Week 4 Flashcards
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
Q
Describe squamous intraepithelial neoplasia:
A
- 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
Q
Describe vulvar cancers:
A
- 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
Q
Describe vulvar cancers:
A
- 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
Q
What is the normal structure of the fallopian tube?
A
- Lined by ciliated columnar epithelium
- Complex plicae
- Layers of smooth muscle
- Peritoneum
29
Q
What are the main pathologies of the fallopian tubes?
A
- Salpingitis
- Ectopic pregnancy
- Endometriosis (tubal involvement can compromise tube function)
- Tubal malignancies
- Serous tubal intraepithelial carcinoma (STIC)
30
Q
Describe salpingitis and its complications:
A
- 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
Q
Describe salpingitis caused adherence of FT and risk with ectopic pregnancy:
A
- 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
Q
Describe tubal malignancies:
A
- 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
Q
Describe ‘STIC’:
A
- 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
Q
Describe the normal structure of the ovaries:
A
- Flat surface epithelium
- Cortex:
- compact ovarian stroma
- small functional cysts
- germ cells
- Medulla:
- hilus cells
- vessels
- nerves
35
Q
Describe non-neoplastic cysts (such as polycystic ovaries):
A
- 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
Q
Describe ovarian neoplasms:
A
- 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
Q
What are the clinical correlations for all ovarian tumours?
A
- 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
Q
How else can surface epithelial tumours be described?
A
- 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
Q
Describe endometriosis:
A
- 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
Q
Describe endometrial polyps:
A
- 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
Q
What is adenomyosis?
A
The presence of endometrial tissue within the myometrium
42
Q
Describe endometrial hyperplasia and adenocarcinoma:
A
- 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
Q
What causes endometrial hyperplasia and adenocarcinoma?
A
- 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
Q
Describe leiomyoma:
A
- 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
Q
Describe the pathology and management of leiomyoma:
A
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
Q
Describe leiomyosarcoma:
A
- 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
Q
Describe endometrial stromal sarcoma:
A
- 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
Q
What is gestational trophoblastic disease?
A
An umbrella term for several conditions including hydatidiform moles (partial and complete) and malignant tumours including choriocarcinoma
49
Q
What is partial mole?
A
- 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
Q
What is complete mole?
A
- 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
Q
What are the main classes of chemotherapy drugs?
A
- Alkylating agents
- Antimetabolites
- Cytotoxic antibiotics
- Microtubule inhibitors
- Steroid hormones and antagonists
52
Q
Describe alkylating agents:
A
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
Q
Describe cyclophosphamide:
A
- 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
Q
Describe antimetabolites types:
A
Nucelotide synthesis: anti-folates - methotrexate - ralitrexed - pemetrexed Nucleotide analogues - 5-fluorouracil - Cytarabine - Gemcitabine - Fludarabine - Capectabine
55
Q
How do antimetabolites act?
A
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
Q
How does cytarabine act?
A
- 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
Q
How do cytotoxic antibiotics work?
A
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
Q
How do steroid hormones work?
A
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
