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.
The endometrial cavity, linings of the fallopian tubes and peritoneal covering of all of the gynaecological organs are derived from…
the coelomic lining
Abnormalities of the uterus are related to abnormalities in…
the fusion of the mullerian (paramesonephric) ducts
e.g. dysmorphic uterus, bicorporeal uterus
Basic histology of the uterus
Endometrium - consists of glands and stroma and has a variety of normal appearances depending on the phase of the menstrual cycle, menopausal status etc.
Myometrium - smooth muscle comprising much of the uterus
Endometriosis
The presence of endometrial tissue outside of the uterus.
Sites of endometriosus: ovaries peritoneal surfaces (including uterine ligaments and rectouterine septum), large and small bowel, appendix, mucosa of cervix, vagina and fallopian tubes, laparotomy scars…
Adenomyosis
the presence of endometrial tissue within the myometrium.
Clinical symptoms of endometriosis and adenomyosis
Dysmenorrhoea, pelvic pain, infertility
Pathogenesis of endometriosis and adenomyosis
Diagnosis and treatment of endometriosis
The metastatic theory - retrograde menstruation or surgical procedures introduce endometrium to sites outwith the uterine cavity.
The metaaplastic theory - endometrium arises directly from the coelomic epithelium (i.e. peritoneum) of the pelvis, as this is where endometrium originates from during embryological development
Diagnosis = laparoscopy
Treatment = Hormonal therapy (OCP) and analgesia
Describe endometrial polyps
Exophytic masses of variable size which project into the endometrial cavity.
Associated with tamoxifen in some cases.
Can present with abnormal bleeding.
Can be treated via hysteroscope in outpatient clinic.
Micrscopy shows haphazardly arranged glands with preservation of a low gland to stroma ration.
There are often thick walled blood vessels and fibrous stroma.
The glands are usually inactive, but can also show proliferation, secretory changes or metaplasia.
Occasionally cytological atypia or frank adenocarcinoma can be found in polyps.
Describe endometrial hyperplasia and adenocarcinoma - causes and symptoms
These are both associated with prolonged oestrogenic 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
Symptoms: usually postmenopausal bleeding.
Endometrial hyperplasia and adenocarcinoma - characteristics and management
Endometrial hyperplasia is histologically characterised by an increase in the gland to stroma ratio. Can be seen with or without cytological atypica.
Atypical endometrial hyperplasia is a precurosr of endmetrioid adenocarcinoma
Management:
Hyperplasia - progesterone therapy such as Mirena IUS, or hysterectomy.
Endometrial adenocarcinoma - hysterectomy, with subsequent management depending on tumour grade and stage
Leiomyoma - symptoms
Benign smooth muscle tumour of the myometrium.
Very common - mostly seen in women of reproductive age.
Symptoms - asymptomatic, abnormal bleeding, urinary frequency if large, impaired fertility
Leiomyoma - pathology and management
Pathology - sharply demarcated round grey-white tumours with a whorled cut surface, very variable in size.
Microscopically resemble normal smooth muscle
Management - varies depedning on number, size and symptoms.
Medical - progesterone secreting IUS, hormonal therapies, tranexamic acid, GnRH agonists
Surgical - uterine artery embolisation, myomectomy, hysterectomy
Describe leiomyosarcoma
Uncommon malignant smooth muscle tumour of the myometrium.
Peak incidence age 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
Micro - overt cytological atypia, necrosis, mitotic activity, infiltrative margin.
Prgnosis - spread to lungs, liver and brain, 40% 5 year survival
Describe endometrial stromal sarcoma (ESS)
rative ‘worm like’ growth pattern macroscopically (and microscopically)
A rare group of tumours of the endometrial stroma
Rare
Can be low grade (more common) or high grade (rare).
Both have diffusely infiltrative ‘worm like’ growth pattern.
Micrscopy - low grade tumour cells resemble cells of proliferating endometrial stroma, with mitoses.
Prognosis: recurrence of metastasis can occur many years after primary tumour and is not predictable
Gestational trophoblastic disease…
& molar pregnancies
is an umbrella term for several conditions including hydatidiform moles (parital and incomplete) and frankly malignant tumours including chroiocarcinoma.
Hydatidiform moles present with either spontaneous miscarriage or abnormalities detectd on ultrasound.
Partial mole: fertilisation of one egg by 2 sperm, resulting in a triploid karyotype. Micrscopy shows oedematous villi and subtle trophoclast proliferation. There is a risk of invasive mole, which invades and destroys the uterus.
Gestational pathology - 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 markedly enlarged oedematous villi with central cisterns and circumferential trophoblast proliferation.
Carries a mall risk of invasive mole and an even smaller risk of choriocarcinoma (which is malignant, rapidly invasive and metastases widely, but is treatable with chemotherapy)
Special characteristics of cancer cells
Uncontrolled proliferation
Loss of original function (anaplasia)
Invasiveness
Metastasis (malignant cells)
3 forms of treatment available for cancer therapy
Surgical removal - only for solid tumours, dependent on location, only if non-metastasised
Irradiation - only if localised
Chemotherapy with anticancer drugs - often only treatment available, selective toxicity required
What are the 2 main categories of genetic change in cancer cells
Inactivation of tumour suppressor genes
Activation of proto-oncogenes to oncogenes
General toxic effects of chemotherapy
Bone marrow suppression - anaemia, immune depression, prone to infection, impaired wound healing. Loss of function. Damage to gastro-intestinal epithelium. Liver, heart, kidney. In children - depression of growth. Sterility. Teratogenicity (damage to embryo)
Solid tumours consist of
Diving cells - sensitive to cell cycle specific drugs
Resting cells - insensitive to many drugs, cause many relapses.
Cells which can no longer divide but contribute to tumour size - not a problem
Name the 5 main classes of drugs fro cancer chemotherapy
Alkylating agens (act directly on DNA) Antimetabolites (prevent or changes DNA synthesis) Cytotoxic antibiotics Microtubule inhibitors Steroid hormones and antagonists
Describe action of alkylating agents
Form covalent bonds with DNA (cross links it)
Interfere with both transcription and replication
Most alkylating agents have 2 reactive groups.
Allow the drug to cross-link:
- within one stand of DNA
- across the 2 strands of DNA
Name examples of alkylating agents
Nitrogen mustards (Melphalan, chlorambucil, cyclophosphamide, ifosfamide)
Cysplatin
Temozolomide
Lomustine (can penetrate brain)
Busulphan (‘selective’ effect on bone marrow
Describe the nitrogen mustard mechlorethamine
First anticancer chemotherapy drug
Used to treat Hodgkins lymphoma, non-hodgkins lymphoma
Highly reactive: must be given iv
Describe the nitrogen mustard melphalan
Fusion of Mechlorethamine with phenylalanine.
Phenylalanine is a precursor for melanin.
Melphalan might accumulate specifically in melanomas
Oral drug
Used to treat multiple myeloma, ovarian and breast cancer.
Describe the nitrogen mustard cyclophosphamide
A prodrug that requires activation by phosphoramidase
High phosphoramidase activity in some tumours.
Aldehyde dehyrdogenase (ALDH) protects against the toxicity of this drug.
ALDHS are present in large concentrations in bone marrow cells, hepatocytes and intestinal epithelium.
Used to treat many cancers.
Describe features of Cisplatin - a chemotherapy agent
Like other DNA cross-linkers it targets N7 of purine nucleotides.
Describe antimetabolites - a chemotherapy agent
Antimetabolites interfere with nucleotide synthesis or DNA synthesis. Nucleotide synthesis: antifolates (methotrexate, ralitrexed, pemetrexed) Nucleotide analogues (5-fluorouracil, cytarabine)
Folate antagonists: Methotrexate - halt to DNA and RNA synthesis
Pyrimidine analogues: FLuoro-uracil (prevents thymidine formation; stops DNA synthesis)
Purine analogues: Mercaptopurines (disrupts purine nucleotide synthesis, disrupts helix of DNA)
Nucleotide analogues:
Cytarabine - Inhibits RNA Polymerase
Describe cytotoxic antibiotics - a chemotherapy agent
Act mainly by a direct action of DNA as intercalators
Dactinomycin - Isolated from Streptomyces; inserts itself into the minor groove in the DNA helix; RNA polymerase funciton is disrupted)
Doxorubicin - Also from Streptomyces; Inserts itself in between base pairs; Binds to the sugar-phosphate DNA backbone; Local uncoiling; Impaired DNA and RNa synthesis
Vinca alkaloids (Vincristine) - Is a microtubule inhibitors; isolated from Madagascar periwikles; No oral absorption; Bind to microtubular protein; Block tubulin polymerisation; Blocks normal spindle formation; Disrupts cell division
Describe steroid hormones - a chemotherapy agent
Prednisone - synthetic adrenocortical steroid hormone; Converted in the body to active form:
Prednisolone - suppresses lymphocyte growth
Describe hormone antagonists - a chemotherapy agent
Tamoxifen - Agonist of oestrogen receptor
Treatment of prostate cancer
Most prostate cancers are dependent on testosterone.
Treatment could be testosterone receptor antagonists - e.g. Flutamide (Drogenil); Now replaced by Bicalutamide (Casodex).
Pituitary downregulators - LHRH agonists (e.g. Prostap); inhibits release of LH; LH normally stimulates testes to produce testosterone.
Common conditions of the ovaries
Cysts
Polycystic ovaries syndrome
Tumours - benign and malignant
Torsion
Common symptoms with problems of the ovary
menstrual irregularities Pain Hirsuitism/Metabolic syndrome (PCOS) Asymptomatic Bloated abdomen (ascites)
Examining the ovaries
Physical examination - normal (ascites)
Serology: CA 125
Ultrasound (can see cysts (e.g. dermoid cyst)) tumours)
CT - pelvic masses, ascites, peritoneal disease
Common conditions in fallopian tube
Tubo-ovarian abscess - pelvic pain, WCC/CRP inc., temperature, discharge
Ectopic pregnancy - pain, missed peroid, bHCG inc., circulatory collapse
Name common conditions in uterus
Uterine fibroids
Endometriosis
Uterine cancer
Symptoms of uterine fibroid
Heavy periods, pain, pressure, anaemia in woman of child bearing age
Symptoms of endometriosis
Progressively painful periods, dyspareunia, pain with bowel movements, abdominal pain
Rx: hormal therapy and analgesia
Diagnosis: Laparoscopy
Symptoms of uterine (endometrial) cancer
Post menopausal bleeding/abnormal bleeding, pain
Conditions of the vagina
Bartholin cyst
Vaginal cancer
What is the 1st test for recognising tumours of the female genital tract
Ultrasound
Glandular tissue 9lobules) and ducts of the breast are lined by a characteristic epithelium with 2 layers
inner (luminal) and outer (myoepithelial)
Benign conditions of the breast include
developmental and inflammatory conditions, fibrocytic change, stroma-only changes, and benign neoplasms
Developmental abnormalities of breast
Ectopic (heterotopic) breast tissue is the commonest congenital breast abnormality, most often on ‘milk line’ between axilla and groin, occasionally elsewhere.
Breast hypoplasia is associated with ulnar-mammary syndrome, Poland’s syndrome, Tuner’s syndrome, and congenital adrenal hyperplasia.
Macromastia
Stromal overgrowth leading to excessive breast size (macromastia) occasionally begins at puberty (juvenile hypertrophy) or during pregnancy (gestational hypertrophy) and may be difficult to manage
Nipple inversion…
is common and usually normal. But new inversion of nipple not previously inverted may be a sign of benign or malignant disease
Acute (puerperal, lactational) 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. Abscesses may require incision and drainage
Granulomatous inflammation of the breast tissue…
can occur in systemic diseases including sarcoidosis, and infections including tuberculosis (rare)
Idiopathic granulomatous mastitis…
is a lobule-centered non-necrotising granulomatous inflammatory process with a tendency to recurrence after excision. It may respond to steroids (infectious causes must be excluded)
Foreign body reactions around breast implants may lead to…
capsular contractures 9causing discomfort and distortion of the breast) and reactions to silicone leakage after implant rupture
Recurrent subareolar abscesses may be associated with…
mamillary fistular and is said to be associated with squamous metaplasia of lactiferous ducts, and smoking
In periductal mastitis/duct ectasia there is a dilation of…
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 a mammogram. It is cimmonest in middle age and associated with smoking.
Fat necrosis (of breast) may follow…
trauma and is a benign process but biopsy may be required to rule out cancer
What is the most frequent benign breast condition?
Fibrocystic change - tends to be multifocal and bilateral, and may cause breast tenderness and nodularity. Is very common.
Fibrocystic change includes small and large cysts, increased amounts of glandular tissue (‘adenosis’), inc. fibrous stroma, epithelial hyperplasia with or without atypia.
Solitary papillomas, papillomatosis and radial scars are also part of the wider spectrum of fibrocystic change..
Fibrocystic change is classified as ‘non proliferative’, ‘proliferative without atypia’ and ‘proliferative with atypia’
Adenosis =
Sclerosinf adenosis
an increase in glandular breast tissue
is a benign prolfieration of distorted gandular tissue and stroma
What is an example of a proliferative variant of fibrocystic change
Microcalcifications
Apocrine metapladia is recognised by…
large, round epithelial cells with copious, granular eosinophilic cytoplasm and characteristic apical projections. It is very common in fibrocystic chnage 9of breast) and is not though to increase cancer risk.
Atypical ductal hyperplasia (ADH) is characteristically….
monotonous and has features in common with low grade ductal carcinoma in situ (DCIS).
It is associated with microcalcifications
Lobular neoplasia includes 2 subtypes…
atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS)
The difference is of extent and amount of cellular proliferation.
Both are markers of increased cancer risk (ALH x ~4; LCIS x ~10)
Columnar cell lesions (of breast) are often associated with…
microcalcifications.
Columnar cell change and columnar cell hyperplasia are both recognised, without and with atypia
Radial scars are…
benign lesions characterised by a fibrotic and elastotic core, trapped glands and a pseudo-infiltrative appearance.
Atypical proliferations be present. On mammography these lesions can look like small cancers, and may need to be excised to rule out cancer
Intraduct papilloma and papillomatosis
Intraduct papilloma is a benign tumour of the epithelium lining the mamory ducts. Solitary central papillomas are thought to be innocuous if there is no epithelial atypia. Multiple papillomas (papillomatosis) are thought to be slightly more likely to be associated with malignancy elsewhere in the same or even the contralateral breast.
In diabetic fibrous mastopathy there is stromal
stromal fibrosis with infiltrating lymphocytes. It is associated with type 1 diabetes and may be clinically suspicious of carcinoma, It usually occurs in women but sometimes in men
in pseudo-angiomatous stromal hyperplasia (PASH) a proliferation of…
myofibroblasts may cause a mass and may require biopsy to exclude malignancy. Cause is known.
Benign neoplasms in breast tissue.
Most common in young people?
Symtpomatic fibroadenomas are commonest in young women (teens-30s).
juvenile fibroadenoma is a related entity in girls <18 years of age and often large.
Characteristically fibroadenomas are a proliferation of epithelium and mesenchyme.
Phyllodes tumour
Phyllodes tumour is a rare benign lesion of the breasts, accounting for less than 1% of neoplasms.
It is a fibroepithelial tumour composed of an epithelial and a cellular stromal component.
Can be benign, borderline or malignant, depending on it histological features: - Stromal cellularity, infiltration at tumour edge, mitotic activity, necrosis.
If malignant treated as a sarcoma
Phyllodes tumours (unlike fibroadenomas) do require surgical excision, with a margin of normal breast tissue.
Phyllodes tumour are like fibroadenoma but have more cellular stroma
Difference between pure adenomas and fibroadenomas
Pure adenomas lack the prominent stromal element of fibroadenomas
Nipple adenomas is benign but can mimic…
Paget’s disease of the nipple (which is manlignant).
Uncommon
Biopsy may be needed to exclude malignancy
Hamartoma of breast
Uncommon
Forms a discrete smooth painless mass of glandular, fatty and fibrous connective tissue.
Benign
usually identified on mammography
Benign granular cell tumours occur…
very occasionally in breast
List 3 routes by which cervical cancer may spread and which organs or structures may be affected in each case
Transcolemic - affects peritoneum, rectum, bladder, GI
Direct Invasion (Extension) - affects ureter, kidney, bladder, rectum, vagina, ovaries
Lymphatics (para-aortic and plevic lymph nodes) - affects bladder, kidney, lungs, bone (via blood)
Blood
Breast anatomy
Breasts are mammary glands, producing and secreting milk in order to feed.
Made of subcutaneous fat which covers and envelopes a network of ducts that converge to nipple
They stretch from 2nd to 6th rib over the pectoralis major muscles
Made up of adipose and glandular tissue:
- There are 12-20 lobes in each breast parenchyma
- Lobules are located within lobes –> cluster of acini/alveoli
- Acini/alveoli ductules produce and store milk
- Ductule leads to terminal ducts which lead to lactiferous ducts.
- Nipple expulses milk when suckled.
- Areolar surrounds nipple, containing Montgomery’s glands which secrete oily fluid for lubrication
Suspensory Cooper’s ligaments support the position and shape of the breast which secrete oily fluid for lubrication.
Give an account of key events, process and effects including the effects of puberty, pregnancy, the menstrual cycle, lactation and menopause on the female breast
At puberty, oestrogen and growth hormones cause breast development (thelarche). Males produce less oestrogens and more androgens, preventing breast tissue development
- Breast develop from the nipple through the breast bud
- The ducts elongate and the stroma develops due to oestrogen
Pregnancy enhances breast development
Name beningn breast conditions
Granulomatous Masititis Pseudo-angiomatous Stromal Hyperplasia (PASH) Papillary lesions Duct ectasia Fibroadenoma Phyllodes tumour Diabetic Mastopathy (traumatiC) Fat necrosis Breast Abscess
DEscribe granulomatous mastitis
A benign breast condition.
This is a distinct hard mass, often assoicated with recent lactation and occassional hyperprolactinaemia.
It results in granulomatous inflammation of lobules, potentially developing an abscess and sinus formation
Can be caused by TB, sarcoid, cat scratch disease, vasculitis or carcinomas.
Can resolve spontaneously, otherwise treat with NSAIDs and steroids
DEscribe Pseudo-angiomatous Stromal Hyperplasia (PASH)
A benign breast condition
This is a hard palpable lump which usually occurs pre-menopausal
Well circumscribed pseudo-encapsulated mass, clearly visible on imaging
Requires dense stroma with anastomosing channels linked by myofibroblasts
Can cause rapidly enlarging mass with skin changes
DEscribe papillary lesions
A benign breast condition
These result in nipple discharge
The mass is often centralised with microcalcification, requiring core biopsy to identify, and excision of mass
Examples include papilloma (in nipple)
Describe duct ectasia
A benign breast condition
This is a condition where the lacteriferous duct becomes blocked
it is most common cause of green discharge from the nipple
Usually painful and can often be misdiagnosed as breast cancer, especially due to its strong association with smoking
Can result in mammary duct fistula, dilated ducts and chronic inflammation
Describe fibrodenoma
A benign breast condition
This is a benign lesion of the stroma and epithelium
Usually appears in young women (20-30)
Presents as discrete mobile lump with well-defined rounded opacity on scan
Describe Diabetic Mastopathy
This is an ill-defined hard mass, usually occurring in women younger than 30
It presents as a dense keloid-like stroma and is thought to have an autoimmune process through perilobular and vascular lymphocytes
Describe (traumatic) fat necrosis
A benign breast condition
This is where fatty tissue breaks down, undergoing necrosis which leaves residue, forming as hard mass
Appreciate the range and significance of alterations gathered under the headings ‘fibrocystic change’ and ‘benign proliferative breast disease’
Fibrocystic change:
This is a condition of the breast which commonly affects at least half of women at child-bearing age
It can be painful and is characterised by appearance of fibrous tissue and a lumpy, cobblestone texture within breast - fibrosis, cysts, apocrine change, epithelial hyperplasia, columnar cell change
Benign Proliferative Breast - increase risk of developing cancer
Name the common pathologies of the ovary
Endometriosis
PCOS
Stromal Hyperplasia
Adnexal torsion
Describe features of endometriosis
This is where parts of the endometrial tissue are found out with the uterus, in places such as:
Ovaries (endometrioma) –> chocolate cyst
Uterine ligaments
Recto-vaginal septum
Pelvic Peritoneum
appendix and colon
Scars within abdominal cavity
Will not affect post-menopausal women as they do not have much endometrial tissue remaining
Presents with dysmenorrhoea and pelvic pain
Can cause infertility due to inflammation and scarring, and also malignancy
Describe features of stromal hyperplasia within the ovary
This is similar ot PCOS but occurs in post-menopausal women
Presents similarly to PCOS but also with bilateral enlargement and increase instromal cellularity, resulting in increased oestrogen production
Describe features of Adnexal torsion within the ovaries
This is twisting of the ovaries, and sometimes the fallopian tube, occluding the ovarian artery, causing possible ischaemia.
Presents with sudden onset of sharpand usually unilateral lower abdominal pain, often accompanied with nausea and vomiting
Can use doppler US to diagnose but more often found in surgery
Can be surgically untwisted and possibly oophoropexy done to fixate ovary, preventing twisting again
Define sensitivity
Measures the proportion of actual positives that are correctly identified as such - The true positive rate
Define specificity
Measure the proportion of actual negatives that are correctly identified as such - The true negative rate
Prognosis scoring for breast cancer
Uses the Nottingham Scoring Index - determines prognosis following surgery.
Its calculated using 3 pathological features:
- the size of the lesion
- the number of involved lymph nodes
- the grade of the tumour
2-2.4 is best prognosis for 5 year survival
>5.4 is worst possible score
Symptoms of uterine fibroid
Heavy periods, pain, pressure, anaemia in women of child bearing age
