Pathology Flashcards
What makes up the ovarian cycle?
Follicular phase
Ovulation
Luteal phase
What makes up the uterine cycle?
Menstrual phase
Proliferative phase
Secretory phase
When is the proliferative phase, and what hormone causes it?
D 1-14
Oestrogen
When is the secretory phase, and what hormone causes it?
D 16-28
Progesterone
What are some indications for endometrial sampling?
Abnormal uterine bleeding
Investigation for infertility
Spontaneous and therapeutic abortion
Assessment of response to hormonal therapy
Endometrial ablation
Work up prior to hysterectomy for benign indications
Incidental finding of thickened endometrium on scan
Endometrial cancer screening in high risk patients
What is menorrhagia?
Prolonged and increased menstrual flow
What is metrorrhagia?
Regular intermenstrual bleeding
What is polymenorrhoea?
Menses occurring at <21 day interval
What is polymenorrhagia?
Increased bleeding and frequent cycle
What is menometrorrhagia?
Prolonged menses and intermenstrual bleeding
What is amenorrhoea?
Absence of menstruation >6mo
What is oligomenorrhoea?
Menses at intervals of >35d
When does post menopausal bleeding become abnormal uterine bleeding?
1 year after cessation of menstruation
What are some causes of AUB in adolescence/early reproductive life?
DUB due to Anovulatory cycles
Pregnancy/miscarriage
Endometritis
Bleeding disorders
What are some causes of AUB in reproductive life/perimenopause?
Pregnancy/miscarriage DUB: anovulatory cycles, luteal phase defects Endometritis Endometrial/endocervical polyp Leiomyoma Adenomyosis Exogenous hormone effects Bleeding disorders Hyperplasia Neoplasia: cervical, endometrial
What are some causes of AUB post menopause?
Atrophy Endometrial polyp Exogenous hormones: HRT, tamoxifen Endometritis Bleeding disorders Hyperplasia Endometrial carcinoma Sarcoma
Endometrial thickness of what in postmenopausal women is taken as an indication for biopsy?
> 4mm, 16mm is premenopausal
How can the endometrium be sampled?
Endometrial pipelle
Dilatation and curettage
What is DUB defined as?
Irregular uterine bleeding that reflects a disruption in the normal cyclic pattern of ovulatory hormonal stimulation to the endometrial lining (no organic cause for bleeding)
What happens in DUB de to anovulatory cycles?
Corpus luteum does not form
Continued growth of functionalis layer
In what conditions is DUB common in?
PCOS
Hypothalamic dysfunction
Thyroid disorders
Hyperprolactinaemia
What is luteal phase deficiency?
Insufficient progesterone or poor response by the endometrium to progesterone. Abnormal follicular development (inadequate FSH/LH) – poor corpus luteum
How is endometritis diagnosed histologically?
Recognising an abnormal pattern of inflammatory cells
What physiological barriers are there to endometritis?
Cervical mucous plug protects endometrium from ascending infection
Cyclical shedding
What organisms can cause endometritis?
Neisseria Chlamydia TB CMV Actinomyces HSV
What can cause endometritis without specific organisms?
Intra-uterine contraceptive device Postpartum Postabortal Post curettage Chronic endometritis NOS Granulomatous (sarcoid, foreign body post ablation) Associated with leiomyomata or polyps
Describe chronic plasmacytic endometritis
Infectious unless proved otherwise
Associated with PID (neiserria gonorrhoea, chlamydia, enteric organisms)
Describe endometrial polyps
Usually asymptomatic, may present with bleeding or discharge
Occur around or after menopause
Almost always benign
Endometrial carcinoma can present as polyp
What are some causes of AUB related to the myometrium?
Adenomyosis- endometrial glands and stroma within myometrium, causes menorrhagia/dysmenorrhoea
Leiomyoma- benign tumour of smooth muscle, may be found elsewhere
How may leiomyoma present?
Menorrhagia
Infertility
Mass effect
Pain
Can there be multiple leiomyoma?
Yes: single or multiple, may distort uterine cavity
What is leiomyoma growth dependent on?
Oestrogens
What is seen in leiomyoma microscopically?
Interlacing smooth muscle cells
What are the normal cell layers of the ectocervix?
Exfoliating cells Superficial cells Intermediate cells Parabasal cells Basal cells Basement membrane
Where is the transformation zone found?
Between ectocervical (squamous) and endocervical (columnar) epithelium
The position of TZ will alter during life as physiological responses to what?
Menarche
Pregnancy
Menopause
What is cervical erosion?
Exposure of delicate endocervical epithelium to acid environment of vagina leading to physiological squamous metaplasia
Describe cervicitis
Often asymptomatic: can lead to infertility due to simultaneous silent fallopian tube damage
What are the causes of cervicitis?
Non-specific acute/chronic inflammation
Follicular cervicitis- sub epithelial reactive lymphoid follicles preset in cervix
Chlamydia Trachomatis
HSV
Describe a cervical polyp
Localised inflammatory outgrowth
Bleeding cause, if ulcerated
Not premalignant
What are some neoplastic pathologies of the cervix?
Cervical Intraepithelial Neoplasia (CIN)
Cervical Cancer: squamous carcinoma, adenocarcinoma
What are risk factors for CIN/Cervical cancer?
Persistence of high risk HPVs, mostly types 16,18,31,33,35,45,48
Many sexual partners
Vulnerability of SC junction in early reproductive life- age at first intercourse, long term use of oral contraceptives, non-use of barrier contraception
Smoking: 3x risk
Immunosuppression
How much of all cervical cancers are caused by HPV 16 and 18?
70%
What is condyloma acuminatum?
Thickened papillomatous squamous epithelium with cytoplasmic vacuolation (koilocytosis)
What HPV’s cause genital warts?
6 and 11
What epithelial changes may be seen in CIN?
Infected epithelium remains flat, but at show koilocytosis, which can be detected in smears
What does the virus do in HPV cervical cancer?
Integrates into host DNA
How long does an HPV infection take to become high grade CIN?
6 months to 3 years
How long does high grade CIN take to become invasive cancer?
5-20 years
What is the prevalence of HPV infection (pre-vaccination)?
15-25yo 30-50%
25-35yo 10-20%
>35yo 5-15%
80% cumulative prevalence in lifetime
Do most people develop immunity to HPV infection?
Yes
What does persistence of the HPV infection increase?
Risk of disease
Describe CIN
Pre-invasive stage of cervical cancer Occurs at TZ Can be large area Dysplasia of squamous cells Not visible to naked eye Asymptomatic Detectable by cervical screening
What delays in maturation/differentiation are seen in CIN?
Immature basal cells occupying more of epithelium
What nuclear abnormalities are seen in CIN?
Hyperchromasia
Increased nucleocytoplasmic ratio
Pleomorphism
Does excess mitotic activity occur in CIN?
Yes- abnormal mitotic forms
Situated above basal layers
How is CIN graded?
I-III depending on histological factors
What is seen in CIN I?
Basal, 1/3 of epithelium occupied by abnormal cells
Raised numbers of mitotic figures in lower 1/3.
Surface cells quite mature, but nuclei slightly abnormal
What is seen in CIN II?
Abnormal cells extend to middle 1/3
Mitoses in middle 1/3
Abnormal mitotic figures
What is seen in CIN III?
Abnormal cells occupy full thickness of epithelium
Mitoses, often abnormal, in upper 1/3
What percentage of CIN I,II,III lesions progress to invasion?
1,5, and >12% respectively
What percentage of CIN I and II progress to CIN III?
11 and 22% respectively
How many malignant cervical tumours are invasive squamous carcinoma?
75-95%
What is the 2nd commonest female cancer worldwide?
Invasive squamous carcinoma
What does invasive squamous carcinoma develop from?
Pre-existing CIN, therefore most cases are preventable by screening
Describe the staging of invasive squamous carcinoma
Stage 1A1 - depth up to 3mm, width up to 7mm
Stage 1A2 - depth up to 5mm, width up to 7mm: Low risk of lymph node metastases
Stage 1B - confined to the cervix
Stage 2 - spread to adjacent organs (vagina, uterus, etc..)
Stage 3 - involvement of pelvic wall
Stage 4 - distant metastases or involvement of rectum or bladder
What are the symptoms of invasive carcinoma of the cervix?
Usually none at microinvasive/early invasive stages
Abnormal bleeding: post coital, post menopausal, brownish or blood stained vaginal discharge, contact bleeding-friable epithelium
Pelvic pain
Haematuria/urinary infections
Ureteric obstruction/renal failure
What is the local spread of squamous carcinoma of cervix?
Uterine body, vagina, bladder, ureters, rectum
What is the lymphatic spread of squamous carcinoma of cervix?
Early>pelvic, para-aortic nodes
What is the haematogenous spread of squamous carcinoma of cervix?
Late> liver, lungs, bone
How are squamous carcinomas of the cervix graded?
Well differentiated
Moderately differentiated
Poorly differentiated
Undifferentiated / anaplastic
Describe cervical glandular intraepithelial neoplasia (CGIN)
Origin from endocervical epithelium
CGIN is preinvasive phase of endocervical adenocarcinoma
More difficult to diagnose on cervical smear than squamous
Screening less effective
Sometimes associated with CIN
Describe endocervical adenocarcinoma
5-25% of cervical cancer
Increasing incidence, particularly young women
Some are mixed, arise from common cell of origin
Worse prognosis than squamous
What are the RFs for endocervical adenocarcinoma?
Higher socio-economic class
Later onset of sexual activity
Smoking
HPV-particularly 18
What other HPV driven neoplasias exist?
Vulvar Intraepithelial Neoplasia
Vaginal Intraepithelial Neoplasia
Anal Intraepithelial Neoplasia
What is associated with VIN?
Paget’s disease
Describe the bimodal presentation of VIN
Young- often multifocal recurrent or persistent causing treatment problems
Older- greater risk of progression to invasive squamous carcinoma
Is VIN HPV related?
Often, but not always
What often occurs with VIN?
Synchronous CIN and VaIN
How does vulvar invasive squamous carcinoma usually present (VISC)?
Elder women- ulcer or exophytic mass
What can VISC arise from?
Normal epithelium or VIN
Are VISC’s well differentiated?
Yes (verrucous are an extremely well differentiated type)
What is the most important prognostic factor in VISC?
Inguinal LN spread
What is the surgical treatment of VISC?
Radical vulvectomy and inguinal lymphadenectomy
What are the 5 year survival rates of VISC?
90% if node -ve
<60% if node +ve
Describe vulvar Paget’s disease
Crusting rash
Tumour cells in epidermis, contain mucin
Mostly no underlying cancer, tumour arises from sweat gland in skin
Who does vaginal squamous carcinoma commonly present in?
Elderly
How many vaginal melanoma appear?
As a polyp
What are the 3 stages of endometrial hyperplasia?
Simple
Complex
Atypical (precursor of carcinoma)
What are the causes of endometrial hyperplasia?
Often unknown
May be persistent oestrogen stimulation
How does endometrial hyperplasia present?
Abnormal bleeding (DUB or PMB)
Describe the distribution, component, glands and cytology for simplex endometrial hyperplasia
General
Glands and stroma
Dilated not crowded
Normal
Describe the distribution, component, glands and cytology for complex endometrial hyperplasia
Focal
Glands
Crowded
Normal
Describe the distribution, component, glands and cytology for atypical endometrial hyperplasia
Focal
Glands
Crowded
Atypical
What is the peak incidence of endometrial carcinoma?
50-60yo, uncommon under 40
What should be considered in young women with endometrial carcinoma?
Consider underlying predisposition e.g. PCOS or Lynch syndrome
What are the two main groups of endometrial carcinoma?
Endometrioid carcinoma (type 1 tumour 80%): precursor atypical hyperplasia
Related to unopposed oestrogen
Serous carcinoma (type 2): precursor serous intraepithelial carcinoma
Not associated with unopposed oestrogen, affects elderly postmenopausal women, TP53 often mutated
How does endometrial carcinoma usually present?
Abnormal bleeding
What are the macroscopic findings of endometrial carcinoma?
Large uterus
Polypoid
What are the microscopic findings of endometrial carcinoma?
Most are adenocarcinomas
Most are well differentiated
What is the spread of endometrial carcinoma?
Directly into myometrium and cervix
Lymphatic
Haematogenous
Describe type 1 endometrial carcinomas
Endometrioid and mucinous phenotypes
PTEN, KRAS, PIK3CA mutations
Associated with atypical hyperplasia as precursor lesion
Microsatellite instability
Germline mutation of mismatch repair genes (Lynch syndrome)
Why is obesity a known RF for endometrial cancer?
Excess risk associated with endocrine and inflammatory effects of adipose tissue
Adipocytes express aromatase that converts ovarian androgens into oestrogens, which induce endometrial proliferation
Insulin/IGF exert proliferative effect on endometrium
Sex hormone binding globulin levels are lower in obese women, and therefore the level of unbound, biologically active hormone is higher
What is Lynch syndrome?
Cancer predisposition syndrome- Hereditary non-polyposis colorectal cancer
High risk of endometrial cancer (28%) and increased probability of developing ovarian cancer
AD Inheritance
What kind of tumour staying for mismatch repair proteins can help identify tumours due to Lynch syndrome?
Immunohistochemistry
What characteristic of defective mismatch repair do Lynch syndrome tumours show?
Microsatellite instability
Describe type 2 endometrial carcinomas
Serous and clear cell phenotypes
TP53 mutation and overexpression
Precursor lesion serous endometrial intraepithelial carcinoma
More aggressive than endometrioid/mucinous carcinoma
Describe the spread of type 2 endometrial carcinomas
Spreads along fallopian tube mucosa and peritoneal surfaces so can present with extrauterine disease
What is serous carcinoma characterised by?
Characterised by a complex papillary and/or glandular architecture with diffuse, marked nuclear pleomorphism
Why does endometrioid carcinoma have a good prognosis?
As usually confined to uterus at presentation
What is the treatment for endometrial carcinoma?
Hysterectomy
Chemo/radiotherapy
How is endometrial carcinoma staged?
I-IV Prognosis depends on: Stage Histological grade Depth of myometrial invasion
Describe endometrial carcinoma grading
Based on architecture
Grade 1 5% or less solid growth
Grade 2 6-50% solid growth
Grade 3 >50% solid growth
Are serous and clear cell carcinoma graded?
Not formally
Describe stage I-IV of endometrial cancer
Stage I Tumour confined to the uterus
IA- No or < 50% myometrial invasion
IB- Invasion equal to or > 50% of myometrium
II- Tumour invades cervical stroma
III- Local and or regional tumour spread
IIIA- Tumour invades serosa of uterus and/or adnexae
IIIB- Vaginal and/or parametrial involvement
IIIC- Metastases to pelvic and/or para-aortic lymph nodes
IV- Tumour invades bladder and or bowel mucosa (IVA) and/or distant metastases (IVB)
Describe endometrial stromal sarcoma
Low and high grade (high has increased atypical, proliferative activity)
Rare, cells resemble endometrial stroma
Infiltrate myometrium and often lymphovascular spaces
How does endometrial stromal sarcoma present?
With AUB but initial may be as mets (commonly ovary or lung)
What is the most important prognostic factor in endometrial stromal sarcoma?
Stage
Describe carcinosarcoma
<5% of uterine malignancies
High grade carcinomatous and sarcomatous elements
Heterologous elements seen in about 50% (rhabdo/chrondro/osteosarcoma)
Usually associated with poor outcome
The present of what component has the worst prognosis in carcinosarcoma?
Rhabdomyosarcomatous
Describe leiomyosarcoma
Malignant smooth muscle tumour commonly displaying spindle cell morphology
Most common uterine sarcoma
1-2% uterine malignancies
Most >50yo
What are the commonest symptoms of leiomyosarcoma?
Abnormal vaginal bleeding
Palpable pelvic mass
Pelvic pain
Does leiomyosarcoma have a good prognosis?
No
How is leiomyosarcoma staged?
Same staging system as endometrial stromal sarcoma, different to that for endometrial cancer
When can follicular cysts form?
When ovulation doesn’t occur (polycystic ovaries)
What are the possible sites of endometriosis?
Ovary (‘chocolate’ cyst) Pouch of Douglas Peritoneal surfaces, including uterus Cervix, vulva, vagina Bladder, bowel etc
What are some complications of endometriosis?
Pain Cyst formation Adhesions Infertility Ectopic pregnancy Malignancy (endometrioid carcinoma)
How are epithelial ovarian tumours categorised?
Benign- no cytological abnormalities, proliferative activity (absent or scant), no stromal invasion
Borderline- cytological abnormalities, proliferative, no stromal invasion
Malignant- stromal invasion
What are most cases of high grade serous carcinoma?
Tubal in origin
What % of ovarian tumours do germ cell tumours make up?
15-20%
Describe Figo staging of ovarian cancer?
1A tumour limited to one ovaries
1B tumour limited to both ovaries
1C Cancer involving ovarian surface/rupture/surgical spill/tumour in washings
2A Extension or implants on uterus/fallopian tube
2B Extension to other pelvic intraperitoneal
3A Retroperitoneal lymph node
Metastasis or microscopic extrapelvic peritoneal involvement
3B Macroscopic peritoneal metastasis beyond pelvis up to 2cm in dimension
3C Macroscopic peritoneal metastasis >2cm in dimension
4 Distant metastasis
