Week 4 Female GU and Breast Flashcards
Pathology of vulva
Skin tags, melanocytic nevi common
Bartholin vestibular gland cysts: dilation of Bartholin gland (adjecent of vaginal canal) - becomes infected and forms abscess
Non infective inflammation:
Lichen planus
Lichen sclerosus (assoc. with increased risk of Vulva SCC) - white plaque, parchment-like skin
Vulva squamous cell carcinoma - HPV related and non-HPV related
HPV related: HPV 16/18 leading to dysplasia/vulva intraepithelial neoplasia (VIN). <60 yrs. Basaloid/warty cancers
Non HPV related (assoc. with dermatoses) - Lichen sclerosus, >60 yrs.
Extra mammary Paget’s disease (pic)
- Malignant epithelial cells in the epidermis of vulva
- Carcinoma in situ
- Presents as erythematous, itchy, ulcerated skin
Pathology of vagina
NK stratified squamous epithelium
Atrophic vaginitis - decreased oestrogen due to menopause. Discomfort, bleeding.
Infections:
Bacterial vaginosis
Trachimonas vaginalis - STI (parasite)
Thrush (candida)
Vaginal carcnioma due to VAIN (vaginal intraepithelial neoplasia) rare. Primary cancers of cervix and vulva can spread to vagina.
Cervix epithelium
Exocervix (outer): NK stratified squamous epithelium (Right)
- as cells migrate up to epithelial surface they accumualte glycogen, giving basket weave appearence)
Endocervix (inner): columnar (glandular) epithelium (Left)
Clear change between the two areas - transformation zone (where neoplasia of cervix commonly develops)
Cervical screening
Women 25-65 yrs
25-50 3 years
50-65 5 years
Detecting change in cells in transformation zone in cervix, for HPV infectiona and CIN
Features suggestive of malignancy:
High nuclear:cytoplasm ratio
Nuclear hyperchromasia (darker staining pattern in nucleus)
Nuclear pleomorphism
What does the current HPV vaccination cover?
HPV 6, 11 (genital warts) , 16, 18 (HPV that causes cervical cancer)
Cervical carcinoma
99% cervical carcinoma due to HPV (usually 16/18)
HPV leads to cervical intraepithelial neoplasia (CIN)
CIN characterised by dyskaryosis (nuclear abnoramlity)
HPV pathogenic for koilocytic change (perinuclear halo (clear area around nucleus) and nuclear enlargment, nuclear hyperchromasia (nucleus is stained darker)
Leads to squamous cell carcinoma
CIN II
Dyskaryosis 2/3 of epithelium
CIN I
If dyskaryosis involves first 1/3 of epithelium
CIN III
Dyskaryosis involving full-thickness epithelium
Cervical carcinoma symptoms
Middle aged women
Irregular vaginal bleeding
Post coital bleeding
Intermesntrual bleeding (between menstruation)
Pain
Adenocarcinoma of cervix
Endocervical glandular epthelium can also undergo pre-malignant change - cGIN (cervical glanduar intraepithepial neoplasia)
Glandular epithelium becomes adenocarcinoma
Also assoc. with HPV
Abnormalities:
Rosette: nuclei lines up and protrudes from edges (looks like rosette)
Pseudostratification: nuclei overalp
Can be picked up on smear (though difficult)
Koilocytic change
Pathogenic of HPV
- High nucleus:cytoplasm ratio (nucleus larger)
- nuclear hyperchromasia (nucleus darker staining)
- perinuclear halo (pale area around nuelcus)
Uterus
Endometrium - consists of glands, stroma, changes in appearence depending on phase on menstrual cycle
- Proliferative
- Secretory
- Menstruation
Myometrium - smooth muscle
Endometrium
Proliferative phase
Can see mitotic figures (dark cells)
Endometrium - what stage?
Secretory phase
Spiral glands are more irregular, luman larger, secrete mucus (looks eosinophilic (pink))
Blood vessels prominent (spiral arteries)
Oedematous stroma
Endometrium - stage?
Menstrual phase
Glands have collapsed
Lots of blood
Stroma was previously oedematous has now shed
Endometriosis
Presence of endometrial tissue (glands and stroma) outside of uterus
Adenomyosis: presence of endometrial tissue in myometrium
Aeitology:
Retrograde theory: retrograde menstruation leading to endomtrium outside of uterine cavity
Metastatic theory: endoemtrial tissue arises from coelomic epithelium e.g. peritoneum
Sites of endometriosis:
Ovaries (leads to chocolate cyst), small/large bowel, appendix, vagina
Histology:
Glands
Stroma
Processed blood (by macrophages) - sign of chronic haemorrhage
Symptoms:
Pelvic pain (endometrial tissue in uterine ligaments), Dysmenorrhea (pain during menstruation), pain with bowel movements (as endometrial tissue can be in pouch of douglas), infertility (endometrial tissue in fallopian tubes)
Diagnosis: Laparoscopy
What happens to endometriosis after menopause?
Graudal regression
Example of an developmental abnormality of the uterus
Bicornuate uterus
Endometrial polyps
Exophytic mass projecting into endometrial cavity
Assoc. with tamoxifen (as has pro-esotrogenic effect on endometrium)
Decreaesd gland:stroma ratio (more stroma than gland)
Fibrous stroma (looks pinker) and thick walled blood vessels
Presents irregular uterine bleeding
Endometrial hyperplasia
Increased gland:stroma ratio (increased endometrial glands compared to stroma) due to prolonged oestrogenic stimulation
Causes:
PCOS, obesity, HRT
Clinical features: post-menopausal bleeding (as during menopause, ovaries stop secreting oestrogen but fat converted to oestrogen)
Atypical endometrial hyperplasia:
Precursor of endometrioid adenocarcinoma (looks like normal endometrium)
Treatments:
Hyerplasia - mirena IUD
Endometrioid Adenocarcinoma - hysterectomy
Leiomyoma - benign proliferation of smooth muscle of myometrium
Common, usually pre-menopausal women
Assoc. with trisomy 12
Symptoms:
Usually asymptomatic
- abnormal bleeding (as endomtrial lining is stretched), increased urinary frequency
Leiomyoma vs Leiomyosarcoma
Leiomyoma:
Pre-menopausal women
Multiple, distinct, white whorled mass
Microscopically resembles normal smooth muscle tissue
Leiomyosarcoma: malignant smooth muscle tumor of myometrium. Arises de novo (does not come from leiomyoma)
Post-menopausal women
Single mass, can be necrotic and haemorrhagic
Microscopically: atypical cytology, mitotic figures
Endometrial stromal sarcoma
Group of tumors from endomtrial stroma
Diffuse worm-like pattern
Gestational trophoblastic disease
Umbrella term for group of diseases including hydatidiform mole, and malignant tumors e.g. choriocarcinoma (tumour of trophoblasts)
Hydaditiform mole
Complete - empty egg fertilised by one/two sperm
46 chromosomes
Enlarged oedematous villi
Circumferential trophoblastic proliferation
Increased risk of choriocarcinoma
Partial - normal egg fertilised by two sperm
69 chromosomes
Oedematous villi
Partial trophoblastic proliferation
Minimal risk choriocarcinoma
Ovary
Covered by flat, coelomic epithelium
Cortex: follicles containing occytes, stroma
Medulla: blood vessels, nerves, hilar cells
In follicle, oocyte surrounded by granulosa cells, and theca cells (outer)
LH acts on theca cells to secrete androgens
FSH acts on granulosa cells to convert androgens to oestrogen
What is this?
Corpus albicans - scarring left when corpus luteum degenerates, if an egg is not fertilised
Shows patient has finished menstrual cycle but is peri- menopause, as no follicles
PCOS
Includes symptoms of annovulation (oligomenorrheoa - few periods) and increased androgen levels (hirsutism, infertility)
Typically in young, obese women
Pathophysiology:
Gonadotropins:
Increased LH - supports theca cells - makes more androgens
Decreased FSH (less conversion of androgens to oestrogen)
Leads to degeneration of follicles forming mulitple sub-cortical cysts
Inreased androgens:
- Due to theca cells producing androgens
- Decreased steroid hormone binding globulin (produced in liver, binds testosterone so won’t be active)
Insulin resistance:
Inuslin stimulates theca cells, reduces SHBG, increased androgens
Increased risk of endometrial carcinoma
Treatment: Weight loss, metformin, clomifene (anti-oestrogen, leading to increased FSH due to negative feedback)
Ovarian neoplasms
- Coelomic epithelium
- Germ cells
- Sex cords/stromal cells (cells which support oocyte e.g. granulosa, theca cells
Clinical presentation:
Aymptomatic, pain, irregular menstruation, hirsutism, ascites (bloated abdomen)
Investigations:
physical examination, bloods: CA-125, ultrasound
Surface epithelial ovarian tumours
Benign - cystadenoma (cystic) or cystadenofibroma (without solid stromal component)
Borderline - has malignant potential but better prognosis
Malignant - cystadenocarcinoma (cystic) or solid adenocarcinoma
Carcinomas can be high grade serous, low grade serous, mucinous, endometrioid (assoc. with endometriosis), clear-cell (assoc with endometriosis),
High grade serous: BRCA1/2 genes, p53
Low grade serous: KRAS
Surface epithelial ovarian tumors - serous ovarian tumours
Benign: women 30-40yrs. Large, bilateral, smooth, shiny covering. Cysts are filled with serous fluid, lined by single columnar epithelium. Some cells cilaited.
Borderline: cellular atypia, no stromal invasion
Malignant: older women. Anaplasia (lack of differentiation) of cells. Stromal invasion.
Psammoma bodies (pic) - concentric calcifications, in papillae of serous tumours. (Also in papillary thryoid carcinoma)
Surface epithelial ovarian tumours: Mucinous
Tumour consists of mucin secreting cells
Most benign. Borderline. Malignant.
Krukenberg tumours - Cancer from GI metastases to ovary. Can mimic primary ovarian mucinous tumour (usually unilateral)
Morphology: large, no psammoma bodies, cysts lined with mucinous cytoplasm
Benign or Malignant?
Serous or malignant?
Malignant mucinous ovarian tumour
Nuclei more atypical, lost polarity, mitotic figures, irregular shaped glands, cells contain mucus
Ovarian endometrioid carcinoma
Histologically characterised by appearence of tubular glands, resembles normal endometrium
Usually malignant (though can be benign, malignant)
Arises from endometriosis
Some have ovarian tumour and endometrium carcinoma (due to loss of PTEN tumour supressor gene)
Germ cell tumour
Young women
Found as ovarian mass or incidentally on abdominal scans
95% are mature cystic teratomas (dermoid cysts) - benign
Germ cells differentiate into 3 germ cells layers: ectoderm (skin, hair), mesoderm (muscle, fat), endoderm (GI, respiratory epithelium)
Morphology - smooth, hair, teeth, bone, GI epithelium
Malignant:
5% immature cystic teratomas (Immature tissue - neuroectoderm)
1%: tissue elements e.g. skin can become malignant. Skin - squamous cell carcinoma
Cystic teratomas prone to torsion
Yolk sac tumour, choriocarcnioma (placental tissue) rare
Ovarian sex cord/stromal cell tumours
Resemble normal sex cord stromal tissue of ovary (granulosa, theca, cells, fibrous tissue, Sertoli, Leydig cells)
Granulosa and theca cell tumours: secrete oestrogen
Sertoli-Leydig cell tumours - secrete androgens
Granulosa cell tumours - not rare. Post-menopausal women. Can lead to endometrial hyperplasia, endometrial carcinoma
Fibroma - benign tumour of fibroblasts
Meigs syndrome - fibroma, ascites and pleural effusion
Ovarian tumour with ascites - usually carcinoma
Brenner tumour
Mixed surface epithelium-stromal tumour
Benign, unilateral, yellowish
Contains urothelium (transitional epithelial cells) with fibrous stroma
Fallopian tube
Ciliated columnar epithelium
Plicae
Layers of smooth muscle
Common conditions of Uterus
Endometriosis
Uterine fibroids (leiomyomas)
Uterine cancer
Clinical presentation: pain, post menopausal bleeding
Uterine fibroids (leiomyomas)
Clinical presentation: heavy periods, pain, pressure, anaemia
Normal structure of breast
Derived from milk line (imaginary line from axilla down to vulva)
Terminal duct lobular unit: functional unit
All ducts (grandular tissue) and lobules are lined by: inner luminal cells and myoepithelial cells (contractile function)
Adolescent breast - ducts in a dense stroma
After puberty - lobules develop, breast expands
Pregnancy - hyerplasia, TDLU enlarged
Lactating - epithelial secretory activity (cytoplasic vacuoles)
Menopause - Atrophy -of TDLU. Ducts are dilated.
Common conditions of Fallopain tube
Tubo-ovarian abcess: pelvic pain, increased CRP/WCC, temperature
Ectopic pregnant: pelvic pain, bHCG increased, missed periods
Developmental abnormalities
Ectopic breast tissue - commonest congenital breast abnormality, usually on milk line
Brest hypoplasia - assoc. with Turner’s syndrome
Inflammtory breast conditions
Infectious:
Acute mastitis - cellulitis of breast, assoc. with breast feeding. Bacteria (S.aureus) enters through cracked nipple
- presents as warm, red breast with purulent discharge
- can form abscess
Non-infectious/inflammatory:
Granulomatous inflammation of breast can occur in systemic diseases e.g. sarcoidosis, TB
Idiopathic granulomatous mastitis: Non-necrotising granulomatous inflammation centred on loubles. Distinct, hard mass. Usually parous (previously pregnant). May repsond to steroids.
- Need to exclude TB, sarcoid, vasculitis
Periductal mastitis - inflammation of subaerolar ducts, leading to dilation of sub-aerolar ducts. Assoc. with smoking. Presents as sub-aerolar mass and nipple retraction (due to granulation tissue which contains myofibroblasts which pull in skin). Multiparous post menopausal women.
Ductal ectasia - Inflammation of duct leading to dilatation of duct. Duct becomes blocked. Debris leads out leading to, peri-aerolar mass with green/brown nipple discharge.
Fat necrosis: related to trauma. Benign. Presents as mass or calcification on mammogram. Biopsy shows necrotic fat with calcifications and giant cells.
Fibrocystic change
Most common breast condition
Development of fibrosis and cysts
Presents as bilateral, diffuse breast lumpiness
Includes:
Fibrosis (increased fibrous stroma)
Cystic
Adenosis (increased glandular tissue) (can show calcifications on MMG)
Apocrine metaplasia (large, epithelial cells with granular eosinophilic cystoplasm and apical projections)
Sclerosing adenosis - benign proliferation of glandular tissue. Can show microcalcifications on US. 2x risk of br. ca
Radial scars - sclerosing lesions, with fibrotic and elastic core >10mm. Myoepithelail cells present (whereas tubular carcinoma doesn’t)
Epithelial hyperplasia (ductal, lobular) - **2x risk of br. ca** Epithelial hyperplasia with atypia - **4x risk of br. ca**
Papillomas also included
Intraductal papilloma
Papillary lesion: finger like projection with epithelial lining
Papillary growth (benign) into a large duct, lined by epithelal and myoepithelial cells with fibrovascular core
Multiple papillomas (papillomatosis) - assoc. with malignancy
Presents as bloody discharge in pre-menopausal (benign)
If malignant (papillary carcinoma) - has no myoepithelial cells (more common in post-menopausal women)
Benign neoplasms: Fibroadenoma
Tumour of fibrous tissue and glands. Characteristically, proliferation of epithelium and mesenchyme.
Most common benign tumour of breast
Most common tumour in pre-menopausal women
Well circumscribed, mobile, marble-like mass
Hormone-sensitive - can shrink during menopasue
Juvenile adenomas can be very large
No increase risk of cancer
Phyllodes tumour
Fibroadenoma-like tumour with overgrowth of fibrous stroma
Overgrowth pushes out “leaf-like” projections
Post-menopausal women
Can be malignant
Needs to be surgically excised with margin
Pure adenomas
Pure adenomas: Tubular or lactating, lack prominent stroma of fibroadenomas
Nipple adenomas
Nipple adenomas:
Presents as erosive lesion on nipple +/- nipple discharge
- Benign but can mimic Paget’s disease of the nipple (malignant)
Paget’s disease of nipple: Ductal carcioma in situ that has gone up to skin of nippple
- Presents as red, scaly rash on nipple (like eczema) , and darker area surrounding nipple. Can be a sign of breast cancer
Harmatoma of breast
Discrete, smooth, painless mass of glandular, fatty, fibrous tissue
Breast cancer
Most common cancer in women
Usually 40-70 yrs
Risk factors:
Earlier menarche, late menopause, obesity, OC use, HRT, alcohol, BRACA1/2, Li Fraumeni Syndrome (p53), pTEN. nulliparity, first child after 30 yrs.
Symptoms: new lump, altered shape/size
skin changes - peau d’orange (resembles skin of an orange, due to lymphatic infilitration), rash
nipple changes - inversion, ezcema-like rash (Paget’s)
Investigations:
Clinical examination
MMG, US (microcalcification often present in invasive carcinoma)
FNA
Core biospy, excisional biopsy
UK women invited from 50-70 every 3 yrs
Treatment
Local excision and radiotherapy
Mastectomy
Sentinel node biopsy
Axillary clearence - if sentinel node positive. However, can cause limitation of arm movement, lymphoedema
Pseudo Angiomatous Stromal Hyperplasia (PASH)
Hard, palpable lump. Radily enlarging mass with skin changes.
Premenopausal
Dense stroma lined with channels lined by myofibroblasts
Differential: angiosarcoma
Breast cancer pharmacology
Tamoxifen: ER (oestrogen receptor) antagonist (80% breast cancers overexpress oestrogen and progesterone receptors)
However, has agonist activity in endometrium so can cause increase risk of endometrial cancer
Aromatase inhibitors - Letrazole (prevents conversion of androgens to oestrogen) - only for post-menopausal women
Transtuzumab (Herceptin) - Those who express HER2 have worse prognosis. Transtuzumab has improved survival
Chemotherapy
Prognostic factors for breast cancer
Size, grade (based on tubules, pleomorphism, mitoses) and lymph node
Type does not add much if take grade into account
Hormone receptor status - important in repsonse to certain treatment
Nottingham Prognostic Index
Estimates prognosis, and determines treatment
Grade of tumour - Grade 1 = 1 pt, Grade 3 = 3 pts
Nodes - 0 nodes = 1 pt, 1-3 nodes = 2 pts, 4+ nodes = 3 points
Size (size x 0.2cm)
Higher, poor prognosis
In situ carcinoma of breast
Malignant epithelial proliferation within basement membrane
Has not expanded into breast stroma
Has not communication with blood vessels, lymphatics
No possibility of metastases
Axillary staging
Need to US axilla in all invasive carcinoma
Sentinel node biopsy - SN (first node which the cancer will spread to from primary tumour). If neg, suggests cancer has not spread to lymph nodes or other organs.
Inject blue dye, assess first lymph nodes
Axillary clearence - if SN postive
Ductal carcinoma in situ
Malignant proliferation of cells in ducts within basement membrane
Most commonly shows calcification on MMG
Presents as lump, nipple discharge, Paget’s disease of breast (DCIS which extends up ducts to skin of nipple)
10x increased risk of breast ca
Histologically - necrosis dystrophic calcificaiton in centre
Treatment
Complete excision
Local excision and radiotherapy
Mastectomy+/-reconstruction
Invasive ductal carcinoma
Forms duct-like structures
Most common invasive carcinoma
Presents as mass detected by physical examination or MMG
May show nipple retraction, skin dimpling
Biopsy: ductal like structures with desmoplastic stroma
Special subtypes of invasive ductal carcnioma
Tubular carcinoma - produces tubules. Desmoplastic stroma (connective tissue which grows with tumour so very dense). No myoepithelial cells
Mucinoid carcinoma - malignant cells flooded in pool of mucus. Usually over 75 yrs.
Both have good prognosis
Lobular carcinoma in situ (LCIS)
Malignant proliferation of cells in lobules, within basement membrane
Usually detected incidentally, no mass or calcification
Bilateral, multi-focal
Dyscohesive cells (not stuck together), loss of E-cadherin
Management:
Follow up (as low risk of become invasive)
Bilateral mastectomy
Invasive lobular carcicnoma
No duct formation, grows in single file (signet ring cells)
Tumor grading
Blood and Richardson
Grade 1-3 (Grade 1: well differentiated, slow growing, Grade 3: poorly differentiated, fast growing)
Tubules (less no. of cells that form tubule, worse)
Pleomorphism
Mitoses
Cancer chemotherapy
Alkylating agents: cross-links DNA between one strand, and across two strands
- Nitrogen mustards: Melphalan, Cyclophosphamide
- Cysplatin
- Busulphan
- Lomustine
Antimetabolites: interferes with DNA/nucleotide synthesis
- Methotrexate
Nucleotide analogues:
- Pyrimidine analogues: Flouro-uracil
- Purine analogues: Mercaptopurines
- Cytarabine (inhibits DNA polymerase)
Cytotoxic antibiotics: acts by direct action on DNA as intercalators
- Dactinomycin:
disrupted RNA polymerase
- Doxorubicin:
impairs RNA/DNA synthesis
Vincristine - Microtubule inhibitors
- Disrupts cell division
Steroid hormones:
Prednisolone - supresses lymphocyte growth
Hormone antagonists:
Tamoxifen - oestrogen antagonist
Flutamide - testosterone antag
Prostap - LH release inhibitors
Salpingitis
Salpingitis: Inflammation of fallopian tubes
Part of inflammtory pelvic disease
Due to bacteria e.g. Chalmydia trachomatis, mycoplasma, coliforms
Fever, low abdo pain, pelvic mass if tube distended with exuate
Complications: tubo-ovarian abcess (adherence of tube to ovary), damage of tube leading to infertility, tubal ectopic pregnancy
Fallopian tube malignancies
Papillary serous carcinoma
BRCA1 mutations
Pseudo angiomatous stromal hyperplasia
Hard palpable lump
Premenopausal
Presents as rapidly expanding mass with skin changes
Diabetic mastopathy
Ill-defined hard mass
Assoc with TMD1
<30 yrs
Keloid like stroma
What kind of cells would you see if you do a FNA of cyst, abscess or lipoma in the breast
Abscess: neutrophils (soft, tender)
Cyst: macrophages (doesn’t appear solid on US)
Lipoma: mature fat cells (soft to palpate, less mobile than fibroadenoma)
Which cancers are signet ring cells present in?
Cell which nucleus is pushed to side due to mucin
Lobular carcinoma of breast
Gastric adenocarcinoma (diffuse)
Pagets disease of breast
DICS that has extended up ducts to kin of nipples
Red, scaly rash
What does this IHC stain show?
That the breast cancer is ER positive (when oestrogen binds to receptor, moves to nucleus)
Brown colour is positive
Progesterone would look similar
What does this IHC stain show?
Breast cancer which is Her2+ (Her2 receptor on cell surface)
Brown colour is positive
Features of heridatry br. cancer
Fx history
Pre-menopausal age
Mulitple tumours
An administrator (29) attends her GP for routine cervical cytology. A sample of cells is reported with squamous cells showing ‘moderate dyskaryosis’. What to do next?
Colposcopy: Looking at the cervix
LETZ Biospy (loop excision of transformation zone)
TNM
Tumour size or depth
N - spread to regional lymph nodes
Metasteses - distant metastasis (most important factor)
