Gynaecological and Breast Pathology Flashcards
1
Q
What are the different types of Intraepithelial Neoplasia?
A
Most of these (below) driven by HPV (human papilloma virus);
• Vulval Intraepithelial Neoplasia- VIN
• Cervical Intraepithelial Neoplasia- CIN
• Cervical Glandular Intraepithelial Neoplasia- CGIN (in glandular epithelium)
• Vaginal Intraepithelail Neoplsia- VaIN
• Anal intraepithelial neoplasia-AIN (affects perianal
2
Q
What is Dysplasia?
A
- Dysplasia- subnormal growth of tissue/ organ (abnormal cells not yet gotten ability to invade so can’t spread)
- Earliest morphological manifestation of neoplasia (multistage process)
- In-situ disease- non-invasive; shows cytological features of malignancy, but no invasion
- No invasion= no metastasis= curable (take out the in-situ cancer)
- Recognising dysplasia gives us chance to treat potential tumour before it arises
- Elim abnormal cells removes basis cancer will develop- cervical screening programme basis
- Chromosomal abnormalities
- Increasing dysplasia, increasing cytological abnormalities
3
Q
What are Human Papillomaviruses?
A
- Double stranded DNA viruses
- 7.9kb circular genome
- 7 ‘early genes’ (involved in subverting cells replicative apparatus- replicate viral genome & integrate into host)
- 2 ‘late genes (package virion into struc- intact virions released & attack other cells)
- > 100 subtypes of HPV based on DNA sequence
- Diff types of HPV affect diff tissues e.g. HPV that causes skin warts diff to HPV causing genital warts
- Lifecycle linked to epithelial differentiation
- Genital HPVs grouped into low & high oncogenic risk of developing neoplasm
- High risk HPVs also involved in penile intraepithelial neoplasia, squamous cell carcinoma & subgroup of oral cell carcinomas (genital HPV types get into mouth)
- In most women HPV won’t cause long term harm, will be cleared by immune system
- Immunosuppression (due to disease/ iatrogenic) can lead to extensive & multifocal intraepithelial neoplasia in lower female genital tract (by uncontrolled HPV infec)
- Smoking important in cervical cancer aetiology; decreases antigen presenting cells in cervical epithelium & causes local immunosuppression (HPV can cause probs)
4
Q
What are low risk Human Papillomaviruses?
A
- BENIGN genital warts & other low-grade cytological abnormalities: 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73 & 81
- Subtypes 6 & 11 linked with genital warts (most common)
‘Low Risk’ HPV 6, 11
• Lower genital tract warts (condylomas= benign squamous neoplasms), low grade ‘IN’s
• Rarley malignant lesions
5
Q
What are high risk Human Papillomaviruses?
A
- High-risk subtypes associated with high-grade pre-invasive & invasive disease are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
- 99.7% of cervical cancers contain HPV DNA
- Types 16, 18 associated with 70% cervical cancers
- (HPV vaccine deals with 16 & 18 but as these only cause 70% cervical cancers vaccine will never eliminate HPV cervical cancer completely)
High Risk’ HPV 16, 18, (31, 33)
• High grade ‘IN’s & invasive carcinomas
6
Q
What are available vaccinations for HPV?
A
- ‘Gardasil’ (Merck) HPV 6, 11, 16, 18
- ‘Cervarix’ (MSK) HPV 16, 18
- Uk vaccination began Sept 2008 using Cervarix
- Age 12-13 with ‘catch-up’ up to 18
- Switch to Gardasil Sept 2012
7
Q
What is the Mode of Action of High Risk HPV?
A
• Early genes (expressed early in viral replication) expressed at onset of infec- control viral replication
• In oncogenic viruses, they’re involved in cell transformation
• Late genes- code caspid proteins
• High risk HPVs integrate into host chromosomes (difficult to get rid of)
• Upregulates E6, E7 viral protein (from early gene) expression
o E6 binds to & inactivates p53 (p53 mediates apoptosis in response to DNA damage)- genetic damage accumul
o E7 binds to RB1 gene product (RB1 is tumour suppressor gene, controls G1/S checkpoint in cell cycle)- dysregulation of cell proliferation
• (P53 recognises DNA damage & causes apoptosis to get rid of damaged DNA- E6 gets rid of this)
• (RB1 gene product- stops cell proliferation- E7 stops this)
8
Q
What is Vulval Intraepithelial Neoplasia?
A
- Varied clinical appearances of VIN
- From L to R; warty, white patches, pigmented patches, visualised by painting with toluidine blue
- Several diff clinical manifestations
9
Q
What are the two types of Pre-invasive stages of Vulval Intraepithelial Neoplasia?
A
Pre-invasive stage- 2 sorts with diff molecular pathology & pathogenesis;
• Classical/ warty/ baseloid
o Graded VIN 1-3
o Related to high risk HPV infec
o Younger people
• Differentiated VIN
o Not graded
o Not HPV related (diff to above disease)
o In chronic dermatoses (chronic inflamm skin disease) esp, lichen sclerosus
o Older people (70 onwards)
o Sep path to vulval cancer
10
Q
What is the Behaviour of Vulval Intraepithelial Neoplasia?
A
- 35-50% recur
- +ve margins predict recurrence
- Progression to invasive cancer in 4-7% treated women (reduced risk in treated) & up to 87% of those untreated
- Invasion more likley in postmenopausal/ immunocompromised
- Spontaneous regression may occur particularly in young, postpartum women (after had a baby)- e.g. immune modulation in pregnancy
11
Q
What is Vulval Squamous Cell Carcinoma?
A
- Most common vulval cancer (90%)
- Associated with VIN (age <60, assoc lower genital tract neoplasia (CIN), HPV +)
- Assocaited with inflaamtory dermatoses (age >70, Lichen sclerous, Lichen planus)
- Symptomatic lichen sclerosis 15% risk of malignancy
12
Q
What is Vulval Squamous Cell Carcinoma?
A
- Associated with VIN
- Associated with inflammatory dermatoses
- Eroded plaque or ulcer
- Can be contralateral depending on if it’s a more central tumour
- Spreads: locally to involve vagina & distal urethra (affects treatment- surgical complications- need to preserve function)
- To ipsilateral inguinal lymph nodes (LNs)
- To contralateral inguinal lymph nodes, deep iliofemoral LNs (25% if inguinal nodes +ve)- can work it’s way up nodes in the body
- Anything deeper than 1mm- risk of lymph node metastasis higher;
- Can do lymph node sampling to check (biopsy) e.g. sentinel node biopsy (inject tumour with radioactive tracer- see where 1st lymph node it goes to)
- Other biopsy methods cause lymphoedema risk
13
Q
What is the prognosis of Vulval Squamous Cell Carcinoma?
A
- Gynaecological cancers staged with FIGO system not TMN system
- Way of practically documenting way tumour spreads (don’t need to know details of the staging)
- 5 year survival: Stage 1 (95%), Stage 2 (90%), Stage 3 (70%), Stage 4a (20%), Stage 4b (<10%),
14
Q
What is Malignant vulval melanoma
A
Malignant melanoma (5% of vulval cancers)
• Mean age 50-60
• Local recurrence in 1/3, spread to urethra freq
• Lymph node/ haematogenous spread common
• Depth of invasion (most important prognostic factor) correlates with LN involvement
• Heavily pigmented (not all are- can get amelanotic ones with no pigment)
• Just as aggressive as cutaneous melanomas
• Histopathological exam; diagnosis, prognostic info (guides treatment)
15
Q
What is Extramammary Paget’s Disease?
A
- 5% vulval cancers, mean age 80
- Pruritic/burning/eczematous patch (like Paget’s disease of the nipple- if looks like eczma e.g. of nipple/ vulva- consider Pagets)
- In-situ adenocarcinoma of squamous mucosa
- Tend to recur following excision- doesn’t have edge to it, don’t know how wide to make excision
- Can develop invasive adenocarcinoma
- Although eczematous eruptions can occur at this site (e.g. allergic contact dermatitis e.g. new washing powder)
- Paget’s disease should be in differential diagnosis (often looks like eczema) & consider biopsy
- In the breast Pagets’s due to underlying ductal carcinoma in-situ spreading into the epidermis.
- In vulva- usually no underlying tumour; can hypothesise glandular malignant cells arise in intraepidermal portion of sweat ducts.
- Usually no underlying tumour
- 5% regional malignant disease (local cancer); bladder, cervix, exclude primary rectal cancer, where there is a prominent perianal component
16
Q
What is Cervical Pathology?
A
- Transformation zone (TZ)= physiological area of squamous metaplasia
- TZ vulnerable to oncogenic effects of HPV- is where cervical intraepithelial neoplasia (CIN) happens so cervical cancer starts
- Transformation zone develops & changes at diff stages in life;
- Want to sample TZ when taking a cervical cytology sample
- Post-menopausal state- TZ retracted up canal (might not be able to see it colonoscopically/ sample it cytologically)
- If CIN there- might not be able to excise it easily completely with a LLETZ.
- So diagnosing & treating CIN postmenopause can be a prob (as can’t reach up the area to get to the junction for the cytology- will get false –ves in cervical screening programme).
17
Q
What is Cervical Intraepithelial Neoplasia?
A
- Pre-invasive stage of cervical SCC
- Detection of pre-invasive stage is aim of cervical screening programme
- Graded according to increasing abnormality (can see on cytology)
- This shows correlation between cytology of cells brushed off epithelium surface, with the underlying dysplastic changes in epithelium.
Look at regression and progression table of the different types
18
Q
What is the Cervical Screening Programme?
A
• Is a test of CIN (pre-invasive stage) not cancer
• Available test has high sensitivity and specificity & test is not harmful
• Defined pre-invasive stage
• Long enough to allow intervention, simple, successful treatment
• Is NOT a test for cancer
• Regular attendance prevents 90% of cancers (rate would be 50% higher without screening)
• Uses liq based cytology & focused high risk HPV testing
• How screening organised periodically changes (recently with intro of HPV testing)
Why no screening below 25 yrs old?
• Evidence doesn’t support its use
• High HPV carriage rate (in most of them was no harm), incl high risk types (70-80% will be eliminated)- would have worried people it wouldn’t have harmed
• Reactive changes produce confusing cytology
• Unnecessary LLETZ (large loop excision of transition zone- used to treat) procedures can have obstetric consequences
19
Q
What is Colposcopy & CIN Treatment ?
A
- Large Loop Excision of the Transformation Zone (LLETZ)
- Colposcopy- cervix examination with low powered stereoscopic microscope
- Cervix often painted with acetic acid- highlights potentially abnormal epithelium which can resect (local anaesthetic) with diathermy loop (this histopathologically examined- guide further treatment)
20
Q
What are the risk factors of Cervical Squamous Cell Carcinoma?
A
• High risk HPV most important causative factor
• Multiple sexual partners
• Male partner with multiple partners
• Young age at first intercourse
• High parity
• Low socioeconomic group
• SMOKING (local immunosupression)
• Immunosuppression (disease related/ induced by drugs)
Looking at ulcerated cervical carcinoma pic- can work out what clinical presentation may be.
Such a lesion will commonly bleed/ cause a discharge.
If tumour presents late, could be signs & symptoms due to local spread, eg into bladder or affecting ureters causing hydronephosis & urinary symptoms.
21
Q
What is Cervical Adenocarcinoma?
A
- Presentation/spread same as SCC (squamous cell carcinomas)
- Related to high risk HPV
- Precursor is Cervical Glandular Intraepithelial Neoplasia (CGIN)
- Treated same as CIN/SCC
- Stage for stage worse prognosis that SCC due to radioresistance
- Can occur further up canal- more false –ves
- Not as sensitive to radiotherapy as squamous cell carcinomas
22
Q
What is Cervical Carcinoma- Staging and prognosis ?
A
Simplified FIGO staging
• I Confined to cervix
• II Invades beyond uterus, not to pelvic side wall
• III Extends to pelvic wall, lower 1/3 vagina, hydronephrosis
• IV Invades bladder or rectum or outside pelvis
Early lesions may not need radical surgery- can be cured by LLETZ (95% 5 yr survival): stage IA1 (73% 5yr survival) has a depth of invasion of <3mm & max lateral dimension of <7mm. Stage IA2 has a depth of invasion of 3-5mm & maximum lateral dimension of <7mm. stage IIA consider chemo and radio, stage 3 and 4 (36/13% 5 year survival- consider palliative chemo/therapy)
23
Q
What is Metastasis of Cervical Carcinoma?
A
- Predictably to pelvic and para-aortic lymph nodes
- Via blood to lungs, bone etc
- Local invasion extending out of cervix to baldder, ureters & rectum make primary surgical treatment inappropriate
- Tumour spreads to lymph nodes- dictates treatment; surgery involves radical hysterectomy with pelvic & paraaortic lymph node dissections, radiotherapy also takes in lymph node fields
- Haematogenous spread
24
Q
What is Congenital or Acquired Disorders of the Females Genital Tract?
A
Congenital: Mainly gonadal failure
Acquired” infection/growth disorder/injury/metabolic/immune disorder
25
What is Endometriosis?
Tissue usually inside uterus (endometrium) grows outside uterus e.g. ovaries, abdomen, bladder
• Ectopic endometrium (regurgitation theory/ metaplasia theory/ stem cell theory/ metastasis theory)=bleeding into tissues= fibrosis
• Normal endometrial tissue back tracks & settles in other parts
• Metaplasia theory- certain cells decide to develop into one type instead of another
• Stem cell theory- stem cell precursor e.g. can get endometrial cells in lungs
• 6-10% of women, 30-40yo
• Hx: 25% asymptomatic, dysmenorrhoea (painful menstruation), pelvic pain, subfertility, pain on passing stool, dysuria (painful/difficult dysuria)
• Ix (investigations): laparoscopy (viewing tube in abdomen to see abdominal organs)
• Rx: medical (COCP (combined oral contraceptive pill), GnRH agonists/ antagonists, progesterone antagonists) or surgical (ablation of deposits/ TAH- BSO)
• Links: ectopic pregnancy, ovarian cancer, IBD
26
What is Endometritis?
Inflammation of the endometrium (uterus lining)
• PID, retained gestational tissue, endometrial TB, IUCD infection
• Histology= predominant lymphocytes/ plasma cells
• Caused by forgein bodies chronic retained products, infection
• Pelvic inflamm disease can be associated with chlamydia
• Hx: abdominal/ pelvic pain, pyrexia, discharge, dysuria, abnormal vaginal bleeding
o Acute- systemic infec (e.g. fever), get neutrophil predominant infec
o Chronic- get lymphocyte & plasma cell predominant response & not as much systemic symptoms
• Ix: biochemistry/ microbiology, USS
• Rx: analgesia, abx, remove cause
27
What is Endometrial Polyps?
Mass in inner lining of uterus, can have flat base (sessile) or be attached to uterus by elongated pedicle (pedunculated)
• Sessile/ polypoid E2- dependant uterine overgrowths
• Outgrowth of endometrium into lumen
• May be asynchronous with rest of endometrium
• May be benign but some can harbour pre-malignant changes of endometrial cancer (so usually removed to prevent carcinoma)
• <10% women (40-50s)
• Hx: often asmptomatic, instrumental/ post-menopausal bleeding, menorrhagia, dysmenorrhoea (painful menstruation)
• Ix: USS, hysteroscopy
• Rx: expectant, medical (P4/ GnRH agonists), surgical (curettage)
28
What is a Leiomyoma?
Leiomyoma (Uterine Fibroids)
Benign smooth muscle tumour that rarely becomes cancer
• Smooth muscle of uterus responsible for contracting
• Benign myometrial tumours with E2/P4 dependant growth
• Usually asymptomatic unless very large, usually responsive to oestrogen in terms of proliferation
• 20% women 30-50s
• Risk factors: genetics, nulliparity (woman who’s never borne a child), obesity, PCOS (polycystic ovary syndrome), HTN
• Hx: often asymptomatic, menometorrhagia (heavy bleeding= Fe deficient anaemia), subfertility/ pregnancy probs, pressures sx
• Ix: bimanual examination, USS
• Rx: medical (IUS (interuterine system contraceptive coil)/ NSAIDs/ OCP/ P4/ Fe2+), non-medical (artery embolization, ablation, TAH (total abdominal hysterectomy- uterus & cervix removal))
• Prognosis: menopausal regression, LOW malignancy risk
29
What is Endometrial Hyperplasia?
Abnormal endometrium prolif (more than that occurs for menstruation)- endometrial carcinoma risk factor
• Excessive endometrial proliferation (↑E2, ↓P2)
• Endometrium overgrowth- high levels/ unopposed oestrogen (oestrogen has antagonistic effect in menstruation, progesterone stops prolif in menstruation)
• Risk factors: obesity, exogenous E2, PCOS (polycystic ovary syndrome), E2- producing tumours, tamoxifen (usually blocks oestrogen signal but in endometrium opposite), HNPCC (PTEN mutations- predispose you to develop colorectal & endometrial cancer)
• Obesity- causes peripheral oestrogen increase- favours metaplasia, polycystic kidney disease (favours this too)
• Cytotopic atypia- pre-malignant lesion
• Types;
o Simple non-atypical, simple atypical
o Complex non-atypical, complex atypical
• Hx: presents as abnormal bleeding- IMB/PCB/PMB (post menopausal bleeding)
• Ix (diagnose by): USS (endometrium thickening), hysteroscopy +/- biopsy (of endometrium- see if atypia or not)
• Rx: medical (IUS, P4- progesterone antagonises effect of oestrogen), surgical (TAH)
30
What is Malignant Progression of Hyperplasia?
* Endometrial hyperplasia= endometrioid carcinoma is progression from simple hyperplasia through complex to atypical hyperplasia & invasive carcinoma
* Simple hyperplasia (relatively common), endometriod carcinoma less freq
* Chances of progression through full spectrum increases further down spectrum woman is
* Caused by excess oestrogens from variety of possible sources
* 1st stage- simple hyperplasia with overgrowth of whole endometrium (thick endometrium on USS)
* In complex hyperplasia- more glandular epithelium &epithelium can be folded in complex architectural patterns
* Atypical hyperplasia (intraepithelial neoplasia) onset- cells show architectural changes of neoplasia with increased nuclear cytoplasmic ratio (bigger nuclei & less cytoplasm), irregular shapes, increased numbers of mitoses (some abnormal)
* Non-atypical hyperplasia hard to diagnose
* Increase in nuclear cytoplasmic ratio
* Stroma strands disappear when cancer
Normal to non-atypical hyperplasia (resembles normal proliferative endometrium) to atypical hyperplasia EIN Endometrial intraepithelial neoplasia (presence of cytological abnormality) to endometrial adenocarcinoma (invasion into myometrium)
31
What is Endometrial Adenocarcinoma?
Cancer that begins in the uterus- carcinoma from glandular tissue (adenocarcinoma)
• Most common cancer of female genital tract (9,200 new cases/ 2,500 deaths per yr UK)
• Hx: PMB (post menstrual bleeding)/ IMB, pain if late
• Ix: USS (endometrium growth), biopsy, hysteroscopy
• Staging: FIGO (1-4)
• Rx: medical (pordesterone- P4), surgery (TAH-BSO- remove ovaries & uterus & tubes), adjuvant therapy (chmo-/radiotherapy)
• Prognosis: stage 1= 90% 5yr survival, stage 2-3= <50%
• Early diagnosis- reduce mortality rate
• Remove oestrogen – help control their development- type 1 (endometroid)
• Type 2 (serous)- not oestrogen sensitive
Type 1: 75% of cases, pre or post menopausal, PTEN/Kras mutations, E2 positive, Grades 1,2 and 3
Type 2: 25% of cases, post menopausal, p53 mutations, E2 negative, Grades 3
32
What is Polycystic Ovary Syndrome?
Oestrogen & progesterone out of balance which leads to growth of ovarian cysts (benign masses on ovaries)
• Endocrine disorder- need 2 out of 3 triad; hyperandrogenism (lots of androgens- hairy, acne, abnormally long cycle length, no ovulation so no progesterone produc, constatnt oestrogen env increases canacer risk), menstrual abnormalities, polycystic ovaries
• Hypothalamic pituitary ovarian axis; hypothalamus makes gonadotrophin releasing hormone, release into hyperpophaseal portal system= gonadotropin RH causes FSH & LH (causes ovulation) release, causes oestrogen release which feedsback to hypothalamus
• Changes in relationship between FSH & LH- pulsatility gnRH released affected
• No feedback mechanism by oestrogen (????)
• Main hormone high in PCOS is LH (released by GnRH), oestrogen has +ve feedback on LH which would then cause more testosterone to be made (clomiphene drug blocks this oestrogen feedback)
• 6-10% women (20-30% have polycystic ovaries)
• Ix: USS, fasting biochemical screen (↓ FSH, ↑LH, ↑ testosterone, ↑DHEAS), OGTT (oral glucose tolerance test)
• Dx: Rotterdam criteria 2/3 of polycystic ovaries, hyperandrogenism (hirsuitism/ biochemical), irregular periods (>35 days)
• Rx: lifestyle (weight loss, exercise- get regression of disorder & reduces risk of type 2 diabetes), medical (metformin, OCP (oral contracp pill), clomiphene- blocks oestrogen feedback system on hypothalamus so upregulation of FSH & LH produc so can resume normal), surgical (ovarian drilling- puncture ovary)
• Links: infertility, endometrial hyperplasia/ adenocarcinoma
• Associated with: metabolic syndrome; obesity, insulin resistance (predisposes you to develop type 2 diabetes)
33
What is Hypogonadism?
Gonadal Failure (Hypogonadism)
Deficiency in secretory activity of ovaries/ testes
• Hypergonadotrophic hypogonadism (primary failure of gonads- don’t get appropriate development of kidneys)
o Congenital causes: Turner syndrome (XO), Klinifelters (XXY)
o Acquired causes: infection, surgery, chemo-radiotherapy, toxins/ drugs
• Pituitary & hypothal working but no –ve feedback from ovaries, get high levels of gonadotrophin but ovaries not functioning
• Hypogonadotrophic hypogonadism (hypothalamic/ pituitary failure= 2nd failure)- Sheen syndrome, pituitary tumours, brain injury PCOS
• Presentation: amenorrhoea/ absent menarche; delayed puberty, ↓ sex hormone levels +/- ↑ LH & FSH levels
• Ix: hormonal profiling (work out what’s missing & replace it), karyotyping (see if congenital cause)
• Rx: difficult- address cause: HRT
• Hypopohaseal portal system
• Woman leeds in during birth= hypovolaemia= pituitary vulnerable (limited vasculature)= pituitary ischaemic & dies so ovaries functional but pituitray’s not
• Prolactinomas- cells make more prolactin, crush other pituitary cells
• Brian injuries- hard impact, jolt of brian shears off pituitary stalk so hypothal can’t communicate with pituitary
34
What is the Origin of Ovarian Neoplasms?
* 3 key areas in ovary that can result in tumours
* Serous carcinomas, 2 types; high & low grade (don’t behave in same way) , sometimes tumours affect tubes but no primary tumours
* High grade carcinomas- originate in tube; cancer cells develop from epithelial cells of fallopian tube, then move & settle on ovary
35
What are Epithelial ovarian Tumours?
```
• Most common group of ovarian neoplasms (90%)
• 3 major histological types;
o Serous (tubal)
o Mucinous (endocervical)- give out mucin
o Endometrioid (endometrium)- not where they come from just morphological appearance
• Each type contains benign/ borderline/ malignant variants
• Benign tumours subclassified based on components; cystic (cystadenomas- filled with fluid), fibrous (adenofibromas), cystic & fibrous (cystadenofibromas- fibrous & cystic)
• Malignant epithelial tumours= cystadenocarcinomas
• Hard to tell if benign or not
```
36
What is Serous Cystadenocarcinoma?
* Inside of a cyst cavity- malignant epithelium, can be benign
* This tumour characterised by complex, branching, papillae & glands incorporating slit-like spaces
* Destructive stromal invasion identified most conspicuously within the confluent solid growth pattern exhibited within the ovarian cortex
37
What are Germ Cell Tumours? What are the 2 types?
Neoplasm from germ cells (germ cells normally in ovary & testis)
• 15-20% of all ovarian tumours
• Cystic struc on ovaries
• Germinomatous
o Dysgerminomas (differentiation- oogonia, malignant, chemosensitive)
• Non-germinomatous
o Teratomas (differentiation towards multiple germ layers); most mature (benign; 1% malignant transformation), malignant in males, benign in females
o Yolk sac tumours (differentiation towards extraembryonic yolk sac, malignant, chemosensitive)
o Choriocarcinomas (differentiation- placenta, malignant, often unresponsive to chemo)
38
What are Sex Chord Stromal Tumours?
Group of tumours from the stromal component of ovary & testis
• Rare; arise from ovarian stroma, which was derived from sex cord of embryonic gonad
• Primordial germ cells- give rise to sperm, oocytes
• Can generate cells from the opposite sex;
o Thecoma/ fibrothecoma/ fibroma
Benign, thecomas & fibrothecomas make E2 (also rarely androgens), fibromas hormonally inactive
Comprised of spindle cells (plump spindle cells with lipid droplets = thecoma appearance)
Meig’s syndrome = occurs usually with ovarian tumour, develop a right sided hydrothorax & ascites (EXAM Q!!!)- remove tumour & hydrothorax & ascites resolves
o Granulosa cell tumours
Low grade malignant, produces E2
o Sertoli-Leydig cell tumours
Produces androgens; 10-25% malignant
Vary in composition- in testis shouldn’t be in ovaries
But if are- give out testosterone
39
What is Thecoma? What syndrome id it associated with?
Sex Chord Stromal Tumours
Benign, thecomas & fibrothecomas make E2 (also rarely androgens), fibromas hormonally inactive
Comprised of spindle cells (plump spindle cells with lipid droplets = thecoma appearance)
Meig’s syndrome = occurs usually with ovarian tumour, develop a right sided hydrothorax & ascites (EXAM Q!!!)- remove tumour & hydrothorax & ascites resolves
40
What is Ovarian Cancer?
* 2nd commonest gynae cancer (>7,100 women >4,300 deaths/yr UK, 80% >50’s, 80-90% epithelial
* Over ½ women end up dying, is post menaupausal disease
* Peripheral fat- makes oestrogen
* Malignant germ cell tumours- affect younger women
* Cyst carcinomsa- affect older women
* Risk factors: FH, ↑ age, PMH breast cancer, smoking, E2- only HRT, Lynch II syndrome, obesity, nulliparity
* Protective factors: OCP, breastfeeding, hysterectomy
* Hx: non-specific symptoms; pain, bloating (as developing ascites), weight loss, PV bleeding, urinary frequency, anorexia
* FIGO staging: 1-4
* Rx: stage <1C (hasn’t breached capsule of ovary so can remove tumour) epithelial tumours TAh/BSO, omentectomy, appendectomy, lymphadenectomy & adjuvant chemo (chemo only sensitive in GCTs)
* Prognosis: overall 5 yrs 43% survival
41
What is Ovarian Metastatic Tumours? (2 types)
Müllerian tumours (most common in ovarian tract, other spread to ovaries e.g. in GI (exam Q!!!)): uterus, fallopian tube, pelvic peritoneum, contralateral ovary
• Non-Müllerian tumours:
o Lymphatic/ haematogenous spread:
GI tract: Large bowel, stomach (Krukenberg tumour), pancreatobiliary
Breast
Melanoma- spreads to ovaries
Less commonly, kidney and lung
o Direct extension (2 adjacent organs- nibbles it’s way to outside of organ & to the next): bladder, rectal
• Any organ with rich vascular supply- vascular deposits
• Can tell if metastatic- look under microscope
• Do immunohistochem- look for specific markers to see where originate
42
What is Endometrial hyperplasia?
oestrogenic stimulation of endometrial proliferation; continuous stimulation may lead to atypical hyperplasia and carcinoma
43
What is Leiomyomata?
benign smooth muscle tumours of the myometrium
44
What are Ovarian neoplasms?
90% epithelial and based on cell type; benign cystadenoma = borderline = malignant cystadenocarcinoma progression; germ cell tumours; sex cord stromal tumours; metastatic tumours
45
What is the Breast Screening Programme?
* Designed to detect breast cancer at its earliest stages
* Invite women between ages 50-70
* Age extension 47-73
* Mammography main tool
46
What is Breast Multidisciplinary Meeting?
* Surgeons, oncologists, radiologists, research nurses, breast care nurses, students, pathologists
* Radiology, histopathology, clinical impression- need to agree
* Ensures the triple diagnosis
* No further action return to breast screening
47
What is Fibrocystic Change?
* Benign condition in which breasts feel lumpy
* At least 50% of women of childbearing age
* Some studies indicate lifetime prevalence of fibrocystic change may be as high as 70% to 90%
* Except for patients with a strong family history of breast cancer where risk is 2 fold- non-proliferative lesions have no increased risk (otherwise no risk you can change in clinic)
* Diff distinct morphological appearances
* Can mimic malignancy e.g. bits of calcification
* Some people have marked fibrocystic change (lumps in breast)- need to check for reassurance that it’s not anything else
* Hard to interpret
* Association with florid fibrous change & breast cancer; more estrodiol exposed to more likely to get fibrocystic change & more likely to get breast cancer
48
What is Fibrocystic Disease?
* Constellation of diff benign changes seen in breast including apocrine change, usual type ductal hyperplasia & sclerosing adenois
* Can form a lump, can be associated with calcium, can mimic cancer- common incidental finding
* Can cause discomfort related to menstrual cycle
* Shares same risk factors as breast cancer
49
What is Fibroadenoma?
* Common- form lumps (usually found as a lump- scare people)
* Usually occur in women- ages 10 & 40 yrs
* Most common breast mass in adolescent & young adult population
* Incidence decreases after 40 years
* Very round on x-ray, or may need ultrasound to find it in young people
* These are NOT fixed/ tethered & doesn’t cause skin dimpling (if normal tissue pulled down as tether)
* Usually not removed
* Cancers grow into adjacent tissue & become tethered, so if mobile may not be cancer
50
What is the Epidemiology of Breast Cancer?
* Rates vary around 5 fold around the world, but increasing in regions that had low rates
* Risk factors linked to oestrogens
* Risk increased by early menarche, late menopause, & obesity in postmenopausal women (higher oestrogen level)
* Prospective studies shown- high endogenous oestradiol concs associated with an increased risk
* Childbearing reduces risk, with greater protection & breastfeeding (dominant breast most protected)
* Slight peak of risk during preg
* Oral contraceptives & hormonal therapy for menopause cause a small increase in breast cancer risk- diminishes once use stops
* Alcohol increases risk (taking folate may reduce this risk)
* Mutations in certain (tumour suppressor e.g. BRCA1) genes greatly increases breast cancer risk (permits sccumul of mutations)- but these account for minority of cases
51
What is DCIS?
* DCIS- stage of cancer BEFORE it invades & is a factor of time (if leave it loing enough will become invasive)
* Pure DCIS can’t produce a metastasis
* Has the potential to progress to invasion if left
52
What should a Path Report Tell You about Malignancy ?
* In situ or invasive
* Type
* Grade
* Size
* Vacular invasion.
* Nodal status
* Relationship to margins
* ER, PR and HER2 status (receptors)
53
What are the Main Recognised Types of Breast Carcinoma?
```
Morphology;
• Ductal - 75%
• Lobular - 12%
• Tubular/cribriform - 3%
• Medullary - 3%
• Mucoid - 2%
• Metaplastic - 1%
• Others - 4%
```
54
What the grades and [prognosis of breast cancer?
Grade
• Score based on how pleomorphic, mitosis etc
• Grade 1 to 3
• Grade 1 tumours do better than grade 3 tumours
Vascular Invasion & Relationship to Margins
• +ve lymph nodes- more likely to give chemo
• If –ve lymphnodes but cancer in lymphatics- can give chemo anywhere
• If down on skin/ near pec muscle- more likely to give radiotherapy
Key Prognostic Factors
For treatment plan;
• Tumour grade
• Tumour size
• Nodal status
Nottingham Prognostic Index
• Grade + nodal status (0: score 1, 1-3: score 2 & 4 or more: score 3) + 0.2 x tumour size)
• 3.4 or less- good 80% + 16 yr survival
• 3.4 or less- good 80% + 16 year survival
• 3.41- 5.4- moderate 46%
• 5.41+ - poor 10%
Prediction versus Prognosis
• The future- ER, PR & HER2 status (receptrors)
• Moving towards more using biological therapies that picks out specific markers
55
What is a Phyllodes Tumour?
* Hard lump of tissue in supportive tissue (stroma) of breast
* Usually benign (but can sometime be malignant)
* Grouped into 3 types; benign, borderline malignant, malignant
* More common in women with fibroadenomas, pre-menopausal women between 40-50
* Noticed as a quick growing lump in breast
* Tests; mammogram, USS, fine needle aspiration, core biopsy
* Treatment; surgery- remove tumour
56
What are the effects of infections on pregnancy?
• Pregnancy doesn’t alter resistance to infec
• But some infecs during preg more severe & can also affect foetus
• Infecs may cause;
o Miscarriage
o Congenital abnormalities
o Fetal hydrops (abnormal fluid accumul in 2 or more fetal compartments- can lead to spontaneous abortion)
o Fetal death
o Preterm delivery (can have neurodevelopmental disabilities)
o Preterm rupture on membranes
• Maternal antibodies cross placenta & give passive immunity to fetus
• Council women about key infecs & how to avoid getting them
57
What is the NHS Infectious Diseases in Pregnancy Screening Programme ?
NHS Infectious Diseases in Pregnancy Screening Programme (minimum 95% uptake of screening in pregnancy for all conditions) – pick up infecs as early as possible to provide management by MDT (obstetrician, paediatrician, infectious disease consultant etc)
• Guidelines if mum +ve for HIV or syphilis
• If mum hep B +ve baby should be offered vaccine/ immunonoglobulin within 24hrs of birth so baby doesn’t get active hep B- whether they get immunoglobulin dpends on how infective mum is
• Get vaccine immediately then in 1, 2 & 12 months of age, then get a blood test to see if baby has hep B
58
What Neonatal Infections can be Acquired During Passage Through Birth Canal?
* Group B Streptococcus (most common cause of neonatal sepsis)
* Herpes simplex virus (HSV)- transmitted in utero/ passage in birth canal
* Gonorrhoea
* Human immunodeficiency virus *
* Hepatitis B virus *
* * = can be transmitted in any stage of preg & post-delivery
59
What is the NICE CG62: Antenatal Care for Uncomplicated Pregnancies?
* Antenatal- before birth, during pregnancy
* Women should be offered routine screening for asymptomatic bacteriuria by midstream urine culture early in preg
* Identification &treatment of asymptomatic bacteriuria reduces pyelonephritis risk in mum
* Mid stream urine culture in 1st antenatal, if organism then repeat urine test, if same organism treatment
* Most caused by E.coli
60
What is Asymptomatic Bacteriuria (ASB) in Pregnancy?
* Asymptomatic bacteruria usually before symptomatic UTI in pregnancy
* 5% prevalence
* Untreated, at least 30%women with ASB develop acute pyelonephritis
* ASB screening cost effective approach to prevent pyelonephritis- reduces risk of pre-term delivery & low birth weight (where they would be particularly susceptible to infecs)
61
What is Group B Streptococci Screening?
• Until it’s clear that antenatal GBS carriage screening does more good than harm &benefits are cost effective, the National Screening Committee doesn’t recommend routine screening in UK
• Prevention of early onset neonatal Group B Streptococcal Disease RCOG Green-top Guideline No.36- intrapartum antibiotic prophylaxis (IAP) for GBS offered to;
o Women with previous baby with neonatal GBS disease
o Women with GBS in current preg
o Women pyrexial in labour should be offered broad-spectrum antibiotics including antibiotic for prevention of neonatal EOGBS disease e.g. IV clomoxiclav
• But as part of screening for asymptomatic bacteriuira offer intrapartum prophylaxis at the time of labour as higher risk of neonatal sepsis
62
What is a Urinary Tract Infection (UTI) During Pregnancy?
* ‘Bacteriuria’ screening indicated in pregnancy
* Asymptomatic bacteriuria= no UTI symptoms & 2 samples containing >105 same organism
* Bacteriuria can develop intro symptomatic UTI if untreated
* Continuing bacteriuria associated with premature delivery & increased perinatal mortality
63
What is Antimicrobial Prescribing in Pregnancy & Puerperium?
* Puerperium- 6 wks after childbirth where mum’s reproductive organs return to original pre-preg condition (normal physiological state)
* Antimicrobials- grouped according to microoganisms they act against e.g. antibiotics against bacteria, antifungals against fungi
* Must consider potential to cause harm to embryo/foetus/neonate
* All antimicrobials cross the placenta to some extent &virtually all appear in breast milk if given in therapeutic amounts to breast feeding women
* Some antimicrobials considered ‘safe’ in pregnancy: penicillins, cephalosporins
* Some antimicrobials unsafe in pregnancy; chloramphenicol, tetracycline, fluoroquinolones e.g. ciprofloxacin), trimethoprim-sulphamethoxazole (adverse consequences on newborn)
64
What are Intra-amniotic Infections?
• Affects 1-2% term pregnancies
• Affects 20-25% pregnancies with pre-term labour (strong associated with intra-amniotic infecs & pre-term labour)
• Major cause of perinatal morbidity &mortality
• ‘Chorioamnionitis’- inflammation of umbilical cord, amniotic membranes or placenta
• Risk factors
o Most common after prolonged rupture of membranes
o Amniocentesis, cordiocentesis, cervical cerclage multiple vaginal examinations, bacterial vaginosis (in some cases)
o Pathogenesis
o Ḅacteria in vagina cause infec by ascending through cervix
o Haematogenous (via blood) infection is rare e.g. Listeria monocytogenes
• Mother presents; fever, purulent amniotic fluid
• Causative organisms;
o Group B streptococcus (most common cause)
o Enterococci
o Escherichia coli (2nd most common cause)
o Management
o Antimicrobials & delivery of foetus
o Should administer antimicrobials at time of diagnosis (not after delivery)- to prevent transmission to new-born
65
What is Puerperal Endometritis?
• Womb infec (of endometrium) during puerperium affects 5% pregnancies
• Puerperal sepsis- major cause of maternal death
• Risk factors; C-section, prolonged labour, prolonged rupture of membranes, multiple vaginal examinations
• Clinical features;
o Fever (38.5°C in first 24h post delivery or >38° for 4 hrs, 24h+ after delivery)
o Uterine tenderness
o Purulent, foul-smelling lochia
o Increased white cell count
o General malaise, abdominal pain
• Causative organisms (frequently mixed);
o Escherichia coli
o Beta-haemolytic streptococci (group a & b streptococcus)
o Anaerobes
o Diagnosis
o Role of transvaginal endometrial swabs controversial
o Treatment
o Broad-spectrum IV antimicrobials (at time of delivery)- continued until patient has been apyrexial for 48hrs
• With group a strep- give antibiotics at time of birth, then prophylactic antibiotics to new born baby 10 days after birth
• Maternal & neonatal infecs REMEMBER- e.coli & group b streptococcus
66
What is the leading cause of neonatal death?
Sepsis & meningitis
67
What is Early Onset Sepsis?
* Early-onset sepsis (usually within 72 hrs)- major cause of mortality & morbidity in newborn babies
* High mortality, particularly in premature & low birth weight babies
* Death: 1 in 4 babies who develop it, even when given antibiotics
* 90% will present within 48hrs of birth
* Can still develop sepsis even if given antimicrobials
* Organisms from maternal genital tract
* Typical to have multisystem involvement/ pneumonia
* Higher mortality, particularly those infections evident within 1st 24hrs
* GBS (46%), E coli (20%, other strep (26%)
68
What is Late Onset Sepsis?
* Mostly in babies after 7 days of life
* Coagulase –ve staphylococci- mostly low weight babies dependant on vascular access & ventilator support
* Diff organisms that cause early & late neonatal sepsis- so treatment for each completely diff
69
What are Childhood Infections ?
• Strep pneumoniae- leading cause of childhood infecs & deaths from infec
• Common symptoms reported in early education settings;
o Respiratory (66%)- most present with Sob, tachypnoea etc
o Fever (14%)
o Gastroenteritis (9%)
o Earache (6%)
o Rash (5%)
70
What is a sore throat aetiology?
* Sore throat- any of various inflammations of the tonsils, pharynx or larynx characterised by pain in swallowing
* Viral 70-80%- don’t need antibiotics
* Group A beta-haemolytic Streptococcus (20-30%)- need to give penicillin B to child
71
What is Otitis Media? What are its causes and features and treatment?
* One of the most common presentations
* Midlle ear effusion
* Unusual irritability
* Difficulty sleeping
* Tugging/pulling at 1/ both ears
* Fever (need otoscope ear examination)
* Fluid draining from ear
* Loss of balance
* Unresponsiveness to quiet sounds/ other signs of hearing difficulty
* Prescribe oral antibiotics
Strep pneumonia (35%), H.influenzae(23%)
72
What are common Lower Respiratory Tract Infections (LRTIs) in Children?
• 30-40 cases/ 1000 children per yr in UK (GP sees 1-2 cases per yr)
• Prevalence;
o Every yr pneumonia contributes to 750,000-1.2million neonatal deaths worldwide
o Includes pneumonia, acute bronchitis & bronchiolitis
o Respiratory viruses remain leading cause of lower resp tract infec in children under 5 yrs
• H.influenzae infec rare amongst UK children due to immunisation
• RSV- resp syncytial virus (especially in children under 2 yrs old) (63%)
• Distinguish if viral or bacterial infec
73
What is Bronchiolitis?
• Bronchiolitis- a seasonal viral illness characterised by feve, nasal discharge, whezzy cough. On examination- fine inspiratory crackles and/or high-pitched expiratory wheeze
• Acute bronchiolitis- one of commonest admissions in winter period
• Causes;
o Respiratory syncytial virus (RSV)- leading casue
o Metapneumovirus
o Adenovirus
o Para-influenza virus
o Influenza
o Rhinovirus
• Rapidly progressive illness- can deteriorate very quickly
• Risk assess child early & make diagnosis
• Can present with apnoea (as inflamm of airways) but may not be present with any other symptoms (this also a symptom of meningitis)
74
What are the common pathogens for pneumonia?
```
• Newborn
o Group B streptococci
o Gram –ve bacilli
o Listeria monocytogenes
o Herpes simplex
o Cytomegalovirus
o Rubella
```
• 1-3 Months
o Chlamydia trachomatis
o Respiratory syncytial virus
o Other resp viruses
```
• 3-12mnths
o Respiratory syncytial virus
o Other respiratory viruses
o Streptococcus pneumoniae
o Haemophilius influenza
o Chlamydia trachomatis
o Mycoplasma pneumoniae
• Under 5 year old viruses leading cause of resp illness
• 2-5 years
o Respiratory viruses
o Streptococcus pneumoniea
o Neamophilus influenza
o Mycoplasma pneumoniae
o Chlamydia pneumoniae
• 5-18 years
o Mycoplasma pneumoniae
o Streptococcus pneumoniae
o Chlamydia pneumoniae
o Haemophilus influenza
o Influenza virus A & B
o Adenovirus
o Other respiratory viruses
```
75
What are the clinical features of pneumonia?
o Presentation: acute febrile illness, possibly preceded by typical viral URTI
o Symptoms;
Breathlessness (poor feeding)
Irritability
Sleeplessness
Cough, chest or abdominal pain in older patients
Audible wheezing rare in LRTI but can occur
Younger children rarely cough, may be present with grunting tachypnoea & chest retractions
76
What is Pertussis?
Pertussis (Whooping Cough)
• Usually affect children before vaccine available, recent resurgence noted
• Clinical illness in 3 stages
• Highly communicable acute resp infec caused by B. pertussis
• Person-to-person transmission through aerosolised resp droplets
• Humans- sole reservoir
• Diagnosis: culture organism (e.g. nose/ throat swab) & PCR in early stages (in 1st couple of wks of infec)
• Serology test if illness >3wks (find out form patient when symptoms started)
• Immunised; adults in older years immunity waning
• Women- booster vaccine to protect newborns getting pertussis
77
What are the stages of Pertussis?
1. CATARRHAL PHASE
o Cold-like symptoms (coryza, conjunctival irritation, occasionally a slight cough)
o 7-10 days
2. PAROXYSMAL PHASE
o Coughing sounds start
o Long duration (2-6 wks), no fever
o Series of rapid, forced expirations, followed by gasping inhalation (typical whooping sound)
o Post-tissue vomiting common
o Very young infants may present with apnea/ cyanosis in absence of cough
3. CONVALESCENT PHASE
o May take up to 6 wks of symptoms to subside
78
What is Meningitis in Children?
* Newborn & infants: non-specific clinical presentation (symptoms) at early age
* Fever
* Irritability
* Lethargy
* Poor feeding
* High pitched cry, bulging AF
* Convulsions, opisthotonus
79
What is the aetiology of Meningitis in Children?
• Neonates: Group B streptococcus, Escherichia coli, Listeria monocytogenes
• >1month- 5 years: Streptococcus pneumoniae, Neisseria meningitides
• Viral meningitis;
o Most common infec of CNS especially in <1 yr
o Enterovirus (commonest meningitis in 50% of children <3mnths), HSV, influenza, EBV, adenovirus, CMV
o Mononuclear lymphocytes in CSF (lumbar puncture- if it was bacterial would see polymorphic response)
o Symptomatic treatment CP
80
What are the features of UTIs in children?
• Up to 7% girls & 2% boys- symptomatic culture-proven UTI before 6 yrs old
• Of febrile neonates (have fever) up to 7% have UTIs
• Most UTIs in children from ascending bacteria
• E.coli (60-80%), Proteus, Klebsiella, Enterococcus & Staphylococcus saprophyticus
• Overall UTI prevalence in febrile infants 5%- varies widely by race & sex
• Caucasian children 2 to 4 fold higher UTI prevalence compared to African-American children
• Females- 2 to 4 fold higher UTI prevalence than circumcise males
Symptoms
• Classic UTI symptoms in older children; dysuria, frequency, urgency, small-volume voids, lower abdo pain
• Infants with UTIs have non-specific symptoms; fever, irritability, vomiting, poor appetite
• So recommend urine culture if child presents with fever & can’t find another cause
81
What is Meningococcemia?
* Mortality 5-10% (90% if DIC)
* Morbidity 10% (deafness, neurological probs, amputations)
* Peak incidence <4yrs
* Immunisation programme includes Men C
* 60% bacterial meningitis in UK due to meninigococcus B
* Fever, non-specific malaise, lethargy, vomiting, meningism, resp distress, irritability, seizures
* Maculopapular rach common in early disease
* Petechial rash seen in 50-60% children
82
What is Impetigo?
* Staphylococcus aureus/ streptococcus pyogenes
* Classically ruptured vesicles with honey- coloured crusting
* May be bullous
* More common in pre-existing skin disease e.g. eczema
* Very contagious, rapid spread
* Commonly infec starts around face/ mouth
* Topical antibiotics or oral flucloxacillin (antibiotics if not responding to normal treatment) or can be self-limiting
* Advice re nursery/ school
83
What is Scarlet Fever?
* Gp A beta-haemolytic Sterptococcus
* 2-4 days post-Streptococcal pharyngitis (sore throat)
* Fever, headache, sore throat, unwell
* Flushed face with circumoral pallor (white area around mouth)
* Rash may extend to whole body
* Rough ‘sandpaper’ skin
* Desquamation (skin peeling) after 5/7, particularly soles & palms
* School age children
* White strawberry tongue
* Diagnosis: throat swab, ASO titres
* Treat: penicillin B for 10 days (need antibiotics)
84
What is Measles?
* Acute viral infection
* Fever, coryza, conjunctivitis, maculopapular rash & koplik spots
* Rash starts at hairline= trunk & extremities, lasts about 6 days
* Transmitted person-to-person by direct contact with infectious droplets/ less commonly by airborne spread
* Peak incidence of infec usually during late winter & spring
* Incubation period: 10-12 days
* Communicable 4 days before to 4 days after rash onset
* Measles is a PUBLIC HEALTH EMERGENCY- rapidly transmitted to other susceptible individuals
85
What is Rubella?
Rubella (German measles)
• Mild febrile viral illness compared to measles
• Children usually few/ no clinical symptoms
• Rash pink maculopapular, starts on face then spreads downward & lasts 2-5 days (3-day measles)
• Transmitted- contact with infected nasopharyngeal secretions
• Incubation perios: 16-18 days
• Communicable period: 5 days before to 5-7 days after rash onset
• Infection can be detrimental to developing foetus
• If mum gets rubella during preg= eye probs, deafness, brain damage, heart abnormalities in baby
86
What is Chicken Pox?
Chicken Pox (varicella)
• Contagious disease caused by member of herpes virus family
• Chickenpox- relatively harmless disease
• Symptoms; fever, runny nose, sore throat, itchy skin rash which can appear anywhere on body
• Rash & disease usually disappear after 1 or 2 wks
• Disease confers permanent life-long immunity- child won’t contract it again
• Complications (e.g. pneumonia) in adults who didn’t have chickenpox as a child, or youngsters with already weakened immune systems or preg women that get chicken pox
