Briefly outline the menstrual cycle
- FSH from a.pit = follicle growth.
- Follicle releases oestrogen = endometrial growth.
- LH surge from a.pit = ovulation
- Corpus luteum releases progesterone = endometrial secretion
- No hCG = luteal death and repetition
What occurs during menopause?
- Reduced number of oocytes = decrease in oestrogen production = reduced inhibition of FSH and LH production
- Loss of oestrogen causes symptoms, also endometrial atrophy
List the causes of irregular premenopausal bleeding
- Hormonal disturbances, especially in the <40yoa
- If uterus enlarged; fibroids or adenomyosis
- Likelihood of carcinoma cause when; high BMI, PCOS, family history
List the causes of irregular perimenopausal bleeding
- Hormonal causes still common; ovulation failure = irregular cycles. If enlarged; fibroids/adenomyosis
- Hyperplasia/adenocarcinoma if obese, diabetic, nulliparous
List the causes of post-menopausal bleeding
- If uterus enlarged, may be hyperplasia or leiomyosarcoma; classically old/thin patients
- Non-old/thin patients may have rare high grade endometrial carcinoma
- Define adenomysosis
- Define endometriosis
- Uterine thickening that occurs when endometrial tissue moves and lines outer muscular walls of the uterus. Associated with trauma breaking barrier
- Growth of endometrial cells outside the uterine cavity, e.g. on ovaries or distal oviducts
What is an endometrial polyps? What are its clinical features?
- An outgrowth of endometrium, affected by circulating oestrogen
- May cause menorrhagia, irregular or post-menopausal bleeding
- When endometrium (secretory) reacts to excess hormone levels, growing excessively.
- Obesity, PCOS, oestrogen secreting tumours etc.
- Division can cause atypia, leading to adenocarcinoma
Outline endometrial adenocarcinoma pathogenesis
- Excess oestrogen = simple hyperplasia (glands not adjacent)
- Continued growth = complex hyperplasia
- Further growth = atypical hyperplasia (cytology shows increased mitotic bodies and structural abnormalities)
- Atypical cells mutate into proliferative, invasive cells
- Usually good; presents in hyperplasia stage with irregular bleeding
- Endometrial biopsy, US (if developed) or hyeroscopy
- Hysterectomy and salpino-oophorectomy performed if atypical hyperplasia/adenocarcinoma present
How is endometrial adenocarcinoma staged?
- 1: Confined to endometrium and inner myometrium [a] or spread to outer myometrium [b]
- 2: Cervical stromal involvement
- 3: Serosal [a], vaginal or parametrial [b] or pelvic/paraaortic l-node [c] involvement
- 4: Bladder or bowel mucosal invasion/distant metastasis
Define a high grade endometrial adenocarcinoma
- A rarer variant of adenocarcinoma - not oestrogen related
- Usually occur after menopause and atrophy
- Examples include uterine serous and uterine mixed mullerian tumour
- What is a leiomyoma?
- What are its clinical features?
- How is it treated?
- Also called 'fibroid', a benign tumour arising from the smooth mucle of the myometrium
- Usually asymptomatic, but may cause menstrual problems, enlargement or pain
- Can be treated with hysterectomy or hormonal suppression (if unresponsive = leiomyosarcoma)
What is a leiomyosarcoma?
What is its prognosis?
- A rare malignant non-epithelial tumour, originating from smooth muscle; causing haemorrhage and necrosis.
- Poor prognosis; commonly spreads haematogenously to the lungs
What are the types of stromal endometrial tumours?
- Low grade stromal sarcoma: Tends to spread locally into pelvis in later stages
- Undifferentiated uterine sarcoma: High grade malignancy, metastasising early and spreading distantly
What is a choriocarcinoma?
- An aggressive, trophoblastic cancer of the preplacenta
- Invasive syncytiotrophoblasts and cytotrophoblasts, without villi formation
- Early vascular spread = poor prognosis
Where are the most severe precancerous lesions in the female GU tract?
The endocervical os, at its squamo-columnar junction
What are the findings in the right cells?
- Large perinuclear halo
- Nuclear enlargement, with dark staining
- Indicative of HPB infection (koilocytosis)
- Cervical intraepithelial neoplasm
- A cervical precancer, with dysplasia or neoplasia and chromosomal abnormalities which is confined to the epithelium
Outline the grading and treatment of CIN
- 1: Mild dysplasia/neoplasia - treated by treating HPV
- 2: Dysplasia, confined to basal epithelium. Treated with excision
- 3: Severe dysplasia, spands more than 2/3 of epithelium. Excised
What is the main sign of VIN
Leukoplakia: Keratosis from squamous hyperplasia. May be malignant changes
- Vaginal intraepithelial neoplasm
- Precancerous lesion, confined to the epithelium
What is a cervical adenocarcinoma?
- When non-squamous cells in glandular epithelium in the cervic becomes malignant
- Cells still attempt to form glands, creating pseudostratificaiton instead of stratification
What are important factors when considering treatment for breast cancer?
- Prognostic factors: grade, size and stage
- Predictive factors: receptor expression (O and P, HER2)
- Surgical margins
Outline the Nottingham prognostic index and its constituents
- Grade + Stage + 0.2 x cm
- Grade: Relies on differentiation of cells (1-3)
- Stage: Number of nodes involved (>3 = 3)
What is the prognosis of breast cancer using the Nottingham index?
- <2.4 = 93% 5 year survival
- <3.4 = 85%
- <5.4 = 70%
- >5.4 = 50%
What is examined in the grading of breast cancer?
- Tubule formation: percentrage of the tumour forms normal duct structures (more differentiation = less cell adherence)
- Nuclear pleomorphism: large/non-uniform/dark
- Mitotic count
Give different treatments used in the management of breast cancer
- Tamoxifen: Oestrogen receptor antagonist if OR +ve
- Aromatase inhibitors: Prevent oestrogen production, mainly in post-menopausal
Describe testing of breast cancer cells when determining prognosis
- Immunohistochemistry: Oestrogen and HER-2: Overexpressed oncogen, poor for prognosis.
- FISH: chromosome 17 and HER2
What factors can affect the quality of breast biopsy specimens?
- Decomposition between surgery and pathology = architecture and cytology loss
- ER can be falsely positive
- Oestrogen and HER2 testing difficult to perform and examine
What is the role of external quality assurance in pathology? What is the governing body?
- Prevents repeated mistakes being made by pathologist when grading or treating
- UK national external quality assurance service; monitors results of grading in national scaleto detect unusual figures
What are the classes of anti-cancer chemotherapy?
- Cycle-specific: Drugs that are only active in dividing cells
- Cycle-non-specific: Drugs also active on resting cells
What are the main classes of anti-cancer drugs, and what is their mechanism of action?
- Alkylating agenta
- Cytotoxic antibiotics
- Microtubule inhibitors
- Steroid hormones and antagonists
What is the mechanism of action of alkylating agents?
- Forms covalent bonds with DNA to interfere with transcription and replication
- Can be toxic to normal differentiated cells, due to transcription inhibition
- E.g. cyclophosphamide; only works in undifferentiated cells
What are the mechanisms of action of different antimetabolites?
- Antifolates: bind with dihydrofolate reductase reduce and reduce folate's availability = inhibit thymidine production
- Nucleotide analogues: compete with nucleotides for enzymes like DNA polymerases, preventing synthesis. If it enters DNA, disrupts helix formation
- E.g. Methotrexate (antifolate)
What is the mechanism of action of cytotoxic antibiotics?
- Act by 'intercalating' DNA: bindings to either major or minor groove
- This binding inhibits RNA polymerase function, preventing cell division. Also impairs DNA synthesis
Outline the changes of the breast in puberty, and the hormones involved
- Duct elongation: P, O, GH
- Stromal development: O, GH, steroids
- Lobuloalveolar differentiation: P, ILGH
Outline the cyclical changes in breast tissue during the menstrual cycle
- In luteal phase
- Myoepithelial proliferation
- Increase in water content
Outline the changes in breast tissue during pregnancy
- Lobular enlargement into stroma
- Secretory changes
- Involution of the nipple
Outline the changes in breast tissue during menopause
- Menopause = decrease in steroid production
- Epithelial and lobular atrophy
- Stromal thickening
What is periductal mastitis, and what are its clinical features?
- Inflammation of the lactiferous ducts, caused by infection; usually S.A.
- Breast may be tender, with discharge and nipple retraction. Also possible abscess formation
What is duct ectasia, and what are its clinical features?
- Dilation of a lactiferous duct, due to secretory stasis. Also squamous metaplasia, infiltration and fibrosis
- Mimics breast cancer; nipple retraction, inversion, pain and bloody discharge
What is plasma cell mastitis?
Duct ectasia and periductal mastitis, with plasma cell infiltration
What is the pathogenesis of traumatic fat necrosis? What are its clinical features?
- Traumatic lipases released and digest fats. Digested fats bind to calcium and create deposits
- Presents with skin thickening and tethering
What is a fibroadenoma?
- A discrete, mobile lump of both stromal and epithelial tissue.
- Normally found in young women
What is a phyllodes tumour?
- A large, fast growing mass composed of periductal stromal cells. Always considered malignant, due to potential for malignancy
- May be benign, borderline or malignant depending on grading and staging
What is an intraductal papilloma? What are its clinical featuers?
- A benign epithelial tumour, with a fibrovascular core and hyperplasia
- Usually too small to be palpated or felt, although bloody discharge can occur
Outline fibrocystic change in the breast
- Menstrual hormones cause hypertrophy and hyperplasia
- Creates small, numerous fibrous or cystic areas
- Cells can develop atypical features
What is adenosis?
Fibrocystic change; with a disturbance in the normal functioning of a gland, usually with abnormal formation or enlargement
What is benign proliferative breast disease, and how does it affect breast cancer risk?
- A group of non-cancerous conditions that may incerase the risk of developing breast cancer (around 2x)
- If the benign proliferation becomes atypical, there is a 5x risk
Define salpingitis, give clinical features and list causative organisms
- Inflammation of the fallopian tube
- Pelvic pain, adnexal renderness, fever and vaginal discharge
- Gonococcus, chlamydi, enteric bacteria
What is the pathophysiology of acute salpingitis?
- Suppurative disease
- Pyosalpynx and tubo-ovarian abscesses form
What is the pathophysiology of chronic salpingitis?
- Lack of neutrophils = no pus = hydrosalpinx
- Fused plica, pelvic adhesions and tubal fibrosis
- Infertility and bowel obstruction via fibrotic adhesions
What are predisposing factors for a tubal ectopic pregnancy? What are its clinical features?
- Pelvic inflammatory disease and endometriosis
- Severe abdominal pain 6 weeks after last menses, pelvic haemorrhage, shock
- Clinical features
- The presence of endometrial glands or stroma outwith the uterus
- Found normally in 3rd or 4th decards, 1/10 women. Not post-menopausal
- Dysmenorrhea, pelvic pain. Infertility
- Clinical features
- Multiple cortical cysts in ovaries, with surrounding stromal hyperplasia.
- Anovulation, obesity, hirsutirm, infertility
- Androgen biosynthesis disorder = abnormal growth
Describe stromal hyperplasia of the ovaries
- Bilateral enlargement and stromal hyperplasia
- Similar disease to PCOS in pathology and features
- May be oestrogen-producing, leading to endometrial hyperplasia or malignancy
- Type 1 ovarian malignancy
- Type 2 ovarian malignancy
- Borderline malignant tumours, including low grade serous, endometrioid and mucinous carcinomas
- High grade serous carcinomas only; solid and cystic, bilateral, necrotic and haemorrhagic
List the risk factors of malignant ovarian tumours
- Family history
- Contraceptive pill
- Genetics (BRCA1 and 2)
Describe the findings of:
- Benign serous tumours
- Borderline serous
- Mucinous serous
- 1/5 bilateral. Single layer of cuboidal/tubal epithelium. Fibrosis
- 1/3 bilateral. Similar to benign. May be extra-ovarian
- Large, unilateral, multiloculated and lined by epithelium