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Describe the normal anatomy of the breast


The breast consists of

  • 15-20 lobules separated by ligaments of Cooper
  • Lobes contain alveoli, which contain lactocytes
  • Alveoli are surrounded by myoepithelial cells (contractile)
  • Lobes are connected by a ductal system
  • Oxytocin stimulates the contraction of myoepithelial cells, pushing milk into lactiferous ducts & towards the nipple
  • Ducts converge at the lactiferous sinus, below the nipple
  • Glandular tissue (lobules) and lactiferous ducts are lined by a characteristic epithelium with 2 layers: inner (luminal) & outer (myoepithelial)
  • Nipple has an average of 9 openings, surrounded by the areola
  • Montgomery tubercles (glands) secrete a sebaceous fluid that lubricates the nipple

Describe the blood supply of the breast

  • Internal thoracic artery (medially)
    > Anterior perforating branches
  • Axillary artery (laterally)
    > lateral thoracic artery
    > pectoral branch of acromioclavicular artery
    > subscapular artery
  • Intercostal arteries (lateral perforating branches)

Describe the lymphatic drainage of the breast

  • Axillar nodes
    > Apical group
    > Central group
    > Anterior group
    > Lateral group
  • Internal thoracic nodes

Describe the investigations used in breast pathology

  • Clinical examination: both breasts, axilla, supraclavicular nodes
  • Imaging: ultrasound, 2 view mammography, MRI
  • Biopsy
    > Fine needle aspiration (FNA): cytology
    > Core biopsy or vacuum assisted biopsy: histology

List and describe developmental abnormalities of the breast

  • Ectopic (heterotopic) breast tissue
    > Often on the milk line between axilla and groin
    > Nipple-areolar and glandular tissue may be present +/- nipple
    > Any breast disease may occur in heterotopic breast tissue
  • Breast hypoplasia
    > Associated with ulnar-mammary syndrome, Poland’s syndrome, Turner’s syndrome & congenitla adrenal hyperplasia
  • Macromastia
    > Stromal overgrowth leading to excessive breast size
    > Can begin at puberty (juvenile hypertrophy) or pregnancy (gestational hypertrophy)
  • Breast asymmetry
    > Mild is common, severe developmental may be distressing (corrective surgery)
  • Nipple inversion
    > Common and usually normal unless it is a new inversion

Describe 1) acute mastitis 2) periductal mastitis/duct ectasia

  1. Acute mastitis (puerperal or lactational)
    > Cellulitis associated with breastfeeding
    > Skin fissuring may let bacteria in - milk stasis favours their growth leading to infection of breast tissue
    > Abscesses may require incision & drainage as well as antibiotics
  2. Periductal mastitis/duct ectasia
    > Dilation of central lactiferous ducts
    > Periductal chronic inflammation
    > Scarring
    > Calcified luminal secretions may be seen on mammogram
    > Symptoms may include discomfort, mass, nipple retraction/inversion, green-brown nipple discharge
    > Associated with smoking and aging

Describe the conditions which may lead to granulomatous inflammation of the breast tissue

  • Systemic disease including sarcoidosis and infections such as tuberculosis, leprosy
  • Idiopathic granulomatous mastitis
    > Lobule-centred non-necrotising granulomatous inflammatory process
    > Tendency to recur after excision but may respond to steroids

Describe the following inflammatory conditions of the breast
> Foreign body reactions
> Recurrent subareolar abscesses
> Fat necrosis


> Foreign body reactions can occur around breast implants & may lead to scarring, fibrosis, capsular contractures
> Lead to discomfort and distortion of the breast
> Includes reactions to silicone leakage after implant rupture

> Recurrent subareolar abscesses
> May be associated with mamillary fistula, squamous metaplasia of lactiferous ducts and smoking

> Fat necrosis
> May follow trauma, is benign but biopsy may be required to rule out cancer


List the conditions which fall into the class of inflammatory pathology of the breast

  • Acute mastitis
  • Periductal mastitis/duct ectasia
  • Granulomatous inflammation of the breast
  • Inflammatory breast cancer
  • Foreign body reactions
  • Recurrent subareolar abscesses
  • Fat necrosis

List the conditions which may fall under the class of benign conditions of the breast

  • Fibrocystic changes
  • Fibroadenoma
  • Phyllodes tumour (also malignant)
  • Pure adenomas
  • Nipple adenoma
  • Hamartoma of the breast
  • Benign granular cell tumours

List the conditions which may fall under the class of malignant conditions of the breast

  • Ductal carcinoma in situ
  • Invasive ductal carcinoma
  • Lobular carcinoma in situ
  • Invasive lobular carcinoma

Describe the spectrum of fibrocystic change in the breast

  • Cysts: small & large
    > A galactocoele is a rare milk-filled cyst in the breast
  • Adenosis: increased amounts of glandular tissue
    > Sclerosing adenosis refers to a benign proliferation of distorted glandular tissue & stroma
  • Stromal proliferations
    > Diabetic fibrous mastopathy
    » Stromal fibrosis with infiltrating lymphocytes associated with type I diabetes
    > Pseudo-angiomatous stromal hyperplasia (PASH)
    » Proliferation of myofibroblasts causes a mass & may require biopsy to exclude malignancy

> Epithelial hyperplasia +/- atypia (increased cancer risk)
> Includes ductal and lobular hyperplasia
> Both have features in common with low grade ductal or lobular carcinoma in situ, different in terms of cell proliferation
> Associated with microcalcifications

> Apocrine metaplasia of cyst epithelium
> Characterised by large, rounded epithelial cells with copious granular eosinophilic cytoplasm & apical projections

> Columnar cell lesions
> Columnar cell change and columnar cell hyperplasia +/- atypia; associated with microcalcifications

> Intraductal papilloma
> benign tumour of the epithelial lining of the mammary ducts; harmless if no atypia
> Can present with bleeding from nipple
Multiple papillomas (papillomatosis) are more likely to be associated with breast malignancy

> Radial scars
> benign lesions characterised by a fibrotic core with elastic fibres, trapped glands & pseudo-infiltrative appearance
> Complex sclerosing lesions if >10mm
> Atypical proliferations may be present and increase cancer risk


Describe the different types of benign neoplasms which may be found in the breast

  • Fibroadenoma
    > Characteristic overgrowth of epithelium and stroma, resembling a giant lobule
    > Patterns; pericanalicular, intracanalicular
    > Hormone sensitive & regress after menopause
    > Firm, non-tender, mobile, <25-30mm
    > Stroma is similar to the stroma of normal terminal ductal lobular unit (TDLU)
    > Giant fibroadenoma - 100+mm, juvenile fibroadenoma in girls <18
  • Phyllodes tumour aka cytosarcoma phyllodes
    > Combines epithelium and mesenchyme but with more cellular stroma, mitotic activity cytological atypia & infiltrative border compared to fibroadenoma
    > Behaviour can vary (malignant or benign)
  • Pure adenomas: tubular or lactating
    > Lack prominent stromal element of fibroadenomas
  • Nipple adenoma aka papillomatosis of nipple ducts/erosive adenomatosis (uncommon):
    > Benign but can mimic Paget’s disease of the nipple (malignant)
  • Hamartoma of the breast (uncommon
    > Benign - forms a discrete, smooth, painless mass of glandular, fatty & fibrous connective tissue

Describe Paget’s disease of the nipple


Rare type of cancer of the nipple-areolar complex often associated with underlying carcinoma

Mimics eczema - persistent soreness, itching, erythema & scaling


List the risk factors for breast cancer (& protective factors)

  • Early menarche
  • Late menopause
  • Being older at first pregnancy/childbirth
  • Oral contraceptive use
  • Hormone replacement therapy (HRT)
  • Obesity
  • Tallness
  • Denser breast tissue on mammography
  • Alcohol
  • Positive family history
  • Breast cancer genetic syndromes: BRCA1/2, P53 - Li Fraumeni Syndrome

Protective: early pregnancy and childbirth, exercise and breastfeeding


Describe the symptoms of breast cancer

  • New lump or thickening in the breast of axilla
  • Altered shape, size or feel of the breast
  • Pain
  • Skin changes
    > Puckering or dimpling
    > Peau d’orange (skin oedema)
    > Rash or redness
  • Nipple changes
    > Tethering/inversion
    > Discharge
    > Eczema-like changes (Paget’s disease)

Describe the investigations used in breast cancer

  • Clinical examination: inspection in different positions, palpation
  • Imaging: ultrasound, X-ray mammography, MRI
  • Fine needle aspiration cytology with microscopy of cells recovered
  • Core biopsy (guided by imaging) with microscopy of tissue sections
  • Excisional biopsy - diagnostic or therapeutic

Describe breast screening


Women between 47-73 are invited for 2-view mammographic breast screening every 3 years

  • Microcalcification is often present in invasive carcinoma and may be detectable on X-ray mammography

Describe the surgical treatments for breast cancer

  • Surgery aims to remove all cancer tissue with margins free of cancer
  • Wide local excision (WLE) or lumpectomy + radiotherapy - achieves comparable local control + overall survival to mastectomy
  • Larger cancers may still require mastectomy to achieve clear margins
    > Axillary clearance is not necessary if sentinel node biopsy is negative; axillary clearance has significant morbidity e.g. lymphoedema, restriction of arm movement

Describe non-surgical treatments for breast cancer

  • Steroid hormone receptors: 80% of breast cancers overexpress oestrogen & progesterone receptor
    > ER/PR positive carcinomas respond to endocrine treatment
    > E.g. Tamoxifen: in breast, an ER antagonist but in bone & endometrium, it is an agonist, elevating endometrial cancer risk
  • Aromatase inhibitors e.g. letrazole, anostrazole
    > Block conversion of adrenal androgens to oestrogens as it does in adipose tissue; prevents oestrogen stimulation of tumour growth
  • Her2 positive cancers: overexpression of Her2 has a worse prognosis
    > Can be treated with monoclonal antibody trastuzumab (Herceptin)
  • Chemotherapy
    > Important to prevent metastatic relapse, especially in ER-PR-HER2- cancers as these do not respond to endocrine treatment

Describe the grading and staging of breast cancer

  • Stage: carcinoma size, lymph node involvement & metastasis
  • Grade: based on 3 histological properties
    > Nuclear pleomorphism
    > Number of mitoses per mm2
    > Degree of gland formation by cancer cells

Grade 1: well-differentiated & slow growing
Grade 3: poorly differentiated & fast growing


Describe the Nottingham Prognostic Index (NPI)


Combines grade, tumour size in cm and stage into a numerical prognostic index

Graed + stage + size (cm) / 5


Describe the divisions of breast cancer

  • Invasive ductal carcinoma (IDC)
  • Invasive lobular carcinoma (ILC)
  • Special types
    > 70% ductal
    > 10-15% classical lobular & variants - alveolar, solid, pleomorphic, tubular-lobular
    > Papillary/micropapillary
    > Medullary
    > Tubular, cribriform
    > Mucinous
    > Acinic cell, adenoid cyst, apocrine, glycogen-rich, lipid-rich, oncocytic, secretory, sebaceous

Describe precursor lesions for breast cancer

  • Ductal epithelial hyperplasia +/- atypia (low grade dysplasia)
  • Lobular epithelial hyperplasia +/- atypia (low grade dysplasia)
  • Carcinoma in situ (high grade dysplasia)
    > aka ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS)
    > Proliferation of markedly abnormal epithelial cells within the basement membrane
    > No extension into breast stroma
    > No communication with blood vessels or lymphatics so no possible metastases

Describe the histology of the Fallopian tube

  • Tubal structure with a muscular wall covered by peritoneum
  • Has a fimbrial end with finger-like projections
  • The internal aspect has a complex arrangement of plical folds
  • These are covered by serous epithelium, which contains cuboidal cells with round/ovoid nuclei, cilia and secretory cells

Describe the histology of the ovary

  • Appearance varies depending on patient’s age, menopausal status and in pregnancy
  • Peripheral cortex contains numerous follicles containing ova (germ cells)
    > Corpora lutea and corpora albicantes are seen here during menstruation (corpora albicantes remain post-menopausally)
  • Central medulla
    > Stroma: spindle-shaped cells and collagen fibres
    > Blood vessels
    > Leydig cells
  • Mesothelial cells form the peritoneal covering

Describe the embryological development of the ovary and Fallopian tube

  • Germ cells (endodermal) originate from the yolk sac and by week 5-6 of gestation migrate to the urogenital ridge
  • Mesodermal epithelium of this ridge then forms the epithelium & stroma of the ovary
  • Around week 6, invagination and fusion of the coelomic epithelium and stroma form the 2 Mullerian ducts
    > Ducts grow downwards towards the pelvis
    > Fuse together and then with the urogenital sinus
    > Unfused portions become the Fallopian tube
    > Fused portion becomes the uterus & vagina

Describe non-neoplastic ovarian cysts

  • Follicular cysts: normally part of the menstrual cycle so contain a central oocyte
  • Luteal cysts: large corpus luteum which remains after ovulation
  • Inclusion cysts: infoldings of the surface peritoneum which become trapped within the ovarian stroma
    > result in small cysts lined by mesothelial cells within ovarian cortex
  • Polycystic ovary syndrome (PCOS): ovaries contain a large number of follicular cysts, many of which lack a central oocyte
    > Patients may be anovulatory or have irregular periods
    > Androgen excess can result in hirsutism, acne and weight gain as well as fertility issues

Describe ovarian stromal hyperplasia

  • Uniform enlargement of the ovary usually affecting post-menopausal women
  • Stromal hyperplasia but no luteinised cells
    > if luteinised cells are present, this is termed stromal hyperthecosis - greater incidence of hyperandrogenism
  • Histologically appears as
    > Ill-defined white/yellow nodules macroscopically
    > Microscopy shows replacement of the cortex and medulla by nodules of ovarian stroma

Describe pelvic inflammatory disease (PID) and tubo-ovarian abscess

  • Part of the spectrum of pelvic inflammatory disease
  • Underlying cause is usually sexually transmitted: Chlamydia trachomatis, Neisseria gonorrhoea
  • Enters the gynecological tract via the vagina and initially causes cervical inflammation
    > Ascending infection results in salpingitis
  • PID presents with abdominal/pelvic pain, adnexal tenderness, fever and vaginal discharge
  • PID is treated with antibiotics and occasionally surgical resection of abscesses
  • Complications of PID include tubo-ovarian abscess formation and fibrosis or fusion of tubal plicae resulting in increased risk of infertility and ectopic pregnancy

Describe the histological appearance of acute salpingitis

  • Aggregates of macrophages and neutrophils
  • Apoptotic debris
  • Pus filling the lumen of the fallopian tube

Describe endometriosis, including sites, clinical symptoms and causes

  • Endometrial constituents (glands and stroma) occur outwith the endometrial cavity

> Myometrium, uterine surface, ovaries, large and small bowel, appendix, mucosa of cervix, vagina and fallopian tube, laparotomy scars, pleural cavity, peritoneal surfaces (uterine ligaments, rectovaginal septum)

  • Ovarian endometriosis can result in the formation of blood-filled cysts (endometriomas aka chocolate cysts)
  • Abnormally located endometrium continues to bleed and can result in scarring and adhesion formation in adjacent tissues (rarely tumours can develop)
  • Clinical symptoms: dysmenorrhoea, pelvic pain, infertility
  • Causes
    > Metastatic theory: retrograde menstruation/surgical procedures introduce endometrium to sites outwith uterine cavity
    > Metaplastic theory: endometrium arises directly from the coelomic epithelium (i.e. peritoneum) of the pelvis (supported by endometriosis reaching pleural cavity sometimes)

List the types of ovarian tumours

  • Serous cystadenoma
  • Serous carcinoma
  • Mucinous cystadenoma
  • Clear cell carcinoma
  • Endometrioid carcinoma
  • Mature teratoma
  • Other germ cell tumours
  • Fibroma
  • Adult granulosa cell tumour
  • Elsewhere in the body metastasising to the ovaries

Describe ovarian serous cystadenomas

  • Can be benign, borderline or malignant, derived from surface epithelium

Benign serous cystadenoma:
- Cyst has a thin wall which is lined by epithelium
identical to tubal/serous epithelium in the fallopian tube
> One cell thick with no tufts, papillary areas or solid growth; no cytological atypia
> Treatment: removal of cyst; no risk of malignancy

Borderline serous cystadenoma:
- Borderline tumours have more complex growth patterns compared to benign tumours; some cytological atypia
- Behaviour is difficult to predict; can recur or develop into low grade serous carcinoma
- Frank evidence of invasion is absent - no growth into underlying structures of ovary
- Histology - papillary & micropapillary structures grow
> Branches of stroma covered with epithelium
> Aggregates of epithelial cells with no stromal core
> Calcified areas can appear - psammoma bodies


Describe ovarian serous carcinoma


Low grade serous carcinoma
- Slowly progressive surface epithelium tumour with recurrences following excision
> Do not respond well to chemotherapy
> Molecular abnormalities: BRAF/KRAS mutations
- Histology shows areas of frank invasion

High grade serous carcinoma
- Commonest type of ovarian carcinoma
- Usually present in peri-menopausal or post-menopausal women
- Originates in the Fallopian tube but present in the ovary & elsewhere after metastasis

  • Causes:
    > Precursor lesions in the fallopian tube (serous tubal intraepithelial carcinoma)
    > Can be seen in younger patients with BRCA or P53 mutations
  • Treatment: surgery + chemotherapy
  • Histology: abnormal differentiation (no resemblance to original tissue), mitotic figures and areas of necrosis

Describe ovarian mucinous cystadenomas

  • Can be benign, borderline or malignant
  • Borderline mucinous cystadenoma
    > Mucin vacuoles within luminal aspect of the cell
    > No frank invasion of stroma making up the wall of the cyst

> Frank invasion - malignant mucinous tumour (carcinoma); can be difficult to differentiate from metastases from GI tract


Describe ovarian clear cell carcinoma

  • Associated with endometriosis; usually large and solid or cystic
  • Treatment: surgery; resistant to platinum-based chemotherapy
  • Histology
    > High trade tumours with different growth patterns - tubular, cystic, papillary, solid (don’t always have clear cytoplasm)

> Can be difficult to differentiate from high grade serous carcinoma but do NOT have mutations in p53

> Hobnailing: large nuclei, little cytoplasm means nuclei stick to lumen of glands

> Formation of hyalin globules (pink structures within lumen of glandular structures or inside cells)


Describe mature teratomas

  • Usually found in women of reproductive age
  • Consist of mature tissues derived from one or more embryonic germ layers (ectoderm, mesoderm, endoderm)
  • Most are cystic but have solid areas depending on the tissues which have developed
    > Contain hair and greasy sebaceous material, sometimes cartilage, bones & teeth
    > Microscopically different tissues are identified: skin, respiratory epithelium GI, thyroid, adipose, glial tissue…
  • Require thorough sampling
    > Immature teratomas: embryonal/foetal tissue can be malignant and recur/metastasise
    > Somatic malignancies: small number of cases

Describe an ovarian fibroma

  • Benign: vary in size and are firm & white with a lobulated surface, can be bilateral
    > Often present with non-specific symptoms e.g abdominal pain if mass is large or are incidental findings

> Meig’s syndrome: some patients have an ovarian fibroma associated with ascites

> Microscopy
- Small bland spindle-shaped cells & collagen
- No cytological atypia, few mitotic figures, no necrosis


Describe adult granulosa cell tumours


Low grade malignancy, usually unilateral & confined to ovary
> Variable size, solid/cystic appearance

Most do not recur or metastasise

  • Oestrogen-secreting tumour
    > results in abnormal vaginal bleeding e.g. menorrhoea, amenorrhoea, post-menopausal bleeding
  • Occasionally, androgen-secreting tumour

Describe symptoms of ovarian cancer

  • Abdominal distension
  • Urinary symptoms
  • GI symptoms (due to compression by ovarian mass)
  • Torsion (larger neoplasms), obstruction of venous return causing severe pain and peritonitis

Describe developmental abnormalities of the uterus


Developmental abnormalities of the uterus are related to abnormalities in the fusion of the Mullerian ducts

  • Class U1: dysmorphic uterus
    > T-shaped, infantilis, others
  • Class U2: septate uterus
    > Partial or complete
  • Class U3: bicorporeal uterus
    > Partial, complete, bicorporeal septate
  • Class U4: hemi uterus
    > With or without rudimentary cavity
  • Class U5: aplastic uterus
    > With or without rudimentary cavity

Describe the histology of the endometrium during the different phases of the menstrual cycle

  • Proliferative phase
    > Oestrogen drives thickening of the endometrium
    > Dividing cells can be seen (mitotic figures)
    > Gland:stroma ratio is low - each gland is separated by stroma
    > Tubular glands
    > Cells within glands: cuboidal cells, elongated, ovoid nucleus, stratification (different heights of cells)
    > Cells within stroma: small with round/ovoid nuclei
  • Secretory phase
    > Following ovulation, corpus luteum starts to produce progesterone
    > Coiled glands
    > Gland:stroma ratio is still low
    > Small gap between nucleus and basement membrane - subnuclear vacuoles found here
    > As secretory phase progresses, glands become more complex, vacuoles disappear and secretions appear in lumen of gland
  • Menstrual phase
    > Fragmentation of endometrium
    > Condensation of stroma - epithelium has surrounded stromal cells
    > Inflammatory cells (neutrophils) can be seen
    > Areas of necrosis and blood

Describe the histology of the endometrium in post-menopausal women

  • Cystic atrophy
  • Thin endometrial lining as it is not simulated by hormones
  • Nuclei are small, no mitotic figures, no evidence of secretion - atrophic endometrium

Describe the histology of the myometrium

  • Smooth muscle bundles comprising much of the uterus; long nucleus
  • No mitotic activity as the muscle does not change during the menstrual cycle

Define adenomyosis


Presence of endometrial tissue within myometrium


Describe endometrial polyps and their microscopy

  • Exophytic masses of variable size which project into endometrial cavity
  • Associated with tamoxifen in some cases
  • Microscopy
    > Haphazardly arranged glands with preservation of a low gland:stroma ratio
    > Thick walled blood vessels & fibrous stroma
    > Glands are usually inactive but can show proliferation, secretory changes or metaplasias
    > Can resemble post-menopausal atrophic endometrium
    > occasionally cytological atypia or frank adenocarcinoma can be found in polyps
  • Presentation: abnormal bleeding
  • Treatment: hysteroscopy in outpatient clinic

Describe endometrial hyperplasia and adenocarcinoma

  • Conditions associated with prolonged oestrogenic stimulation of the endometrium
  • Causes
    > Anovulatory cycles
    > Endogenous sources of oestrogen e.g. obesity, PCOS, oestrogen-secreting ovarian tumours
    > Exogenous sources of oestrogen e.g. oestrogen-only HRT
  • Symptoms
    > Postmenopausal bleeding
    > Menorrhagia, oligomenorrhoea in pre-menopausal women
  • Microscopy:
    > Endometrial hyperplasia - increase in the gland:stroma ratio +/- cytological atypia
    > Atypical endometrial hyperplasia is a known precursor of endometrioid adenocarcinoma (stroma is lost & glands fuse together)
  • Management:
    > Hyperplasia: progesterone therapy (Mirena IUS) or hysterectomy
    > Endometrial adenocarcinoma: hysterectomy

Describe leiomyomas including symptoms, appearance and management

  • Benign smooth muscle tumour of the myometrium aka fibroid
  • May be single or multiple
  • Macroscopic appearance
    > Sharply demarcated round grey-white tumours with a whorled cut surface
    > Variable in size and resemble normal smooth muscle
  • Symptoms
    > Asymptomatic
    > Abnormal bleeding
    > Urinary frequency if large
    > Impaired fertility
  • Management
    > Medical:
    » Progesterone-secreting IUS
    » Hormonal therapies
    » Tranexamic acid
    » GnRH agonists

> Surgical
> Uterine artery embolisation
> Myomectomy
> Hysterectomy


Describe the symptoms and pathology of leiomyosarcoma

  • Uncommon malignant smooth muscle tumour of the myometrium

Symptoms: initially asymptomatic, then bleeding or pain

> Macroscopy:
» Bulky invasive masses or polypoid
» Necrosis
» Haemorrhage
» Variable cut surface

> Microscopy
> Overt cytological atypia
> Necrosis
> Mitotic activity
> Infiltrative margin


Describe endometrial stromal sarcoma (ESS)

  • Rare groups of tumours of the endometrial stroma; can be low or high grade
  • Diffusely infiltrative “worm like” growth pattern
  • Microscopy: low grade tumour cells resemble cells of proliferating endometrial stroma with mitoses
    > no glands, unlike adenomyosis

Describe gestational pathology

  • Gestational trophoblastic disease

> Hydatidiform moles aka molar pregnancy
Present with either spontaneous miscarriage or abnormalities detected on ultrasound

> > Partial mole: fertilisation of one egg by 2 sperm: triploid karyotype
- Microscopy shows no foetus and oedematous villi & subtle trophoblast proliferation
- Risk of invasive mole - invades & destroys the uterus

> > Complete mole: fertilisation of an egg with no genetic material, usually by one sperm which duplicates its chromosomal material OR egg with no genetic material fertilised by 2 sperm (diploid karyotype, usually 46XX)
- Microscopy: markedly enlarged oedematous villi with central cisterns and circumferential trophoblast proliferation
Risk of invasive mole & choriocarcinoma

  • Frankly malignant tumours: choriocarcinoma
    > Rapidly invasive & metastasises widely but treatable with chemotherapy

Describe the histology of the endocervix and ectocervix


Endocervix: lined by mucin-secreting columnar glandular mucosa

> Physiological squamous metaplasia occurs between endocervix and ectocervix epithelial

Transformation zone: zone where glandular cells and squamous cells meet, usually around neck of cervix leading onto endocervical canal

> Vagina: non-keratinising stratified squamous epithelium
> Vulva: keratinising stratified squamous epithelium (nuclei may disappear)


List infections which may affect the vagina and cervix

  • Human Papilloma Virus (HPV)
  • Chlamydia trachomatis
  • Gonorrhoea
  • Herpes simplex virus (HSV)
  • Trichomonas vaginalis
  • Candida albicans or “thrush”
  • Actinomyces
  • Bacterial vaginosis

Describe cervical polyps

  • Benign growth most of the time
  • overgrowth of connective tissue with epithelial covering; may bleed post-coitally

Describe cervical screening


Women aged 20-60 are invited to have a cervical smear every 3 years

  • Designed to identify pre-cancerous changes (dyskariosis) in cervical smears so patients can be referred for colposcopy

> Dyskariosis: nuclear enlargement, dense hyperchromasia, coarse chromatin clumping

  • In cervical biopsies, precancerous changes are called cervical intraepithelial neoplasia (CIN)
  • Smear reporting

> Negative: repeat routinely in 3yrs

> Borderline nuclear abnormality: repeat 6 months, x3 BNA refer for colposcopy
e.g. koilocytosis: clearing of cytoplasm around nuclei due to HPV infection

> Dyskariosis, any severity: refer colposcopy
> Low grade is CIN1
> High grade is CIN2 or CIN3: expanded proliferation zone, mitotic further up in epithelium (not just basal layer) due to abnormal cell proliferation & failure of maturation


Describe cervical carcinoma including symptoms, risk factors and treatment

  • Invasive squamous cell carcinoma when basement membrane is breached
    > Other variants include adenocarcinoma, clear cell carcinoma & adenosquamous carcinoma
  • Symptoms:
    > Post-coital bleeding
    > Intermenstrual bleeding
    > Irregular vaginal bleeding
    > Pain
    > Asymptomatic
  • Risk factors
    > HPV
    > Age at first sexual intercourse & number of sexual partners
    > Smoking
    > Method of contraception: OCP v barrier
    > Immunosuppresion
    > Circumcision in males - protective
  • Treatment
    > Early lesions treated surgically via Large Loop Excision of Transformation Zone (LLETZ) or simple/radical hysterectomy

> Advanced: radiotherapy + chemotherapy


What is meant by cGIN?


Endocervical glandular epithelium undergoing premalignant change: cervical glandular intraepithelial neoplasia
> Malignant change from glandular epithelium is adenocarcinoma
> HPV associated and less common


Which structures does the vulva consist of?

  • Mons pubis
  • Labia minora
  • Clitoris
  • Vestibular bulbs
  • Vulvar vestibule
  • Urinary meatus
  • Vaginal opening
  • Hymen
  • Bartholin’s and Skene’s vestibular glands

Describe the different conditions which may affect the vulva (non-neoplastic)

  • Inflammatory skin conditions that affect hair-bearing skin e.g. psoriasis, eczema, allergic dermatitis
  • Infections
    > Vulval warts
    > Candida
    > Infection in hair follicles (folliculitis)
    > Bartholin’s abscess
  • Cysts
    > Epidermal inclusion cyst
    > Bartholin’s cyst - obstruction of Bartholin’s duct

Describe the different neoplastic conditions which may affect the vulva


Leukoplakia may represent benign, premalignant or malignant lesions
» may be caused by lichen sclerosus et atrophicus - inflammatory dermatitis associated with neoplastic progression
» Caused by squamous hyperplasia

  • Rarely, may be benign or malignant
    > Neurofibromas, angiomas
    > Skin adnexal tumours
    > Carcinomas, melanomas
    > Sarcomas
  • Mainly invasive squamous cell carcinoma
    > associated with VIN (vulval intraepithelial neoplasia), also CIN & invasive cervical cancer
    > Usually related to high risk HPV 16/18
    > Warty or basaloid cancer
    > Can be associated with dermatoses in older women; mostly well-differentiated & keratinising cancers, not associated with HPV infection
    > Adjacent squamous hyperplasia and/or lichen sclerosus et atrophicus are common

Describe the general toxic effects of chemotherapy

  • Bone marrow suppression
    > Anaemia
    > Immune depression
    > Infection risk
    > Impaired wound healing
  • Loss of hair
  • Damage to gastrointestinal epithelium
  • Liver, heart, kidney
  • In children - depression of growth
  • Sterility
  • Teratogenicity

List the different types of cancer chemotherapy drugs

  • Alkylating agents
  • Antimetabolites
  • Cytotoxic antibiotics
  • Steroid hormones & antagonists

Describe the different types of alkylating agents and their mode of action


Alkylating agents form strong covalent bonds with DNA
> Interfere with transcription and replication
> Most have 2 reactive groups which allow the drugs to cross-link within one DNA strand or across 2 strands of DNA

  • Nitrogen mustards
    > Mechlorethamine: lymphoma (HL & NHL)
    > Melphalan: fusion of mechlorethamine w/ phenylalanine - multiple myeloma, ovarian & breast cancer
    > Cyclophosphamide: prodrug requiring activation in the liver, used to treat many cancers
    > Chlorambucil, cyclophosphamide, ifosfamide
  • Cisplatin: stops DNA replication, targets N7 of purine nucleotides; resistance from nucleotide excision repair mechanisms and efflux transporters for copper
  • Temozolamide
  • Lomusine: active in CNS
  • Busulphan: selective effect on bone marrow

Describe the different types of antimetabolites and their mode of action

  • Antimetabolites interfere with nucleotide synthesis or DNA synthesis

> Nucleotide synthesis: antifolates

> > Methotrexate:
- Higher affinity for dihydrofolate reductase than folic acid
- Inhibition of dihydrofolate formation
- Inhibition of purine/pyrimidine nucleotide synthesis
- Ultimately halt DNA and RNA synthesis

> > Ralitrexed, pemetrexed

> Nucleotide analogues

> > 5-fluorouracil: pyrimidine analogues - prevents thymidine formation & stops DNA synthesis

> > Mercaptourines: purine analogues which are converted into false nucleotides & disrupt purine nucleotide synthesis - may be incorporated in DNA, disrupting helix

> > Cytarabine (Ara-C): sugar moiety of cytidine is arabinosine rather than ribose (poses as 2’ deoxy); cellular activation to ara-CTP
> S-phase cell cycle specific, targets DNA replication and inhibits DNA polymerases; incorporation into DNA causes chain termination

> > Gemcitabine, fludarabine, capecitabine


Describe cytotoxic antibiotics and describe their mechanism of action

  • Act mainly by a direct action on DNA as intercalators
  • Dactinomycin (isolated from Streptomyces)
    > Inserts itself into the minor groove in the DNA helix & binds
    > RNA polymerase function is disrupted
  • Doxorubicin (isolated from Streptomyces)
    > Inserts itself between base pairs
    > Local uncoiling leading to impaired DNA and RNA synthesis
    > Effective against many cancers
  • Microtubule inhibitors
    > Vinca alkaloids e.g. Vincristine, isolated from Madagascar periwinkles
    » Binds to microtubular protein blocking tubulin polymerisation
    » Blocks normal spindle formation & disrupts cell division

Describe the types of steroid hormones and antagonists used in cancer treatment

  • Prednisone
    > Synthetic adrenocortical steroid hormone converted in the body to active form
  • Prendisolone
    > Suppresses lymphocyte growth
  • Tamoxifen
    > Antagonist of oestrogen receptor used in oestrogen-dependent breast cancers
  • Testosterone receptor antagonists
    > e.g. flutamide or bicalutamide. are used in the treatment of testosterone-dependent prostate cancers
  • Pituitary downregulators
    > LHRH agonists e.g. Prostap
    > Inhibit release of LH which normally stimulates testes to produce testosterone

List 5 causes of menorrhagia

  • Fibroids (uterine leiomyomas)
  • Endometriosis
  • STIs e.g. chlamydia, gonorrhoea
  • PCOS (anovulatory menorrhagia)
  • Coagulation disorders e.g. von Willebrand disease

Describe the diagnosis and symptoms of PCOS

  • Diagnosis
    > Total testosterone
    > Sex hormone binding globulin
    > Free androgen index calculation
    > Prolactin
    > TSH
    > LH:FSH ratio is 2:1
    > Ultrasound showing polycystic ovaries
  • Symptoms
    > Signs of hyperandrogenism e.g. hirsutism, acne
    > Obesity (signs of insulin resistance)
    > Oligomenorrhoea or amenorrhoea, anovulatory cycles
    > Infertility
    > Type II diabetes

Describe the treatment of PCOS

  • Weight loss & encourage healthy lifestyle
  • Contraceptive pill (can induce regular periods)
  • Metformin
    > Drug for diabetes, can lower glucose levels
    > Increases sensitivity to insulin & induces ovulation
  • Fertility treatment: ovulation induction with clomiphene, IVF
  • FSH stimulation: with clomiphene or pulsatile LH releasing hormone analogues
  • Spironolactone: anti-androgen
  • Finasteride & flutamide: reduce hirsutism