chemically-caused cancer teaches us about carcinogenesis?
There is a long delay between exposure to a carcinogen and the onset of malignant neoplasia
Risk of cancer depends on the dosage of carcinogen
There is sometimes a specific organ affected depending on the chemical e.g. 2-napthylamine -> bladder cancer
What is the Ames test?
Test for possible mutagens
Shows that initiators are mutagens and promoters are proliferative
Use histidine-dependent Salmonella + liver extract (to provide CP450) + potential mutagen and plate on agar with NO histidine
Control: little growth (some revertants by chance mutation)
Mutagen: lots of growth (mutagen has caused many revertants)
What is the difference between an initiator and a promoter in terms of neoplasia?
INITIATOR = mutagen
PROMOTER = proliferator
Give some examples of the different types of chemical carcinogens.
Polycyclic aromatic hydrocarbons (cigarette smoke)
Aromatic amines (cigarette smoke)
N-nitroso compounds (smoked/cured meat)
Alkylating agents
Aflatoxin (from Aspergillus fungus)
Asbestos (needle-shaped fibres inhaled -> burrow into lungs -> pleura –> mesothelioma)
What is the difference between pro-carcinogens and complete carcinogens?
PRO-CARCINOGEN = only converted to carcinogens by CP450 (hence why liver extract added in Ames test)
COMPLETE CARCINOGEN = carcinogens acting as both initiators and promoters
e.g. cigarette smoke contains initiators and the heat injures the lung; promoting proliferation
How does radiation cause cancer?
Indirectly = generation of free radicals
Directly = altered bases + single/double strand breaks
How does infection cause cancer? Give examples for each.
Indirect = chronic tissue injury -> regeneration
Regeneration promotes existing mutations & increases chance of DNA replication errors occurring
e.g. Hep. B & C cause chronic liver cell injury and regeneration
Heliobacter pylori causes chronic gastric inflammation (gastric cancer)
Parasitic flukes cause inflammation in bile ducts and bladder mucosa
Direct = affects genes controlling cell growth
e.g. HPV expresses proteins which inhibit p53 and pRB
note: HIV suppresses immune system, making it more likely for a carcinogenic infection to occur
e. g. herpes -> Kaposi’s sarcoma
In terms of the two-hit theory, what is the difference between hereditary and sporadic cancers?
Hereditary:
1st hit = germline mutation (all cells of a tissue)
2nd hit = somatic mutation in any cell of the tissue
Sporadic:
Both hits occur as somatic mutations (less likely that one cell will acquire both mutations)
What is the difference in function of tumour suppressor genes and oncogenes?
Tumour suppressor genes = put the “brakes” on (check cell cycle)
e.g. pRB gene resists cell proliferation by inhibiting passage through restriction point
Oncogenes = enhance neoplastic growth
e.g. RAS (mutated in 1/3 of neoplasms; cell cycle restriction point)
For neoplasia to result, either both tumour suppressor genes need to be inactivated OR one proto-oncogene needs to be activated to an oncogene
Give some examples of cancer-related conditions caused by mutations affecting DNA structure. What phenotype do these all lead do, in general?
Point mutation (nucleotide instability) -> nucleotide excision repair affected -> xeroderma pigmentosum (skin cancer)
Mismatch repair affected -> microsatellite instability -> hereditary non-polyposis colon cancer
Double strand break -> chromosomal instability -> translocation/deletion -> breast/ovarian cancer
+ abnormal chromosome segregation in malignant cells
All these lead to genetic instability
Describe cancer progression. Give an example.
Cancer progression = steady accumulation of multiple mutations in malignant neoplasms
e.g. colon cancer (adenoma -> carcinoma)
What are the six hallmarks of cancer?
- Self-sufficiency of growth signals
- Resistance to growth stop signals
- Cell immortalisation (no senescence)
- Angiogenesis
- Resistance to apoptosis
- Ability to invade and metastasise
+ genetic instability (enabling characteristic)
Give some examples of infections/lifestyle factors that affect the risk of cancer in developing countries.
Schistosomiasis/aflatoxin -> +bladder carcinoma
Human papilloma virus/(early 1st pregnancy*) -> +cervical carcinoma
*assuming intercourse at an earlier age -> earlier exposure to HPV
Early 1st pregnancy -> -breast carcinoma
(change in oestrogen/progesterone balance happens earlier)
Epstein-Barr virus/malaria -> +Burkitt’s lymphoma
(solid tumour of lymphocytes; occurs in children in Africa)
High fibre diet -> -colonic carcinoma
(constipation -> diverticulitis -> carcinoma)
Hep. B/aflatoxin -> +liver cell carcinoma
Why does leukaemia develop before solid tumours in those exposed to ionising radiation?
Leukaemia = bone marrow cells
High turnover rate of cells compared to other organs, therefore greater chance of mutation
What is the oncogene associated with thyroid cancer following exposure to radiation?
ret
Encodes a tyrosine kinase receptor
Outline the differences in histology, appearance, and prognosis of skin cancers.
BASAL CELL CARCINOMA =
- locally invasive (eats away at skin) but rarely metastasises; surrounded by rim of normal cells (palisading)
- on face, pearly rolled edge (so smooth it reflects light), indentation in the middle, ulcerating
- caused by UV radiation
- excise
SQUAMOUS CELL CARCINOMA =
- focus of keratinisation, disordered malignant keratinocytes
- irregular margin, crusted centre, on sun-exposed area (back of hand)
- related to UV, but can occur without sun-exposure e.g. cervix
- excise
MALIGNANT MELANOMA =
- irregular/disorganised cells, stripped keratin, blue and brown cells invading dermis
- caused by UV exposure
- depth of invasion in the skin determines prognosis
- metastasises aggressively
- spread to lymph nodes -> lymph node dissection
What does p53 do?
- activates DNA repair
- acts at restriction point of cell cycle
- initiates apoptosis
What are the most common cancers in adults and children?
Adult: breast, lung, bowel, prostate (50%<)
Children: leukaemia, CNS tumours, lymphomas
What factors help predict favourable outcome in cancer patients?
Age General health status Tumour site Tumour stage Tumour grade Availability of effective treatments
Define tumour staging. What is the standardised system for tumour staging?
Measure of malignant tumour burden
TNM (size of primary tumour, extent of node metastases, extent of distant metastases)
-> converted into stages
Stage I: early local disease (N0)
Stage II: advanced local disease (N0)
Stage III: regional metastases (N1, M0)
Stage IV: advanced disease with distant metastases
note: each cancer has its own TNM criteria
Describe how lymphomas are staged.
Ann Arbor staging:
Stage I: indicates lymphomas in a single node region
Stage II: two separate node regions involved on the same side of the diaphragm
Stage III: spread to both sides of the diaphragm
Stage IV: diffuse/disseminated involvement of one or more lymphatic involvement of extra-lymphatic organs e.g. bone marrow, lungs
Describe how colorectal carcinomas are staged.
Dukes’
A: Invasion into but not through the bowel wall
B: Invasion through the bowel wall
C: Involvement of lymph nodes
D: Distant metastases
Define tumour grading. Give some examples of how different cancers are graded.
Degree of differentiation
Squamous/colorectal carcinoma = G1: well-differentiated G2: moderately diffused G3: poorly differentiated G4: undifferentiated/anaplastic (highly pleiomorphic & atypical - does not at all resemble normal tissue)
Breast carcinoma = Bloom-Richardson
Tubule formation, nuclear variation, number of mitoses
Prostate cancer = Gleason
Dominant (primary) pattern score + next most frequent (secondary) pattern score = /9
note: tumour grade is important for planning treatment & estimating prognosis for soft tissue sarcoma, primary brain tumours, lymphomas, breast, prostate cancers
Outline the treatment of cancer.
Surgery Radiotherapy Chemotherapy Hormone replacement therapy Molecular therapy
ADJUVANT TREATMENT = given after surgical removal of primary tumour to eliminate subclinical disease
NEOADJUVANT TREATMENT = given to reduce the size of a primary tumour before surgical removal
Describe how radiotherapy is used in the treatment of cancer.
Fractionated doses (to minimise damage to normal cells) Healthy tissue shielded
Ionising radiation causes direct and indirect free radical-induced DNA damage -> cell cycle checkpoints activated -> apoptosis
Damaged chromosomes -> prevents M phase completing correctly
Describe how chemotherapy is used in the treatment of cancer.
ANTIMETABOLITES e.g. antifolates (methotrexate)
- mimic normal substances used in DNA replication
ALKYLATING/PLATINUM BASED e.g. cyclophosphamide
- cross-links the two strands of a DNA molecule (suppresses bone marrow)
ANTIBIOTICS e.g. streptomyces (variable actions)
- e.g. inhibits DNA topoisomerase
- e.g. double-stranded DNA breaks
PLANT-DERIVED e.g. vincristine
- blocks microtubule assembly -> interferes with mitotic spindle formation
note: these treatments are non-specific, leading to a lot of side-effects
Describe how hormones can be used in the treatment of cancer.
Selective oestrogen receptor modulators (SERMs) e.g. tamoxifen
Oestrogen receptor antagonists
Treat hormone receptor positive breast cancer
note: tamoxifen is an oestrogen agonist in the endometrium -> increased risk of endometrial cancer
Androgen blockage - prostate cancer
Describe how molecular treatments can be used in the treatment of cancer.
Targets oncogene mutations
Herceptin blocks HER-2 signalling, reducing growth (used for treating breast cancers with overexpressed HER genes only ~ 25%)
Imatinib inhibits oncogenic fusion protein expressed by abnormal “Philadelphia” chromosomes (formed by translocation) -associated with chronic myelogenous leukaemia
Resistance can develop if the target undergoes a conformational change
List some common tumour markers and the cancer which produces them.
human chorionic gonadotrophin (hCG) - testicular cancer (germ cell cancer -> differentiates into placental cells -> choriocarcinoma)
note: most common type of germ cell tumour - seminoma (~40%)
alpha-fetoprotein - testicular & hepatocellar carcinomas
prostate-specific antigen (PSA) - prostate cancer
note: produced by hypertrophy, hyperplasia, & neoplasia (therefore may not indicate a malignant tumour; basal amount increases with age, anal sex, inflammation)
mucins/glycoproteins - ovarian cancer
carcino-embryonic antigen - bowel cancer
What are some of the problems of cancer screening?
LEAD TIME BIAS - detecting cancers early makes it look like survival time was increased as a consequence just because it was known about earlier (time of death may have been the same)
LENGTH BIAS - fast-growing tumours may be missed by screening
OVER-DIAGNOSIS - people picked up who would have never have developed cancer
Describe the characteristics of Hodgkin’s lymphoma.
Intermittent fever & itching
Lymph node biopsy: eosinophils & Reed-Sternberg cells (large, multinucleated irregular cells with macronucleoli)
B symptoms (indicating worse prognosis) (severe systemic symptoms)
- weight loss 10%<
- unexplained fever
- drenching night sweats
Symptoms due to eosinophils releasing histamine & bradykinin
Why might cancer cause back pain?
Spinal metastases compress spinal cord
Consider in cancers which commonly metastasise to bone
Describe cervical carcinoma.
Aetiology: exposure to HPV (early age at 1st intercourse, freq. of intercourse, no. of sexual partners)
Pathophysiology:
puberty
Endocervical epithelium ———-> eversion/ectopy (physiological) —>
low pH of vaginal mucus
——————> reserve cell hyperplasia (physiological) ————->
——> squamous metaplasia
