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Mechanisms of Disease > Neoplasia > Flashcards

Neoplasia Flashcards

0
Q

What is a carcinoma? How do they spread? Give some examples.

A

Malignant epithelial neoplasm

Spread via lymphatics

Lung, breast, prostate, colon, pancreas, ovaries

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1
Q

How did the G6PDH enzyme help establish that neoplasms are monoclonal?

A

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)

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2
Q

What is a sarcoma? How does it spread? Give some examples.

A

Malignant neoplasm of mesenchyme

Spreads via bloodstream

e.g. lipoma, chondrosarcoma, osteosarcoma, leiomyosarcoma (smooth muscle)

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3
Q

What are the differences between benign and malignant tumours?

A

BENIGN:

  • enlarges but does not invade/destroy surrounding tissue
  • does not metastasise
  • defined perimeter

MALIGNANT:

  • invades and destroys surrounding tissue
  • metastasises to secondary sites
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4
Q

What is the difference between in situ and invasive neoplasms?

A

IN SITU = neoplasm has not invaded the epithelial basement membrane

INVASIVE = neoplasm has invaded the epithelial basement membrane

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5
Q

What is tumour burden?

A

Total mass of tumour tissue in an individual with cancer

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6
Q

How does a neoplasm invade and metastasise?

A
  1. Grow and invade the primary site
  2. Enter a transport system
  3. 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
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7
Q

What routes can neoplasms spread by?

A

Lymphatic system

Bloodstream

Transcoelomic spread (via fluid in body cavities e.g. pleura, peritoneum, pericardium )

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8
Q

What is a cancer niche?

A

Combination of malignant neoplasms and the surrounding normal tissue

The normal cells provide growth factors and proteases for the malignant cells

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9
Q

What determines the site of secondary tumours?

A
  • 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
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10
Q

What are the most common sites of metastases?

A 
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
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11
Q

What are the most common tumours which metastasise to the bones?

A

BLTKP: (breast,lung, thyroid, kidney, prostate)

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12
Q

What are the local effects of neoplasms?

A
  • direct invasion and destruction of normal tissue
  • ulceration -> bleeding
  • compression of adjacent structures
  • blocking tubes and orifices
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13
Q

What are the systemic effects of neoplasms?

A

(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
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14
Q

What is the difference in appearance between primary and secondary tumours?

A

PRIMARY = one tumour which enlarges

SECONDARY = many seedings of small tumours

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15
Q

What is the most common type of brain primary neoplasm?

A

Gliomas

  • astrocytomas (most common; worst grade = glioblastoma)
  • ependymoma
  • mixed/oligodendroglial

+ meningioma, craniopharyngioma

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16
Q

What is the response of lymph nodes to infection in the body?

A

Follicles enlarge and become germinal centres in response to the detection of infection (become active lymph nodes)

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17
Q

Describe the pathology of carcinoid tumours. What is carcinoid syndrome?

A

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)

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18
Q

Why do neoplasms of the head of the pancreas cause jaundice? Why can this cause a DVT?

A

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

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19
Q

What are the three ways that jaundice may occur?

A

PRE-HEPATIC = e.g. haemolytic anaemias, hereditary spherocytosis

HEPATIC = e.g. liver cancer obstructing ciliary branches

POST-HEPATIC = e.g. obstructed gallbladder

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20
Q

Define carcinogensis.

A

Causes of cancer (in particular carcinomas)

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21
Q

Give some examples of intrinsic and extrinsic risk factors for cancer.

A

INTRINSIC:

  • hereditary
  • age
  • gender (effects of oestrogen)

EXTRINSIC:

  • radiation
  • chemicals
  • infection
  • lifestyle
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22
Q

What are the three things that chemically-caused cancer teaches us about carcinogenesis?

A

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

23
Q

What is the Ames test?

A

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)

24
Q

What is the difference between an initiator and a promoter in terms of neoplasia?

A

INITIATOR = mutagen

PROMOTER = proliferator

25
Q

Give some examples of the different types of chemical carcinogens.

A

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)

26
Q

What is the difference between pro-carcinogens and complete carcinogens?

A

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

27
Q

How does radiation cause cancer?

A

Indirectly = generation of free radicals

Directly = altered bases + single/double strand breaks

28
Q

How does infection cause cancer? Give examples for each.

A

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

29
Q

In terms of the two-hit theory, what is the difference between hereditary and sporadic cancers?

A

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)

30
Q

What is the difference in function of tumour suppressor genes and oncogenes?

A

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

31
Q

Give some examples of cancer-related conditions caused by mutations affecting DNA structure. What phenotype do these all lead do, in general?

A

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

32
Q

Describe cancer progression. Give an example.

A

Cancer progression = steady accumulation of multiple mutations in malignant neoplasms

e.g. colon cancer (adenoma -> carcinoma)

33
Q

What are the six hallmarks of cancer?

A
  1. Self-sufficiency of growth signals
  2. Resistance to growth stop signals
  3. Cell immortalisation (no senescence)
  4. Angiogenesis
  5. Resistance to apoptosis
  6. Ability to invade and metastasise

+ genetic instability (enabling characteristic)

34
Q

Give some examples of infections/lifestyle factors that affect the risk of cancer in developing countries.

A

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

35
Q

Why does leukaemia develop before solid tumours in those exposed to ionising radiation?

A

Leukaemia = bone marrow cells

High turnover rate of cells compared to other organs, therefore greater chance of mutation

36
Q

What is the oncogene associated with thyroid cancer following exposure to radiation?

A

ret

Encodes a tyrosine kinase receptor

37
Q

Outline the differences in histology, appearance, and prognosis of skin cancers.

A

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
38
Q

What does p53 do?

A
  • activates DNA repair
  • acts at restriction point of cell cycle
  • initiates apoptosis
39
Q

What are the most common cancers in adults and children?

A

Adult: breast, lung, bowel, prostate (50%<)

Children: leukaemia, CNS tumours, lymphomas

40
Q

What factors help predict favourable outcome in cancer patients?

A 
Age 
General health status
Tumour site 
Tumour stage 
Tumour grade 
Availability of effective treatments
41
Q

Define tumour staging. What is the standardised system for tumour staging?

A

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

42
Q

Describe how lymphomas are staged.

A

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

43
Q

Describe how colorectal carcinomas are staged.

A

Dukes’

A: Invasion into but not through the bowel wall
B: Invasion through the bowel wall
C: Involvement of lymph nodes
D: Distant metastases

44
Q

Define tumour grading. Give some examples of how different cancers are graded.

A

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

45
Q

Outline the treatment of cancer.

A 
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

46
Q

Describe how radiotherapy is used in the treatment of cancer.

A 
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

47
Q

Describe how chemotherapy is used in the treatment of cancer.

A

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

48
Q

Describe how hormones can be used in the treatment of cancer.

A

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

49
Q

Describe how molecular treatments can be used in the treatment of cancer.

A

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

50
Q

List some common tumour markers and the cancer which produces them.

A

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

51
Q

What are some of the problems of cancer screening?

A

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

52
Q

Describe the characteristics of Hodgkin’s lymphoma.

A

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

53
Q

Why might cancer cause back pain?

A

Spinal metastases compress spinal cord

Consider in cancers which commonly metastasise to bone

54
Q

Describe cervical carcinoma.

A

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

Mechanisms of Disease (8 decks)

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