Female GU/Breast Flashcards
Describe the normal anatomy of the breast
Nipple: mostly smooth muscle fibres
Areolae: pigmented area surrounding the nipple and contains sebaceous glands that enlarge during pregnancy
90% of the breast is fat
The rest: epithelium which is organised into 2 structures
- Lobules: clusters of glands that make milk during lactation, drained by a single lactiferous duct
- Ducts: transport milk to the nipple from the lobules
Mammary glands: modified sweat glands that consist of ducts and 15-20 lobules
Terminal Duct Lobular Unit (TDLU) - Composed of the lobule and terminal ductal (ie. far from the nipple) ie. where the ducts and lobules meet
What cell types make up ducts in breast tissue?
Luminal cells and myoepithelial cells (lost in malignancy) which form two layers
How does the breast respond to hormonal stimuli throughout life?
Puberty: ducts sprout from the breast bud
- In females, puberty initiates further development, establishing the adult mammary gland
Pregnancy/Lactation: Increased number and size of lobular epithelial cells
- Vacuolated cytoplasm (necessary for making milk) and paler cells
- Secretions in lactation
- Lobules are bigger with milk being expressed into them
Menopause: lobules atrophy and less fibrous stroma
Describe hyperplasia, neoplasia and dysplasia pathologies
Hyperplasia: pathologies caused by an increase in the number of cells. Will cease when the stimulus is removed
Neoplasia: pathologies caused by an increase in the number of cells, however will not cease when the stimulus is removed. Ie. abnormal, uncontrolled growth of cells or tissues. Both benign and malignant neoplasms exist
Dysplasia: describes tissue which is not normal and not invasive malignancy yet, somewhere in between the two. Characteristics: neoplastic, non-invasive and no capacity to metastasise
Describe dysplasia
- Dysplasia, carcinoma in-situ and in-situ neoplasia are all the same process just in different sites
- Describes tissue which is not normal nor invasive malignancy yet, but is somewhere in between i.e. stepwise progression to malignancy
Characteristics:
- Neoplastic, not invasive and no ability to metastasise
(Whereas carcinoma: neoplastic, invasive and has the ability to metastasise)
List 3 examples of congenital benign breast conditions
- Ectopic breast tissue
- Breast hypoplasia
- Congenital nipple inversion
Define ectopic breast tissue.
Where are the most common sites for ectopic breast tissue to form and what does it consist of?
Def: breast tissue outside the breast
- Found along the milk line between the axilla and groin
- Sometimes it’s just the nipple, sometimes glandular material only
- All other types of breast disease can happen in ectopic breast tissue
What is breast hypoplasia and what conditions is it associated with?
- Incompletely formed breast
- Associated with Turner’s syndrome, Poland’s syndrome and congenital adrenal hyperplasia
What is the relevence of congenital nipple inversion?
- It’s a benign congenital anomaly
- New nipple inversion in someone who has never had an inverted nipple may be a sign of cancer
- Therefore need a well detailed history
Define mastitis
A condition causing a woman’s breast to become painful and inflamed
What is the main cause, pathology and symptoms of acute mastitis?
- Associated with breast feeding
- Skin fissures in a lactating women, allowing access of micro-organisms (usually bacteria) into the breast
- Stagnant milk allows growth of these micro-organisms and acute inflammation can occur
Symptoms:
- Usually unilateral
- Cellulitis
- Abscesses
- Inflammation: Red, swollen area on the breast that may feel hot and painful to the touch
How are granulomatous conditions of the breast characterised and list the causes?
Characterised by formation of granulomas (special macrophage aggregates)
- The breast becomes inflamed, developing a mass of tissue within the breast that can present as a lump
Causes
- Systemic granulomatous disease e.g. TB, sarcoidosis
- Idiopathic granulomatous mastitis: make sure infection has been excluded. Mimics breast cancer and breast abscess
- Reactions to ruptures implants
List the processes involved in idiopathic granulomatous mastitis and how to treat it
What does it mimic
- Granuloma formation (presents as a lump) and inflammation
- Ensure to exclude infection as the cause
- Mimics breast cancer and abscesses
- Treat with steroids
Describe the pathology of periductal mastitis
Aka mammary duct estasia (= dilation)
- Central ducts around the areola become infected, inflamed, blocked and dilated
- Ducts get clogged with secretions and burst
- Associated with chronic inflammation and scarring
- Known relationship to smoking
What are the symptoms of periductal mastitis / mammary duct ectasia?
What can it cause?
- Redness, swelling and pain around the nipple
- Sometimes there’s a mass beneath the nipple
- Nipple retraction/inversion
- Nippe discharge
Periductal mastitis can cause a breast abscess along with acute lactational mastitis
What is fat necrosis, what causes it in breast tissue and how would it present?
- An inflammatory reaction caused by damage to the breast tissue and rupture of fat cells
- Caused by trauma: external trauma, previous surgery, other inflammatory conditions
Presentation
- May cause a hard, round lump
- Often painless but sometimes tender
- Skin dimpling
- May look red and bruised (trauma)
- Nipple retraction
- Clinically or mammographically may be mistaken for cancer
What is ‘inflammatory cancer’?
- A presentation of breast cancer
- Lots of lymphatics are blocked by the tumour, causing inflammation
- Breast is diffusely oedematous, red and tender
- Mimic of inflammatory conditions
What are the types of benign proliferative breast disease?
- Fibrocystic change
- Radical scar
What causes fibrocystic change in the breast and how would it present?
- An atypical response of normal breast tissue to fluctuations in cyclical hormones, very common
Presentation
- Lumpy breasts
- Multiple lesions
- Swelling, pain, tenderness
- Nipple discharge
- Worse before menstruation
What microscopic abnormalities can be seen with fibrocystic breast change?
- Small and large cysts
- Adenosis: more glands in lobular tissue
- More fibrous stroma
- Epithelial hyperplasia: the duct or lobular epithelium gets thicker and forms unusual shapes
- Apocrine metaplasia: the epithelial cell of cysts changes to look like apocrine sweat glands
- Micro-calcification: flecks of calcium, seen on mammography
- Columnar cell changes: apical snouts lining cysts
What does a radical scar look like microscopically?
- Fibrosis and elastic material at the centre
- Star shaped appearance
- Trapped glands only ‘pseudo-infiltrative’ i.e. look like they’re infiltrating but actually just pushing things aside
- Myoepithelial cells present (would not be seen in cancer)
Define benign proliferative breast conditions
A group of non-cancerous conditions marked by an increase in cell growth of certain cells in the breast. Having one of these conditions may increase your risk of developing breast cancer
What is a fibroadenoma?
What would be the clinical and microscopic findings?
- Benign neoplasm
- Forms from both fibrous and glandular tissue
Clinical findings
- Younger patient (different demographic to breast cancer)
- Often asymptomatic
- Lump, firm but not hard (breast cancer is very hard, this is more like a squash ball)
- Mobile: free to move around the breast
- Painless
Microscopically
- Giant lobule: all the TDLU tissue is expanded and distorted
- Epithelial cells are squashed and elongated
- Lots of variably cellular fibrous tissue
Describe Phyllodes Tumour
How does it compare to a fibroadenoma?
How is it treated?
- Similar to fibroadenoma but commoner in older patients
- More cellular and more mitotic activity (more rapid cell division)
- More atypical and usually larger than fibroadenomas
- Only most Phyllodes are benign
- Usually removed surgically
What is an intraductal papilloma?
How does it present?
- Frond-like growth in large ducts near the nipple
- Benign, often excised to ensure nothing worse is lurking
Presentation
- Nipple discharge
- Painful lump
What are the risk factors for breast cancer?
Reproductive:
- Early menarche, late menopause, late 1st npregnancy
Hormonal: HRT, OCP
Anatomical/Physiological: Dense breast on mammography
Behavioural: alcohol, smoking
Genetic: +ve family history, BRCA1&2
What is the patient pathway in breast cancer?
- Presentation
- Investigation
- Treatment: surgical or oncological
- Pathology report: diagnostic categories, prognostic categories
What are the signs and symptoms for breast cancer?
Breast:
- Lump and thickening
- Skin changes: skin over lump looks orange and dimply (pei d-orange) or redness (inflammatory carcinoma)
Nipple:
- New inversion
- Rash or redness
- Discharge
Axilla: Lump
What is involved in breast screening?
What are the age ranges for breast screening?
What is the benefit of screening?
- Includes: examination, imaging (mammography, US or both), needle biopsy
- Age: 50-70yrs every 3 years
>70yrs can attend through self-referral
- Tumours discovered at screening are often asymptomatic, small and lower grade and stage than symptomatic tumours
How do you investigate for breast cancer?
Examine: palpate the lesion
Image: US, mammography, MRI
Tissue diagnosis: pathology
- Fine Needle Aspiration (FNA) = cytology. quickest, best option and takes fluid-like material from the lesion
- Core biopsy = histology. Easier to make a diagnosis and easier to see ER and PR with core biopsy
- Excision biopsy = diagnostic or therapeutic. If the above aren’t useful, the whole lump is removed to diagnose
What are the surgical options for breast cancer treatment?
- Wide local excision or mastectomy
Aim of surgery: excise malignancy and leave none of it behind
Type of surgery dependent on:
- size, number and type of tumour
- size of breast
- location of tumour
Describe a wide local excision for breast surgery
WLE
- Aim: to remove just the tumour with a rim of normal tissue to preserve the remaining breast
- Combined with radiotherapy to reduce risk of recurrance
- Need pathological assessment of margins
When is a mastectomy chosen over WLE?
- For large, multiple or extensive tumours
- Neo-adjuvant chemotherapy can shrink some of these large tumours to make WLE possible
- May be clinically safer to do a mastectomy due to size, extent or location of tumour
Besides breast surgery for breast cancer, what other surgery needs completed?
Sentinel node biopsy
- The way the lymphatics are located, the cancer would reach one node before the others (the sentinel node)
- The sentinel node: the node the cancer is likely to spread to first before it involves any other axillary nodes
- Identify and remove the sentinal node, and assess whether there is a tumour in that node
- If no tumour: can leave the rest of the axilla
- Tumour present: axillary clearance, axillary radiotherapy or no other treatment as long as oncological treatment is being implemented to mop up residual carcinoma e.g. radiotherapy
Why is axillary surgery required for breast cancer?
- Breast cancer has a tendency to spread to local lymph nodes via lymphatics
- Local lymph nodes for the breast: in the axilla
What oncological treatment is accessible for breast cancer patients?
Radiotherapy
- To the breast following WLE to reduce risk of recurrance
- Sometimes targets the axilla if +ve nodes are found
Hormonal therapy
- For tumours with high levels of residual hormone receptors (ER/PR +ve), drugs can be used to block hormone function e.g. Tamoxifen
- Used post-surgery once the type of tumour has been identified
- In post-menopausal women, no endogenous oestrogen is produced from ovaries, but can be produced from soft tissue. Aromatase inhibitors can inhibit this process
Chemotherapy
- Neo-adjuvant before surgery to reduce size of tumour
- Adjuvant: after surgery to reduce risk of metastasis at a different site
- Useful for triple neg breast cacinoma which lack targets for the usual hormonal therapies (ER, PR, HER2 negative)
What dysplastic lesions are seen in the breast?
How do they present?
- Dysplastic lesions = pre-invasive
- In breast: carcinoma in-situ (first stage before true carcinoma)
- 2 types: ductal and lobular carcinoma in-situ (DCIS and LCIS)
- Both arise from TDLU
- LCIS: less clinically concerning and more of a ‘RF’ rather than true dysplasia
These usually are asymptomatic and found on mammography
What do breast carcinoma in-situs look like microscopically?
- Malignant looking proliferation of epithelial cells within the basement membrane
- No extension into breast stroma
- No communication with blood vessels or lymphatics
- No possibility of metastases
Describe features ductule carcinoma in-situ (DCIS)
How is it treated?
- Risk of developing cancer
- Can be extensive and form a significant mass/lesion without progressing into invasive cancer (can spread through a lot of ducts but not spread outside them)
- Can co-exist with invasive malignancy
- Treated with surgery but axillary treatment not required
- Tamoxifen can be used if residual hormone receptors present
What types of malignancy can be seen in the breast?
Ductal carcinoma: commonest type
- Classical histological features of malignancy
Lobular carcinoma
- More likely to be bilateral and multifocal
- Characteristics: small, bland, discohesive cells (loss of E-cadherin, a cell adhesion molecule)
- These are not classical malignancy features
Others
- Malignant phyllodes
- Sarcoma
- Lymphoma
What are common prognostic factors for breast cancer?
Hormone receptor status: ER, PR (predicts sensitivity to hormonal treatment)
HER2 status: HER2 amplification predicts poorer prognosis but allows treatment with Herceptin
Stage: measure of how far a tumour has spread
- TNM: Tumour (factors and size), Nodes (no. of axillary nodes involves), Metastasis (y or no)
Grade: measures intrinsic aggressiveness of tumour ie. how fast it will spread
- grade 1 (slow) to grade 3 (fast)
Nottingham Prognostic Index: combines grade and stage
What is the function of BRCA 1 and 2
They produce TSGs (tumour suppressor genes)
What are the four inflammatory conditions of the breast?
- Acute mastitis
- Periductal mastitis / Mammary duct estasia
- Granulomatous conditions of the breast
- Fat necrosis
What are the two hyperplastic conditions of the breast?
ie. benign proliferative conditions
- Radical scar
- Fibrocytic change
What are the 3 benign neoplasms of the breast?
- Fibroadenoma
- Phyllodes tumour
- Intraductal papilloma
Where is the cervix?
What are the two regions of the cervix?
Location: continuous with uterus and connects the vagina to the uterus
Regions: ectocervix and endocervix
Where is the ectocervix located?
What is the epithelium prior to puberty?
Ectocervix: projects into the vagina
Epithelium: stratified squamous non-keratinised epithelium
Where are the internal and external os located?
External os: marks transition from ectocervix to endocervical canal
Internal os: between the endocervical canal and uterine cavity
What is the epithelium lining the endocervical canal prior to puberty?
Simple columnar glandular epithelium
What happens to the cervix during puberty and then menopause?
Where the two types of epithelium meet: the squamocolumnar junction
- The cervix grows during pregnancy, causing the squamocolumnar junction to evert onto the vagina
- The lower pH of the vagina causes the now exposed columnar epithelium to undergo squamous metaplasia to adapt to environment, and so become squamous epithelium at the ‘transitional zone’ at squamocolumnar junction
These changes are reversed during menopause
What is the clinical significance of the transformation zone in the cervix?
Cells undergoing metaplasia are vulnerable to agents that induce neoplastic change
- It’s this zone that cervical carcinoma’s commonly arise
What is the main cause of cervical carcinoma?
The human papilloma virus (HPV)
- Some strains are more oncogenic than others
How is HPV acquired?
How can it cause cervical cancer?
What strains are most prevalent in Scotland?
- Sexual activity
- Persisting/recurrent infection with an oncogenic strain of HPV is thought to be a cause of cervical cancer and precancer
- HPV 16 and HPV 18
Who is the HPV vaccine aimed at?
What strains are included?
12 and 13ry old girls and boys
Strains: HPV 6, 11, 16, 18
What are the screening demographics for cervical cancer?
Women ages 25-65
- Screened every 3 years until 50, then every 5 years
- Included those who have been vaccinated
What does cervical cancer screening involve?
Cervical cytology
- Cells from the transformation zone
- Detect changes associated with HPV and CIN (cervical intraepithelial neoplasia)
Define cervical intraepithelial neoplasia (CIN)
Define dyskaryosis
What is the connection between the two?
CIN: presence of atypical cells within the squamous epithelium (pre-malignant)
Dyskaryosis: nuclear abnormalities of cells in the cervix (larger nuclei with frequent mitoses)
- Presence of dyskaryosis is suggestive of CIN and prompts referral to colposcopy for biopsy
What is the connection between human papilloma virus and CIN?
HPV is the main cause of CIN
- High risk HPV in the cervix increases risk of CIN and it’s absence implies low risk at that time
- Most HPV infections don’t progress into CIN or cancer
What are the levels of severity of dyskaryosis and what do they indicate?
Low grade dyskaryosis with koilocytosis
- Koilocytosis: halo cells, a type of epithelial cells that develops following HPV infection
- Dyskaryosis: large nucleated cells with frequent mitoses
Low grade dyskaryosis
- Usually HPV infection or CIN I
High Grade (moderate) squamous dyskaryosis
- Nuclear:Cytoplasmic ratio has increased
- Indicative of CIN II
High Grade (Severe) dyskaryosis
- Indicative of CIN III
- Nuclear enlargement with dense hyperchromasia and coarse chromatin clumping
How is cervical intraepithelial neoplasia (CIN) characterised?
Presence of atypical cells within the squamous epithelium
- Atypical cells are dyskarocytic (larger nuclei with frequent mitoses)
What are the features of Grades I-III cervical intraepithelial neoplasia (CIN)?
CIN I
- mild dysplasia
- atypical cells found in lower 1/3 of epithelium
- don’t treat as it usually regresses (has ability to progress to CIN II/III)
CIN II
- moderate dysplasia
- atypical cells found in lower 2/3rd of epithelium
CIN III
- severe dysplasia with atypical cells occupying full thickness of epithelium
- this is carcinoma in-situ: cells similar to malignant lesion cells but no invasion
- if these abnormal cells invase through BM: malignancy ensues
What is the treatment for CIN II/III?
Large loop excision of transformation zone
- transformation zone excised with cutting under local anaesthetic
- LLETZ allows diagnosis and treatment
- specimen viewed histologically
What are 2 immediate and 2 delayed complications of a large loop excision of the transformation zone?
What is this procedure used to treat?
Treatment for CIN Grades II/III
Immediate complications: pain and haemorrhage
Delayed complications: secondary haemorrhage, infection and cervical stenosis
What are premalignant changes called in the squamous epithelium of the cervix?
What are premalignant changed called in the glandular epithelium of the cervix?
What is malignancy of glandular epithelium
Squamous: cervical intraepithelial neoplasia (CIN)
Glandular premalignancy: cervical glandular intraepithelial neoplasia (cGIN)
Malignancy of glandular e.: adenocarcinoma
What are the most common cervical carcinomas?
90% - squamous cell malignancies
10% - columnar epithelium (adenocarcinoma)
- Worse prognosis and increasing in proportion as screening prevents proportionally more squamous carcinomas
What causes cervical cancer?
- CIN is premalignant stage therefore same aetiologies
- HPV found in all cervical cancers
- Common when screening is inadequate
- Immunosuppression accelerates process of invasion from CIN
List 3 early and 3 late symptoms of cervical cancer
Early:
- Post-coital bleeding
- Intermenstrual bleeding
- Irregular vaginal bleeding
- Postmenopausal bleeding
- Can be asymptomatic
Late:
- Involves ureters, bladder, rectum and nerves
- Uraemia, Haematuria, rectal bleeding, pain
What changes can be seen in the vagina after menopause and what causes these changes?
Low oestrogen post menopause can lead to atropic vaginitis
- Oestrogen helps with elasticity of the vagina
- Loss of oestrogen: vagina walls become thin, dry, and inflamed
What are the 3 main clinical characteristics of atrophic vaginitis and what commonly causes it?
Usually seen after menopause due to low oestrogen levels
Main characteristics:
- Discomfort
- Dyspareunia: difficult or painful sexual intercourse
- Bleeding
(- Polyps and cysts are not uncommon)
What are the premalignant and malignant cells in the vagina called?
Premalignant: vaginal intra-epithelial neoplasia (VAIN)
Malignant: squamous carcinoma of the vagina
List 3 common infections of the vagina
- Bacterial vaginosis
- Thrush
- Trichomonas vaginalis (STD)
- Herpes Simplex virus (HSV)
What is Herpes Simplex Virus and where is it found?
- a sexually transmitted infection of the skin
Type 1: affects the mouth or eyes - cold sores
Type 2: affects the genitals - genital herpes
What is the pathology of Herpes simplex virus?
- It travels to local sensory nerves and lies dormant until reactivation (recurrance of the herpes infection)
What is the function of the vulva?
It acts as a gate for the uterus, providing protection by opening the lips of the vulva (labia majora and minora)
What is a common infection of the vulva?
Candidiasis (thrush)
What are the risk factors for developing candidiasis of the vulva?
What is it’s pathology?
ie. thrush
Associated with pregnancy or diabetes
Pathology:
- Vestibular gland cysts may become infected with abscess formation
- Can develop Lichen planus and lichen sclerosus et atrophicus: both are non-infective inflammations
What is cancer of the vulva called?
Small cell carcinoma (SCC)
What are the two associations that could lead to small cell carcinoma of the vulva?
- Vulval intraepithelial neoplasia (VIN)
- Dermatoses
What is the epidemiology of SCC of the vulva associated with VIN?
- Mostly in females <60yrs
- Associated with high incidence of lower genital tract neoplasia esp. CIN and invasive cervical cancer
- Usually related to high risk type HPV 16/18
What is the epidemiology of SCC of the vulva associated with dermatoses?
- Most occurs in the >60yrs
- Well differentiated and keratinising
- Not associated with HPV infection or VIN
- Adjacent squamous hyperplasia and/or lichen sclerosus
What week in gestation does reproductive development diverge?
Week 7
What determines development of male or female gonads?
Sex determining region on the Y chromosome (SRY)
- SRY present: development proceeds as male
- No SRY: development proceeds as female
Describe male reproductive development in the embryo
- SRY directs gonad to become a testis with spermatogonia, leydig cells and sertoli cells
- Testosterone from Leydig cells: stimulates development of mesonephric duct
- Mesonephric duct: forms rete testis, efferent ducts, epididymis, vas deferens, seminal vesicle, trigone of bladder
- Dihydrotestosterone: development of prostate, penis and scrotum
- AMH from Sertoli cells: induces regression of paramesonephric ducts
- Urogenital sinus: bladder, prostate gland, bulbourethral galnd, urethra
Descrie female reproductive development during embryogenesis
No SRY: gonad develops into ovaries with oogonia and stromal cells
No testosterone: regression of mesonephric ducts
No anti-mullarian hormone: paramesonephric ducts persist
- Fallopian tubes, uterus, cervis, upper 1/3 of vagina
- These ducts are located laterally and progress toward the pelvis where they fuse and fuse with urogenital sinus
- Unfused portion: fallopian tubes. Fused: uterus, cervix and vagina
Urogenital sinus: bladder (except trigone), lower 2/3rd of vagina, bulbourethral gland and vestibule
Remains of mesonephric ducts: trigone of bladder
Describe the anatomy of the fallopian tubes
- Muscular, tubal structures
- Covered by peritoneum
- Extend laterally and open into the abdominal cavity near the ovaries
- Layers of smooth muscle with a complex internal arrangement of plical folds
Describe the structure of the fallopian tubes
- What epithelium is present?
- How does the structure relate to function
- Fimbria (finger like, ciliated projections), infundibulum, ampulla, isthmus (narrowest part of the tube)
- Inner complex arrangement of plical folds
Layers of smooth muscle with an inner mucosa layer (this structure facilitates the function of the tubes)
Inner mucosa: ciliated simple cubodial epithelium and secretory peg cell. Waft ovum toward uterus and provide nutritents
Smooth muscle: contracts to assist with transportation. Sensitive to sex hormones so greatest peristalsis with high oestrogen levels
Describe the anatomy of the ovary
Surface: simple cubodial epithelium, underlying which is a dense CT capsule
Peripheral cortex:
- Connective tissue stroma (stromal cells) and numerous ovarian follicles with central oocyte surrounded by a layer of follicular cells
- Corpus luteum and corpus albicans are seen here duing menstration
Central medulla
- contains stroma, loose CT, blood vessels and Leydig cells
What are the corpus luteum and corpus albicans?
Luteum: temporary endocrine structure involved in high PR and moderate oestradiol and inhibin production. It is the remains of the dominant folcile one the mature ovum is released
Albicans: ovarian scar composed of CT after the corpus luteum degeenrates
- It remains in post-menopausal women
Give 3 examples of non-neoplastic ovarian cysts
- Luteal cysts (proliferation of cells around oocyte)
- Follicular cysts
- Inclusion cysts (involutions of surface epithelium, typically seen in post-menopausal women)
- Tiny cysts (oocytes that haven’t developed into a follicle at all)
- Polycystic ovary syndrome
What histological feature is seen with polycystic ovary syndrome (POS)?
What are the main symptoms?
What complications can occur?
Histological: ovaries will contain a large number of follicular cysts, many of which lack central oocyte
Main symptoms:
- Anovulatory or irregular periods
- Related to androgen excess: hirsutism, acne, weight gain
Complications:
- Fertility issues (no egg released and no secretory phase endometrium)
What are the prcoesses involved in ovarian stromal hyperplasia?
How does it present clinically and with imaging?
Who is most commonly affected
Processes:
- Uniform enlargement of the ovary
- Stromal hyperplasia has no luteinised cells: less risk of hyperandrogenism
(If luteinised cells present: stromal hyperthecosis with hyperplasia of stroma and theca interna, greater chance of hyperandrogenism)
Clinically: none
Macroscopically: ill-defined white/yellow nodules
- Microscopically: replacement of cortex and medulla with nodules of ovarian stroma
Usually affects post-menopausal women
Define salpingitis
Inflammation of the fallopian tubes
Define Pelvic Inflammatory disease
An ascending infection of the female upper genital tract (above the cervix), usually resulting in salpingitis
What is the main aetiology of pelvic inflam disease (PID)?
Sexually transmitted disease (Chlamydia and Gonorrhoea)
Give 4 clinical features of PID
What microscopic feature is seen?
- Fever
- Vaginal discharge
- Lower abdo/pelvic pain
- Pelvic masses if tubes distended with exudate or secretions
- Adnexal tenderness
Microscopic: neutrophil aggregates
How is pelvic inflam disease treated
antibiotics
What is the main complications of salpingitis?
- Tubo-ovarian abscess (adherence of the tube to the ovary): can lead to sepsis if it ruptures
- Ahesions involving tubal plicae inc. risk of ectopic pregnancy (inflammation changes architecture of the f. tubes, therefore altered transportation of ovum)
- Damage or obstruction of the tube lumen may produce infertility
Define endometriosis
What occurs in ovarian endometriosis?
The presence of endometrial constituents (stroma and glands) occuring somewhere other than the endometrial cavity
- the abnormally located endometrium continues to bleed and can result in scarring and adhesion formation in adjacent tissues
Ovarian endometriosis: blood filled cysts (endometriomas)
Where can tumours in the ovaries arise from?
- Surface epithelium
- Germ cells
- Ovarian stroma
- Elsewhere (metastases to ovaries)
List 3 clinical features of non-hormone secreting tumours of the ovary?
Not usually detected until reaches a relatively large size
- Abdominal distension
- Urinary symptoms
- GI symptoms (compression from ovarian mass)
- Large neoplasms can result in torsion (twisting on arterial blood suplly) causing severe abdo pain
Give 3 examples of epithelial tumours of the ovaries
- Serous cystadenoma: benign or borderline
- low-grade serous carcinoma
- high-grade serous carcinoma
- mucinous
- clear cell carcinoma
- endometrioid carcinoma
Describe the histological features seen in a benign serous cystadenoma
What is the treatment
- The cyst has a thin wall lined by epithelium resembling normal fallopian tube epithelium
- No cytological atypia
- Epithelium is one-cell thick with no tufts, papillary areas or solid growth
Treatment: removal and no follow-up required
Describe the histology and cells of a borderline serous cystadenoma
What is the main complication if left untreated?
More complex growth patterns
- Larger with multiple locules and papillary areas (solid mass/solid projections)
- Usually no solid growth, haemorrhage or necrosis
Cell: slight cytological atypia
- Not very abnormal and similar to each other but not the same as normal cells
- No necrosis
No evidence of invasion
A small number can develop into areas of low-grade serous carcinoma
What are the demographics seen in low-grade serous carcinoma of ovary?
How is low-grade serous carcinoma treated
What molecular abnormalities are associated with low-grade serous carcinoma?
Demographics: usually in 40s (younger pts.)
Treatment:
- Surgical Excision (risk of recurrance)
- Don’t respond well to chemo (slowly progressive so cells aren’t rapidly dividing)
Molecular abnormalities: BRAF or KRAS mutations
What molecular abnormalities are seen in low-grade and high-grade serous carcinoma (ovary)?
Low-grade: KRAS and BRAF mutations
High-grade: BRCA1/2 mutations and p53 gene mutations
Who usually presents with high-grade serous carcinoma?
What is the pathology?
Demographics: peri- or post-menopausal women
- Seen in younger patients with BRCA1/2 mutation
Pathology: thought to originate from a serous tubal intraepithelial neoplasoa (STIN)
- Has usually spread at time of presentation
What is the presentation of a high-grade serous carcinoma?
How is it treated?
- Peri- or post-menopausal women
- Pelvic pain/ discomfort
- Abdominal fullness
- GI/Urinary issues
Treatment: surgery and chemotherapy (rapidly dividing cells)
Describe the morphology of clear cell carcinomas
- What is it associated with
- How is it treated
- >90% clear cell tumours are carcinomas
Morphology:
- Large
- Microscopically: high grade tumour with many different growth patterns - solid/cystic/form lobules/capillary structures
- Can be difficult to differentiate from high grade serous tumours but don’t have p53 mutation
Association: endometriosis
Treatment: surgery (resistant to chemotherapy)
What tumours of the ovary are associated with endometriosis?
- Clear cell carcinoma
- Endometrioid carcinoma
What is the most common germ cell tumour?
Mature, benign teratoma aka dermoid cysts
Describe the pathology of a mature teratoma
What is the demographics
How is it diagnosed
Pathology:
- Tumour consisting of mature tissues derived from one or more of the embryonic germ layers (ectoderm, endoderm, mesoderm)
- Most are cystic, but can have solid areas
- May contain hair, grease sebaceous material, cartilage, bone, teeth
- Microscopically: GI tract, skin, resp. epithelium, thyroid, bone, adipose tissue etc.
Demographics: women of reproductive age (20-50yrs)
Diagnosis: biopsy
Give an example of an ovarian stromal tumour and if it’s benign or malignant
- Ovarian fibroma (benign)
- Adult granulosa cell tumour (low-grade malignancy)
-How does a ovarian fibroma present?
What are the microscopic and macroscopic morphologies?
= benign ovarian stromal tumour
Presentation
- All ages
- Non-specific symptoms
- Abdominal pain/mass if large
- Can be incidental finding
- Meig’s syndrome: ovarian fibroma associated with ascites
Macroscopic: firm and white with lobulated surface
Microscopic: small bland spindle shaped cells and collagen
At what age do ovarian stromal develop?
Ovarian fibroma: all ages
Adult granulosa cell tumour: 45-55
What is the pathophysiology of an adult granulosa cell tumour?
How does it present?
What is it’s appearance?
Pathophys:
- Low grade malignant ovarian stromal tumour
- Ostrogen secreting tumour: results in abnormal vaginal bleeding (menorrhoea, amenorrhoea or PMB)
- Occassionally androgen secreting tumours
Will present with abnormal bleeding
- Unilateral and confined to the ovary
- Variable size
Appearance: solid/cystic
What is the cause for developmental abnormalities of the uterus?
Abnormalities in the fusion of the Mullerian ducts
Describe the anatomy of the uterus
- A muscular organ capable of expansion to accomodate a growing foetus
Made up of:
- Fundus: above entry of uterine tubes
- Body: site of implanation of the blastocyst
- Cervix: links uterus to vagina
Describe the histology of the uterus
Myometrium:
- Smooth muscle comprising most of the uterus
- Cells here undergo hypertrophy and hyperplasia during pregnancy in prep for childbirth
Endometrium:
- Consists of glands and stroma and has a variety of appearances depending on the phase of the menstrual cycle, menopause status etc
- Deep stratum basalis: changes little throughout menstrual cycle and is not shed during menstruation
- Superficial stratum functionalis: proliferates in response to oestrogen and becomes secretory in response to progesterones. Shed during menstruation and regenerated via cells from the stratum basalis
What hormones are involved in menstruation and what are their roles?
Low PR/ER stimulates ant. pituitary to release FSH
FSH: binds to granulosa cells to stimulate follicular growth, permitting conversion of androgens (from theca cells) to oestrogen and progesterone and stimulates inhibin secretion
When oestrogen levels rise to very high levels, it stimulates a peak of LH release
LH: acts on theca cells of the corpus luteum to stimulate production and secretion of androgens (PR) to prepare the uterus for a growing foetus
What feedback systems are involved in menstruation?
Moderate oestrogen: negative feedback
High oestrogen (and absence of progesterone): postive feedback
- Oestrogen in presence of progesterone: negative feedback
- Inhibin: selectively inhibits FSH at the ant. pituitary
List the phases of the uterine cycle during menstruation
- Proliferation phase (runs alongside follicular phase)
- Secretory phase (runs alongside luteal phase)
- Mensus (in absence of fertilisation)
Describe the proliferative phase of the uterine cycle in menstruation
- Runs alongside the follicular phase, preparing the repro tract for fertilisation and implantation
- Hormone: oestrogen
- Endometrium: thickening, richly vascularised, tubular glands in stratum functionalis open out onto the surface
- Inc. growth and motility of the myometrium
- Production of a thin alkaline cervical mucus (better environment for sperm)
Describe the secretory phase of the uterine cycle in menstruation
- Runs alongside the luteal phase
- Hormone: progesterone
- Endometrium: thickening into a glandular secretory form and glands become spiralled and fill with glycogen
- Myometrium: further thickening and reduced motility
- Thick acidic cervical mucus production (hostile environment to prevent polyspermy)
Describe the mensus phase of the uterine cycle in menstruation
- Occurs in the absence of fertilisation once the corpus luteum has broken down and internal lining of uterus has shed
- Spiral arterioles of the stratum functionalis layer contract resulting in ischaemia and degeneration of the functionalis layer
- The arteries rupture and the rapid blood flow dislodges and is lost
List 3 common sites for endometriosis?
- ovaries
- Peritoneal surfaces
- large and small bowel
- mucosa of cervix
- vagina
- fallopian tubes
Define adenomyosis
The present of endometrial tissue within the myometrium
- A subtype of endometriosis
What are the clinical features of endometriosis
- Dysmenorrhoea (painful menstruation) eg. abdo cramps
- pelvic pain
- infertility
Describe the possible pathogenesis theories with endometriosis
Metastatic theory: retrograde menstruation or surgical procedures introduce endometrium to sites outwith uterine cavity
Metaplastic theory: endometrium arises from coelomic epithelium (ie. peritoneum), as this is where the endometrium originates during embryological development
What are endometrial polyps?
What are they associated with?
How may they present?
How are they treated?
- Exophytic massess which project into the endometrial cavity
- Associated with tamoxifen
- Can present with abnormal bleeding
Treatment: hysteroscope
Describe the microscopic morphology of endometrial polyps
Microscopically
- Haphazardly arranged glands with preservation of a low gland to stroma ratio
- Glands are usually inactive but can also show proliferation, secretory changes or metaplasia
- Often thick walled blood vessels
- Fibrous stroma
What is a primary cancer in the uterus called?
Endometrial adenocarcinoma
What is the over-riding cause of endometrial hyperplasia and give 3 examples of a cause
Associated with prolonged oestrogenic stimulation of the endometrium
Possible underlying causes
- Anovulatory cycles
- Endogenous sources of oestrogen: obesity, PCOS, oestrogen secreting ovarian tumours
- Exogenous sources of oestrogen: HRT, OCP
What is the clinical presentation of endometrial hyperplasia?
- Post-menopausal bleeding
What is the histological characterisation of endometrial hyperplasia?
- Increase in the gland to stroma ratio
- Seen with or without cytological atypia
Atypical endometrial hyperplasia: precursor of endometrioid andeocarcinoma
How are endometrial hyperplasia and endometrial adenocarcinoma managed?
Hyperplasia: progesterone therapy or hysterectomy
Adenocarcinoma: hysterectomy, with subsequent management depending on grade and stage
What is a leiomyoma?
A benign smooth muscle tumour within the myometrium
- Common (at least 25% women)
What are the symptoms of a leiomyoma?
(= beningn SM tumour within myometrium)
- asymptomatic
- abnormal bleeding
- urinary freq if large
- impaired fertility
What is the pathology of a leiomyoma?
- Sharply demarcated round grey-white tumours with a whorled surface
- Microscopically resemble normal smooth muscle
What is the management for a leiomyoma?
- Varies depending on size, number and symptoms
- Medical: progesterone secretion IUS, hormonal therapies, GnHR agonist
- Surgical: uterine artery embolisation (blcoks blood supply to the uterine body), myomectomy, hysterectomy
What is a leiomyosarcoma?
- An uncommon malignant smooth muscle tumour of the myometrium
What are the clinical features of leiomyosarcoma?
What age does it usually occur?
- Age: 40-60yrs (pre or post menopausal)
- Initially no symptoms, then bleeding or pain
What is the pathology of a leiomyosarcoma?
Macro:
- Bulky, invasive mass or polypoid (a growth resembling a polyp)
- Necrosis, haemorrhage
Micro:
- Cytological atypia
- Necrosis, mitotic activity, infiltrative margin
What are endometrial stroma sarcomas?
What is their specific feature?
A group of tumours of the endometrial stroma
Can be low or high-grade
Feature: have a diffusely infiltrative worm-like growth pattern macroscopically
Give 2 examples of types of gestational trophoblastic disease
- Partial hydatidiform moles
- Complete hydatidiform moles
- Choriocarcinoma
What are hydatidiform moles?
How do they present
Rare mass/growth that forms inside the uterus at the beginning of a pregnancy (foetus doesn’t form properly)
Presentation: either spontaneous miscarriage or abnormalities detected on ultrasound
Compare partial and complete hydatidiform moles
Partial: Fertilisation of one egg by two sperm resulting in a triploid karyotype
Complete: Fertilisation of an egg with no genetic material, usually one sperm which duplicates its chromosomal material. Diploid karyotype, usually 46XX
Microscopic:
Partial: oedematous villi and subtle trophoblast proliferation
Complete: markedly enlarged oedematous villi with central cisterns and circumferential trophoblast proliferation
Risks:
Partial: Risk of invasive mole which invades and destroys the uterus
Complete: risk of invasive mole and choriocarcinoma
What are trophoblasts?
Form the outer layer of the blastocyst and are present for 4 days post-fertilisation
What is a choriocarcinoma?
How is it treated
A fast-growing cancer occuring in the uterus
- The abnormal cells start in the tissue that would normally become the placenta
- Frankly malignant, rapidly invasive and metastasises widely,
Treatment: chemotherapy
- Results in almost 100% remission for gestational choriocarcinomas
List the general characteristics of cancerous cells
- uncontrolled proliferation
- loss of original function (anaplasia)
- invasiveness
- metastasis (malignant cells)
What genetic changes occur for normal cells to become cancerous?
- normal cells become cancerous through a change in DNA
Two categories:
- inactivation of tumour suppressor genes (TSG): TSGs try to half proliferation and can induce apoptosis
- activation of protooncogenes to oncogenes: proto-oncogenes stimulate proliferation
Usually, regulatory genes become mutated
List the types of cancer treatment available and outline what situations they would be used in
Surgical removal
- only for solid tumours, dependent on location
- only if non-metastasised
Irradiation (Radiotherapy)
- only if localised and non-metastasised
Chemotherapy with anti-cancer drugs
- often only treatment available
- selective toxicity required
- main effect on rapidly dividing cells (including normal rapidly dividing tissue)
All three forms may be combined for optimal patient care
List 3 general toxic effects of chemotherapy
- bone marrow suppression: anaemia (fatigue etc.), neutropenia (risk of infection), thrombocytopenia (inc. risk of bleeding)
- hair loss
- effects on heart, kidney, liver
- damage to gastro-intestinal epithelium
- sterility (fertility)
- teratogenicity: damage to embryo
What cell types are found within a solid tumour?
- Dividing cells progressing through the cell cycle (sensitive to many anti-cancer drugs)
- Resting cells that are not currently dividing but have ability to do so (insensitive to many drugs and can cause relapses)
- Cells which can no longer divide but contribute to tumour size (do not need to worry about these cells)
What is the target for chemotherapy anti-cancer drugs?
Outline the effectiveness of chemotherapy and the clinical application of this
Target: Rapidly dividing tissue
Effectiveness:
- even in a dividing cell population, cells are not all undergoing mitosis at any one time
- therefore any cell cycle drugs will only attack a subpopulation of cancer cells
- a therapeutic course of cytotoxic drug kills a constant fraction of malignant cells, however the host immune system cannot destroy the remining cells therefore aim of chemo is total kill
Application: prolonged treatment and repeated doses required to reduce chance of relapse from resting cells
List the 5 main classes of anti-cancer chemotherapy
- alkylating agents
- antimetabolites
- cytotoxic antibiotics
- microtubule inhibitors
- steroid hormones and antagonists
Outline the mode of action of alkylating agents and give two examples
Mode of action:
- form covalent bonds with DNA
- interfere with both transcription and replication
- most have two reactive groups allowing the drug to cross-link: within 1 strand of DNA or across two strands of DNA
- therefore the DNA can’t separate so no DNA transcription so no cell division
- don’t differentiate between types of dividing cells
Examples:
- nitrogen mustards: mechlorethamine (lymphoma’s), melphalan (myeloma, breast and ovarian cancer), cyclophosphamide (many cancers)
- cysplatin
- temozolomide
Outline the mode of action of antimetabolites and give two examples
Mode of action:
- interfere with nucleotide synthesis or DNA synthesis
- Nucleotide synthesis: antifolates eg. methotrexate
- Nucleotide analogues: 5-fluoro-uracil, metcaptopurine
Examples:
- Folate antagonist (Methotrexate): inhibits dihydrofolate formation, inhibiting purine/pyrimidine nucleotide synthesis. Ultimately halts DNA and RNA synthesis
- pyrimidine analgue (Fluoro-uracil): prevents thymidine formation therefore stops DNA synthesis
- purine analogue (Metcaptopurines): converted into false nucleotides and incorporated into the DNA, disrupting the double helix
Outline the mode of action of cytotoxic antibodies and give two examples
Mode of action:
- act mainly by a direct action on DNA as intercalators
Examples:
- Dactinomycin: inserts itself into the DNA helix, disrupting RNA polymerase function
- Doxorubicin: inserts itself between base pairs, binds to the sugar-phosphate DNA backbone causing local uncoiling. This impairs DNA and RNA synthesis
Outline the mode of action of microtubule inhibitors
- bind to microtubular protein
- block tubulin polymerisation
- block normal spindle formation
- disrupt cell division
Outline the mode of action of steroid hormones and antagonists for anti-cancer chemotherapy
Mode of action:
- tumour may be responsive to a specific hormone which makes it regress
- may be stimulated or inhibited by a hormone
Steroid Hormone:
- Prednisone: synthetic adrenocortical steroid hormone, converted in the body to active prednisolone. Used to suppress lymphocyte growth
Hormone Antagonists:
- A tumour may be dependend on a hormone to grow therefore a antagonist will suppress growth
- Tamoxifen: antagonist of oestrogen receptors. Some breast cancers are oestrogen dependent
- Bicalutamide: testosterone receptor antagonist for prostate cancers
What imaging modalities are used for viewing the female reproductive tract and what are they used to view?
Ultrasound
- transvaginal ultrasound: assess endometrium
MRI
- soft tissue detail
- endometrial (bright), junctional zone (dark), myometrium (in the middle)
CT
- IV contrast gives better detail
- used to view the uterus
List 3 ovarian pathologies that can be identified on radiological imaging
Benign
- ovarian follicles
- ovarian cysts
- haemorrhagic cysts
- endometriosis
- PCOS
- ovarian torsion
Malignant tumours
How do ovarian follicles present clinically and radiologically?
When are ovarian follicles mentioned to a patient?
Clinically: common, benign, asymptomatic
US: look like a cyst
Pre-menopausal:
- <3cm: not mentioned
- <5cm: no follow up
- 5-7cm: annual follow up
Post-menopausal:
- <1cm: not mentioned
- <3cm: no follow up
- 3-5cm: follow up with ultrasound and CA-125 for a year
If very large follicle: it’s a functional cyst (pathological)
What is a haemorrhagic cyst?
How does it present clinically and radiologically?
What management is required?
- Haemorrhage in a dominant follicle or functional cyst
Clinically: asymptomatic or pain
US: cyst with haemorrhage debris
Management: follow-up in 6 weeks to ensure it’s getting smaller/gone (ie. ensure the bleeding has stopped)
What is an endometrioma?
How does it present clinically and radiologically?
= localised form of endometriosis in the ovaries
Clinically: chronic pelvic pain associated with menstruation
Radiologically:
- US: cyst with haemorrhagic debris which remains stable with follow-up (doesn’t disappear like haemorrhagic cysts)
- MRI: used to assess further, shows haemorrhagic material within the cyst
What is a dermoid cyst?
How does it present clinically and radiologically?
= common slow-growing benign neoplasm containing elements from multiple germ layers eg. teeth, hair, fat
Clinically: incidentally discovered in young women
X-Ray: calcification or teeth
US: hetergeneous mass, solid nodule
CT: fat/fluid/calcification/soft tissue
What is ovarian torsion?
How does it present clinically and radiologically?
Ovary twists on its own vascular supply
Clinically: afects young women, abdo/pelvic pain, nausea, vomiting
US: enlarged ovary, free fluid in the pelvis, absent vascularity, may be associated with ovarian mass eg. dermoid cyst
Diagnose quickly: emergency
List 3 symptoms associated with ovarian malignancy
Symptoms
- abdominal distension
- pelvic or abdominal pain
- feeling full / loss of appetite
- inc. urinary urgency or frequency
- irritable bowel disease
How do you determine a patient’s risk of ovarian malignancy
Risk of Malignancy Index
= ultrasound score x menopausal score x CA-125
Menopausal score:
- premenopausal: 1
- postmenopausal: 3
Ultrasound score:
- none (0), one abnormality (2), 2+ abnormalities (3)
- RMI >200 is concerning for malignancy
List 3 features of ovarian malignancy on ultrasound
- irregular solid or multi-loculated cystic mass
- solic components on cyst wall
- bilateral ovarian lesions
- ascites, peritoneal nodules or other evidence of metastases
List the cateogories of ovarian carcinoma and give 3 examples of each
Epithelial (90%)
- Serous (80%)
- endometroid
- mucinous
- clear cell
- squamous
Non-epithelial (10%)
- germ cell (teratoma)
- sex cord (granulosa cell)
- metastatic (uterus, stomach, colon, breast)
How do ovarian serous tumours present on ultrasound
What features would suggest a malignant serous tumour?
25% are malignant
- Large cystic mass
Malignant features:
- thick septations, solid components
- ascites, peritoneal metastases, lymphadenopathy, distant metastases
How are ovarian carcinomas staged?
Stage I: confined to the ovary
Stage II: confined to the pelvis
Stage III: Extends into the upper abdomen including serosal metastases to the liver and bowel
Stage IV: Implies metastases including liver parenchyma
List 3 cases in which surgery would not be indicated for ovarian carcinomas
How would these patients be treated?
- multiple liver metastases
- lymphadenopathy in porta hepatis
- suprarenal para-aortic lymph nodes
- diffuse liver metastases
- evidence of pleural or parenchymal lung disease
Treated with neoadjuvant chemotherapy
List 2 benign and 1 malignant uterine pathologies
Benign:
- fibroids
- adenomyosis
Malignant:
- endometrial cancer
What are fibroids?
How do they present clinically and radiologically?
= non-cancerous growths in the uterus made up of muscle and fibrous tissue
Clinically: pain, infertility, menorrhagia
US: hypoechoic (dark) mass
CT: bulky/lobulated
What is adenomyosis?
How does it present clinically and radiologically?
Adenomyosis: endometrial tissue has migrated to the myometrium
Clinically:
- asymptomatic
- dysmenorrhagia, menorrhagia, dyspareunia, chornic pelvic pain
US: thickening of the junctional zone
How does endometrial cancer present?
What investigations would be needed?
Presentation: post-menopausal women who present with vaginal bleeding
Investigations:
- transvaginal ultrasound: would see thickening >5mm
- MRI: local invasion
- CT: distant metastases
