1
Q
What are significant developmental abnormalities involving the breasts?
A
- Ectopic breast tissue is the most common abnormality, most often on the milk line between axilla and the groin
- Nipple-areolar and glandular tissue may all be present but there may be glandular tissue without an obvious nipple or a nipple with little glandular development
- Breast hypoplasia can occur, associated with many syndromes (CAH)
- Nipple inversion is common and usually normal, new can however be a sign of benign or malignant disease
2
Q
What are general inflammatory conditions affecting the breast?
A
- May be infective or non-infective
- Granulomatous inflammation of the breast tissue can occur in systemic diseases (sarcoid), and infections (TB)
- Foreign body reactions around breast implants, and reactions to silicone leakage after implant rupture
- Recurrent subareolar abscesses may be associated with maxillary fistula and smoking
- Fat necrosis may follow trauma and is a benign process, but biopsy may be required to rule out cancer
3
Q
What is idiopathic granulomatous mastitis?
A
A lobule centred, non-necrotising granulomatous inflammatory process with a tendency to recurrent after excision
4
Q
What is acute mastitis?
A
- Acute mastitis is a cellulitis associated with breast feeding
- skin fissuring may let bacteria in, and milk stasis favour their growth, leading to infection of breast tissue
5
Q
What is periductal mastitis/ductal ectasia?
A
- Dilation of central lactiferous ducts, periductal chronic inflammation, and scarring
- Often asymptomatic but there may be discomfort, a mass, nipple retraction or inversion
- Calcified luminal secretions may be seen on mammogram
- May progress to squamous metaplasia of lactiferous duct
6
Q
What is fibrocystic change?
A
- The most frequent benign breast condition, tends to be multifocal and bilateral and may cause breast tenderness and nodularity
- Spectrum of change includes small and large cysts, increased amounts of glandular tissue, increased fibrous stroma, epithelial hyperplasia (without atypia, occasionally with)
- Apocrine metaplasia of cyst epithelium is frequent
- Solitary papillomas, papillomatosis and radial scars are also part of the wider spectrum of fibrocystic change
7
Q
What is an intraduct papilloma?
A
- Benign tumour of the epithelium lining the mammary ducts
- Solitary central papillomas are thought to be innocuous if there is no epithelial atypia
- Papillomatosis (multiple) is thought to be slightly more likely to be associated with malignancy elsewhere in the same or even contralateral breast
8
Q
How is fibrocystic change classified?
A
- Non proliferative: with no excess risk of subsequent BCR
- Proliferative without atypia: up to 2-fold excess risk of BCR
- Proliferative with atypia: about 5x the risk, especially with FH
9
Q
What are specific variants in fibrocystic change?
A
- Adenosis refers to an increase in glandular breast tissue
- Specific types include sclerosing adenosine, which is a benign proliferation of distorted glandular tissue and stroma
- Microcalcifications may be observed on mammography
- Apocrine metaplasia is recognised by large, rounded epithelial cells with copious granular eosinophilic cytoplasm and characteristic apical projections
- Radial scars are benign lesions characterised by a fibrotic and elastic core, trapped glands and a pseudo-infiltrative appearance
10
Q
Describe epithelial hyperplasia:
A
- Associated with increased cancer risk
- Different patterns recognised as ductal or lobular
- Ductal hyperplasia may be mild, moderate or florid with a mixture of cell types
- Atypical ductal hyperplasia (ADH) is associated with microcalcifications and has features in common with low grade ductal carcinoma in situ
- Lobular neoplasia includes atypical lobular hyperplasia and lobular carcinoma in situ; difference is extent and amount of cellular proliferation
11
Q
What are columnar cell lesions?
A
- Often associated with micro calcifications
- Columnar cell change and columnar cell hyperplasia without and with atypia
12
Q
Describe fibroademona of the breast:
A
- Common (25% of asymptomatic women)
- Overgrowth of epithelium and stroma, resembling a giant lobule
- Benign neoplasm, hormone sensitive, regress after menopause
- Firm, non-tender, mobile and usually < 25-30mm
13
Q
Desciribe Phyollodes tumour:
A
- Overgrowth of epithelium and stroma but with increased stromal cellularity, mitotic activity, cytological atypia and an infiltrative border
- Tendency to local recurrence and can become malignant
- Requires surgical excision
14
Q
What factors pre-dispose to BCR?
A
- Increasing risk with age
- Earlier menarche and later menopause
- Older age at first pregnancy
- OC use
- HRT
- Obesity and tall height
- Denser breast tissue
- Alcohol
- Positive FH
- Uncommon BCR genetic syndromes (BRCA1,2, p53)
15
Q
How are breast abnormalities investigated?
A
- Clinical exam
- Imaging: Xray mammography, ultrasound, MRI
- FNA cytology with microscopy of cells recovered
- Core biopsy (often guided by imaging) with microscopy of tissue sections
- Excision biopsy: diagnostic, therapeutic or both
- Screening
16
Q
What are signs of BCR?
A
- New lump or thickening in breast or axilla
- Altered shape, size or feel of the breast, pain
- Skin changes; puckering, dimpling, skin oedema, rash, redness, feels different
- Nipple changes; tethering/inversion, discharge, eczema-like changes in Paget’s disease
- Rarely, widespread inflammation, redness, pain in inflammatory cancer can stimulate infection
17
Q
Describe steroid hormone receptors in BCR:
A
- ~80% BCRs overexpress oestrogen receptor and progesterone receptor
- ER/PR positive carcinomas are likely to respond to endocrine treatment eg with tamoxifen which in breast is predominantly an ER antagonist, or aromatase inhibitors
18
Q
Describe HER2 positive cancers:
A
- Over-expression of HER2 has worse prognosis than other BCRs but treatment with monoclonal antibodies is effective
- Adjuvant therapy can reduce risk of relapse
19
Q
Describe Nottingham prognostic index:
A
- Combines grade (based on histological properties, as well as differentiation and growth), tumour size in cm and stage into a numerical prognostic index
20
Q
How is BCR morphologically graded?
A
- BCR grading is based on three histological properties:
1. Nuclear pleomorphism
2. Number of mitosis per mm*2
3. Degree of gland formation by the cancer cells - Grade 1 are well differentiated and slow growing while grade 3 are poorly differentiated and fast growing
21
Q
How is BCR morphologically and molecularly classified?
A
- Molecularly by presence or absence of ER, PR, Her 2 and androgen receptor (AR)
- ER positive split into luminal A and B
- ER negative split into normal breast like, HER2 and basal-like
- Morphologically major divisions are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC)
- lobular can mean ‘having lost E-cadherin’
22
Q
Describe ductal/lobular carcinoma in situ:
A
- Malignant looking proliferation of epithelial cells within basement membrane
- No extension into breast stroma
- No communication with blood vessels or lymphatics
- No possibility of metastases
23
Q
Describe changes in the cervix at puberty and menopause:
A
- Prior to puberty the ectocervix is covered by non-keratinising stratified squamous epithelium and the endocervix is lined by columnar (glandular) epithelium
- Squamo-columnar junction is everted into the vagina and the squamous epithelium adapts to the vaginal environment by squamous metaplasia in the ‘transformation’ zone
- Changes are reversed at menopause
- This zone of unstable differentiation is where most cervical neoplasia develop
24
Q
Describe the effect of HPV on the lower female genital tract:
A
- More than 99% of cervical carcinomas are associated with HPV infection
- Early genes E1 to 7 interact with intracellular molecules to interfere with cell proliferation machinery to replicate the virus
- Late genes L1,2 encode capsid proteins. Disruption of cell cycle checkpoints may contribute to accumulation of oncogenic mutations and carcinogenesis
- Causes dyskaryosis suggestive of cervical intraepithelial neoplasia (CIN)
25
Describe squamous intraepithelial neoplasia:
- Invasive squamous carcinoma of the cervix almost always develops from pre-existing CIN, but not all CIN will become squamous cancer
- CIN II and III are more likely to progress than CIN I
26
Describe vulvar cancers:
- SCC associated with VIN
- females less than 60
- associated with high incidence of lower genital tract neoplasia particularly CIN and invasive cervical cancer
- usually related to high risk type HPV 16/18
- warty or basaloid cancers
- SCC associated with dermatoses
- most over 60/70
- well differentiated and keratinising
- not associated with HPV or VIN
- adjacent squamous hyperplasia and/or lichen sclerosis common
27
Describe vulvar cancers:
- SCC associated with VIN
- females less than 60
- associated with high incidence of lower genital tract neoplasia particularly CIN and invasive cervical cancer
- usually related to high risk type HPV 16/18
- warty or basaloid cancers
- SCC associated with dermatoses
- most over 60/70
- well differentiated and keratinising
- not associated with HPV or VIN
- adjacent squamous hyperplasia and/or lichen sclerosus common
28
What is the normal structure of the fallopian tube?
- Lined by ciliated columnar epithelium
- Complex plicae
- Layers of smooth muscle
- Peritoneum
29
What are the main pathologies of the fallopian tubes?
- Salpingitis
- Ectopic pregnancy
- Endometriosis (tubal involvement can compromise tube function)
- Tubal malignancies
- Serous tubal intraepithelial carcinoma (STIC)
30
Describe salpingitis and its complications:
- Part of spectrum of pelvic inflammatory disease
- Most commonly infective (chlamydia, mycoplasma, gonorrhoea)
- Usually considered to be ascending infection
- Symptoms include fever, lower abdominal or pelvic pain and pelvic masses if tubes distended with exudate or secretions
- Complications include adherence of tube to ovary, causing tubo-ovarian abscess
31
Describe salpingitis caused adherence of FT and risk with ectopic pregnancy:
- Adhesions involving tubal plicae increase risk of tubal ectopic pregnancy
- Damage or obstruction of tube lumen may produce infertility which may not be easy to treat
- Ruptured tubal ectopic pregnancy can be potentially life-threatening
32
Describe tubal malignancies:
- Primary adenocarcinomas involving and identified as arising from the FTs alone are rare
- the most common is papillary serous carcinoma
- endometrioid carcinomas are also seen
- FT tube carcinomas occur in women with BRCA1 mutations (some occur after prophylactic oophorectomies)
- FT carcinomas often involve momentum and peritoneal cavity at time of presentation
33
Describe 'STIC':
- Recent concept of serous tubal intraepithelial carcinoma
- Abnormal epithelium in the distal fallopian tube
- Lined by basement membrane so no carcinoma in situ
- Nuclear atypia clearly seen, and is likely a precursor for high grade serous carcinoma
- Similar mutations to invasive tumour, including p53
34
Describe the normal structure of the ovaries:
- Flat surface epithelium
- Cortex:
- compact ovarian stroma
- small functional cysts
- germ cells
- Medulla:
- hilus cells
- vessels
- nerves
35
Describe non-neoplastic cysts (such as polycystic ovaries):
- Symptoms of polycystic ovaries include (usually after menarche):
- oligomenorrhoea
- hirsutism
- infertility
- obesity
- over-production of androgens by multiple cystic follicles in the ovaries
- LH high, FSH low
- Enlarged ovaries with many subcortical cysts seen
- Thickened, fibrotic outer surface over cysts lined by granulose cells with a hypertrophic and hyperplastic lutenised theca interna
- Absence of corpora lutea and corpora albicantes
36
Describe ovarian neoplasms:
- Tumours related to three cells that make up ovary:
1 surface (coelomic) epithelium
2 germ cells
3 sex cord/stromal cells
- Benign surface epithelial tumours are usually cystic (cyst adenoma) with/out a solid stroll component
- Malignant epithelial tumours may be cystic or solid
- 95% of germ cell tumours are mature cystic teratomas, mostly benign
- Sex cord tumours can be granulosa and theca cell tumours
- granulose usually occur in postmenopausal women and are not rare
- ovarian fibromas and thecomas are usually benign and not rare
37
What are the clinical correlations for all ovarian tumours?
- Often asymptomatic until well advanced
- Clinical presentations often similar despite biological diversity: local pressure symptoms (pain, GI complaints, urinary frequency)
- Sometimes they become twisted on their pedicles (torsion) producing severe abdominal pain
38
How else can surface epithelial tumours be described?
- Intermediate, borderline category referred to as low malignant potential
- Carcinomas may be high grade serous, endometrioid, clear-cell, low grade serous or mucinous
- HGSC are though to arise from epithelial precursor lesions in the ovarian end of the FTs
- Endometrioid and clear cell carcinomas probably arise from ovarian endometriosis
39
Describe endometriosis:
- The presence of endometrial tissue outside the uterus
- Common sites of endometriosis include ovaries, peritoneal surfaces, large and small bowel, appendix, mucosa of cervix, vagina and fallopian tubes and laparotomy scars
- Clinical symptoms include dysmenorrhoea, pelvic pain and infertility
- Pathogenesis is by metastatic theory (retrograde menstruation) or metaplastic theory (arising from coelomic epithelium)
40
Describe endometrial polyps:
- Exophytic masses of variable size which project into the endometrial cavity
- Associated with tamoxifen in some cases
- Appearance:
- Microscopically haphazardly arranged glands with preservation of a low gland to stroma ratio
- Often thick walled blood vessels and fibrous stroma
- Glands are usually inactive but can also show proliferation, secretory changes or metaplasia
- Can present with abnormal bleeding and be treated via hysteroscope
41
What is adenomyosis?
The presence of endometrial tissue within the myometrium
42
Describe endometrial hyperplasia and adenocarcinoma:
- Symptoms: usually postmenopausal bleeding
- Histologically characterised by an increase in the gland to stroma ratio, and can be seen with or without cytological atypia
- Hyperplasia is known precursor of adenocarcinoma
- Management:
- hyperplasia: progesterone therapy or hysterectomy
- adenocarcinoma: hysterectomy with subsequent management depending on tumour grade and stage
43
What causes endometrial hyperplasia and adenocarcinoma?
- Associated with prolonged oestrogen stimulation of the endometrium
- Possible underlying causes include:
- anovulatory cycles
- endogenous sources of oestrogen (obesity, PCOS, oestrogen secreting ovarian tumours)
- exogenous sources of oestrogen such as oestrogen only HRT
44
Describe leiomyoma:
- Benign smooth muscle tumour of the myometrium
- Very common- at least 25% of women, mostly of reproductive age, incidence is over 70% by age 50
- May be single or multiple
- Symptoms:
- asymptomatic
- abnormal bleeding
- urinary frequency if large
- impaired fertility
45
Describe the pathology and management of leiomyoma:
Pathology:
- sharpy demarcated round grey-white tumours with a whorled cut surface, very variable in size
- microscopically resemble normal smooth muscle
Management:
- varies depending on number, seize and symptoms
- Medical; progesterone secreting IUS, hormonal therapies, transexamic acid, GnRH agonists
- Surgical; uterine artery embolisation, myomectomy, hysterectomy
46
Describe leiomyosarcoma:
- Uncommon malignant smooth muscle tumour of the myometrium (commonest uterine sarcoma)
- Peak incidence age is 40-60 years, can be pre or post menopausal
- Symptoms initially none, then bleeding or pain
- Pathology
- macro: bulky invasive masses or polypoid necrosis, haemorrhage and variable cut surface
- micro: overt cytological atypia, necrosis, mitotic activity, infiltrative margin
47
Describe endometrial stromal sarcoma:
- A group of tumours of the endometrial stroma
- Can be low grade (common) or high grade (rare)
- Both have diffusely infiltrative 'worm like' growth pattern macroscopically
- Microscopy
- low grade tumour cells resemble cells of proliferating endometrial stroma, with mitoses
48
What is gestational trophoblastic disease?
An umbrella term for several conditions including hydatidiform moles (partial and complete) and malignant tumours including choriocarcinoma
49
What is partial mole?
- Fertilisation of one egg by two sperm resulting in a triploid karyotype
- Microscopy shows oedematous villi and subtle trophoblast proliferation
- Risk of invasive mole which invades and destroys the uterus
50
What is complete mole?
- Fertilisation of an egg with no genetic material, usually by one sperm which duplicates its chromosomal material
- Diploid karyotype, usually 46 XX
- Microscopy shows enlarged oedematous villi with central cisterns and circumferential trophoblast proliferation
- Carries a 10% risk of invasive mole and a 2.5% risk of choriocarcinoma
51
What are the main classes of chemotherapy drugs?
- Alkylating agents
- Antimetabolites
- Cytotoxic antibiotics
- Microtubule inhibitors
- Steroid hormones and antagonists
52
Describe alkylating agents:
```
Function
- Form covalent bonds with DNA
- Interfere with both transcription and replication
- Most alkylating agents have two reactive groups
- Allow the drug to cross-link
- within one strand of DNA
- across the two strands of DNA
Drugs
- Nitrogen mustards
- Cysplatin
- Temozolomide
- Lomustine (can penetrate brain)
- Busulphan ('selective' effect on bone marrow)
```
53
Describe cyclophosphamide:
- A prodrug that requires activation by phosphoramidase
- High phosphoramidase activity in some tumours
- Much less toxic than other nitrogen mustards
- Aldehyde dehydrogenase (ALDH) protects against the toxicity of the drug
- Used to treat many cancers
54
Describe antimetabolites types:
```
Nucelotide synthesis: anti-folates
- methotrexate
- ralitrexed
- pemetrexed
Nucleotide analogues
- 5-fluorouracil
- Cytarabine
- Gemcitabine
- Fludarabine
- Capectabine
```
55
How do antimetabolites act?
Methotrexate:
- higher affinity for dihydrofolate reductase than folic acid
- inhibition of dihydrofolate formation
- inhibition of purine/pyrimidine nucleotide synthesis
- ultimately halt to DNA and RNA synthesis
Fluoro-uracil:
- prevents thymidine formation
- stops DNA synthesis
Mercaptopurines
- converted into false nucleotides
- disrupts purine nucleotide synthesis
- may be incorporated into DNA, disrupting helix
56
How does cytarabine act?
- Sugar moiety of cytidine is arabinosine rather than ribose
- Cellular activation to ara-CTP
- S-phase cell cycle specific
- Inhibits DNA polymerases
- Incorporation into DNA causes chain termination
57
How do cytotoxic antibiotics work?
Act mainly by direction action on DNA as intercalators
- Dactinomycin
- inserts itself into the minor groove in the DNA helix
- RNA polymerase function is disrupted
- Doxorubicin
- inserts itself between base pairs
- binds to the sugar-phosphate DNA backbone
- local uncoiling
- impaired DNA and RNA synthesis
- Vincristine
- bind to micro tubular protein, block tubulin polymerisation and normal spindle formation and disrupt cell division
58
How do steroid hormones work?
Work on tumours that are responsive to a specific hormone which makes it regress
- Tamoxifen (antagonist of oestrogen receptor)
- treats oestrogen dependent breast cancers
- In prostate cancer treatment can be testosterone receptor antagonists and pituitary down regulators
Phase 3
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