Week 4 Flashcards
Describe breast development
8 weeks in foetus
branches establish ductal structure
glandular tissue
at puberty the ducts elongate in females
Describe the glandular tissue of the breast
lobules and ducts are lined by characteristic epithelium with 2 layers - inner (luminal) and outer (myoepithelial)
What is the most common congenital breast abnormality?
ectopic breast tissue
in the “milk line”
What is breast hypoplasia associated with?
ulnar-mammary syndrome, Poland’s syndrome, Turner’s syndrome and congenital adrenal hyperplasia
Describe acute mastitis
cellulitis associated with breast feeding
skin fisturing may let bacteria in, and milk stasis favour their growth leading to infection of breast tissue
Describe granulomatous inflammation of the breast
rare
systemic diseases including arcoidosis
infections including TB
Describe idiopathic granulomatous mastitis
a lobule-cantered non-necrotising granulomatous inflammatory process with a tendency to recur after excision. It may respond to steroids
Describe foreign body reactions in the breast
around breast implants may lead to capsular contractions and reactions to silicon leakage after implant rupture
Describe recurrent subareolar abscesses
may be associated with maxillary fistula and is said to be associated with squamous metaplasia of lactiferous ducts, and smoking
Describe periductal mastitis/duct ectasia
dilation of central lactiferous ducts, peridcutal 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, It is commonest in middle age and associated with smoking
Describe breast fat necrosis
may follow trauma and is a benign process but biopsy may be required to rule out cancer
Describe fibrocystic change
the most frequent benign breast condition. it is so common that disease might not be appropriate. it tends to be multifocal and bilateral, and may cause breast tenderness and nodularity
Describe the spectrum of fibrocystic change
includes small and large cysts, increased amounts of glandular tissue, increased fibrous stroma, epithelial hyperplasia of usual type,
Describe scelrosing adenosis
a benign proliferation of distorted glandular tissue and stroma
micro calcifications may be observed on mammography and it may cause clinically suspicious mass.
What is apocrine metaplasia?
recognised by large. rounded epithelial cells with copious granular eosinpjilic cytoplasm and characteristic apical projections
very common in fibrocystic change and is not an increased cancer risk
Describe atypical ductal hyperplasia
is characteristically monotonous and has features in common with low grade ductal carcinoma in situ. it is associated with microcalcifiations
Describe lobular neoplasia
includes atypical lobular hyperplasia and lobular carcinoma in situ. The difference between ALH and LCIS is the extent and amount of cellular proliferation.
both are markers of increased cancer risk
Describe columnar cell lesions
have been more recognised with the introduction of mammography breast screening. Columnar cell change and hyperplasia are both recognised, without and with atypic. Atypia may be a marker of risk and if identified in a needle core biopou, excision biopsy of the area may be needed to exclude in situ or invasive malignancy
Describe radial scars
benign lesions characterised by fibrotic and elastotic core, trapped glands and pseudo-infiltrate appearance
look like small cancers on mammography
Describe introduction papilloma
a benign tumour of the epithelium lining of the mammary ducts
solitary papillomas are thought to be innocuous if there is no epithelial atypia
Describe papillomatosis
Multiple papillomas
thought to be slightly more likely to be associated with malignancy elsewhere in the same or even contralateral breast
Describe diabetic mastropathy
there is stroll fibrosis with infiltrating lymphocytes. type 1 diabetes and may be clinically suspicious of carcinoma
Describe pseudo-angiomatous stromal hyperplasia
PASH
a proliferation of myofibroblasts may cause a mass.
biopsy required to exclude malignacy
Describe fibroadenomas in breast
very common
overgrowth of epithelium and stroma, resembling a giant lobule
benign neoplasm, hormone sensitive and regress after menopause.
usually firm, non-tender m mobile
Describe phyllodes tumour
closest to FA but there is a spectrum of behaviours and there is a tendency to local recurrence and at the other extreme are unequivocally malignant tumours. Require surgical excisions with a margin of normal breast tissue
Describe pure adenomas
lack the prominent stromal element of FA.
Describe nipple adenoma
benign but can mimic page’s disease
Describe hamartoma of breast
discrete smooth painless mass of glandular, fatty and fibrous connective tissue. Benign
what are the risk factors for breast cancer?
earlier menarche, later menopause being older at first pregnancy OC use HRT tallness denser breast tissue on mammography alcohol positive family history
What are the symptoms of a possible breast cancer?
a new lump or thickening in breast or axilla
altered shape, size, feel of the breast
skin changes - puckering, dimpling, peau d’orange , rash, redness, feels differnet
nipple changes
rarely can be widespread inflammation
Describe the importance of steroid hormone receptors in breast cancer
overexpression of oestrogen receptor and progesterone receptor.
ER/PR postive carcinomas are likely to respond to endocrine treatment -
Describe tamxifen
ER antagonist is breast
ER agonist in endometrium and bone
Describe aromatase inhibitors
in post menopausal women oestrogen stimulation of tumour growth may be prevented by aromatase inhibits which prevent the conversion of adrenal androgens to oestrogen in a process that normally occurs in adipose tissue
Describe Her2 positive breast cancers
cancers which overexposes Her2 have a worse prognosis than others but treatment with monoclonal antibody Trastuzumab (perception) and other Her2 targeted therapies has improved the situation
How are breast cancers graded?
1) nucelar pleomorphism
2) number of mitoses per mm squared
3) degree of gland formation by cancer cells
Describe carcinoma in situ
so called “DCIS and LCIS” are still recognised in the terminology of breast pathology . the correspondingly less abnormal atypical ductal hyperplasia and atypical lobular neoplasia are roughly equivalent to low grade dysplasia
malignant looking proliferation of epithelial cells within basement membrane
no extension into breast stroma
no possibility of metastases
Describe the distinction between IDC and ILC
morphological
in iLC there is sometimes widespread invasion of dicohesive malignant cells often in single files and whorls around pre-existing parenchyma; also multifocality and possibly hilarity
these features are related to the loss of E-cadherin
Describe basal-like carcinomas
express genes associated with basal/myoepithlial cells of the breast
tend to be aggressive
overlap with the cancers that occur in BRCA 1 mutation carriers
What causes a foetus to develop as male?
SRY from the y chromosome
Where do the gonads arise from?
the embryonic urogenital ridges
Where do the genital ducts arise from?
the paired mesonephric and paramesonephric ducts
What do the leydig cells produce?
testosterone
stimauts the development of the mesonephtic duct structures.
dihydrotestosterone promotes the development of prostate, penis and scrotum
What do the sertoli cells produce?
anti-mullerian hormone
induces the regression of the paramesonephric ducts
What do the mesonephric ducts become?
rete testes, efferent ducts, epididymis, trigone of the bladder
What does the urogenital sinus form in males?
bladder (apart from trigone) prostate gland, bulbourethral gland, urethra
What do the gonads develop into in the female?
an ovary with oogonia and stromal cells
What do the paramesonephric ducts give rise to?
the oviducts, uterus, cervix, and upper 1/3 of vagina
What does the urogenital sinus form in females?
bulbourethral glands and lower 2/3 of vagina and vestibule
Describe the histology of the fallopian tube
lined by ciliated columnar epithelium
complex picae
layers of smooth muscle
peritoneum
What is salpingitis?
part of the spectrum of pelvic inflammatory disease
most commonly infections
mainly bacterial
usually ascending infection
TB is uncommon
fever, lower abdominal or pelvic pain and pelvic masses
What are the complications of salpingitis?
adherence of tube to ovary
tubo-ovarian abscess
adhesions involving tubal place increase risk of ectopic pregnancy; damage or obstruction of tube lumen ay produce infertility
Can be involved in endometriosis
What is the most common cause of tubal malignancies?
papillary serous carcinoma
Describe polycystic ovaries (stein-leventhal syndrome)
oligomennorhea hirsutism infertility obesity - usually after menarche over-production of androgens by multiple cystic follicles in ovaries LH high FSH low
What is seen in PCOS?
enlarged ovaries
multiple subcortical cysts 5-15mm in diameter
thicked, fibrotic outer surface
over cysts lined by granulosa cells with hypertrophic and hyperplastic leutinized theca interna
absence of corpora lutea and corpora albicantes (ovulation not occurring) insulin resistance may lead to type II diabetes
What are the three cell types that can develop into ovarian cancer?
surface (coelomic) epithelium
germ cells
sex cord / stromal cells - granulosa and theca cells
What are the risk factors for epithelial ovarian cancers?
nulliparity and family history
What are common mutations in sporadic ovarian cancer?
BRCA
HER2
KRAS
p53
Describe the borderline category of surface epithelial tumours in the ovary
tumours of low malignancy potential, much better prognosis than overtly malignant carcinomas
What are the types of of malignant epithelial tumours of the ovary?
cystadenocarcinpmas or adenocarcinomas
What are the categories of ovarian carcinomas?
High grade serous endometroid clear cell low grade serous mutinous
Describe an ovarian endometrioma
presence of endometrium tissue outside of the endometrial cavity
problems occur when menstrual changes occur in tissue but blood can not go anywhere - causes accumulation of blood
What mutations are likely in HGSC?
p53 and BRCA1
What mutations are common in LGSC?
KRAS and BRA
What are psammoma bodies?
concentrically laminated calcified concentrations common in the papillae of serous tumours in general
Describe the appearance of borderline serous tumours
more complex architecture
mild cytologic atypia but no stromal invasion
peritoneal implants may be present
What are Krukenberg tumours?
metastases to the ovary for the GI tract
can mimic primary ovarian mucinous carcinoma,as
large unilateral tumours are more likely to be primary
Describe the morphology of mucinous ovarian tumours
large, multlocular, no psammoma bodies
cysts lined by cells with abundant mucinous cytoplasm
Describe mature cystic teratomas
totipotent germ cells differentiate into mature tissues of all 3 germ cell layers: ectoderm (skin, hair, teeth), endoderm (GI, respiratory tract) mesoderm (fat, muscle(
Describe granulosa cell tumours
usually occur in post-menopausal women
oestrogen over production may lead to endometrial hyperplasia or endometrial carcinomas
What is Meig’s syndrome?
the combination of ovarian fibroma with ascites and pleural effusion
What are Brenner tumours?
uncommon mixed surface epithelial-stomal tumours. usually benign, unilateral, size variable, solid, circumscribed, yellowish,
often found incidentally
histologically nests of transitional epithelial cells with longitudinal nuclear grooves and abundant fibrous stroma
Describe the normal uterus
flat triangular cavity
resistant to infection due to natural drainage, cycles and endocervix
What can cause infection in the uterus?
canal blockage
tumour or foreign materiall (I.U.D)
Describe what happens in the endometrium
follicular phase of the menstrual cycle, FSH stimulates proliferation of granulosa cells, follicular antralization and ovulation is stimulated by mid-cycle LH surge
the granulosa cells secrete oestrogen which stimulates the growth of the endometrium
the post-ovulatory follicle transforms into the corpus lute which secretes progesterone and transforms the endometrium into its secretory phase
What happens to the corpus lute?
it involutes after 14 days and with decreasing progesterone levels the endometrium falls apart and is shed except basal endometrium which remains
if implantation occurs the corpus lute persists and is maintained by placental hCG
What happens to the endometrium after menopause?
it ceases to cycle and becomes atrophic, with only its basal part persisitng
What can be a consequence of high oestrogen levels after menopause and how does this occur?
peripheral aromatisation of adrenal androgens may stimulate some endometrial proliferation and may cause bleeding associated with endometrial polyps or withdrawal bleeding
Why is peripheral oestrogen production associated with obesity?
adipose tissue contains aromatase enzymes
What situations can lead to over-stimulation of the endometrium by excess oestrogen?
obesity
PCOS
oestrogen secreting (ovarian) tumours
anovulatory cycles, tamoxifen and some forms of HRT
What is dysfunctional uterine bleeding?
irregularity of menstruation unrelated to an anatomical cause
includes intramenstrual bleeding and menorrhagia
anovulatory cycles, irregularity established secretory change in the endometrium, and irregular menstrual shredding may all contribute
What are endometrial polyps?
common, usually benign
they may bleed
they are composed of endometrial glands around a fibrocartilage-vascular core
Describe endometrial hyperplasia
may be simple, complex or atypical
a risk factor for endometrial carcinoma
may be associated with persistent oestrogen stimulation
What is the other name for an endometrial carcinosarcoma?
malignant mixed mullein tumour (MMMT)
How are low risk endometrial tumours treated?
saplpingo-oophorectomy
How are high risk endometrial tumours treated?
may require lymphadenectomy
adjutant radiotherapy and chemotherapy
Describe fibroids
leiomyomas
extrememly common
often multiple
benign but may cause symptoms
smooth muscle of the uterus is responsive to oestrogen
more active during the reproductive years
Describe leiomyosarcoma
commonest malignant non-epithelial tumour in the uterus
softer mass, less well circumscribed outsline
haemorrhage, necrosis
much more abnormal histology
vascular invasion - spreads via bloodstream to lungs, long term prognosis is poor
What is an adenomyosis?
basal endometrium extends abnormally into the hyper plastic myometrium
may co-occur with endometriosis
What is endometriosis?
the presence of endometrial glands and stroma outside the body of the uterus, most commonly involving the ovaries, tubes and other pelvic sites including the pouch of douglas
What is gestational trophoblastic disease?
a group of conditions characterised by excessive proliferation of trophoblast
How are complete moles formed?
unispermic fertilisation of an empty egg followed by endereduplication or disperjic fertilisation of an empty egg
How is a partial mole formed?
when a haploid egg is fertilised by one sperm which reduplicated itself or two sperm
Describe molar gestation
no foetus
can become invasive or malignancy - choriocarcinomas
What is monitored after a molar gestation?
hCG levels since it implies persistent trophoblastic disease
Describe the cervix prior to puberty
the ectocervix is covered by non-keratinising stratified squamous epithelium and the endocervix is lined by columnar (glandular) epithelium
What happens to the cervix at puberty?
the squamous-columnar junction is everted into the vagina and the columnar epithelium adapts to vaginal environment by squamous metaplasia in the transformation some
What is CIN
cervical intraepithelial neoplasia
there is a replacement of normal squamous epithelium by neoplastic squamous cells
the basement membrane remains intact
What are the features of the neoplastic cells in CIN?
abnormally intense staining (hyperchromasia), greater variability (pleomorphism) and tail to mature normally as they migrate from the base of the epithelium to its surface
What do the early genes in HPV do?
interact with intracellular molecules to interfere with cell proliferation machinery to replicate the virus
What do the late genes of HPV do?
encode capsid proteins
disruption of cell cycle checkpoints may contribute to accumulation of oncogenic mutations and carcinogenesis
What effect does HPV have on cervical squamous cells even without dysplasia?
forms kilobytes
What are the high risk strains of HPV?
16 and 18
In cervical screening , what finding will suggest that a colposcopy is needed?
dyskaryosis
What is the treatment of CIN?
loop excision of the transformation zone (LETZ)
What are the risk factors for squamous carcinoma of the cervix?
early age at first intercourse, number of sexual partners, low socioeconomic status and HPV infection
Why are post coital bleeds a common presentation of cervical cancer?
exophytic, ulcerating masses protrude into the vagina and ulceration
What are the special characteristics of cancer cells?
uncontrolled proliferation
loss of original function (anaplasia)
invasiveness
metastasis
What are the general toxic effects of chemotherapy?
bone marrow suppression loss of hair damage to gastro-intestinal epithelium liver, heart, kidney in children depression of growth sterility teratogenicity
What sort of drugs are actively dividing cells sensitive to?
cell-cycle specific drugs
What do solid tumours consist of?
dividing cells - progressing through cell cycle
resting cells - not dividing but could do so
cell which can no longer divide but contribute to tumour size
What are the main classes of chemotherapy drugs?
alkylating agents antimetabolites cytotoxic antibiotics microtubule inhibitors steroid hormones and antagonists
Describe alkylating agents
form covalent bonds with DNA
interfere with both transcription and replication
most have two reactive groups
allow the drug to crosslink - within one strand of DNA, across the two strands of DNA
Describe nitrogen mustards
derived from mustard gases of world war 1
melphalin, chlorambucil, cyclophosphamide, ifosfamide
cisplatin
temozolomide
lomustine - cam penetrate brain
busulphhan - selective for bona marrow
Describe mechlorethamine
first chemo drug
blister agent
used to treat lymphoma
highly reactive, must be given IV
Describe melphalin
fusion of mechloroethamine with phenylalanine
originally designed to treat melanoma but did not work
much more stable, less aggressive
oral drug
used to treat multiple myeloma,, ovarian and breast cancer
Describe cyclophosphamide
Prodrug that requires activation by phosphoradmidase
(specific in situ activation did not work)
activated in the liver
much less toxic
ALDH protects against toxicity of the drug
ALDH is present in bone marrow cells, hepatocytes and intestinal epithelium
used to treat many cancers
Describe cisplatin
Peyrone’s salt
platinum electrodes reacted with ammonia produced by bacteria to produce cisplatin
targets N7 of purine nucleotides
resistance from nucleotide excision repair mechanisms
efflux transporters for copper
What do antimetabolites do?
interfere with nucleotide synthesis or DNA synthesis
Give examples of antifolates
methotrexate
ralitrexed
pemetrexed
give examples of nucleotide analogues
5-flurouracil cytarabine gemcitabine fludarabine capecitabine
Describe methotrexate
higher affinity for dihydrofolate reductase than folic aicd
inhibition of dihydrofolate formation
inhibition of purine/pyridimine nucleotide synthesis
ultimately, halt DNA and RNA synthesis
Describe fluro-uracil
prevents thymidine formation
stops DNA synthesis
Describe mercaptopurines
converted into false nucleotides
disrupts purine nucleotide synthesis
may be incorporated into DNA, disrupting helix
Why are antimetabolites not used as anti-parasitic drugs despite them having potential to be effective
toxicity is less acceptable in infectious disease than in cancer
Describe bytarabine
sugar moiety of cytidine is arabinosine rather than ribose
isolate from the sponge cryptotheya crypto
cellular activation to ara-CTP
inhibits DNA polymerase
incorporation into DNA causes chain termination
How do cytotoxic antibiotics work?
a direct action on DNA as intercalates
Describe dactinomycin
isolated from streptomyces
inverts into the minor groove of DNA helix
RNA polymerase función is disrupted
Describe doxorubicin
also from streptomyces inserts itself between base pairs bines to the sugar phosphate DNA backbone local uncoiling impaired DNA and RNA synthesis
vincristine
microtubule inhibitor no oral absorption bind to micro tubular protein block tubular polymerisation block normal spindle formation disrupt cell division
Describe steroid hormones in cancer treatment
hormones are key regulators of physiological functions including growth
tumour may be responsive to a specific hormone which makes it regress
Describe prednisone
synthetic adrenocortical steroid hormone
converted to active form in the body
prednisalone suppresses lymphocyte growth
How can prostate cancers be treated with hormone antagonists?
most are dependent on testosterone
treatment could be testosterone receptor antagonists - bicalutamide (casodex)
pituitary downregulators _LHRH agonists
inhibit the release of LH
LH normally stimulates testes to produce testosterone
