Wk4 - Female GU and breast Flashcards
Normal structure of fallopian tube
Common pathologies of fallopian tube?
Lined by ciliated columnar epithelium (to beat egg along tube towards uterus)
Complex plicae
Layers of smooth muscle
Peritoneum
Common pathologies = Salpingitis and PID & Ectopic tubal pregnancy
Pathology - name of inflammation of fallopian tubes
Salpingitis - part of the spectrum of pelvic inflammatory disease.
Commonly presents with pelvic pain, adnexal tenderness, fever and vaginal discharge.
Most commonly infective, mainly bacterial (Chlamydia trachoatis, Streptococci, Neisseria gonorrhoeae).
Usually considered to be ascending infection.
The tube becomes blocked off due to inflammation. Can form tubo-ovarian abscess
Inflammatory cells include many pus cells (neutrophils).
- Acute Suppurative Salpingitis
- Chronic Salpingits
Complications of salpingitis
Adherence of tube to ovary; tubo-ovarian abscess.
Adhesions involving tubal plicae increase risk of tubal ectopic pregnancy.
Damage or obstruction of tube lumen may produce infertility (as spermatogonia not able to pass through) which may not be easy to treat.
Ruptured tubal ectopic pregnancy can be potentially life-threatening.
Tubal malignancies
Primary adenocarcinomas involving and rising from the fallopian tubes are rare. The most common is papillary serous carcinoma. Endometrioid carcinomas are also seen.
Fallopian tube carcinomas occur in women with BRCA1 mutations.
Fallopian tube carcinomas often involve omentum and periotenal cavity at time of presentation.
Describe features of STIC (serous tubal intraepithelial carcinoma)
Likely precursor for high grade serous carcinoma.
Abnormal epithelium in distal fallopian tube (dysplasia).
Limited by basement membrane so in situ.
Nucelar atypia.
Similar mutations to invasive tumour, including p53.
Structure of ovary
Flat surface epithelium.
Cortex: compact ovarian stroma, small functional cysts, germ cells (primordial follicles etc.
Medulla: hilus cells, vessels, nerves
Granulosa and theca cells present.
Cysts in the ovaries:
Non-neoplastic cysts include inclusion, follicular and luteal cysts
Polycystic ovaries (Stein-Leventhal syndrome)
- Oligomenorrhea, hirsutism, infertility, obesity - usually after menarche. Overproduction of androgens by multiple cystic follicles in the ovaries; high LH, low FSH.
- Enlarged ovaries, multiple sub-cortical cysts. Thickened, fibrotic outer surface. Cysts lined by granulosa cells with a hypertrophic and hyperplastic theca interna. Absence of corpora lutea, cropora albicantes. insulin resistance may lead to type 2 diabetes.
Ovarian neoplasms
Tumours of the oavry are pathologically diverse, related to the 3 cell types that make up the normal ovary: surface (coelomic) epithelium, germ cells, sex cord/stromal cells
Genetic alterations in sporadic ovarian cancer
BRCA mutations only present in ~9% of sporadic ovarian cancers.
HER2 overexpressed in 35% of ovarian cancers (poor prognosis)
KRAS mutations are present in ~30% of ovarian tumours, mostly mucinous cystadenocarcinomas.
p53 is mutated in ~50% of all ovarian cancers, particularly high grade serous cancers.
Surface epithelial tumours of ovary
Thought to arise from coelomic mesothelium on surface of the ovary.
Benign lesions usually cystic (cystadenoma) with or without a sold stromal component (cystadenofibroma)
surface epithelial tumours have a boderline catergory - have low malignant potential with better prognosis.
Malignant epithelial tumours (carcinomas) may be cystic (cystadenocarcinoma) or solid (adenocarcinoma)
Carcinomas may be HGSC (70% (p53 mutated)). endometrioid (10%), clear-cell (10%), LGSC (5%) or mucinous (3%)
HGSC are though to often arise from epithelial precurose lesions in the ovarian end of the fallopian tubes.
Endometrioid and clear cell carcinomas porbably arise from ovarian endometriosis.
Ovarian endometrioma - ‘chocolate cyst’.
Describe HGSC (high grade serous carcinoma) and LGSC
In HGSC, p53 and BRCA1 mutations are almost always HGSC. Inability to repair double stranded DNA breaks leads to chromosomal instability and genomic chaos.
LGSC - KRAS, BRAF is tpypically abnormal - is often assocuiated with a borderline serous component
Most women with ovarian cancer present late and in many the prognosis is poor, Successful early diagnosis has not been achieved in ovarian cancer.
The difference in morphology between benign serous, borderline serous and serous caricnomas
Benign - large, cystic. May be biltaeral. Smooth shiny serousal covering. Cysts filled with a clear serous fluid, lined by single layer of tall columnar epithelium. Some cells are ciliated.
Borderline - mild cytologic atypia, but no stromal invasion. Peritoneal implants may be present.
Serous - analplasia of cells, obvious stromal invasion.
Psammoma bodies (concentrically laminated calcified concretions) common in the papillae of serous tumours in general.
Prognosis of serous tumours
Benign and borderline tumours have an excellent outcome (borderline almost 100% survival rate and even with peritoneal involvement nearly 75%)
Invasive serous carcinomas have poor prognosis, depends on satge at diagnosis
Mucinous serous tumours
These tumours consist of mucin-secreting cells.
80% are benign, 10% are borderline, 10% are malignant
Morphology: lage, multilocular, no psammoma bodies, Cysts lined by cells iwth abundant mucinous cytoplasm.
Prognosis of mucinous cystadenocarcinoma slightly better than serous, but stage is more important than histologic type.
Ovarian endometrioid carcinoma
Microscopically characterised by neoplastic tubular glands, similar to those of the endometrium.
Usually malignant.
Like endometrial cancer, endometrioid carcinomas have often lost the PTEN (phosphate and tensin homolog) tumour supressor gene
Associated with endometriosis.
Ovarin clear cell carcinomas is aslo associated with endometriosis.
Germ cell tumours
95% of ovarian germ cell tumours are mature cystic teratomas (‘dermoid cysts’)
Most found in young women incidentally on abdominal scans. May contain foci calcification associated with bone or teeth.
Grossly: smooth capsule, often filled with seaceous secretion and matted hair. Sometimes focci of bone and cartilage, nests ofbronical or Gi epithelium, teeth and other recognisbale lines of development also present e.g. thyroid.
Ovarian sex cord-stromal tumours
These include granulosa and theca cell tumours, which often secrete oestrogen, and uncommonly Sertoli-Leydig cell tumours, which may secrete androgens.
Granulosa cell tumour usually occur in postmenopausal women and are not rare. Oestorgen overproduction may lead to endometrial hyperplasia or endometrial carcinoma. - most often present with postmenopausal bleeding due to overproduction fo oestrogen.
Ovarian fibromas and thecomas are usually benign and not rare. They too can over-produce oestrogens, especially thecomas.
The combination of ovarian fibroma with ascites and pleural effusion is…
Meig’s syndrome.
Removal of the tumour cures the problem.
Pathophysiology is not clear.
An ovrian tumour with ascites is more likely to be a carcinoma.
Brenner tumours
These are uncommon mixed surface epithelial-stromal tumours.
Usually benign, unilateral size very variable, solid, circumscribed, yellowish.
Often found incidentally.
histologically, nests of transitional epithelial cells with longitudinal nuclear grooves and abundant fibrous stroma.
Incidence of breast cancer rises steadily from…
Later 30s to about 60, after which it does not change much.
Female to male ratio for breast cancer
~150:1
Risk factors for breast cancer.
Protective factors?
Earlier menarche, later menopause, being older at first pregnancy/child brith, OC use, HRT, obesity, tallness, alcohol, positive family history.
there are uncommon breast cancer genetic syndromes (BRCA1/BRCA2, p53 (Li-Fraumeni syndrome).
Exercise and breast feeding are thought to be somewhat protective
Symptoms of breast cancer
A new lump or thickening in breast or axilla.
Altered shape, size or feel of the breast; pain (not often).
Skin changes: puckering, dimpling, ‘peau d’orange’ (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 simulate infection.
Investigation of breast abnormalities
Clinical examination - onspection in different positions, palpation.
Imaging - ultrasound, X-ray mammography, MRI
Fine needle aspiration cytology, with microscopy of cells recovered; Core biopsy (often guded by imaging), with microscopy of tissue sections.
Excisional biopsy - diagnostic, therapeutic, or both
What is often present in invasive carcinoma of breast - detectable on histology and on x ray mammography?
Microcalcification
Treatment of breast cancer
Surgery aims to remove all cancer tissue with margins free of cancer.
Wide local excision (lumpectomy, WLE) alone has an unacceptably high risk of lcoal recurrence, but WLE followed by radiotherapy achieves comparable local control, long term disease-free and overall survival as mastectomy.
Larger carcinomas may still require mastectomy to achieve clear margins but neoadjuvant treatment (chemotherapy or endocrine therapy) may cause enough tummour regression for breast-conserving surgery to be possible.
The axilla in breast cancer
Like carcinomas at other sites, breast cancer has a tendency to spread to local lymph nodes.
Staging the axilla is important for prognosis and treatment. Axillary clearance is usually not necessary if sentinel node biopsy is negative may not always be required even if positive.
Axillary clearance has significant morbidity (limitation of arm movement, lymphoedema)
About 80% of breast cancers overexpress…
and treatment
Oestrogen receptor (ER) and progesterone receptor (PR). ER/PR-positive carcinomas are likely to respond to endocrine treatment e.g. with Tamoxifen which in breast is predominantly an ER antagonist. In endometrium and bone, Tamoxifen has significant agonist activity, and there is some elevation of endometrial cancer risk in women treated with Tamoxifen
Using aromatase inhibitors for breast cancer treatment
In postmenopausal women especially oestrogen stimulation of tumour growth may be prevented by aromatase inhibitors which prevent conversion of (adrenal) andorgens to oestrogens (tesosterone, androostenedione –> estradiol, estrone), a process which normally occurs in adipose tissue and may partly explain the link between obesity and breast cancer.
E.g.s of aromatase inhibitors = Letrazole, Anostrazole
HER2 positive breast cancers
- treatment
Cancers which overexpress Her2 have a worse prognosis than other breast cancers, but treatment with monoclonal antibody Trastuzimab (HErceptin) and other Her2- targeted therapies has improved the situation
Adjuvant Hereptin reduces the risk of relapse in women with Her2+ breast cancer and prolongs survival in women with systematised (metastatic) breast cancer.
Chemotherapy for breast cancer
Surgery and radiotherapy usually achieve local control of breast cancer, but cannot prevent metastatic relapse at distant sites (lung, pleura, bone liver etc.). Endorcine treatments can, and treatment with Tamoxifen or aromatase inhibition for five years or longer is standard care for ER+PR+ breast cancer.
Adjuvant chemotherapy in breast cancer
ER-/PR- breast cancers and EP-PR-Her2- breast cancers –> adjuvant chemotherapy is used –> prevents metastatic relapse
The main pathological prognostic factors in breast cancer are…
- What criteria is used to stage and assesses for prognosis
carcinoma grade and stage, which includes carcinoma size and lymph node involvement
Grade is based on 3 histological properties: 1. nuclear pleomorphism, 2. the number of mitoses per mm2, 3. the degree of gland formation by the cancer cells.
Grade 1 are well differentiated and slow growing, grade 3 are poorly differentiated and fast growing. Grade 2 cancers are in between.
- Nottingham prognostic index
What are the types of breast cancer - & main features
Conventionally, 2 major divisions and less frequent types of breast cancer are recognised…
Ductal carcinoma in situ - malignant looking proliferation of epithelial cells within basement membrane but no extension into breast stroma. No possibility of metastasis
Lobular carcinoma in situ - most mammographically detected carcinoma. Malignant looking proliferation of epithelial cells within basement membrane but no extension into breast stroma. No possibility of metastasis
Invasive ductal carcinoma - Most common type of breast cancer (>70%)
Invasive lobular carcinoma - 10% of all invasive breast carcinomas. Loss of E-Cadherin. Often bilateral so need to do careful examination of both breasts.
Mucinous carcinoma - Most common in 75+. Well circumscribed with lakes of mucin, well differentiated cells.
Tubular carcinoma - Rare.
Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). The corresponding less abnormal ‘atypical ductal hyperplasia’ and ‘atypical lobular neoplasi’ are roughly equivalnet to low grade dysplasia.
Malignant looking proliferation of epihtelial cells iwthin basement membrane
No extension into breast stroma.
No communication with blood vessels or lymphatics
No possibility of metastases
Spread of breast cancer
Invades nearby tissue - pectoralis muscle and skin
Blood - lung, liver, bone and brain
Lymph - axillary and internal mammory nodes
Difference between luminal A ER+ cancers and luminal B ER+ cacners
A - tend to be low grade, less proliferative and have better prognosis
B - tend to be high grade, more proliferative and potentially do less well.
In the ER- cancers there are 3 subtypes:
normal breast like, ‘HER2’ and basal-like
Basal-like carcinomas (in breast)
These express genes associated with the basal/myoepithelial cells of the breast. They tend to be aggressive, and there is overlap with the cancers which occur in RRCA1 mutation carriers
The cervix (anatomy
Prior to puberty, the ectocervix is covered by non-keratinising stratified squamous epithelium and the endocervix is lined by columnar (glandular) epithelium.
With growth of the cervix after puberty the squamo-columnar junction is everted into the vagina and the squamous epithelium adapts to the vaginal environment by squamous metaplasia in the ‘transformation zone’.
These changes are reversed at the menopause. This zone of unstable differentiation is where most cervical neoplasia develop.
What can be used to help distinguish squamo-columnar junction of cervix on examination
Features of Cervical Intraepithelial Neoplasia (CIN)
Acetic acid - shows up something that is thicker (white)
CIN:
Replacement of normal squamous epithelium by neoplastic squamous cells. The basement membrane remains intact.
CIN does not cause any symptoms
How can human papilloma virus be associated with cancer
HPV is a persisting infection, an oncogenic strain of HPV is thought to be a necessary cause of cervical cancer and precancer
Describe cervical cytology (the screening test)
Cytological screening samples cells from the cervical transformation zone. It is designed to detect changes associated with HPV infection and Cervical Intraepithelial Neoplasia.
The presence of dyskaryosis (nuclear abnormalities) suggestive of CIN promopts referral to colonoscopy clinic for biopsy to detect CIN.
CIN does not cause any symptoms.
The cervical cytology screening brush is turned about 6 times clockwise to pick up cells.
Women aged 25-65 are invited for screening. That is inclusive of those that have been vaccinated.
Age 25-50 = 3 yearly
Age 50-65 = five yearly
If smear report comes back and is borderline nuclear abnormality…
Staging of cervical cancer
Repeat in 6 months
I is confined to the cervix
II invades beyond it
III to pelvic wall, uterus or lower vagina
IV bladder, rectum or beyond the pelvis
High grade dyskaryosis found on cervical smear
Refer to colposcopy
High risk HPV in the cervix increases risk of …
CIN
HPV vaccination - Gardasil - targets high risk HPV….
HPV 6, 11, 16, 18
Risk factors to CIN or cancer
HPV infection
Smoking
Number of sexual partners
Low socioeconomic status
Describe colposcope (the follow up of abnormal cervical smear test)
Cervix visualised Washed with acetic acid Application of iodine Green light filter Abnormal area can be biopsed or treatment performed at the time or at a further appointment
Describe the relationship between HPV infection and the cervix
More than 99% of cervical carcinomas are associated with HPV infection.
Early genes E1 to E7 interact with intracellular molecules to interfere with cell proliferation machinery to replicate the virus.
Late genes L1, L2 encode capsid proteins. Disruption of cell cycle checkpoints may contribute to accumulation of oncogenic mutations and carcinogenesis
What histological change is seen with HPV
Low grade dyskaryosis and koilocytes
What type of lesions is picked up by cervical screening
Squamous lesions
Cervical cancer symptoms
Post coital bleeding Intermenstrual bleeding. Irregular vaginal bleeding Pain None
Invasive squamous carcinoma of the cervix almost always develops from…
pre-existing CIN, but not all CIN will become squamous cancer.
CIN II and CIN III are more likely to progress than CIN I
What features are seen on cytology with invasive squamous cell carcinoma?
Polymorphs
Low oestrogen after the menopause may lead to…
atrophic vaginitis - with discomfort, dyspareunia, and bleeding. Polyps and cysts are not uncommon.
E.g.s of infections identified in smears
Bacterial vaginosis, thrush (candida, yeast), and trichomonas vaginalis
What type of infection is always associated with intrauterine coil?
Actinomyces
What pathology/features are often seen in vulva
Skin tags, melanocyte nevi and benign cysts are common.
Candidiasis (thrush) is also common and may be associated with pregnancy or diabetes. Bartholin’s vestibular gland cysts may become infected with abscess formation.
Lichen planus and lichen sclerosus et atrophicus are both non-infective inflammations. Lichen sclerosus is especially associated with anogenital.
Vulva cancer - SCC associated with VIN
Occurs almost exclusively in females less than 60 y/o.
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.
Vulval cancer - SCC associated with dermatoses
Occur in an older age group - most over 60, many over 70.
Most of the cancers are well differentiated and keratinising.
Not associated with HPV infection or VIN
Adjacent squamous hyperplasia and/or lichen sclerosus common.
The vulva - 2 pathways to squamous cancer
Although the risk of malignancy in lichen sclerosus is geenrally low, in a minority of cases a subtle non-HPV related entity called ‘differentiated VIN’ may have a much greater risk of progression.
Unlike the cervix, in which almost all squamous cancer is HPV related, only about 20% of vulval cancer is thought to be HPV dependent.
Like cervical intraepithelial neoplasia (CIN), vulval HPV-associated intraepithelial neoplasia (VIN) may –> invasive squamous carcinoma. The squamous epithelium of the vagina and perianal skin may also be affected by pre-neoplastic field change.
