Uterine Pathology Flashcards
What is endometriosis?
Ectopic endometrial tissue elsewhere in the body e.g. in pelvis
Epidemiology of endometriosis?
6-10% of women aged 30-40 years
Now thought 1 in 10 women of reproductive age suffer from it
Aetiology of endometriosis?
unknown but regurgitation theory/metaplasia theory/ stem cell theory/ metastasis theory
What is the ‘regurgitation theory’?
Menstrual flow backs up through fallopian tubes, with subsequent implantation of endometrial tissue in the peritoneum.
What is the metaplasia theory?
The metaplastic theory suggests that pelvic endometriosis may be derived through the metaplastic transformation of peritoneal mesothelium. Endometriosis may manifest as a serial change from the adjacent mesothelial cells.
What is the stem cell theory for endometriosis?
The stem cell theory suggests that the stem cells in the uterus may be able to migrate outside of the uterus where they can form endometrial-like tissue.
Pathogenesis of endometriosis?
i.e. how does it lead to fibrosis?
Each month these ectopic foci react in the same way to endometrium in the uterus, building up and then breaking down and bleeding. However, this blood has no way to escape leading to pain/inflammation/scarring/cyst formation or nodules. I.e. bleeding into tissues –> fibrosis
Clinical features of endometriosis?
o 25% asymptomatic o Dysmenorrhoea o Dyspareunia o Pelvic pain, pain during intercourse o Subfertility o Pain on passing stool o Dysuria
Treatment for endometriosis?
- NSAIDs are first-line, with progesterone-only or combined contraceptive pills.
- Disease recurrence is common.
- Surgical ablation of lesions is the definitive treatment.
Gold standard for diagnosis of endometriosis?
laparoscopy and biopsy
What are endometrial polyps?
Localised overgrowth of endometrial tissue that projects into the uterine cavity and is attached by a pedicle. Can be single or multiple.
Endometrial polyps can be either sessile or pedunculated. What does this mean?
Sessile - broad based
Pedunculated - on a narrow stalk
Epidemiology of endometrial polyps?
<10% of women aged 40 – 50 years
How does the incidence of endometrial polyps change with age?
The incidence of polyps rises steadily with increasing age and it varies according to population studied, but about one in ten women will have a polyp in their lifetime.
Aetiology of endometrial polyps?
unknown
Proposed that they arise as the inappropriate reaction of foci of endometrium to oestrogenic stimulation
Clinical features of endometrial polyps?
o Often asymptomatic
o Intermenstrual/post-menopausal bleeding
o Menorrhagia
o Dysmenorrhoea
Investigations for endometrial polyps?
o Ultrasound
o Hysteroscopy
Are endometrial polyps benign?
- Almost all polyps are benign (malignant changes reported in <1% of polyps)
- The risk of malignancy in polyps increases with age and carries a risk of 2.3% in symptomatic postmenopausal women (0.3% if asymptomatic)
How many layers does the uterus have? What are they?
3:
- Outer perimetrium/serosa
- Middle myometrium (smooth muscle layer)
- Inner endometrium
What are the 4 parts of the uterus?
- Fundus
- Body
- Isthmus
- Cervix
The endometrium itself is divided into 2 layers. What are they?
- Stratum functionalis
2. Stratum basalis
What is the stratum functionalis of the endometrium made up of?
Made up of glands and supporting connective tissue, called stroma
How is the stratum functionalis of the endometrium affected during the menstrual cycle?
During the menstrual cycle, this layer expands and vascularises and is subsequently sloughed off during menstruation (i.e. functional)
How is the stratum basalis affected during the menstrual cycle?
This layer stays relatively constant
Regenerates the overlying functional layer after each menstrual cycle
What is the growth of the functional layer of the endometrium regulated by?
Hormones secreted by the ovaries –> Oestrogen stimulates the growth of endometrial glands and stroma.
What does each ovary consist of?
Each ovary is made up of a number of ovarian follicles:
Each follicle consists of an oocyte (female germ cell) surrounded by theca cels and granulosa cells
REVISE THIS!! (IMS/Body Systems?)
Function of theca cells and granulosa cells?
Oestrogen synthesis:
- Theca cells produce androgens in response to LH.
- Granulosa cells respond to FSH mainly by synthesising androgens to oestrogens
Effect of oestrogen on the uterus?
Oestrogen stimulates the growth of endometrial glands and stroma of the endometrium
What part of the menstrual cycle does oestrogen dominate?
First phase of the menstrual cycle
What is the first phase of the menstrual cycle called?
Proliferative phase (follicular phase) because it’s when the lining of the endometrium grows (proliferates).
At the end of the follicular phase of the menstrual cycle, what happens?
Ovulation occurs due to LH surge from the pituitary:
o One ovarian follicle expels the oocyte into the fallopian tube and it travels to the uterus.
o Follicle then collapses to form a corpus luteum
What is the 2nd phase of the menstrual cycle called?
Luteal phase / secretory phase
What is the corpus luteum responsible for?
Progesterone production in luteal phase
What are the effects of progesterone in the luteal phase of the menstrual cycle?
o Counteracts the effect of oestrogen on the endometrium by preventing further proliferation.
• At the same time, it causes the glands to produce secretions that acts as nutrients for any developing embryo
What is endometrial hyperplasia?
Hyperplasia of the endometrium that most often results when the endometrium is exposed to high levels of oestrogen for a prolonged time (and low levels of progesterone).
What are the effects of the endometrium being exposed to oestrogen for a prolonged time?
o This leads to excessive growth of endometrial glands relative to stroma; meaning a high gland-to-stroma ratio.
o This is also accompanied by low levels of progesterone, which (as mentioned previously) normally has an opposing effect to oestrogen
Epidemiology of endometrial hyperplasia?
> 40 years 3 times more incidence than endometrial cancer
Aetiology of endometrial hyperplasia?
All situations where there is high oestrogen and low progesterone
How can obesity lead to endometrial hyperplasia?
Adipose tissue allows conversion of androgens to oestrogen
How can polycystic ovarian syndrome lead to endometrial hyperplasia?
Increased production of androgens that are then converted to oestrogen
What type of tumour can lead to endometrial hyperplasia?
Oestrogen-secreting tumours e.g. granulosa cell tumour (granulosa cells produce oestrogen)
How can age of:
a) menarche
b) menopause
affect endometrial hyperplasia?
Early menarche
Later menopause
Leads to more exposure to oestrogen –> higher risk
How can pregnancy affect endometrial hyperplasia?
If you have never given birth –> increased number of cycles to be exposed to oestrogen as during pregnancy oestrogen secretion is inhibited
What are 2 drugs that can lead to endometrial hyperplasia?
- Oestrogen-only hormone replacement therapy (relieving menopause symptoms)
- Tamoxifen (Breast cancer medication)
How can Tamoxifen lead to endometrial hyperplasia?
Blocks oestrogen receptors of breast cancer BUT stimulates oestrogen receptors in uterine lining
Mutations of which gene can lead to endometrial hyperplasia?
PTEN
How can mutations of PTEN gene lead to endometrial hyperplasia?
o Normally acts as brake on cell cycle
o When this gene becomes defective, the cells of the endometrium will proliferate out control and lead to hyperplasia
Pathogenesis of endometrial hyperplasia?
Unopposed oestrogenic stimulation of the endometrium
Clinical features of endometrial hyperplasia?
o Abnormal bleeding; heavy or prolonged menstrual bleeding, intermenstrual bleeding and postmenopausal bleeding.
o In some cases, there could also be amenorrhea
What is the most concerning issue with endometrial hyperplasia?
Increases the risk for endometrial cancer (the most common cancer arising from the female reproductive system)
Histological features of endometrial hyperplasia?
If biopsy of endometrial tissue shows an increased thickening of the endometrial functional layer
What 2 categories can hyperplastic change be divided into?
1) simple
2) complex
What defines simple hyperplastic change?
Normal stroma to gland ration
What defines complex hyperplastic change?
Increased glands and less stroma
What is nuclear atypia?
When looking at the tissue at higher magnification and looking at the columnar glandular cells that are lining the endometrial glands, there may be nuclear atypia:
o Large and hyperchromatic nucleus
o Nuclear atypia is the most important factor for cancer progression
What is the most important factor for cancer progression?
Nuclear atypia
Can can nuclear atypia affect the risk of progression of
a) simple
b) complex
hyperplasia to endometrial cancer?
Simple:
Risk of 1% progress to endometrial cancer BUT up to 10% if associated with nuclear atypia
Complex:
Risk of 5% progress to endometrial cancer BUT to 30% if associated with nuclear atypia
Treatment for endometrial hyperplasia?
- Eliminating excess oestrogen!
- Surgical removal of the uterus especially for endometrial cancer risk (hysterectomy)
- Progesterone medications to counteract the effects of oestrogen
Treatment for endometrial hyperplasia if cause is:
a) obesity
b) Polycystic ovarian syndrome
c) oestrogen therapy
a) lose weight
b) correcting anovulation
c) Stopping unopposed oestrogen therapy
What type of cancers are most endometrial cancers?
Adenocarcinomas
What are adenocarcinomas?
cancer that forms in mucus-secreting glands throughout the body
What are the 2 types of endometrial adenocarcinomas? Which is the most common?
- Type 1; endometroid (more common)
2. Type 2; serous
Pathogenesis of endometroid adenocarcinoma vs serous adenocarcinoma?
Endometroid; a natural progression of endometria hyperplasia into malignancy (due to unopposed oestrogen)
Serous; completely independent of background endometrial hyperplasia but instead is a background of atrophy
Incidence of endometroid vs serous adenocarcinoma?
Endometroid; 75% of endometrial cancer cases
Serous; 25% of cases
Typical age of onset of endometroid vs serous adenocarcinoma?
Endometroid; pre or perimenopausal
Serous; Post menopausal
Mutations of which genes are associated with:
a) endometroid
b) serous adenocarcinoma?
a) PTEN, KRAS
b) P53
Which type of endometrial cancer is more aggressive?
Serous (type 2)
Clinical features of endometrial cancer?
Similar to endometrial hyperplasia and sometimes present with features of advanced metastatic disease; abdominal or pelvic pain, bloating, feeling full quickly when eating, and changes in bowel or bladder habits, weight loss, pallor, loss of appetite, etc
What system is used to stage endometrial cancer?
FIGO Staging of Endometrial Cancer
Describe stages 1-4 of endometrial cancer
o Stage 1; Carcinoma confined to within uterine body.
- 1a; confined to inner ½ of myometrium
- 1b; involves outer ½ of myometrium
o Stage 2; Carcinoma may extend to cervix but is not beyond the uterus.
o Stage 3; Carcinoma extends beyond uterus but is confined to the pelvis.
o Stage 4; Carcinoma involves bladder or bowel or has metastasised to distant sites.
What is Lynch syndrome?
Hereditary non-polyposis colorectal cancer (HNPCC)) that is an autosomal dominant, inherited cancer predisposition syndrome that causes individuals to have a high lifetime risk of colorectal cancer.
What are those with Lynch syndrome at a higher risk of?
- colorectal cancer
- endometrial cancer
- ovarian cancer
Aetiology of Lynch syndrome?
Lynch syndrome occurs due to the inheritance of an alteration in one of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2).
What are myometrial tumours?
Are the majority benign or malignant?
Smooth muscle tumour of the myometrium. Usually benign; is the commonest benign tumour of the female genital tract.
What are myometrial tumours associated with?
infertility
What are the 3 types of myometrial tumours?
- Submucosal (projects into endometrial cavity)
- Intramural
- Subserosal (just under outer layer of uterus)
Appearance of myometrial tumours?
White nodules with a whorled cut surface
Epidemiology of myometrial tumours?
Commonest gynaecological condition. Black women at an increased risk.
Aetiology & pathogenesis of myometrial tumours?
A: unknown (E2/P4 stimulation)
P: benign monoclonal proliferation of smooth muscle cells
Clinical features of myometrial tumours?
o Presents usually in later reproductive life and associated with low parity (although uncertain if this is the cause or an effect)
o Vast majority are asymptomatic; Those with symptoms usually have abnormal bleeding
o Abdominal mass, bladder problems (pressure)
o Abnormal uterine bleeding
What is polycystic ovarian syndrome?
An endocrine disorder characterised by hyperandrogenism, ovulatory dysfunction, menstrual irregularities, +/- polycystic ovaries (despite name) and insulin resistance
Epidemiology of polycystic ovarian syndrome?
6 to 10% of women of reproductive age
Aetiology of polycystic ovarian syndrome?
Unknown
Pathogenesis of polycystic ovarian syndrome?
A dysfunction in the hypothalamic-pituitary-ovarian axis:
- Anterior pituitary makes too much LH (at least double the amount as FSH)
- Excessive LH causes the theca cells to produce excess amounts of androstenedione (way too much for those granulosa cells to convert)
- The excess androstenedione flows into the blood and some of it gets converted into oestrone by aromatase in fat or adipose tissue.
- Oestrone (a member of the oestrogen family) acts as a negative feedback signal, stopping the anterior pituitary from releasing FSH.
- Because LH levels are really high, there’s no LH surge to trigger the dominant follicle to break away from the ovary, so it may remain there, appearing as a cyst, or it might degenerate with the other follicles.
Ovulation doesn’t occur (due to too much LH but no LH surge).
Polycystic ovarian syndrome leads to:
a) Increased androstenedione
b) insulin resistance
c) lack of ovulation
Clinical features of all of these?
a)
Hirsutism (hair on chin, upper lip, chest and back)
Male pattern baldness (thinning from crown)
Acne (face, chest and back)
b)
Leads to overweight/obese
Acanthosis nigricans (dark, velvety patches – creases of neck, groin, underarm)
c)
Amenorrhea (an absence of menstruation) or oligomenorrhea (infrequent and irregular menstrual bleeds), both of which can lead to infertility.
Diagnosis of polycystic ovarian syndrome? (think LH, FSH and androstenedione)
o A a high ratio of LH to FSH, as well as high levels of androstenedione in the blood.
o A pelvic ultrasound may reveal follicles on one or both ovaries that look like small cysts, but these aren’t necessary for the diagnosis.
Treatment for polycystic ovarian syndrome?
o Weight loss; to decrease insulin resistance and improve symptoms o Metformin o Spironolactone o Oral contraceptives o Clomiphene citrate o Ovarian drilling
Why is Metformin used to treat polycystic ovarian syndrome?
increases insulin sensitivity
Why is Spironolactone used to treat polycystic ovarian syndrome?
used to treat hirsutism by blocking effects of androgens and reducing hair growth
Why is contraception required for women taking Spironolactone?
As is teratogenic
Why is Clomiphene citrate used to treat polycystic ovarian syndrome?
induces ovulation
Why are oral contraceptives used to treat polycystic ovarian syndrome?
regulate menstrual cycle
What is ovarian drilling?
involves puncturing a cystic ovary which can induce ovulation (but doesn’t resolve the overall hormonal imbalance)
Which layer of the endometrium is lost during menstruation?
Stratum functionale
Which layer of the endometrium regenerates the overlying functional layer after each menstrual cycle?
Stratum basalis
Which hormone released by the hypothalamus is involved in the menstrual cycle?
What is the effect of this hormone?
GnRH
Stimulates anterior pituitary to release FSH and LH
Which hormone is implicated in PCOS?
Androgens –> in a state of hyperandrogenism
What is the defining feature of PCOS?
Hyperandrogenism
Which hormone counteracts the effects of oestrogen?
Progesterone
What is the most common type of endometrial cancer?
Adenocarcinoma
Which type of endometrial adenocarcinoma is COMPLETELY INDEPENDENT of endometrial hyperplasia?
Type 2 serous
Which type of endometrial adenocarcinoma is a progression of endometrial hyperplasia?
Type 1 endometrioid
