Case 13 Flashcards
Typical sequence leading to neoplasia
Mutation inactivates tumour suppressor
Cells proliferate
Mutation inactivates DNA repair genes
Mutation of proto-onco gene creates oncogene
Mutations inactivate several more tumour suppresor genes
What are the molecular hallmarks of cancer?
Provide own growth signals Insensitive to stop signals Unlimited proliferative potential Avoidance of apoptosis Sustained angiogenesis Tissue invasion and metastatic ability Unstable genome
Multistep, multigene model of tumorigenesis
Mut. 1: cell seems normal but is predisposed to excessive proliferation
Mut. 2: cell proliferates too much but is otherwise normal
Mut.3: cell proliferates more rapidly and undergoes structural changes
Mut. 4: cell proliferates uncontrollably and looks obviously deranged
Categories of cancer risk factors
Genetics
Chemicals
Viruses or bacteria
Radiation
Name 5 cancer viruses and their associated malignancies
EBV - Burkitt's lymphoma HPV - cervical carcinoma HBV - HCC HTLV1- Adult T cell leukaemia HHV8 - Kaposi's sarcoma
Role of E7 in cervical carcinoma
Overrides G1/S restriction point
Rb normally binds E2F transcription factors, preventing promoter DNA regions from being switched on
E7 binds Rb, allowing excessive E2F to bind to DNA promoter sequences and driving the cell into the S phase
Role of E6 in cervical cancer
Inactivates p53 tumour suppressor
E6 causes ubiqitination of p53, causing its breakdown
Role of p53
DNA repair
Arrests abnormal cells at the G1/S checkpoint
Initiates apoptosis
Establishing a link between a virus and a cancer
Cancer is prevalent in viral prevalent regions
Individuals with cancer have evidence of persistent viral infection
Viral cell tropism is thecame as the cancer cell of origin
Viral nucleic acids are present in tumour cells
Incidence of cancer reduced by infection control measures
Role of viruses in oncogenesis
Inactivation of tumour suppressor proteins
Trans-activation of cellular proteins by viral TFs
Action of viral oncogenes
Failure of immune surveillance
Cofactors
HPV mucosal subtypes
6 and 11
HPV common cutaneous subtypes
1,2,3,4,5,8
Which HPV subtypes are associated with laryngeal papillomas?
6 and 11
Risk factors in multifactorial genetic disorders
Baseline risk
Number of affected relatives, esp FDRs
Age of onset in affected relatives
Predisposing environmental factors
Knudson’s 2 hit hypothesis
AD inheritance of one mutated TS/DNA repair allele
Born with one functional allele
Relevant protein still produced at 50% of normal levels, sufficient for function
2nd hit occurs with somatic mutation causing loss of tumour suppression/DNA repair
Loss of tumour suppressor genes may be due to…
Loss of function mutation
Epigenetic silencing
What is the role of the BRCA gene mutations and what is their inheritance?
Role in DNA repair
AD inheritance
Distinguishing hereditary from multifactorial breast cancer
Suspect hereditary if: Pedigree suggests AD pattern Early onset Muftifocal/bilateral disease Male Ovarian CA
List 5 signalling modalities present int he female genital tract and give an example of each.
Endocrine - FSH acts on GCs to increase aromatase activity
Paracrine - inhibin from GCs acts on theca interna, assists LH in stimulating androstenedione synthesis
Autocrine - activin from GCs increases GC FSH receptors
Synaptic - parasympathetic stimulation results in arousal
Cell-cell - gap junctions between GCs and oocyte
Histological components of the ovarian cortex
Lined by germinal epithelium Resting follicles Maturing/developing follicles Atretic follicles Fibrous stroma Corpus luteum (after ovulation)
Histological components of the ovarian medulla
Connective tissue
Interstitial cells
Nerves
Blood vessels
What stage of oocyte do primordial and primary (pre-antral) follicles contain?
Primary oocytes, arrested in prophase 1
Functions of the ovary
Production of the female gamete
Secretion of oestrogen and progesterone
Regulation of postnatal growth of reproductive organs
Development of secondary sexual characteristics
Phases of the ovarian cycle
Follicular
Ovulatory
Luteal
Phases of the uterine cycle
Menstrual
Proliferative
Secretory
Ischaemic
Histological appearance of primordial follicles
Squamous, flattened granulosa cells
Histological appearance of primary follicles
Cuboidal granulosa cells, unilayer
Zona pellucida begins to form
Histological appearance of early secondary follicles
Stratified cuboidal granulosa cells
Zona pellucida fully assembled
Theca differentiating
Histological appearance of pre antral secondary follicle
Well differentiated theca
Beginnings of antrum are seen as liquor-filled spaces between granulosa cells
Histological appearance of tertiary/antral/Graafian follicle
Antrum
Cumulus oophorus
Corona radiata
Follicular events following ovulation
LH stimulates fibroblasts at the stigma to degrade the theca externa
Mural granulosa layer folds inwards
Basement membrane breaks down, blood vessels from theca interna invade folding granulosa layer
Antral cavity fills with blood
Histological appearance of atretic follicles
Thick, folded basement membrane
Delaminating granulosa cells
Invading macrophages
Development of the corpus luteum
Breakdown of basal lamina
Invasion of blood vessels
Transient corpus haemorrhagicum invaded by blood vessels, fibroblasts and collagen fibres
Mural GCs transform into granulosa lutein cells
Theca interna cells become theca lutein cells
Characteristics of steroid secreting cells
Lipid droplets
Well developed smooth ER
Mitochondria with tubular cristae
Histological appearance of the corpus albicans
Fibrous ovarian stroma with blood vessels
Theca interna cell functioning
LH stimulation causes uptake of cholesterol from the blood and steroidogenesis
The steroid products are progesterone and androstenedione
Androstenedione is translocated to the granulosa cells for aromatisation
Granulosa lutein cell functioning
Under the control of both LH and FSH
Store cholesterol for progesterone synthesis
Convert androstenedione to estradiol
Granulosa cell functioning
FSH stimulates GC proliferation and the production of oestrogen and progesterone
Activin, placental lactogens and prolactin enhance FSH sensitivity
FSH stimulates inhibin secretion which enhances theca lutein sensitivity to LH
When do GCs acquire LH receptors?
Graafian follicle stage
What maintains the oocyte in arrested prophase 1?
Oocyte maturation inhibiting factor
When is the first polar body formed and where is it found?
Following completion of meiosis 1 just before ovulation.
Found in the perivitilline space
What type of molecule makes up the zona pellucida?
Glycoproteins
Effects of the LH surge on the Graafian follicle
Halts oestrogen production
Initiates second meiotic division
Local prostaglandin production causes vascular follicular swelling and proteolytic enzyme activity
After ovulation,causes luteinisation
Histology: uterine proliferative phase
Endometrium increases in thickness
Straight tubular glands become tortuous
Cells change from low to tall columnar with mitotic figures
Mesenchymal mitotic figures, slight oedema
Histology: uterine secretory phase
Endometrial thickness increases further
Glands become more tortuous, glycogen/glycoprotein secretions visible in lumen
Tall columnar cells with basal glycogen accumulation/displaced nucleus
Stroma: fewer mitotic figures, cells enlarge, increasing oedema, lymphocytic infiltrate
Histology: endocervix
Large branched tubular glands
Columnar mucous secreting epithelium with some cilia
Fibroelastic stroma
Histology: ectocervix
Stratified squamous epithelium
Potential risks: cervical transformation zone
Early puberty - infections
Nabothian cysts
Dysplasia
Carcinoma
Pap cytology
Acidophilic cells: fully differentiated, from superficial layer, pyknotic nuclei. Abundant at ovulation
Basophilic cells: from deeper layers, plumper normal-looking nuclei. Abundant postovulatory
Anatomic regions of the uterine tube
Infundibulum
Ampulla
Isthmus
Intramural
Uterine tube histology
Epithelium: columnar cells - cilliated cells and non-cilliated peg cells with apical microvilli
Lamina propria
Muscle layer: inner circular outer longitudinal
Mesothelial serosa
Characteristic sign of HPV on pap smear
Koilocytosis
Structure of the vagina
Mucosa: stratified squamous epithelium with lamina propria
Muscularis layer with circular and longitudinal layers
Outer dense adventitial layer
Mucosa,epr moist by endocervical and Bartholin’s glands in lower vagina.
Where are Skene’s glands found?
Adjacent to the urethral meatus
What constitutes an unnatural death?
Application of force, physical, chemical or other factors
Act of omission or comission
Procedure-related death
Unexpected/unexplained death
Pathogenesis of TB in the female genital tract
Haematogenous spread to the uterine tubes
Chronic inflammation with granulomas and caseous necrosis
Direct spread to the uterus causes tuberculous endometritis
Commonest site of extrauterine pregnancy
Uterine tube
Causes of tubal ectopic pregnancy
Partial obstruction following salpingitis
Delayed pickup of the ovum by the fimbriae
Major complication of a tubal ectopic
Rupture and haemorrhage due to trophoblastic invasion of the wall of the uterine tube
Ectopic endometrial tissue may arise due to…
Retrograde spread during menstruation Implantation during c/s Metaplasia Lymphatic spread involving nodes Blood spread
Endometriosis sites
Ovary, tubes, pouch of Douglas GIT (recto-sigmoid) Umbilicus and surgical scars Pelvic lymph nodes Distant sites - lungs
Macroscopic appearance endometeiosis
“Chocolate cysts” with fibrosis due to cyclical haemorrhage
Microscopic appearance endometriosis
Endometrial glands plus steoma
Haemosiderin-laden macrophages
Complications of endometriosis
Infertility
Adhesions
Intermittent intestinal obstruction
Endometrioid carcinoma
Cervical CA epidemiology
Commonest non-cutaneous malignancy in SA
Age 20-80 (commonest 35-50)
Regarded as STD
Risk factors for cervical cancer
High risk HPV infection Promiscuity, early debut, parity, STIs Cigarette smoking Oral contraceptive Long interval since last pap smear Low SES
Cervical biopsy grading
CIN 1, 2 and 3 (British system)
Cervical cytology grading
LSIL/HSIL (Bethesda system)
Macroscopic appearance of cervical carcinoma
Ulcerating, exophytic or nodular
Microscopic appearance of cervical carcinoma
Squamous carcinoma with or without keratin
Adenocarcinoma
Much less common
Some related to HPV
Age 30-60
Staging cervical carcinoma
FIGO staging
0. Carcinoma in situ
- Carcinoma confined to the cervix visible microscopically (1A) or macroscopically (1B)
- Upper 2/3 vagina (2A) or parametrium (2B)
- Lower 1/3 vagina (3A) or pelvic sidewall/hydronephrosis/non-functioning kidney (3B)
- Mucosa of bladder/rectum (4A) or distant sites (4B)
Spread of cervical carcinoma
Local
Lymphatic - iliac nodes, retrograde to lower vagina
Haematogenous - uncommon. Vaginal plexus to portal circulation
Causes of death in cervical carcinoma
Renal failure Haemorrhage Super-added infection Blood-borne metastasis Iatrogenic (PE post surgery)
What constitutes an adequate pap smear?
Endocervical cells show TZ has been sampled
Cells not obscured by blood/exudate/drying out
Protocol for epithelial cell abnormalities on pap smear
ASC-US: repeat after 1 year. Colposcopy if 3x consecutive
LSIL: repeat smear after 1 year. Colp if LSIL x2
HSIL: immediate colposcopy
Squamous carcinoma: immediate colposcopy
Pap smear report includes…
- Adequacy of smear
- Epithelial or glandular cell abnormalities
- Organisms
Treatment based on cervical biopsy
CIN1: follow up at colp clinic. Consider LLETZif persistent
CIN2-3: LLETZ. Cone biopsy/hyterectomy if margins involved
Stage 1A1 and no lymphovascular invasion: cone biopsy
1A2: total abdominal hysterectomy and PL
1B1: radical hysterectomy and PL
Higher stages: chemoradiation + brachytherapy
Post op chemoradiation if lymph nodes prove positive
SA pap smear policy
3 smears in lifetime
Begin at the age of 30
Repeated 10 yearly
Endometeial carcinoma type 1
Unopposed oestrogen (PCOS, HRT, obesity)
Hyperplasia pathway
Tendency for contiguous spread
Good prognosis with surgery
Endometrial carcinoma type 2
Older, atrophic epithelium Serous pathway, p53 mutation Tendency to disseminate in the pelvis Needs chemotherapy Bad prognosis
Types of gestational trophoblastic disease
- Hydatidiform mole: partial, complete or invasive
2. Choriocarcinoma
Hydatidiform mole
Fertilisation of one ovum by 2 spermatozoa
Molar tissue with grape-like clusters of chorionic villi and varying degrees of trophoblastic proliferation
Partial mole
Usually triploid
Molar tissue with moderate trophoblastic proliferation
Often stillborn fetus or fetal parts
Little malignant potential
Complete/classical mole
46XX, totally paternal origin
Molar tissue without normal villi/fetal parts
Marked trophoblastic proliferation and malignant potential
Invasive mole
Variant of complete mole with extension to the parametrium
May metastasize haematogenously
Choriocarcinoma
Highly malignant with propensity for haemotogenous spread
Syncytio/cytotrophoblastic origin
Follows hydatidiform mole or normal/aborted pregnancy
Good response to chemotherapy
Ligamentous supports of the uterus
Pubovesical Transverse cervical Uterosacral Round ligament Broad ligament
Chem path perimenopause
FSH rises 1-2 years before menopause
LH initially unchanged
Chem path post menopause
FSH and LH rise significantly. FSH > LH
>90% decrease in oestrogen
