Uterine

Question 1

For uterine cancer, the 1st line treatment is:

What is a controversial add on?

Answer 1

Surgery:
TAH/BSO (or radical hysterectomy if cervical
stromal involvement) with peritoneal cytology.

Need for pelvic and PA lymphadenectomy for staging is controversial and could be considered for risk factors such as large, deeply invasive, or highgrade tumors.

Question 2

For post-op endometrial patients, Mx is dictated by?

Define the broad groupings of patients:

Answer 2

Mx dictated by path features.

1) Early-stage patients grouped into:
low-, intermediate-, or high-risk groups, which were defined by GOG 33, GOG 99, and
PORTEC studies.

2) Locally advanced endometrial Mx generally consists of surgery followed by CHT or chemoRT.

Question 3

Very basic Epidemiology for endometrial Ca:

Answer 3

Most common gynaecological cancer
Median age 60
Incidence increasing - faster in NZ comaped to other OECD countries.

Question 4

Endometrial Ca risk factors can be divided into?

The approach is changing to?

Answer 4

Molecular classifaction is gaining ground, traditionally divided into 2 groups:
Type I = Oestrogen related ~80% cases. Subdivide into metabolic and exposure.
Type II = Non-oestrogen related ~20% cases. More elderly patients. No clear risk factors

Question 5

Type I endometrial Ca risk factors:

Answer 5

1) Metabolic: Obesity, PCOS, diabetes
2) Oestrogen exposure: Nul parity, early menarche, late menopause, tamoxifen use (NSABP – RR 2-3 with 5-year tamoxifen)
3) Genetics - Lynch syndrome, Cowden.

Question 6

Macro and Histologic features of Type 1 endometrial Ca:

Answer 6

Lesion is typically exophytic and soft.

Endometriod endometrial carcinoma most common type:
Precursor lesion atypical endometroid hyperplasia/endometroid intraepithelial neoplasia.

Diagnosis based on features of invasion into the surrounding mesenchyme:
- Microcystic, elongated and fragmented (MELF) pattern of growth
- Stromal Invasion = loss of individual glandular contours with gland fusion, lack of intervening stroma and back to back architecture. Also associated with stromal necrosis, stromal desmoplasia (stroma has myofibroblasts, edema, inflammatory cells and myxoid change)

Question 8

Histologic features of Type II endometrial Ca:

Answer 8

G3 non-endometroid, clear cell, serous carcinoma, carcinosarcoma, atrophic endometrium

Question 9

Overall, the most common histo subtypes of endometrial Ca:

Answer 9

1) Endometrioid carcinoma of the endometrium (Type 1): commonest ~85%
2) Serous carcinoma 5-10% (Type II)
3) clear cell carcinoma of the endometrium: 1-5.5% (type II)

Question 10

What blood test marker typically correlates well with papillary/serous endometrial Ca?

What IHC markers are positive?

Answer 10

CA-125

Positive: p53+, p16+ (often strong and diffuse), AE1/AE3 and CK7+ (strong membranous staining), PAX8+

Question 11

Microscopic features of endometriod tumours?

Answer 11

Infiltrative, with desmoplastic reaction, atypical cells. Key thing: Architecture (malignant glandular with solid component)

Question 12

What is the 3rd most common histological type of endometrial cancer?

Microscopic features?

Answer 12

About 2% are clear cell.

Characterised by papillary, tubule-cystic, or solid architecture with clear
cytoplasm (due to glycogen content) and ‘hob-nailing’, variable genetic mutation
* Biological behaviour: worse prognosis than serous carcinoma

Question 13

Microscopic features of the second most common type of endometrial cancer?

Answer 13

Papillary serous (~10%): high-grade anaplastic cells in complex papillary, glandular, or solid growth pattern (other features seen: necrosis, psammoma bodies, myometrium invasion,
vascular invasion).

Question 14

Compare Type I and II endometrial cancers in terms of:
1) Average age of onset
2) Main histo subtype
3) Typical pattern of spread
4) Prognosis
5) Role of estrogen

Answer 14

1) Age: Type I = 50-60yrs, Type II = around 70
2) Main histo subtype:
Typ1 = Endometroid, Typ2= non-endo (e.g clear cell, serous papillary).
3) Typical pattern of spread: Typ1 Nodes and Ovarian. Typ2 peritoneum
4) Prognosis favourable in Typ1. Unfav typ2
5) Typ1 - main risk factors related to chronic estrogen exposure without opposing progestin
Typ2 - arrise from atrophic endometrium and estrogen indepedant.

Question 15

Molecular classification of endometrial Ca is based on:

Answer 15

ProMisE (proactive molecular risk classifier for endometrial cancer) using IHC and Sanger sequencing:

1) MMR deficient =mismatch repair; surrogate poor prognosis as leads to micro satellite instability.
2) POLE=polymerase ε; surrogate for ultramutated. So mutated become immunogenic, good predictive value (to chemo or RT for HR pts)
3) p53abn. High-risk/poor prog feature.
4) Non-specified molecular profile (NSMP) subtypes (e.g. POLE-wt). Poor prognostic factors.

Question 16

Uterine cancer protective factors:

Include biomarkers

Answer 16

1) OCP – 1 year OCP reduce lifetime risk by half - Progestin-containing intra-uterine device (e.g. Mirena)

2) Exercise
3) Smoking (is protective!)
4) POLE exonuclease domain mutations (EDM)

Question 17

Endometrial carcinomas (ECs) classified by The Cancer Genome Atlas (TCGA) in 4 groups:

The Key biomarkers in endometrial cancer are indicators of which molecular subtypes:

Answer 17

MOLECULAR SUBTYPES (based on TGA, PROMISE Covers the actual biomarkers):
1) Ultramutated - POLE-EDM so mutated that cells are immunogenic - better prognosis and response to Chemo or ChemoRT (PORTEC 3).
2) Hypermutated - high MSI and high mutation level (not as high as ultra- mutated) - MMRd (i.e like Lynch syndrome)
3) Copy number low = Most common, intermediate prognosis. No specific molecular profile! =+ve oestrogen/progesterone receptors, low tumour mutational burdens when compared with the POLE and dMMR/MSI-H groupings.
4) Copy number high (or “serous-like”): poor prognosis - TP53 +ve in 88%

Question 18

Key genetic syndromes that increase risk of endometrial Ca:

Answer 18

1) Lynch syndrome: germline mutation or deletion in DNA mismatch repair gene (MMR) (MSH2, MLH1, MSH6, PMS2). >30% life time risk of endometrial cancer (compared to 3% in general population)
- MLH1 or MSH2 mutation = life time risk 40-60%, median age 48 y/o (generally population 63 y/o)
- MSH6 = median age 53 y/o

2) Cowden syndrome: PTEN mutation.

Question 19

Lynch syndrome is caused by?

Answer 19

Autosomal dominant condition caused by germline mutation in DNA mismatch repair gene (MMR) (MSH2, MLH1, MSH6, PMS2), or a deletion of the last few exons of the gene EPCAM that results in epigenetic silencing of MSH2.

Question 20

Genetic screening should be considered in patients Dx w/endometrial Ca at age < ?

Answer 20

Consider when age <50

Question 21

Consider screening for endometrial cancer in patients with HNPCC with what Ix? From what age?

What intervention may be offered to this group?

Answer 21

Consider screening for endometrial cancer in patients with HNPCC with annual endometrial sampling and TVUS from age 30-35 onwards.

Prophylactic TAH+BSO can be considered in this group of patients (after child-bearing completed)

Question 22

FIGO grading of endometrial Ca is based on?

WHO classification is based on?

Answer 22

FIGO Grade: Degree of glandular differentiation, which is described as percentage of non-squamous (or non-morular) solid growth pattern. Grading is upgraded by 1 if there is severe nuclear atypia

WHO class based on tumour lineage:
* Epithelial:e.g. endometroid adenocarcinoma, papillary serous carcinoma, clear cell carcinoma,
* Mesenchymal: e.g. leiomyoma (i.e. fibroid), leiomyosarcoma, rhabdomyosarcoma
* Mixed epithelial/ mesenchymal: adenomyoma, adenofibroma, adenosarcoma, carcinosarcoma
* Other: e.g. germ cell tumour

Question 23

FIGO grading of endometrial Ca can be upgraded if:

Define what is meant by that term..

Answer 23

Grading is upgraded by 1 if there is severe nuclear atypia.

Atypia := nuclear pleomorphism, nuclear enlargement and nucleoli evident at lower power magnification

Question 24

FIGO tumour grades:

Answer 24

Degree of glandular differentiation, which is described as percentage of non-squamous (or non-morular) solid growth pattern:

Grade 1: 5% non-squamous solid growth pattern

Grade 2: 6-50% non-squamous solid growth pattern

Grade 3: >50% non-squamous solid growth pattern (i.e. more solid, and less gland)

Question 25

In endometrial cancer what are the key molecular groups:

Their utility (in regards to what?) was demonstrated in what recent key study?

How are they detected?

Answer 25

PORTEC-3 - molecular classification has strong prognostic value in high-risk:

1) Mismatch repair deficient (MMRd),
2) p53 abnormal (p53abn),
3) POLE-mutated (POLE) - HR pts respond well to chemo or ChemoRT
4) Non-specified molecular profile (NSMP) subtypes.

To determine most of these profiles, immunohistochemistry (IHC) can be used. However, POLE mutations still need to be confirmed via DNA sequencing.

Question 26

PORTEC-3 looked at what cohort of patients?

Answer 26

Adjuvant chemoradiotherapy versus radiotherapy for HR endoCa:

p53abn tumours had significantly improved survival rates with adj chemoRT (vs chemo)

POLE-mutated EC had incredibly good prognoses regardless of treatment arm (can prob just have chemo).

Question 27

Initial investigations of a 55yro women presenting with post menopausal PV bleeding:

What if Pt on Tamoxifen

Answer 27

Speculum Exam, cervical screening and pipelle biospy of endometrium.

Pelvic USS, w/assessment of endometrial thickness.

Bloods: coags, FBC, Iron studies (I.e anemia and possible haem cause), thyroid function (for atrophic uterus), LFT. CA-125 (elevated in 20% of cases, esp. serous, carcinosarcoma)

If on Tamoxifen - High suspicion of Ca, Pipelle, dont wait for USS, refer to gynae.

Question 28

USS findings for post menopausal bleeding:

Answer 28

PV bleeding allows stratification of USS findings:

PV bleed: endometrium >5 mm has 96% sensitivity for endometrial ca

No bleed: endometrium of >11 mm has been proposed as a threshold for endometrial Bx

Question 29

What does endometrial cancer look like on USS?

Answer 29

Endometrial carcinoma usually appears as thickening of the endometrium though may appear as a polypoid mass.

Question 30

A 55yro, post menopausal woman presenting w/PV bleeding should be referred to gynae following Ix if:

Answer 30

The endometrial thickness is:

< 5 mm and there is persistent bleeding despite treatment for atrophia
5 – 8 mm and the pipelle biopsy sample is inadequate
> 8 mm, irrespective of the results from pipelle biopsy.

Question 31

Comment on the prognostic implications of MMR deficiency in endometrial Ca

Answer 31

Patients with MSI-hypermutated tumours have an intermediate prognosis and may be eligible for treatment with immune checkpoint inhibitors, not clinical routine.

The MSI-hypermutated subgroup can be detected by immunohistochemical (IHC) staining of the DNA mismatch repair (MMR) markers MSH6, MSH2, PMS2 and MLH1, where the loss of any of these defines MMR deficiency (MMR-D), a surrogate marker for MSI.

Question 32

Relate MMRd to Lynch syndrome:

Answer 32

While only 10% of pts whose tumours are MMRd have Lynch, pretty much all Lynch patients are MMRd

Question 33

Define low-risk endometrial cancer:

Answer 33

Low-risk = IA grade 1 or 2.
where 1A = <50% myometrial invasion

Question 34

Which endometrial cancer patients may benefit from immunotherapy?

What type?

Answer 34

The GY020 trial of 168 planned patients (NCT04214067) evaluates the addition of one year of pembrolizumab to standard-of-care radiotherapy in high intermediate risk dMMR tumours.

Question 35

DDx for a 55yro, post menopausal woman presenting w/PV bleeding

Answer 35

Maligancy: Endometriod/Type 1 cancers, cervical cancer, type II (e.g. serous), primary uterine sarcomas, lymphomas, mets.
Haem: clotting disorder/iatrogenic (blood thinners.
Benign: Atrophic uterus, fibroids, trauma.
Infectious: PID

Always say pregnancy related if pre-menopausal.

Question 36

Comment on the prognostic implications of MMRdeficiency in endometrial Ca

Answer 36

Patients with MSI-hypermutated tumours have an intermediate prognosis and may be eligible for treatment with immune checkpoint inhibitors, not clinical routine. PD-1 inhibitors are currently being investigated.

The MSI-hypermutated subgroup can be detected by immunohistochemical (IHC) staining of the DNA mismatch repair (MMR) markers MSH6, MSH2, PMS2 and MLH1, where the loss of any of these defines MMR deficiency (MMR-D), a surrogate marker for MSI.

In low-risk (IA grade 1 or 2) endometrioid endometrial cancers, mismatch repair deficiency is associated with a higher recurrence rate than mismatch repair proficiency

Question 37

IHC finds MMRd +Ve in a 60yro woman with Advanced endometrial Ca. What further testing should be considered>

Answer 37

10% of MMRd patients have Lynch syndrome. All Lynch syndrom patients are MMRd.

MMRd +ve status is usually a trigger for formal germline testing.

Question 38

Which endometrial cancer patients may benefit from immunotherapy?

What type?

Answer 38

The GY020 trial of 168 planned patients (NCT04214067) evaluates the addition of one year of pembrolizumab to standard-of-care radiotherapy in high intermediate risk dMMR tumours.

Question 39

DDx for a 55yro, post menopausal woman presenting w/PV bleeding

Answer 39

Maligancy: Endometriod/Type 1 cancers, cervical cancer, type II (e.g. serous), primary uterine sarcomas, lymphomas, mets.
Haem: clotting disorder/iatrogenic (blood thinners.
Benign: Atrophic uterus, fibroids, trauma.
Infectious: PID

Always say pregnancy related is pre-menopausal.

Question 40

What LYNCH mutations confer the most malignancy risk?

Answer 40

MLH1, MSH2, MSH6 have highest risk:

Colorectal Ca: 31-47% risk by age 70 for MLH1 and MSH2

Endometrial: MLH1 or MSH2 mutation = life time risk 40-60%, median age 48 y/o (generally population 63 y/o)

Question 41

Women with Lynch sydrome are at risk of which malignancies (in order)?

Define the risk:

Answer 41

Depending on mutations - i.e. MLH1, MSH2 & 6 are bad:

Colorectal cancer 20% to 80%
Endometrial cancer 15% to 60%

Ovarian cancer 1% to 38%

lower risk than the above:
Stomach
Urinary tract
Pancreas
Hepatobiliary
Small bowel
Brain
Sebaceous adenomas of the skin

Question 42

How common is Lynch syndrome as a cancer cause?

Answer 42

Approximately 3% to 5% of all cases of colorectal cancer and 2% to 3% of all cases of endometrial cancer are thought to be due to Lynch syndrome.

Question 43

A set of criteria, called the ? is used to help decide who should be tested for Lynch syndrome:

Answer 43

Bethesda guidelines consider testing if any:

1) Developing colorectal or endometrial cancer <50yrs

2) Colorectal, endometrial, or other type of cancer* with mismatch repair deficiency (MMR-D) or highmicrosatellite instability (MSI-H) in tumor

3) Developing more than 1 type of Ca associated with Lynch syndrome separately or at the same time.

4) Colorectal ca in 1 or more 1st-degree relatives who also has or has had another Lynch -related cancer, with 1 of these developing before age 50.

5) Colorectal cancer in 2 or more 1st- or 2nd-degree relatives w/ another Lynch related cancer.

Question 44

Most common presentation of endometrial cancer? List some others…

Answer 44

CLINICAL PRESENTATION
Most common: vaginal bleeding (90%)

Other: abdo/ pelvic pain, abdo distension, urinary/rectal bleeding, constipation.

Question 45

Serum CA-125 can be elevated in patients who have?

What is its utility?

Answer 45

CA-125 can be elevated in:
Ovarian cancer (80% advanced ca, 50% with early)
Endometrial cancer,
fallopian tube cancer,
lung cancer,
breast cancer,
GI cancer.

It can also be increased in pregnant women. As many conditions can increase CA-125, it is not used to detect Ca, but is often used to monitor Tx response to chemo, relapse/progression in ovarian ca pts.

Question 46

For endometrial Ca:
Stage I defined as? Divided into:
Stage II is

GOG33 defines what as intermediate stage? It defines 2 subgroups

Answer 46

Stage I limited to endometrium, and not reached serosa:
1A = <50% myometrium
1B = >50%

Stage II - Has invaded the cervix.

GOG33 - calls 1B and II intermediate risk. Can be further divided into Low and High risk:
Where high risk has any of: LVSI, GRD 2or3, or deep myo invasion (>50%, but SEER meta-analysis suggest >33.3%)

Question 47

Stage III endometrial cancer spans what disease extent?

Answer 47

IIIA Invasion of serosa and/ or adnexa (ovary)
IIIB Vagina or parametrium
IIIC pelvic node +Ve (C1) para-aortic (C2)

Question 48

Stage IV endometrial cancer is definied as:

Answer 48

IVA - organ invasion
IVB - Distant spread.

Question 49

Outline the structural anatomy (structure and layers) of the uterus (lymphatic drainage ect is another card):

Answer 49

Muscular organ, flattened pear-shaped, about 8x5x3cm

Uterine corpus = upper 2/3 of uterus above internal cervical os (composed of tube-like fundus inferiorly and body superiorly). Cervix and lower uterine segment (bottom of fundus) comprise lower 1/3. Lies withing the fold of double fold of the broad ligament such that the anterior and posterior surfaces are covered by the broad ligament (to the level of the cervix)

Oviducts (fallopian tubes) and round ligaments enter uterus at upper outer cornu of the body.

Uterine wall is composed of endometrium, myometrium, and serosa from innermost to outermost layers. The thickness of endometrium varying with menstrual cycle.

Question 50

Describe the broad ligament:

Answer 50

Lax double fold of peritoneum lateral to the uterus (not a ligament).
Medial edge attached to side wall of uterus, covering the vesicle and intestinal surface of the uterus as serous coat.
Lateral edge is attached to side wall.
The upper lateral part contains the ovarian vessels/lymphatics, and extends over external iliac vessels. Below that and lateral is the round ligament.
Between the two layers of broad ligament is a mass of areolar tissues = parametrium

Question 51

Where and what is the parametrium?

What are the contents?

Answer 51

Between the two layers of broad ligament is a mass of areolar tissues = parametrium.

Contains: the uterine vessels and lymphatics, the round ligament, ligament of the ovary, and vestigial remnants of the mesonephric tubules.

Question 52

Lymphatic drainage of upper part of the body/ fundus/ uterine tube?

Answer 52

Upper part of the body/ fundus/ uterine tube
* accompanies those from ovaries and drains to para-
aortic nodes
* some lymphatic vessels follow the round ligament to superficial inguinal lymph nodes (vertical group)
Lower part of uterus
* external iliac lymph nodes

Question 53

Compare Type I and II endometrial cancers in terms of:
1) Average age of onset
2) Main histo subtype
3) Typical pattern of spread
4) Prognosis
5) Role of estrogen

Answer 53

1) Age: Type I = 50-60yrs, Type II = around 70
2) Main histo subtype:
Typ1 = Endometroid, Typ2= non-endo (e.g clear cell, serous papillary).
3) Typical pattern of spread: Typ1 Nodes and Ovarian. Typ2 peritoneum
4) Prognosis favourable in Typ1. Unfav typ2
5) Typ1 - main risk factors related to chronic estrogen exposure without opposing progestin
Typ2 - arrise from atrophic endometrium and estrogen indepedant.

Question 54

Lymphatic drainage of the cervix

Answer 54

Cervix:
* Along broad ligament to external iliac nodes and obturator nodes
* Along uterine vessels to internal iliac nodes
* Via the uterosacral ligament to sacral nodes

Question 55

Define the endometrial cancer risk groups:

Answer 55

1) Low:
Stage IA, G1-2 (LVSI-) (i.e less <50%DOI) (observation)
2.1) Int:
Stage IB, G1-2 (LVSI-) (vault Brachy)
2.2) Int High:
Stage IA, G3 Stage IB, G3 S (Pelvic RT)
3) High risk:
Stage II (invades stroma)-III/ IV (ChemoRT)

Question 56

Outline the typical treatment paradigm for each endometrial cancer risk group

Answer 56

Surgery if fit = TAH/BSO (or radical hysterectomy if parametrial involved). Node sampling/dissection based on risk.

1) Low:
Stage IA, G1-2 (LVSI-) (i.e less <50%DOI) = observation. Consider VBT if higher risk features (age >60, LVSI)
2.1) Int:
Stage IB, G1-2 (LVSI-) OR stage 1A grd III = vault Brachy
2.2) Int High:
Stage IA G3 or Stage IB, G3 S = Pelvic RT
3) High risk*:
Stage II (invades stroma)-III/ IV (ChemoRT)

*all clear cell and papillary serous = high risk

Question 57

Which low risk endometrial cancer patients may require further treatment (what type?)

Answer 57

consider VBT if higher risk features (age >60, LVSI)

Question 58

What key study favours intervention for intermediate low-risk patients?

Also,
Define Intermediate Low risk
What is the intervention and dose (and prescribed to)

Answer 58

Stage IB, G1-2 (LVSI-)

PORTEC2 favours vaginal brachy:

21Gy/ 3 fractions, 7Gy/ fractions, 1-2 fractions/ week (similar to keloid)
* Dose prescribed to 5mm from surface of cylinder

Question 59

For endometrial Ca: What pathologic findings correlate with risk of nodal involvement?

Answer 59

Early studies from GOG suggest that depth of invasion and grade highly correlate with nodal involvement.

Question 60

Which patients benefit from adjuvant RT after TAH/BSO?

Answer 60

Early-stage patients with adverse path features are at risk for extrauterine disease and recurrence. High-risk features vary but overall include deep myometrial invasion, tumor grade, cervical involvement, older age, LVSI, and tumor size (from GOG 33).

Question 61

Is there benefit to adding pelvic RT to those endometrial ca patients who would normally have adj mono- vaginal brachytherapy?

Answer 61

Older prospective RCT data suggests:
Only patients with Gr 3 tumors and >50% MI or LVSI may benefit from pelvic RT. All other stage I pts should receive mono VBT.

This has bourne out in more recent (2012) Swedish RCT - Despite some local recurrence benefit, stage I’s should only have brachy.

Question 62

For endometrial ca. How do you select between adj VCB and adj vaginal EBRT? (this is not a question about pelvic RT)

Answer 62

PORTEC 2:
EBRT (46 Gy /23) vs. VBT (21 Gy/3 fx HDR or 30 Gy LDR).

Eligibility:
Age ≥60, IB G1–2 or IA G3;
OR
Endocervical glandular involvement grades 1–3, any age, but >50% myometrial invasion w/ G3 excluded.

No difference in vaginal recurrence, OS, and DFS for VBT vs. EBRT.
BUT brachy had better QOL: social function, diarrhea, fecal incontinence, and limit of ADLs
And less GI toxicity.

Therefore:
Stage IA, grade III or
stage IB, grade I–II
Do vaginal cuff brachytherapy