Gynaecologic Flashcards
What is the Epidemiology of Uterine cancers
Incidence (Australian statistics)
- 3224 annual cases
- 5th most common cancer in women
Incidence is increasing, likely due to increasing rates of obesity
Most common gynaecological malignancy in developed countries, second most common in developed counties
Most common in post-menopausal women (i.e. >50yo)
Incidence increasing
Median age 65
What are the risk factors for developing Uterine cancers?
1) Exposure to unopposed oestrogen (Exogenous or endogenous) - type 1
a. Results in excess cell proliferation, endometrial tissue hyperplasia> maligancy
b. Obesity (increased aromatase activity)
c. Early menarche, late menopause and nulliparity/infertility
d. Polycystic Ovarian Syndrome
e. Use of unopposed exogenous oestrogen HRT, Tamoxifen (SERM acts as agonist/antagonist depending on baseline estrogen/menopause status; RR 7.5); AI is protective
2) Metabolic syndrome –> linked to obesity
a. HTN
b. Diabetes
c. Poor diet and physical exercise
3) Use of tamoxifen
a. Small increased risk (minor oestrogen agonistic activity in endometrium, RR 7.5)
4) Previous pelvic radiotherapy (small increase in risk)
5) Previous breast cancer (overlapping risk factors)
6) Family history
a. First degree relative imparts RR = 1.8x
Type 2 malignancies are much more likely to have relevant family history
1) Lynch syndrome (dMMR)
a. HNPCC with high risk extracolonic ca, esp endometrial ca
2) Cowden syndrome (PTEN mutation)
Protective factors
1) Increased progestogen exposure
a. Use of opposed oestrogen (i.e. with progestogens) is protective COCP and AI
b. Increased gravida/parida
c. Age at last birth
d. Breast-feeding
2) Smoking
a. Small decrease in risk for post-menopausal
Describe the key clinicopathological subtypes of Uterine Cancer
- Type 1
○ 80%
○ Includes endometroid and mucinous carcinoma
○ Favourable prognosis
○ Associated with long term elevated estrogen exposure, which leads to persistent stimulation of the endometrium
○ Responsive to progestins
○ Histology G1-2
○ Sequential pattern of spread: May be proceeded by atypical endometrial hyperplasia, exophytic macroscopic, Contiguous LN spread
○ PTEN and Kras alterations common- Type 2
○ 20% , but responsible for half of endometrial cancer deaths
○ Worse prognosis, not estrogen related
○ Histology G3 adenoca, papillary serous, clear cell, carcinosarcoma, mucinous
TP53 mutation, HER2 overexpression
- Type 2
Describe the molecular subtypes of Endometrial cancer
Molecular Subtypes
- Molecular classification particularly relevant in context of high-grade and/or high risk disease
- In low risk endometrial carcinomas, molecular classification may not be required
1) POLEmut (ultramutated) a. Mutations in DNA polymerase-E (POLE) --> high-burden of somatic mutations (majority not pathogenic) b. Most commonly present as endometrioid adenocarcinoma c. Younger patients with favourable prognosis (even in the presence of poor pathology --> LVI, high-grade) 2) MMRd: Hypermutated MSI tumours (Microsatellite unstable) a. Mutation (or epigenetic silencing) of MMR genes --> MSI and high-burden of somatic mutations b. Highly sensitive to RT (due to DNA repair deficiency) & ICIs (due to mutational burden) c. Intermediate prognosis 3) No specific molecular profile (NSMP) Copy number low (MS stable) tumours a. Associated with endometrioid morphology --> PI3K/AKT pathway b. Intermediate-to-favourable prognosis; ER/PR positive 4) P53 abnormal (p53abn): Copy number high (serous-like) tumours; a. Aggressive pathology, associated with p53 mutation b. Poor prognosis
Describe the pathological features of Serous Carcinoma of uterus.
Serous Carcinoma (PP= Papillary and psammoma bodies)
- Much more aggressive than endometrioid carcinomas
○ P53 mutation in 90% of cases
○ High proppensity of intraperitoneal, transtubal mets
- Can arise from within existing polyps
- Typically estrogen independent carcinomas arising from post-menopausal women
- Macroscopic ○ No distinguishing features - Microscopic ○ Multiple architectural appearances, though almost always high-grade § Papillary § Gland-like (but less defined than endometrioid) § Solid ○ Cells have scant cytoplasm with significant nuclear atypia ○ Psammoma bodies common - Immunohistochemistry ○ Similar to endometrioid, few differences § More likely to have p53 and p16 mutation § Less likely to have ER/PR expression ○ Need to assess MMR stains (MLH1, PMS2, MSH2, MSH6) - Surgery like ovarian. TAH bso inferior omentectomy
List the different histological types of endometrial cancer
1) Epithelial tumours (SEM-CUT) - all PAX8 positive (mullerian)
a. Endometrioid (75%) - Adenocarcinoma
b. Serous (10%)
c. Mucinous (3%)
d. Clear cell (5%)
e. Squamous cell
f. Undifferentiated
2) Carcinosarcoma (MMMT - malignant mixed Mullerian tumour)
3) Sarcoma
a. Leiomyosarcoma
b. Endometrial stromal tumour
Small cell carcinoma
Describe the pathological features of Endometrioid adenocarcinoma of uterus.
Endometrioid Adenocarcinoma (type 1)
- Most common histology in endometrial cancers
- Arises in younger women and is estrogen dependent
- Can emerge from any of the molecular/genetic subgroups (hence heterogenous group)
- Typically arises from a precursor lesion (atypical hyperplasia)
- Macroscopic ○ Highly variable § Can be well-defined and polypoid/exophytic, friable § Can be diffuse and infiltrative ○ Tends to invade myometrial layer first - Microscopic ○ Tall columnar cells with some atypia § Smooth luminal border ○ Glands lie back to back (confluent or crowded) without intervening stroma § Can have cribriform, papillary or villoglandular patterns ○ Grade based on preservation of glandular growth pattern ○ May have squamous differentiation ○ MELF patten (microcystic) higher rate of lvi and nodes - Immunohistochemistry ○ POS = PAX8, CK7, ER, PR, vimentin NEG = CK20, CEA, Napsin A, p16
Describe the pathological features of Clear cell carcinoma of uterus
Clear Cell Carcinoma
- Rare subtype (<5%)
- Behaviour is dependent on underlying mutations (i.e. p53mut do poorly)
- Macroscopic ○ No distinguishing features - Microscopic ○ Diagnosis based on classic architecture and cytology ○ Architecture § Solid, glandular or papillary are possible ○ Cytology § Polygonal cells with marked & abundant clear to eosinophilic cytoplasm § Clear cytoplasm (presence of glycogen) with hobail cells § Hobnail cells & flat cells are seen § Variable degrees of nuclear atypia § Automatically Grade 3 - Immunohistochemistry ○ POS = CK7, AMACR, Napsin A, HNF-1b NEG = ER/PR, CD10
Describe the pathological features of Carcinosarcoma of uterus
- Rare and very aggressive tumour
- Characterised by biphasic epithelial/sarcomatoid differentiation
○ Sarcomatoid component represents EMT transition - Macroscopic
○ Polypoid lesions with fleshy and friable appearance
○ Haemorrhage/necrosis is common
○ Extensive myometrial invasion +/- local invasion - Microscopic
○ Characterised by biphasic epithelial and sarcomatoid appearances
§ Carcinoma –> high-grade and most often serous or high-grade endometrioid
§ Sarcoma –> most often appear spindles and pleomorphic
§ 50% may have heterologous elements (rhabdomyosarcoma or chondrosarcoma most common) - Immunohistochemistry
○ Carcinomatoid component is similar to endometrioid
○ Sarcomatoid component
§ POS = desmin & myogen
If liposarcoma/chondrosarcoma present –> S100 POS
- Characterised by biphasic epithelial/sarcomatoid differentiation
Describe the pathological features of Leiomyosarcoma of uterus
Leiomyosarcoma
- Very rare de-novo tumour arising from the myometrium
- Three subtypes: spindle, epithelioid, myxoid
- Macroscopic ○ Large bulky tumours generally with myometrial infiltration ○ Often haemorrhagic/necrotic ○ Myxoid subtype will have gelatinous cut surface - Microscopic ○ ○ Typical spindled tumour cells ○ Classic features (need 2 of 3 features) § Marked cellular atypia § >10 mitosis/10hpf § Tumour necrosis ○ Mitotic index high - Immunohistochemistry ○ POS = desmin & SMA (smooth muscle), ER/PR, keratins & EMA (epithelial) ○ NEG = HMB45 & MelanA - Stage 1-2 No adjuvant treatment - Stage 3+ -chemo
How is endometrial cancer graded?
Grade
- FIGO grading system (primarily based on architecture and cytology) ○ Grade 1 = 1 <=5% solid pattern (95% or more glandular squamous growth) ○ Grade 2 = 6-50% solid pattern ○ Grade 3 = >50% solid pattern - The presence of marked/severe nuclear atypia raises the grade by 1 ○ Pleomorphic nuclei ○ Prominent nucleoli - WHO 2020 update = FIGO binary scheme ○ FIGO Low-grade = G1-2 FIGO High-grade = G3
Describe Cowden syndrome.
Describe Lynch Syndrome
What are the prognostic factors for endometrial cancer?
atient Factors
- Age (older imparts worse prognosis)
- Race (African/African-American patients have worse prognosis)
- Performance status & co-morbidities
Tumour Factors
- Histological subtype (endometrioid is positive; serous/clear cell is poor)
- FIGO stage
○ I = Myometrial invasion (50% or 66% threshold)
○ II = Cervical stromal invasion
○ IIIA/B = adnexal/vaginal involvement
○ IIIC = nodal involvement (micromets = positive, no evidence ITCs impact prognosis)
○ IV = local invasion
- LVI (does not influence LR, instead pelvic/distant metastasis; 25% risk of LN+)
- Grade
- MSI instability
- Molecular pattern (POLE is positive; p53 is poor)
- MELF pattern (microcystic, elongated and fragmented)
Treatment Factors
- Extent of surgical resection
- Residual disease post surgery
Describe the risk grouping for endometrial cancer.
Risk Groups
Low Risk (all of the below)
- Endometrioid histology
- Grade 1 or 2
- <50% myometrial invasion (i.e. FIGO IA)
- No LVI
Intermediate risk
- Endometrioid histology, AND
○ G1-2 & <50% myometrial invasion & LVI
○ G1-2 & >50% myometrial invasion
○ G3 & <50% myometrial invasion
High-risk
- FIGO stage III-IV
- High-risk histology (serous, clear cell, carcinosarcoma, etc.)
- Special case –> G3 endometrioid with >50% myometrial invasion
Stratification of Intermediate Risk Patients
- Stratify low-intermediate and high-intermediate - Two key stratification systems with similar inputs ○ Age ○ Grade ○ Myometrial invasion ○ LVI
How would you work up a patient with Endometrial cancer?
- History
○ HPI
§ Abnormal vaginal bleeding (90% of patients)
* Hypermenorrhea, menometrorrhagia, postmenopausal bleeding
* IMB
§ Vaginal discharge
§ Pelvic or Abdominal pain/ bloating (mass symptoms)
* Bladder, rectal, pelvic pain
§ Abnormal cervical screening cytology
§ Incidental finding on other imaging or hysterectomy for other purpose (e.g. fibroids)
○ PMHx:
§ Other malignancies (e.g. GI or breast –> Lynch)
§ Previous radiotherapy (especially for uterine sarcoma)
○ Medications
§ Use of tamoxifen or unopposed oestrogen
○ Gynae History
○ Family History
§ Lynch syndrome
○ Social
§ Performance status and fitness- Examination
○ Abdominal palpation
○ Vaginal examination including bimanual examination
○ Size, cervical/vaginal involvement
○ Ascities, nodes
Work-Up - USS –Pelvic or transvaginal
○ Assess endometrial thickening (>5mm= 7% risk of carcinoma in post menopausal woemn)
○ Transvaginal preferred= higher sensitivity for myometrial invasion - MRI Pelvis for Stage ≥II
○ If suspicious of cervical stromal invasion
○ Highly specifi in assessment of myometrial invasino, cervical stromal invasion and LN mets - D+C & hysteroscopy
○ Establish histological diagnosis - Cystoscopy/sigmoidoscopy if Sx suggestive of bladder or bowel invovlement
- CT CAP (staging)
○ May be reasonable to image CT AP only in low risk groups
○ Extrauterine spread - PET
○ Can be considered to assess ovarian, nodal, peritoneal and other mets
○ Not PBS funded - Bloods
○ FBC, EUC, CMP, LFT, coags (pre-op suitability)
○ CA125 (baseline), raised in ~50% of cases - Hysterectomy Specimen
Surgical staging system (FIGO)
- Examination
What are the differentials for a uterine mass?
Differentials
Benign
-Endometrial hyperplasia or polyp
-Uterine fibroid
-Endometriosis
Malignant
-Endometrial carcinoma
-Leiomyosarcoma
-Carcinosarcoma of the uterus
-Cervical cancer with uterine invasion
Metastatic
-Metastasis to the uterus (rare)
-Lymphoma
Describe the Staging for Endometrial cancer.
FIGO 1A
<50% myometrial invasion
FIGO 1B
>50% myometrial invasion
FIGO 2
Cervical stromal invasion, but not beyond uterus
- NOTE: endocervical glandular involvement is only stage 1
FIGO 3A
Invasion of uterine serosa or adnexa
FIGO 3B
Invasion of vagina or parametrium
FIGO 3C
Lymph node involvement (both macro and micro <2mm)
IIIC1: Pelvic
IIIIC2: Para aortic +/- pelvic
FIGO 4A
Bladder or rectal mucosal involvement
FIGO 4B
Distant metastases (non loco regional nodes e.g. inguinal, peritoneal and ascites)
Discuss surgical management for endometrial cancer
Hysterectomy + Bilateral Salpingoophorectomy + Sentinel Node Biopsy
* Surgical management is the mainstay of therapy in all cases of non-metastatic disease (unless medically inoperable) ○ Therapeutic necessity (cytoreduction) - Complete or optimal cytoreduction= OS and PFS longer ○ Surgical staging * Total Abdominal Hysterectomy/ Extrafascial hysterectomy (TAHBSO) is the standard, unless there is cervical stromal involvement ○ Aim for minimally invasive approaches (laparoscopy +/- robotic), including in those with high-risk endometrial ca - Multiple studies comparing open vs. minimally invasive (LACE, LAP2) □ Minimally invasive showed similar survival with quicker recovery □ Including those with high risk endometrial carcinoma □ Shorter hospital LOS, enhanced recovery, equal detection rates for overall disease; fewer post op complications: blood loos, transfusion, wound complication, ICU admission ® More cost effective ® Longer operation times ® Most patients early stage, one study in 2020 IIIC= equallty safe without impairing survival and complete resection achieved - Intra-peritoneal spillage, including tumour rupture of morecellation (incuding in a bag) should be avoided - Can have vaginal hyst, however consider other approaches if concern with vaginal extraction (eg. Mini laparotomy, use of endobag) § Cavet: Restricts exploration of the abdo cavity, peritoneal washing, LND, omentectomy ○ Note peritoneal cytology should not be routinely perofrmned, as posiitive results could be attributed to uterus handling ○ High risk histology –infracolic omentectomy ○ Stage 1a gd 1 –can have ovarian preservation. * If cervical stromal involvement then Type II/III operation
Discuss surgical management of lymph nodes for endometrial cancer
Management of Lymph Nodes:
* Lymph node staging does not have a therapeutic value but is done to assess extent of disease and guide adjuvant therapies * The preferred nodal staging approach is sentinel node (for all risk categories, in high volume centres) ○ Resection of the sentinel nodes (tracer injected around cervix x8) ○ Resection of adjacent or suspicious nodes ○ Reduced morbidity and potential increase in detection of positive LN with ultastaging technoiques § Especially lower limb oedema ○ Prospective trials show high Sn and high Sp; and similar prognosis ○ Can consider omission if no myometrial invasion (suggestive on MRI preoperatively) ○ Indocyanine green >methylene blue * Extensive elective nodal dissection/ sampling is discouraged ○ Pros: may guide tailing or adjuvant treatment and fields ○ Cons: No survival benefit, Increased risk of lymphoedema and surgical morbidity * If pelvic LN involvement is found intraoperatively, further systematic pelvic LN dissection should be omitted ○ Debulking of enlarged LNs and paraAo staging can be considered
Describe the endometrial cancer risk grouping as per ESGO/ESTRO/ESP (molecular classification unknown)
Describe the trial definition of high-intermediate risk in endometrial cancer.
Discuss the potential management for a patient with low risk endometrial cancer.
- Fertility sparing option
○ All criteria must be met of:
§ Stage 1A, Grade 1, Endometrioid adenocarcinoma on D&C (confirmed on expert pathology review),
§ Disease limited to endometrium on MRI,
§ no contraindications to medical therapy.
§ Pregnancy test negative.
○ Patients should undergo counselling that fertility sparing is not standard of care.
○ MDT discussion and supervision
○ Molecular evaluation
○ Continuous progestin-based therapy: Megestrol (or one of the below for medically unfit)
§ C/I to megestrol: breast cancer, stroke, MI, PE, DVT, smoking.
○ Endometrial evaluation every 3-6 months
§ Hysteroscopy D&C
§ MRI
○ If complete response at 6 months (only 50% get durable complete response) -> Encourage conception
○ If persistent adenocarcinoma at 6 months -> Progress to surgery- Non-fertility sparing option
○ All criteria of: Stage 1A , G1-2 disease, endometroid histology, No LVI
○ May be cured with surgery alone
- Non-fertility sparing option
Discuss adjuvant therapy for patients with low and low-intermediate risk endometrial cancer
- Generally, no role for adjuvant therapy (RT or chemo)
○ GOG-99 did not show any benefit for the low-intermediate risk cohort- EviQ: consider vault brachytherapy in 1A/B with substantial LVSI; or 1B G3, or stage 2
○ No set standard for “substantial LVSI”
○ ESGO/ESTRO/ESP =
§ single focus around tumour = focal
§ Tumour in 5 or more LV spaces - When molecular classification is known
Stage I-II, low risk, POLEmut - omission should be considered
- EviQ: consider vault brachytherapy in 1A/B with substantial LVSI; or 1B G3, or stage 2
Describe adjuvant therapy for patients with high-intermediate risk endometrial cancer.
- Adjuvant vaginal vault brachytherapy is favoured over pelvic radiotherapy
○ PORTEC-2 trial
§ Reduction in toxicity (GI G1-2 12.6% vs 53.8%)
§ No detriment to locoregional control
□ Majority of relapses occur within the vagina (not in the pelvic LN)
§ Benefit EBRT over vault brachy: LVSI, p53-abN, L1CAM over-expression
□ LVSI favour EBRT, although if focal can treat with VBT alone (if no other RF)○ Note that if VBT is not available, pelvic EBRT is better than observation alone
- No role for adjuvant chemotherapy after brachytherapy
○ GOG 249: no diff RFS, OS - 1BG3: EBRT is standard, especially with substantial LVSI
○ Consider addition of VBT (controversial)
○ Consider adjuvant chemo (controversial) - If risk factors lean towards EBRT, consider addition of VBT for lower uterine seg involvement
○ Strongly recommended for cervical stromal invasion in many trials
- No role for adjuvant chemotherapy after brachytherapy
pN0 after LN staging:
- Consider EBRT: substantial LVSI and/or Stage II
○ Decreased risk of pelvic & paraAo nodal relapse
- Consider chemo: G3 and/or substantial LVSI
○ NSGO/EORT, PORTEC3: addition of chemo to EBRT: inc RFS, OS
cN0/pNx (LN staging not performed)
- *EBRT: LVSI and/or stage II (PORTEC-3 GOG99)
- Consider brachy alone: gr3 + LVSIneg or for Stage II grade 1 endometrioid
- Consider chemo: especially: gr3 (PORTEC-3)
Molecular (PORTEC-3): no benefit with chemo for MMR-d
Describe the adjuvant therapy for patients with high risk endometrial cancer
- Early-stage with adverse histology (i.e. stage I-II serous or clear cell adenocarcinoma)
○ Recommend pelvic EBRT alone
§ GOG 249
○ Alternative would be adjuvant chemotherapy +/- VBT alone
§ GOG 258- For stage III patients
○ Recommend cisplatin chemoradiotherapy with adjuvant chemotherapy (carboplatin/paclitaxel x4)
§ PORTEC-3 trial
□ Add’n chemo: ↑5yr 5% OS, ↑7% FFS (PORTEC-3; XRT vs CRT)
□ GOG249: vault brachy + 2c carbo/taxol: no diff 5yr RFS, OS vs pelvic EBRT
□ LN relapse lower with EBRT
□ Note that patients with stage III and serous histology benefited most
□ Patients with stage I/II disease did not benefit much
□ Molecular:
® P53-abN (stage I-III): Signif OS benefit for add’n chemo
® NSMP: some benefit for chemo
® MMR-d: no benefit from chemo
POLEmut: almost no recur in either arm§ If vaginal involvement (stage IIIB), consider vaginal brachytherapy boost (10Gy/2F)
○ Alternative approach is adjuvant chemotherapy +/- VBT alone
§ CRT (PORTEC-3) vs 6c carbo/taxol: no diff RFS, OS (GOG-258)
§ Higher rates LN relapse - concerns about local and nodal recurrences
§ GOG 258
□ 6x carboplatin/paclitaxel
□ ChemoRT improved vaginal recurrence rate (2% vs 7%)
□ ChemoRT improved nodal recurrence rate (11% vs 20%)
□ No difference in RFS or OS
□ More distant recurrences and slightly reduced QoL with chemoRT
- For stage III patients
List the indication for adjuvant Vault brachytherapy in patients with endometrial cancer.
- Indications for Vaginal brachytherapy post-op
○ Stage 1a with: Grade 3 or Clear cell carcinoma, or Serous carcinoma
○ Stage 1b with: Grade 3 or Clear cell carcinoma, or Serous carcinoma
○ Stage II (cervical involvement) for boost post EBRT
○ Stage III/IVa - consider VBT boost for Endocervical stromal invasion( mucosal invasion not enough), vaginal involvement
Vaginal hysterectomy with piece meal resection.
Discuss the management of advanced endometrial cancer (stage III-IVb)
- Stage III-IVA with residual disease,
- Maximal cytoreduction if macroscopic complete resection is possible
- Chemo RT +/- VBT + adjuvant Chemo or Chemotherapy alone
○ GOG 258
§ 6x carboplatin/paclitaxel
§ ChemoRT improved vaginal recurrence rate (2% vs 7%)
§ ChemoRT improved nodal recurrence rate (11% vs 20%)
§ No difference in RFS or OS
§ More distant recurrences and slightly reduced QoL with chemoRT - Stage IVB (of any molecular subtype)
○ Carboplatin/ Paclitaxel
Debulking surgery –improve symptoms –local compression,
What are the management options for patients with endometrial cancer who are medically unfit?
- Medical contra-indications to standard surgical management by minimally invasive surgery are rare
- Vag Hys + BSO if feasible should be considered in pt unfit for recommended standard surgery
- Definitive XRT when surgery contraindicated for medical reasons
○ Stage Ia: Uterine brachytherapy alone (EBRT alone if not suitable for brachytherapy)
○ Stage ≥Ib: EBRT + Uterine brachytherapy boost +/- Chemotherapy (EBRT+/- chemo if not suitable for brachytherapy) - Hormone therapy (unfit for surgery or XRT)
○ Megestrro
○ Medroxyprogesterone
○ Levonogesterel IUD
Vaignal Recurrence (after observation or adjuvant treatment)
* No prior RT:
○ EBRT 45-50Gy + brachytherapy (vault +- needle) 18-21/3
§ Aim 80Gy eqd2 for cure
* After prior RT –aim cumulative dose 80-90Gy (10% risk gd 3 toxicity)
○ EBRT + brachy
○ Or just brachy
Or surgery
Discuss systemic therapy regimens for concurrent, adjuvant and metastatic endometrial cancer treatment.
PORTEC 3:
Concurrent:
- Cisplatin 50mg/m^2
○ Q3w, Day 1, 22
Adjuvant:
- Paclitaxel 175mg/m2 IV + Carboplatin 5AUC IV day 1, q21d x4
METASTATIC:
Hormone therapy (first line for low-grade without rapid progression)
- Medroxyprogesterone and tamoxifen, alternating
- Megestrol and tamoxifen, alternating
- Medroxyprogesterone
- Megestrol
- AIs: aromatase inhibitors
- Tamoxifen
- Fulvestrant
First line (chemo)
- Carboplatin, paclitaxel
- Category 1 for carinosarcoma
- Carboplatin, paclitaxel, trastuzumab
- HER+
Targetted therapy
- Pembrolizumab: TMB-H, MSI-high (PD-1) (deficient MMR, PolE = 40% long term survival 3 years)
- Nivolumab (PD-L1)
- Larotrectinib, entrectinib: NTRK gene fusion
Is there evidence to support elective lymph node dissection in endometrial cancer?
There is no role for routine elective lymphadenectomy
ASTEC (ASTEC group, 2008)
- 1408 women with endometrial adenocarcinoma were randomised to:
○ TAHBSO +/- elective lymphadenectomy
○ More than half of intermediate/high risk patients in both groups received adjuvant radiotherapy
- Outcomes
○ No difference in OS (HR 1.16; p=0.31)
○ No difference in RFS (HR 1.25; p=0.14)
○ Trend to worse OS with lymphadenectomy (including worse OS with increasing number of nodes dissected)
- Although RT was given, it was equally split across treatment arms and is felt to not influence broad conclusions
- Pattern of recurrence
○ Total (11%)
§ Vaginal (25% –> 3% of all)
§ Pelvic (15% –> 2% of all)
§ Distant (53% –> 6% of all)
Both pelvic and distant (7% –> <1% of all)
What is the evidence for adjuvant management in stage I-II, low risk Endometrial cancer?
Low risk Endometrial cancer, Sorbe 2009
- Safe to omit VBT if 1A, G1-2, endometrioid, no LVSI
- Obs vs VBT
- Vaginal recurrences 3.1% vs 1.2% (not significant)
Benefit of Pelvic RT
MA Kong et al. Cochrane, 2012 (of GOG99, PORTEC1, ASTEC, Sorbe, PORTEC) ○ Pelvic EBRT improves locoregional control (but not OS) in high risk stage I ○ The benefit is in HIR patients (low and LIR patients can be observed) Norwegian trial (Onsrud, 2013) ○ 568 patients with stage I endometrial cancer were randomised to EBRT + VBT vs VBT alone § VBT = LDR (60Gy to surface over 96 hours) § EBRT = 40Gy/20F (centrally reduced to 20Gy) ○ Outcomes § No difference in OS (HR 1.13) □ Subgroup analysis --> possible benefit if G3 and >50% MMI § Increased mortality in women < 60 years of age with EBRT □ Increased risk of second malignancy § EBRT reduced risk of pelvic recurrence (6.9% vs 1.9%) MRC ASTEC RT trial + meta-analysis (ASTEC group, 2009) ○ ASTEC RT randomised women after the initial randomisation to lymphadenectomy (intermediate or high risk) § EBRT 40-46Gy/20-25F vs observation ○ Meta-analysis includes ASTEC, PORTEC 1, GOG99 & Norwegian trial ○ Outcomes from ASTEC RT § No OS advantage to EBRT (HR 1.05) § Improved recurrence rates with EBRT (6.1% vs 3.2%; HR 0.46) □ Majority of recurrences were distant (55%) □ Vaginal was the most likely local site ○ Outcomes from meta-analysis § No OS benefit with EBRT (HR 1.04)
What is the evidence for adjuvant management in stage I-II, high intermediate risk Endometrial cancer?
PORTEC-1 (Creutzberg, 2011)
○ 714 women with Stage IB/C endometrial cancer and found to have high-intermediate risk disease (PORTEC criteria)
§ Women needed 2 of 3 risk factors for HIR (>60 y, deep invasion, G3)
§ After hysterectomy+BSO, no LND, randomised to EBRT (46Gy/23F) vs observation
○ Outcomes
§ EBRT improved LRR at 15 years (15.5% vs 5.8%)
§ EBRT appeared to improve OS in total cohort (60% vs 52%; p=0.14)
□ No benefit in HIR group (48% vs 41%; p=0.35)
○ Patterns of recurrence
§ 74% of failures were at the vagina
○ Toxicity
§ Long term G2 GI/GU 25%
GOG 99 (Keys, 2004) ○ 448 women with intermediate risk patients were randomised to § WPRT (50.4Gy/28F) vs observation § HIR group defined as per GOG criteria ○ Outcomes § No difference in OS (HR 0.86) § WPRT associated with improvement in RFS (HR 0.42; 12% vs 3%) □ Majority of benefit in the HIR group (26% vs 6%; HR 0.42) ○ Patterns of recurrence § Majority (2/3rds) of recurrences occurred in the vaginal vault
Vaginal Brachytherapy vs Pelvic EBRT
Summary:
- VBT is associated with high rates of vaginal LC, and much lower toxicity than pelvic EBRT
- Whilst VBT has higher pelvic nodal recurrences, these are rarely isolated nodal recurrences
○ Addition of chemotherapy does not compensate
Both GOG99 and PORTEC 1 showed most initial recurrences with uterine confined tumours were limited to the vagina
PORTEC-2 (Wortman, 2018) RCT ○ VBT noninferior to EBRT for vaginal recurrence for HIR patients , with better QOL § Fewer acute toxic GI effects with VBT. § There is around a 1 in 8 chance of "bowel bother" after WPRT ○ 427 women with high-intermediate risk endometrial carcinoma were randomised to § Adenocarcinoma with: Age >60 and ≤IBG3 or, any age and old IIA § VBT (21Gy/3F at 5mm depth) vs EBRT (46Gy/23F) ○ Outcomes § No difference in vaginal recurrence rate (3.4% vs 2.4%) § VBT resulted in inferior rates of pelvic recurrence (6.3% vs 0.9%) □ Only 1.5% had isolated pelvic recurrence (remainder in conjunction with distant mets) § No difference in DM or OS (69.5% vs 67.6%) No LVI vs Focal LVI vs substantial LVI in PORTEC 1-2 (2015 subgroup analysis review) ○ Substantial LVI predicts pelvic relapse, distant metastasis and overall survival § Substantial LVI should receive WPRT § Not part of the original PORTEC risk factors, but part of GOG risks GOG 249 (Randall, 2019) ○ VBT + Chemo not superior to WPRT § Acute toxicity much worse with VBT + Chemo (Acute G3+ 11% vs 64%) ○ 601 women with HIR or high-risk stage I-II (including serous/clear cell carcinomas) were randomised to § Pelvic RT (45-50.4Gy/25-28F) § Vaginal brachytherapy (multiple fractionations) with adjuvant chemotherapy 3x carboplatin/paclitaxel ○ Outcomes § No difference in RFS between arms (HR 0.92) § No difference in OS between arms (HR 1.04) § Increase in early toxicity with VBT + chemotherapy ○ Patterns of recurrence § Marked increase in pelvic or para-aortic recurrence with VBT + chemo (9% vs 4%) § No difference in rate of vaginal or distant recurrences
Describe the evidence for management of high risk serous + clear cell endometrial cancer
High-Risk Histology (Serous + Clear Cell)
Summary
- There is no clear benefit to the addition of chemotherapy for stage I-II serous or clear cell adenocarcinomas
○ GOG-249 –> nodal recurrence was higher in the VBT + chemotherapy arm (no OS difference)
○ PORTEC-3 –> limited benefit in the stage I-II subgroup
- EBRT alone is the preferred treatment approach VBT would be associated with up to 10% risk of pelvic recurrence (borderline)
Describe the evidence to support adjuvant treatment in Stage III endometrial cancer
Summary:
- For patients with stage III disease, chemoRT remains the preferred option
○ GOG-258 –> chemoRT reduced vaginal and pelvic nodal recurrence
- For patients with stage I-II disease, minimal benefit is gained from addition of chemotherapy to RT (PORTEC-3)
- For patients with serous histology, serous consideration to addition of chemotherapy should be given (PORTEC-3)
○ Consider VBT with adjuvant chemotherapy (risk of pelvic nodal recurrence as per above)
PORTEC 3 (de Boer, 2019) ○ Landmark trial, introduced idea of treatment de-escalation for certain molecular subtypes ○ There was an OS benefit and failure free survival benefit with addition of concurrent/adjuvant chemotherapy added to adjuvant WPRT, for high risk patients § On subgroup analysis, benefit is for Stage III, serous histology and p53abn molecular type § POLEmutant subtype did profoundly better (>95% OS) than others in both OS and RFS in both arms □ may be a group suitable for de-escalation of chemotherapy ○ 686 women with high-risk endometrial cancer (stage I to III, including those with serous + clear-cell histology) § Randomised to EBRT (48.6Gy/27F) +/- chemotherapy (2x concurrent cisplatin and 4x sequential carboplatin/paclitaxel) § Addition of vaginal vault brachytherapy allowed if cervical involvement (10Gy/2F at 5mm) ~50% used in each arm ○ Outcomes § OS higher in the chemoRT arm (HR 0.70; p=0.03) □ Stage III cancers had a trend towards OS benefit with chemoRT (78.5% vs 68.5%; p=0.043) □ Stage I-II disease did not have an OS benefit with chemoRT (83.8% vs 82%; p=0.50) § 5 year failure free survival was improved in the chemoRT group (HR 0.70; p=0.016) □ Stage I-II disease did not have a FFS benefit with chemoRT (HR 0.87; p=0.54) § Serous histology was associated with a particular benefit from chemoRT □ Improved OS (71.4% vs 52.8%; p=0.037) □ Improved FFS (HR 0.45; p=0.008) □ Absolute numbers were small, not clear if beneift for all stages ○ Note that OS benefit was only revealed at long-term follow-up ○ Toxicity § Marked increase in G3+ acute toxicity [mostly haematologic 45%] with chemoRT (61% vs 13%) § The only difference in late toxicity was sensory neuropathy ○ Patterns of recurrence § Isolated vaginal or pelvic relapse were very rare in both arms (<1%) GOG 258 (Matei, 2019) ○ 813 patients with stage III or IVA endometrial cancer (and stage I-II serous/clear-cell with peritoneal washings) were randomised to § Chemoradiotherapy (45Gy/25F with concurrent cisplatin; followed by 4x carboplatin + paclitaxel) § Chemotherapy alone (6x carboplatin + paclitaxel) ○ Study design was pseudo non-inferiority § Null hypothesis was chemoRT would not achieve higher RFS than chemo alone ○ Outcomes § No difference in 5 year RFS between arms (59% vs 58%; p=0.20), or OS § Higher rates of vaginal recurrence in the chemo alone arm (2% vs 7%) § Higher rates of pelvic/para-aortic nodal recurrence in the chemo alone arm (11% vs 20%) The null hypothesis could not be rejected (i.e. chemoRT cannot be declared superior to chemo alone)
Describe the adjuvant EBRT radiation technique for endometrial cancer.
Patients
1) No Chemotherapy
1. High-risk stage I-II (G3 + >50mm MMI)
2. Stage I-II serous or clear-cell adenocarcinoma
2) Concurrent chemotherapy
1. Stage III
Pre-simulation
MDT discussion
Fertility discussion
If stage II (cervical involvement)
- Consider brachytherapy boost (10Gy/2F)
Aim to start within 6-8 weeks post op, or in relation to chemo
Simulation
Supine with arms on chest
- If treating extended para-aortics, arms above head
Vacbag, knee-block and ankle-stocks
Generous CT (2mm with IV contrast)
- Diaphragm to below ischial tuberosity (include entire kidneys)
- Full and empty bladder scans
- Empty rectym
Vaginal swab/contrast
Consider IV and oral contrast for bowel and nodal deliniation
Fusion
MR and FDG-PET fusion (if available)
Dose prescription
Single Dose Level
- 50.4Gy/28F prescribed to PTV as per ICRU 83
- 45gy/25#
ECE/margin + (micro): 55-60Gy EQD2
Marco/bulky:66Gy
Concurrent chemotherapy if stage III, serous, and/recurrent
- Cisplatin at 50mg/m2 every 3 weeks
VMAT technique
9 days per fortnight
Consider VBT boost (10Gy/2F)
Volumes
* CTVp
○ Upper half of vagina (min 3cm) including paravaginal soft tissue and
○ Parametrium (including surgical clips)
* CTVn
○ Internal iliac, external iliac and obturator nodes
○ If any pelvic nodes involved, include common iliac nodes
○ If any common/para-aortic nodes involved, ensure coverage of at least 2cm above involved node
○ If cervical invasion, include pre-sacral nodes (S1-2) ○ Para Ao: superior limit 7mm below T12 * ITVp ○ CTVp on both full and empty bladder scans
- PTV
○ (ITVp + CTVn) + 7mm
Target Verification
Daily CBCT
OARs
Bladder
- V45 < 35%
- V40 < 60%
Rectum
- V40 < 60%
- Dmax >=0.03cc <=110%
Small Bowel
- V45 < 195cc
- V40 < 250cc; <30%
Duodenum
- V55<15cc
Kidneys
- Mean < 10Gy
Femoral heads
- Dmax < 50Gy
- V45<50
- V50<10
Spinal Cord
- Dmax < 45Gy
Ovaries (if surgically transposed)
- Mean < 5Gy
Manage anaemia, transfuse if Hb <100
Describe the definitive radiation technique for endometrial cancer
Definitive ChemoRT +/- Uterine Brachytherapy
Patients
Pt preference or not medically operable
Pre-simulation
As per Adj
Simulation
EBRT as per Adj
Uterine brachytherapy as per cervical brachytherapy procedure except ideally Y applicator
Dose prescription
EBRT: 45-50.4Gy/25-28x to pelvis and nodes
55-57.5Gy nodal boost (Radiologically involved)
Uterine brachy (Total dose= EBRT+Brachy):
-GTV: 80-90Gy EQD2
-HR-CTV D90: 70Gy EQD2
Example uterine brachy fractionation: 12Gy/2#
Volumes
GTVp clinically and imaging
GTVn involved nodes (>1cm or PET avid)
CTVp = GTVp +
entire uterus, cervix, fallopian tubes and ovaries + parametrium
+upper 50% of vagina including paravaginal ST and parametrium
CTVn_boost= 0-7mm margin
CTVn_elective
- Obturator
- Ext + Int iliac LN
- If cervical invovlement, include presacral LN
- High risk: consider common iliac
- 2cm above highest level LN
- Lower 1/3 vagina include inguinal
ITV as per adj
PTV = CTV + 7mm
GTVbrachy= Visible abnormality of T2 MRI
High risk CTVbrachy= GTVbrachy + Entire uterus, cervix. Include cervix/vagina if involved.
Target Verification
kV bone
CBCT review ST
OARs
OARs are combined with EBRT (EQD2 with a/b = 3)
Bladder
- D2cc < 80Gy
Rectum
- D2cc < 70Gy
Sigmoid
- D2cc < 70Gy
Bowel
- D2cc < 70Gy
Describe the vaginal vault brachytherapy technique
Vaginal Vault Brachytherapy (VBT)
Patients
1) High-intermediate risk
2) Boost for cervical stromal invasion
Pre-simulation
MDT discussion
Fertility discussion
Simulation
Procedure
o Consent
o Pelvis examination - inspecting vaginal cuff to rule out early recurrence and ensure adequate healing
§ Estimate diameter of vaginal diameter and length
o Selection of cylinder size (use largest possible)
o Lubrication of applicator prior to insertion of applicator
o External immobilization
o CT simulation (D1 only)
o Volume upper half of vagina
o Dose to 5mm
o Proceed with fraction 1 on same day
o Brief examination prior to each fraction
Prescribed Dose
Brachy alone
- 21Gy/3F (7Gy/F) prescribed to 5mm depth
○ (95% of vaginal lymphatics lie within 3mm of surface)
Boost following EBRT:
- 10Gy/2F,
- 11Gy/2Fx
- (60Gy EQD2)
No concurrent chemotherapy
Aim for 1-2 fractions per week
Volumes
- CTV
* Upper half or 4cm of vagina, whichever is greater
○ Consider treating whole vagina if extensive LVI, clear cell/serous or IIIb disease
* Max dose to upper 120-140Gy
* Max dose to lower 1/3 = 0.3333 80-90Gy
- No specific planning required (library), regimen within tolerance of OAR
* Or can do CT based plan
OARs
No strict constraints
- Avoid hot spots
List the acute and late side effects of endometrial EBRT and Brachytherapy. Discuss management of these
Management:
- Vaginal stenosis/ shortening
○ Result of circumferentially narrowing of vault or adhesions within vagina
○ Sexual dysfunction, difficulty of surveillance
○ When not contraindicated: topical oestrogens
○ Vaginal dilators
○ Topical mitomycin
Vaginal stenosis- narrowing or shortening of the vaginal vault as a late effect from RT due to the formation of adhesions. Can be caused by EBRT or vaginal vault brachytherapy. Management strategies supportive
- Vaginal Dilation
Use of vaginal dilators starts >6 weeks after finishing RT, to allow acute inflammation to settle
Start with smallest size dilator and gradually increase the size with time
Guideline for using daily for 10-30 mins for first 6 months
Ensure +++ water based lubrication used with vaginal dilators - Sexual activity
-Gentle penetrative sexual activity, similar to use of dilators.
-Psychosocial support of patient from physician and partner with this
-It is important to emphasise no one to feel rushed or pressured into sexual activity and it is done in a safe and supportive environment - Allied health support- Pelvic floor physio, sex therapist, counsellor
-Help relax the pelvic floor
-Psychosocial support
Monitoring and management of late toxicities
- Vaginal stenosis and shortening: encourage sexually intercourse, use of regular vaginal dilators, start off 3 x weekly
○ Use lubrication
- Smoking: cessation encouraged
- Bone health and pelvic insufficiency fractures: maintain bone health, commence vitamin D and calcium supplementation
- Pelvic floor exercises
- Skin dry desquamation can be treated with skin hygiene, water-based creams
- If lymphoedema of lower limbs – monitor for skin breach, infections, exercises, lymphoedema clinic, compression devices
- Weight loss: Maintain
- Bladder and bowel dysfunction
○ Cystitis: ural, cranberry juice
○ Bowel: probiotics
- Psychosocial support- support groups, etc
Pelvic Insufficiency fractures:
- ABCD
- Ensure neurovascularly intact
- History and examination
- Manage pain - analgesia, consider referral to chronic pain specialist
- Check Bone density (BMD, QCT)
- WBBS + MRI to assess extent (CT relatively insensitive)
- Calcium and vitamin D
- Physiotherapy
- Referral to endocrinologist for complex bone strengthening/health agents
- Weight bearing exercises/rehabilitation
- Can consider vertebroplasty/sacroplasty
- Consider referral to orthopaedic surgeon
Discuss prognosis and follow up for endometrial cancer
Approximate recurrence rates
- Low-intermediate risk
○ Total recurrence = <10%
○ Majority are isolated vaginal
- High-intermediate risk
○ Total recurrence = 20%
○ 75% are isolated vaginal
- High-risk
○ Total recurrence = 30-40%
○ Isolated locoregional relapse is rare
Follow-Up
- Clinical review every three months for the first two years
○ Gynae examination
- Clinical review every six months for years 3 to 5
○ Gynae examination
- NOTES
○ No benefit to routine vault cytology (low detection rate)
○ No benefit to routine imaging
○ CA125 only indicated if elevated at baseline
Describe the epidemiology for cervical cancer and natural history.
Incidence (Australian statistics)
* 913 annual cases
* 11th most common cancer in women
Marked reduction over past 30 years due to HPV screening and vaccination
Age
* Mid 40s, mean age is around 40-50 years
* Earliest is expected in mid 20s (due to latent period for HPV infection)
Marked geographic disparity
* Much higher incidence in developing world – without adequate cytological screening
* Australia lowest mortality, second lowest incidence
Decreasing incidence of invasive disease – due to screening, but increasing incidence of pre-invasive disease
* 75% decrease incidence over past 50 years in countries with screening programs
* 85% women with cervix Ca have not had a PAP test in last 10 years, or never
Cervical Cancer is an AIDS defining illness
Reasons for Rising Adenocarcinoma Incidence – 5-20% of cervical ca
- Rising incidence of similar risk factors for endometrial adenocarcinoma
○ Obesity
○ Metabolic syndrome (diabetes and HTN)
○ Nulliparity or late first pregnancy
○ Use of unopposed oestrogens
- Adenocarcinoma has less dependence on smoking in pathogenesis ○ As smoking rates decline, adenocarcinoma rates will be less proportionally impacted
Discuss the risk factors for cervical cancer
1) HPV exposure
○ Pathogenic variants
▪ Highest-risk (16 & 18)
* Gardasil in Ph3 trials prevents 100% HGIL + CIN2/3 assoc with HPV 16,18,6,11
▪ High-risk (31, 33, 35, etc.)
○ Risk factors
▪ Early first sexual contact
▪ Number of sexual partners (includes sexual history of partners)
▪ History of other STIs
○ Almost all Cervix ca associated with HPV infection; HPV detectable in > 99% of Cx ca
▪ Women with persistent infection at higher risk
▪ >70% cervical ca due to HPV 16/18, 31+35 responsible for ~10%
▪ HPV 31, 33, 45, 52 and 58 cause ~20% (Covered in new Gardasil 9)
▪ HPV 18 and 58 genotypes are predictive for response to chemoRT
○ HPV vaccine
▪ Gardasil: HPV 6,11 (genital warts) and 16,18 (oncogenic) + 31,45
▪ Gardasil 9 (replaced Gardasil): same types as above + FIVE oncogenic HPV types most frequently detected in cervical cancer (31,33,45,52,58) 🡪 will increase level of protection again invasive and high-grade cervical lesions
* 2 doses, six months apart. Funded by Federal government part of National Immunisation Program
▪ For girls and boys aged 12-13yrs
* Can recommend to men who have sex with men, immunocompromised (needs 3 doses), women who are treated for HSIL
▪ Most effective before sexually active + exposed to HPV
▪ Shown to ↓incidence of genital warts in women <26yrs + heterosexual men
▪ Impact in Australia:
* Rates of CIN 2/3 <20years decreased by 53%
* Rates of CIN 2/3 20-24 years decreased by 21%
* Prevalence of oncogenic HPV stains in 18-24 years decreased by 78%
2) Smoking (RR 1.50)
3) Immunosuppression/ HIV +ve
4) Family history
○ No clear genetic link, but known association/familial clustering
5) Long-term OCP use (RR 1.90)
○ Likely related to sexual patterns
○ Some suggestion of gene expression changes
6) Use of DES (diethylbestrol) –> clear cell carcinoma - present in younger females (10-30yrs)
○ Anti-miscarriage drug in the 1950s
Describe the pathogenesis for cervical cancer
HPV infection implicated in >99% of cases
* HPV 16 (60%)
* HPV 18 (10%)
* Others (30%)
1. Initiation –Exposure, infection, integration ○ Mucosal break (e.g. coital) allows penetration of virus into basal epithelial layer □ Transformation zone ( junction of squamous epithelium of ectocervix and columnar/glandular epithelium of endocervix; metaplastic region) is most susceptible due to lack of squamous protection ○ HPV viral integration results in transcription of pathogenic E6 & E7 proteins 2. Promotion – Cell transform into cancer (accumulation of genetic changes) ○ E6 --> binds to p53 which promotes degradation § Key for apoptosis and cell cycle arrest as a result of DNA damage § Allows uncontrolled cell-cycle progression § Impairs DNA repair pathways § Upregulates telomerase, leading to cellular immortality ○ E7 --> binds to Rb which promotes degradation § Responsible for stopping progression through S phase ▪ Allows uncontrolled cell-cycle progression ▪ Impairs DNA repair pathways 3. Progression – Carcinoma develops insitu. LSIL -> HSIL 4. Becomes invasive carcinoma -> metastasis ○ Invasion through basement membrane and increasing metastatic potential
Despite HPV infection, majority do not develop malignancy
* 50% are cleared within 8 months
* 90% cleared within 2 years (high-risk subtypes are more likely to persist)
At transitional zone of cervix, cells are undergoing metaplasia
- At increased genomic stress
- Increased risk of pathogenic mutations
Describe the pre-malignant lesions of the cervix.
- Atypical squamous cells of uncertain significance (ASGUC)
○ 2/3 respond spontaneously. May be reactive or neoplastic
○ In cervical smears, often related to SIL
○ Cytology description:
▪ Nuclear changes are more marked than reactive, less then LSIL
▪ Nuclear is 2.5-3x size of intermediate cell nuclear or 1.5x size of nature metaplastic cell nucleus- Low-grade squamous intraepithelial lesion (LSIL)
○ Incorporates CIN 1
○ Features:
▪ Majority will regress spontaneously (60%) –> no management required
▪ Do not progress directly to malignancy (10% progress to HSIL)
* HPV+ LSIL have greater risk of HSIL than HPV –ve
▪ 30% have coincidental HSIL or invasive disease
○ Gross description: often none, may appear white tanish cerebriform lesion or uncommonly as white irregular plaque
○ Microscopic description: Subtle expansion in lower third of epithelium. Mild nuclear enlargement
○ IHC: Biomarkers are used to identify SILs that are at greater risk of progressing to invasive disease
▪ Ki67: proiliferative marker. Helps to distinguish atrophy from HSIL
▪ P16: most reliable marker, intense continuous staining characterizes SIL
▪ High risk HPV = strong expression/staining (low risk = weak expression/staining)
○ Treatment:
▪ Do not treat. Repeat HPV genotype/LBC in 12 months - High-grade squamous intraepithelial lesion (HSIL)
○ Incorporates CIN 2 & CIN 3
○ Features:
▪ High-risk for progression to malignancy (Untreated, 22-72% develop to invasive cancer )
▪ Cytology demonstrates evidence of deregulated cell cycle machinery
▪ Untreated, 22-72% develop to invasive cancer
▪ Predominantly occur at the transformation zone
○ Micro: Atypia in 2/3rds or full thickness of epithelium. Immature cells with high N/C ratio, irregular nuclear membrane contour, coarse chromatin, and inconspicuous nucleoli. Syncytial growth - tumour cells forming anastomosing cords and sheets with minimal to no connective tissue. Frequent mitosis
○ IHC: P16 strong and diffuse positive nuclear and cytoplasmic in at least 2/3 epithelial thickness
▪ Ki67: positive staining in upper 2/3 of dysplastic epithelium
▪ MUC4
○ Treatment: wide excision of transformation zone
▪ Destroy lesion and transition zone: LLETZ/LEEP, cold-knife cone biopsy, Co2 laser ablation
▪ Co test (HPV + liquid based cytology) annually until negative and then return to 5 year screening
▪ If LBC (liquid based cytology/pap smear) predicted HSIL but LSIL on colposcopic biopsy: diagnostic excision TZ. If pt wants to avoid, can have 6 monthly HPV genotype/colposcopy
Old system - CIN 1 –> low-grade mild atypia
- CIN 2 –> moderate cellular atypia involving <2/3 of epithelial thickness
- CIN 3 –> high-grade atypia involving >2/3 of epithelial thickness
- Low-grade squamous intraepithelial lesion (LSIL)
Glandular
* Endocervical adenocarcinoma in situ (AIS)
○ Intraepithelial lesion containing malignant appearing glandular epithelium
○ Carries a significant risk of progression to invasive adenocarcinoma if not treated ~25%
○ Gross: not distinct, often multifocal involving multiple quadrants of cervix. Often superior to squamocolumnar junction
○ Microscopic:
▪ Epithelial cell crowding
▪ Prominent nuclear hypoerchromasia with coarse chromatin
▪ Mitotic figures
▪ Apoptotic bodies at basal portion of gland in 70% cases
○ Stains:
▪ CEA: diffuse cytoplasmic positivity especially endocervical type
▪ Ki67 usually >30%
▪ P16 strong and diffuse
○ Treatment: (controversial)
▪ Colposcopy + diagnostic excision of endocervical transition zone (Cold knife conization) to evaluate extent of AIS and exclude invasive disease
▪ Controversial -Hysterectomy vs diagnostic excision vs observe
* Depends on fertility
What is the differential diagnosis for a cervical lesion?
Epithelial
* SCC (80%)
* Adenocarcinoma (15%)
* Adenosquamous (<5%)
* Adenoid cystic
* Undifferentiated
* Mesenchymal
* LMS
* Botryoid RMS
* Alveolar soft part sarcoma
* Neuroendocrine (<5%)
* Small cell
* Carcinoid
* Haematological
* Lymphoma
* Metastatic disease
* Ovarian
* Other
* Melanoma, undifferentiated carcinoma
Describe the pathology for cervical SCC
Squamous Cell Carcinoma
* Most common subtype
* Most progress from HSIL – which may take decades
* Most commonly arises at squamocolumnar junction
* Macroscopic ○ Friable, ulcerated tumour at the location of cervical os (may be obliterated) ○ Alternative, can be a more exophytic or polypoid mass ○ Areas of haemorrhage are often present * Microscopic ○ Tumour cells infiltrating in tongues (nests or single cells) within a desmoplastic stroma ○ Multiple variants ▪ Keratinising (keratin pearls) and non-keratinising. Variant – large cell (radioresistant) ▪ Verrucous Ca – well diff, hyperkeratotic warty appearance, pushing border, minimal nuclear atypia. Rarely spread to LN. Not HPV related. Well differentiated. No LN. ▪ Warty - warty surface w features of HPV infection ▪ Basaloid ca - immature basal type squamous cells, nests, peripheral palisading, aggressive ▪ Papillary - high degree nuclear atypia, forms finger-like papillae ▪ Lymphoepithelioma-like - minimal squamous differentiation in diffuse stromal chronic inflammatory reaction. EBV+, resembles nasopharyngeal counterpart, better prognosis ▪ Sarcomatoid ▪ Squamotransitional ○ Keratinising subtypes will have keratin pearls and intercellular bridges ○ Polygonal cells with eosinophilic cytoplasm (pink) ○ Koilocytosis is common in HPV associated SCC ▪ Large nuclei, perinuclear halo, raisinoid appearance (irregular nuclear membrane), hyperchromasia ○ Grade not proven to be prognostically significant * Immunohistochemistry ○ POS = CK 5/6, CK7 (usually negative in other SCCs!), EMA, p40, p63, CEA ▪ p16 often positive (not required) * P16 used as a surrogate marker for high risk HPV infection ○ NEG = CK20, Napsin A, MEL-CAM, p53
Describe the pathology for cervical adenocarcinoma
Adenocarcinoma
* Second most common subtype
○ 85-90% of cases are still HPV related
* More likely to be endocervical rather than at transitional zone
* Less responsive to definitive chemoRT than SCC
* More often metastasizes to ovaries and fallopian tubes
* Can be associated with synchronous ovarian tumours.
* Histologic variants:
○ Mucinous – either intestinal type or signet-ring type
○ Minimal deviation
○ Villoglandular
○ Non HPV:
○ Clear cell – most commonly seen in woman exposed to DES in utero, better prognosis, hobnail cells
○ Endometrioid – difficult to distinguish from uterine adenocarcinoma, better prognosis
○ Mesonephric
○ Serous papillary – rare variant; should exclude mets from ovarian / uterine, worse prognosis
* Macroscopic ○ Exophytic, flat, plaque, ulceration ○ May have barrel shaped cervix with diffuse enlargement (endophytic spread) * Microscopic ○ Stromal infiltration of tumour, which may present as ▪ Atypical columnar cells with abnormal glandular architecture (cribriform or acinar) □ More complex and dense glandular forms □ Abundant cytoplasm, pleomorphic/large nuclei □ Frequent mitosis ▪ Fragmented glands with desmoplastic reaction ▪ Individual cells ▪ LVI ○ Can be mucinous/gastric subtype (non HPV-related) ○ Grade not proven to be prognostically significant, same as uterine cancer (based on percentage of solid growth) * Cytology ○ Large endocervical cells with hyperchromatic nuclei ○ Mucin-depleted cytoplasm (dark appearance on H+E) * Immunohistochemistry ○ POS = CK7, CEA, p16 ○ NEG = ER/PR/vimentin (Uterus would be positive), CK 20, p53, p63, CD10,
Describe features of a gynae pathological synoptic report
Hysterectomy report: RCPA/ICCR 2023
* Pre-analytical - demographic information, clinical information (provided to pathologist), tumour location, operative procedure, accompanying specimens (ie lymph nodes), new primary or recurrence, surgeon, other relevant information
* Macroscopic – specimen measurements (length uterus, length canal, diameter ectocervix 3-9 o’clock, 6-12 o’clock, uterine dimensions, vaginal cuff length), macroscopic visible tumour,(location, size, dimensions, margin, thickness, invasion - parametrium), lymph nodes (number and macro involvement)
* Microscopic – number of tumours, histologic type, grade, depth of invasion (deepest location of tumour within cervical stroma (in thirds), width, wall thickness, ulceration, associated pre-invasive disease, involvement other organs, LVSI, PNI, margin status, LN involvement, parametrium involvement
* Ancillary tests – IHC, HPV typing
* Synthesis/ Diagnostic summary
* Overarching comment if required
Pathology Report:
- Specimen type: sample medium, method of collection
- Overall screening risk classification: low risk, int risk, higher risk, unsatisfactory
- HPV test: Method, result: positive 16/8, oncogenic not 16/18, not detected, unsatisfactory
- LBC results: Method, AMBS findings, presence/absence endocervical component, organisms (trichomonas, fungal, bacterial vaginosis, HSV), non neoplastic findings (reactive cellular changes, atrophy)
- Recommendation for management as outlined by cervical cancer screening guidelines
- False –ve: due to collection technique, preparation, interpretation – blood, small dyskaryosis, inflammation
- False +ve: cervicitis, inflammation, atrophy, metaplasia, endometrial cells
- Colopscopy/hysterectomy report: add tumour size, histologic type, grade, depth of stromal invasion, LVSI, LN (if taken), status of surgical margins, LEEP or cone specimens: endocervical, ectocervical, deep margins. Hysterectomy specimens: vaginal/ectocervical, deep/paracervical, lateral/parametrial margins, p16 staining to above (will clarify diagnosis of LSIL vs HSIL in CIN2)
Discuss the prognostic factors for cervical cancer.
Patient Factors
* Smoking status
* Age and performance status/comorbities
○ Fitness of treatment
* Immunosuppression (HIV w. low CD4 count do worse)
* Anaemia (if having chemoradiotherapy), Hb <110 (RR of relapse = 2.2)
Tumour Factors
* FIGO stage
* LN metastases
* Tumour volume (bulky, >4cm do worse)
* Depth of invasion (Increases risk of LN involvement) and cervical wall thickness
* Parametrial/ endometrial extension
* LVI/PNI reduces OS by 20-30%
* Histological variant
○ lymphoepithelial and verrucous are better
○ Adenosquamous and small cell do worse
* Histological grade not important for prognosis
Treatment Factors
* Surgical margins (close = <5mm; <2mm increased LR)
* Treatment within an experienced tertiary centre/ access to treatment
* Suitability for concurrent cisplatin
* DE radiotherapy (with brachy boost - stereo boost = dec LC, inc tox, des OS)
* Overall treatment time (<56days)
* Hb <100-110
Describe the Sedlis and Peters criteria for cervical cancer.
Describe history, examination and investigations for cervical cancer
- History
○ PMHx
§ Commonly asymptomatic (found on surveillance cytology)
□ Pap smears after 1st sexual intercourse, or 18 and ever 2 years after that
§ If symptomatic (progression)
□ Intermenstrual bleeding
□ Pain
□ dyspareunia
□ Vaginal discharge
□ Urinary symptoms (suggestive of locally advanced disease)
□ Bowel symptoms
§ Regional symptoms/Local symptoms
□ Ipsilateral leg lymphoedema
□ Sciatic pain
§ Constitutional symptoms
○ PMHx
§ Cervical screening
□ Previous intra-epithelial lesion
§ Anal or vulval cancers
§ Radiosensitivity conditions and contraindications for radiotherapy
○ Medications
§ Immunosuppression
○ Social
§ Social supports and performance status
§ Smoking history
§ Sexual history
§ Desire for fertility preservation- Examination
○ General appearance
○ Abdomen (SCF, inguinal, abdomen, bimanual)
○ Examination under anaesthesia
§ Gynaecological examination
§ Speculum + bimanual
§ Approximately demarcate disease
§ Check for PID (cervical motion tenderness)
§ PR exam - palpate for parametrial extension
- Examination
Discuss cervical cancer screening
Rationale:
* HPV infection in 30% within 1st yr sexual intercourse, 48% within 3 yrs, >90% population as a whole
* Women with persistent infection at higher risk cervical Ca (>70% cases associated with HPV)
○ HPV 16+: 17% will develop CIN3+ in 10yrs
○ HPV 18+: 14% will develop CIN3+ in 10yrs
* Progression from persistent infection to invasive cervical Ca generally slow
* Natural history well understood
○ Infection/acquisition
○ Viral persistence
○ Progression to pre-invasive Ca
○ Invasion
* Regular pap screening decreases incidence and mortality, in both vaccinated and unvaccinated
* Potential harms:
○ Psychosocial impact abnormal test result
o Guilt HPV infection, shame, anger + mistrust partners, worry about life limitation, worry about infertility, concern about partner
○ Psychosocial impact colposcopy + treatment
o HPV vaccination at 12yrs should decrease colposcopy rate
○ Fertility/successful pregnancy implications
o Falling pregnant: ? cervical mucous reduction, cervical stenosis. Small pooled studies: nil adverse impact fertility
o Miscarriage: MA - no increase miscarriage
o Obstetric complications: MA – increased risk pre-term delivery, perinatal mortality
Guidelines:
* Cervical ca screening every 5 yrs in sexually active, asymptomatic women 25-75 yrs
* Women 70-75 yrs invited to exit program with –ve HPV test
* Self-collection policy if pts under-screened, never-screened and decline invitation
* All women: HPV vaccinated/unvaccinated
* Invitations sent to women
* F/U positive result (see below)
Methods:
* Conventional cytology (PAP) or liquid based cytology and HPV testing
Results:
* HPV test with partial genotyping
○ HPV 16/18: reflex liquid-based cytology (LBC) + colposcopy
○ HPV oncogenic + (NOT 16/18): LBC
§ Unsatisfactory: rpt LBC 6-12 weeks
§ Negative: repeat LBC in 12 months
§ pLSIL/LSIL: rpt LBC in 12 months
□ LGSIL resolves ~50% of the time, 5% progress to invasive.
§ pHSIL/HSIL (CIN2/3, CIS, ASCUS-H): Colposcopy and LEEP/cone
□ HGSIL: > 20% progress to invasive, so go straight to colposcopy.
* Risk of progression to cancer for ASCUS / LGSIL / AGC-NOS / HGSIL of < 1→ 5→ 17→ 22%.
Describe cervical cancer staging
Discuss the side effects with cervical cancer radiotherapy
Discuss the prognosis and follow up for cervical cancer
Follow-Up
- Clinical review every three months for 2 years ○ Vaginal examination ○ Cytology every six months (optional) - Clinical review every six months for years 3-5 ○ Vaginal examination ○ Cytology annually (optional) - Re-staging imaging is not routine ○ Consider PET-CT or MRI or CT CAP at 6 months post-treatment (not rebateable) ○ Otherwise, as indicated only
What are the histological subtypes for ovarian cancer?
1) Epithelial carcinoma (80+% of all)
a. High-grade serous (70%)
b. Low-grade serous (5%)
c. Endometrioid (10%)
d. Clear cell (10%)
e. Mucinous (3%)
2) Germ cell
a. Teratoma
b. Monodermal (e.g. carcinoid)
c. Dysgerminoma
d. Yolk sac tumour
e. Mixed
3) Sex cord stromal tumour
a. Granulosa tumour
Sertoli-Leydig cell tumour
Describe the staging of ovarian cancers.
FIGO Staging
Stage 1→ confined to ovaries
IA – one ovary with intact capsule
IB – ‘B’oth ovaries with intact capsule
IC – ‘C’apsule penetration: surgical spill, capsule ruptured before surgery, or positive peritoneal washings (1, 2, 3)
Stage 2→ Local (pelvic) extension (A – uterus/tubes; B – implants in pelvis)
Stage 3→ RP lymph nodes A/peritoneal mets outside pelvis B (C>2cm)
Stage 4→ DM –pleural effision, liver, spleen, lung, inguinal/chest nodes
Describe adjuvant management of ovarian cancer
Adjuvant chemotherapy
Good evidence for chemo in ovarian cancer
-Meta analysis- 5 % 5 year OS benefit
-GOG and ICON 7 - Adding avastin to 3 weekly carbo/paclitaxel improved PFS and OS for pts with ascites or high risk patients with poor prognosis (ICON 7 - only IS benefit in those with poor prognosis, GOG (Modest PFS benefit, but always added toxicity and largest benefit in Stage III or Stage IV disease)
-GOG 172 Carbo/Paclitaxel +/- intra peritoneal chemo –> Trend to better outcomes with intraperitoneal chemo, but more toxic. Not replicated in modern studies and trend is now towards –> dose dense chemo and avastin instead
Early Stage (1 – low risk) ○ Stage 1 disease without high risk features (Stage 1A/B, G1-2) → 5yr OS > 90% with surgery alone. Observation only ○ No adjuvant treatment required if well-diff encapsulated unilateral disease, or those comprehensively staged, mod-diff grade 1/2 disease. ○ If full surgical staging -> no adjuvant therapy § Evidence: GOG RCT: no benefit in 5 year DFS or OS ○ If not able to have optimal surgical staging -> may be a benefit with adj platinum based chemo § Evidence: EORTC: benefit with LC, DFS, OS compared to observation § GOG157 (Bell, Gyn Onc 2006). 457 pts including stage Ia/B G2-3, IC + 2, randomized post-surgery to 3 vs 6 cycles of carbo/paclitaxel. No diff in 5 year recurrence between 3 and 6 cycles chemo but 6 cycles assoc with greater toxicity Early stage (1-2 – high risk) ○ St1A/B with high grade serous or clear cell or St1C-St2 → adjuvant chemo to ↑RFS and OS based on RCTs. ○ Regime: carbo 5AUC + pacli 175mg/m2 D1, every 21 days for 4 cycles –6 cycles starting 2-4 weeks postop. § Measure Ca125 after 3 cycles re response. § Evidence: ICON and EORTC-ACTION RCT pooled analysis (JNCI 2003): 925 pts, ICON mainly included St1-2, ACTION including 1A/B G2-3, 1C, 2A. □ Randomised to observation vs 4-6 cycles of platinum based chemo (57% single agent, 27% combo chemo). □ Chemo → ↑ 5yr OS by 8% (74% vs. 82%) and 5year RFS by 11%
Maintenance:
MA: No improvement OS with maintenance chemo
BRCA 1/2 positive/HRD: PARP-1 olaparib 400 mg BD
Or Olaparib + bevazciumab
Or Niraparib
SOLO trials phase 3 randomised maintenance olaparib vs placebo–> DFS improved (5 year PFS 55% vs 25%) and OS
Describe prognosis and follow up for ovarian cancer
Review every 3 months for 2 years, then 3-6months then annual
Exam + pelvic
CT CAP +- MRI/PET as indicated
Bloods: Ca 125 or other tumour markers as initial
Rising Ca125 – reimage. Immediate treatment delay until clinical relapse
Discuss screening and risk reduction for ovarian cancer
Describe the staging for vulval cancer.
Describe the management of CIS, Stage 1a, Stage 1b and stage II vulval cancer.
Early-Stage Disease (FIGO I-II)
- Radical local excision is the preferred treatment modality where feasible
○ Minimise deformity and surgical morbidity
○ Requires pathological margins of 8mm (although some use 5mm)
§ 2019 data suggests 40% pt will have local recurrence at 10 years with no relation to SM clearance
- Where this is not feasible (i.e. large T2 disease), modified radical vulvectomy is required
- Positive surgical margins indicate a re-resection where possible
○ If not feasible, need dose-escalated salvage chemoRT
- Surgical nodal management should occur as above
Adjuvant Radiotherapy
- Indications for adjuvant radiotherapy: ○ Primary § Lesions greater than 4cm § Unresected close margins (<8mm) § LVSI § Depth of invasion (>5mm) ○ Positive lymph nodes § Positive sentinel node □ If any macrometastasis or multiple micrometastases, lymphadenectomy should precede RT (treat bilateral groin) □ If micrometastasis (<2mm) in one node, EBRT can replace lymphadenectomy § Lymphadenectomy □ Any macrometastasis □ Multiple micrometastases (i.e. 2 or more) □ Any ECE - Radiotherapy doses: ○ Clear margins and pN0 --> 45Gy/25F § Adverse features for primary ○ Clear margins and node positive --> 50.4Gy/28F § No adverse features for nodes (no ECE or residual disease) ○ Close margins OR node positive with ECE --> 54Gy/30F ○ Gross unresected primary or nodal disease --> 60-66Gy - Concurrent chemotherapy if: ○ Macroscopic nodal disease (>2mm) ○ Multiple micrometastatic nodes ○ Positive margins
Describe the management of Stage III - IVa vulval cancer.
Advanced Disease (FIGO III-IV)
- No formal definition, but generally includes III/IVA or extension to adjacent GU systems, anorectum or fixation to bones
- Also stage II (1/3 lower urethra, 1/3 lower vagina, anuss, as radical vulvectomy is not curative
- Definitive chemoradiotherapy is indicated/treatment of choice in patients with unresectable disease that would otherwise require exenteration and stoma formation ○ 60-66Gy at 2Gy/F with concurrent cisplatin q1w 40mg ○ Dose is dependent on disease bulk ○ Residual disease after definitive doses may render disease resectable in surgical candidates. ○ The use of upfront definitive schedules are preferred to neoadjuvant schedules in view of difficulty of delivering definitive doses if later deemed not resectable. ○ Involved LN 56-70Gy ○ Elective nodes: 50Gy * If medically suitable, biopsy should occur following completion of treatment ○ Assessment should be at 12 weeks (clinical, imaging, Bx) ○ Consider resection of any residual disease * Neoadjuvant chemoradiotherapy ○ Concurrent cisplastin q1w x 6c ○ RT 57.6Gy § pPR→ Resect if possible, o therewise additional CRT. § cCR→ Bx, if neg, observe. If pos, resection or CRT. - Radical vulvectomy - may require pelvic exenteration N2 disease rt better than surgery
Discuss the prognosis and follow up in vulval cancer.
Follow-Up
- Clinical review and examination every 3 months for the first two years ○ If definitive chemoRT, consider: § Re-biopsy at 3-6 months to confirm pCR § PET-CT at 3 months to confirm cCR - Clinical review and examination every six months for years 3-5 - Important components ○ Examine co-located areas at risk (cervix, vulval skin, peri-anal) ○ No routine imaging
Describe the staging in vaginal cancer
Describe the clinical presentation and work up for vaginal cancer
Clinical Presentation
· 20% asymptomatic - detected by PAP smear
· Local
o Post-coital bleeding or post-menopausal bleeding
o Dyspareunia
o Watery / blood-tinged / malodourous discharge
o Vaginal mass
· Direct extension (5%)
o Lower urinary tract symptoms
o Malena
o Tenesmus
o Constipation
o Pelvic pain
Work up
· History:
o Local symptoms (post-coital/post-menopausal bleeding, malodorous/blood-stained discharge, vaginal mass, dyspareunia)
o Sx of direct extension (altered bladder/bowel function, pelvic pain)
o Sx of metastatic disease
o Gynae/obstetric history, family planning
o Most recent pap smear
o Desire to maintain functional vagina
o Fitness for Rx: Comorbidities, performance status, contraindications to RT
· Examination (determine local, regional, distant extent of disease, synchronus anogenital primary):
o External genitalia, bimanual pelvic exam, speculum, PR
o Inguinal LN
o Distant metastases
· Bloods: FBC (Hb prognostic), G+H, EUC, CMP, LFTs, b-hCG (baseline)
· EUA, colposcopy and biopsy (and fiducial placement)
· Imaging
o Evaluation of local disease
§ MRI pelvis (Tumour size, paravaginal/parametrial involvement; RT planing)
o Evaluation of nodal/distant disease:
§ CT CAP
§ FDG PET/CT (superior to other imaging modalities for detecting nodal disease, encouraged by FIGO, also useful for detecting recurrence)
· Special tests:
o Cystoscopy/sigmoidoscopy if bladder or rectal involvement suspected
o Pap smear (synchronous primary)
Describe the management of stage 1 vaginal cancer
As primary vaginal cancer is rare, treatment is complex, often indi- vidualized, and much of the management is extrapolated from cervical cancer owing to its similar etiology and anatomical location.
Describe management of stage II to III vaginal cancer.
Palliative
-Quad shot
-8gy weekly x3
Discuss the toxicity with vaginal radiotherapy
· Acute:
o Genital: Vaginitis, vulvar desquamation
o Urinary: Cystitis
o GI:
§ Large bowel: Proctitis, diarrhoea
§ Small bowel: Nausea
o Skin: Skin epilation adn erythema
· Late:
o Vagina: Stenosis (use vaginal dilator, decreases from 50% to 10%)
o Rectum: Rectovaginal fisutla 5-10%, bleeding
o Bladder: Vesicovaginal fisutla 5-10%
o Ovaries: Sterility (3Gy), menopause (10Gy). Ovarian transposition pre-RT has variable success, consider
o Small bowel: Obstruction (rare)
Femoral heads: Fracture, necrosis
Second malignancy (rare)
Discuss the follow up and prognosis with vaginal cancer
· Followup:
· no standardised guidelines
* 3 monthly for first 2 years - 70-80% recurrence occur within first 2 years
* 6 monthly thereafter until 5 years
* alternating with gynae onc
* Vaginal dialtor educations
* Bone health measures via GP- calcium and vit D
Discuss the management of gestational trophoblastic disease.
Good prognosis
- Low risk:
○ Stage I or Stage II-III WHO score ≤6 - High risk
○ Stage II+III + WHO score 7 or more; or
○ Stage IV
· FIGO Stage
o I: Confined to uterus
o II: Outside uterus, but limited to gynae organs
o III: Lungs
o IV: All other metastases
- Low risk is a score of 6 or less. People with a low-risk tumor have a good prognosis, even if cancer has spread, because treatment is usually very effective.
High risk is a score of 7 or more. People with a high-risk tumor may require more intense treatment even if the tumor has not spread.
Low risk management= Single agent chemo
Chemotherapy: Methotrexate x3 cycles and b HCG normalises. Given with folinic acid to protect MTX related toxcity.
If not wishing to preserve fertility –> Surgery + chemotherapy: Methotrexate x1 cycle + hysterectomy
Aim for weekly HCG levels <5 for 3 consecutive weeks, then monthly surveillance for the first 12 months
High risk management (EMA-CO)
Chemo- Multi agent. Etoposide, methotrexate, actinomycin-S, leucovorin calcium, cyclophosphamide, vincristine
+ Hysterectomt
Methotrexate plus ACTD alternating with cyclophosphamide and vincristine
Associated low toxicity profile and most widely used regimen
