Malignancy of the Reproductive Tract

Question 1

Origins of ovarian cancer

Answer 1

-Medulla
=Vasculature
=Loose stromal cells

-Epithelium
=Extension of the mesothelium which forms peritoneum
=Constant trauma, stimuli, turnover= more likely to be cancer

-Cortex
=Oocytes
=Granulosa cells
=Theca cells
=Fibroblasts
=Steroid cells

-Germ cell tumours

-Sex-cord stromal tumours

Question 2

Cellular origins of ovarian cancer

Answer 2

-Endometrium/ retrograde menstruation
=Endometriosis
==Clear cell carcinoma
==Endometrioid carcinoma

-Fallopian tube epithelium
=High/ low grade serous carcinoma

-Ovarian surface epithelium
=High/ low grade serous carcinoma
=Relapse remitting, presents advanced (high)
=Presents earlier, poor response to chemo, slow turn over (low)

-Unknown
=Mucinous carcinoma
=Acts like GI cancer

Question 3

Ovarian cancer subtypes

Answer 3

-High-grade serous carcinoma (70-74%)
=Most lethal
=Starts in fallopian tube- stick lesion in situ (neoplastic process)
-Clear cell carcinoma (10-26%)
-Endometrioid carcinoma (7-24%) best prognosis
-Low-grade serous carcinoma (3-5%)
-Mucinous carcinoma (2-6%)
-Carcinosarcoma (1-7%) tissues around cancer abnormal
-Other (0.6-7.1%)

Question 4

Factors for increased risk of ovarian cancer

Answer 4

-ANYTHING THAT MAKES YOU OVULATE MORE
-Increased age
-FHx cancer
-Hereditary cancer syndrome
-Obesity?
-Having never given birth
-Hormone replacement therapy
-Increased numbers of lifetime ovulatory cycles

Question 5

Factors for decreased risk of ovarian cancer

Answer 5

-Bilateral salpingo-oophorectomy
-Oophorectomy
-Bilateral salpingectomy with ovarian retention
-Hysterectomy
-Tubal ligation
-Use of oral contraceptives
-Breastfeeding

Question 6

High-risk ovarian cancer susceptibility cancer syndromes with their associated suspected genes

Answer 6

-Hereditary breast and ovarian cancer syndrome (BRCA1/2- repairs breaks in DNA)
-Lynch syndrome (MLH1, MSH2/6, PMS2, EPCAM): common
-Li-Fraumeni syndrome (TP53- tumour suppression, guardian of the genome): rare
-Peutz-Jeghers syndrome (STK11/LKB1): petechiae on lip, bowel polyps
-Sex cord and mucinous tumours

Question 7

Epidemiology and prognosis of Epithelial Ovarian Cancer (EOC)

Answer 7

-70% present with advanced disease (Stage III or IV)
-6th most common cancer among UK women(2014)
=Accounts for 4% of all new female cancer cases
-Highest mortality of all gynaecological cancers (resistant to chemo, advanced)
=36% of all women with EOC die within 1-year of diagnosis
-‘Silent Killer’
-Predominantly a post-menopausal disease
=Peak age 60-64 years

-Overall 5 year survival= 50%
=Stage 1: 90%, 2: 40%, 3: 20%, 4: 5%

Question 8

Symptoms of EOC

Answer 8

-Present for >1 year and > 12 times per month:
=persistent abdominal distension (‘bloating’)
=early satiety and/or loss of appetite
=pelvic or abdominal pain
=increased urinary urgency and/or frequency
=unexplained weight loss
=fatigue
=abnormal uterine bleeding

OFTEN DIAGNOSED WITH IBS- suspect if diagnosed over 40

Question 9

Protective factors in EOC

Answer 9

-COCP
-Pregnancy
-Sterilisation
-Hysterectomy

Question 10

Risk factors in EOC

Answer 10

-Family History (BRCA)
=1 = 63%
=2 = 27%
-Null parity or 1st birth after 35
-Early menarche/late menopause

Question 11

Investigation for EOC

Answer 11

-Bedside (urine dip, pregnancy, obs, BM), blood (FBC for platelets and anaemia of chronic disease, U&Es for renal function, LFT, clotting for invasive diagnostics, TFT for thyrotoxicosis), imaging (USS, CT staging, MRI, PET?), special test (tumour markers)

-CA-125 better for advanced cancers, raised in inflammation/ CA119 and CA15 for pancreatic and breast
=<40-years - AFP (especially germ cell) / BhCG / CA-125/ CEA marker of GI and lung to differentiate from ovarian
-USS Pelvis +/- TV
-CT CAP
-MDM

-RMI score = ultrasound score x menopausal score x CA125level in U/ml
-Screening?

Question 12

RMI Score criteria

Answer 12

A. Menopausal status
=Pre (1)/ Post (3)

B. Ultrasonic features (1=1, >/2=3)
=Multiloculated
=Solid areas
=Bilaterality
=Ascites

C. Serum CA-125 titre absolute value

Tumour Size (7 cm)

Risk of malignancy index= A x B x C
=Cut off value 200 discriminates a benign from malignant mass with sensitivity 87% and specificity 97%

Question 13

Diagnosis of EOC

Answer 13

-Tissue biopsy
=Laparoscopic with assessment of abdominal cavity
=Image guided
=Cytology not accepted alone (COVID-19)

-MDM discussion
=Gynae-oncology MDM
=Complex pelvic

Question 14

Surgical management of EOC

Answer 14

-Aim: complete cytoreduction of all macroscopic disease (surgery beneficial in ovarian)
-Primary surgery is the standard of care where complete or optimal cytoreduction seems achievable in patients with good performance status
-Multi-visceral resection techniques such as peritoneal stripping, diaphragmatic resection, removal of bulky pelvic/ para-aortic lymph nodes, splenectomy and bowel resection.
-SCAN network – 55% of all patients undergo primary surgery (2017), 45%WOSCAN and 34% NCA.

Question 15

EOC early disease treatment

Answer 15

-Staging laparotomy
=Peritoneal washings
=TAH/BSO
=Omentectomy
=Peritoneal biopsies
=Diaphragmatic biopsies
=Pelvic and bilateral para-aortic lymph node assessment up to the level of the insertion of the ovarian vessels in the absence of peritoneal dissemination

-Up to 30% of patients with apparently early stage disease will be upstaged after comprehensive staging

-Adjuvant platinum based chemotherapy offered in all cases except 1a/1b G1

Question 16

EOC fertility sparing surgery

Answer 16

-Stage 1A
-Favourable histology
=Grade 1
=Grade 2 if non-clear cell
=Mucinous, serous, endometroid, or mixed histology
-In combination with appropriate staging

Question 17

EOC advanced disease treatment

Answer 17

-Neo-adjuvant chemotherapy (before surgery)
=lower surgical mortality/ morbidity for unwell and significant comorbidity
=x3 cycles

-Interval imaging and MDM discussion
-Interval debulking surgery
-Baseline post-op imaging
-Adjuvant chemotherapy (carboplatin, paclitaxel x3 weekly for 6 cycles)- after surgery
-Anti-angiogenic (Bevacizumab)

Question 18

EOC Follow up

Answer 18

-Variable ~ every 3 months for the first 2 years and then every 6 months
-Rises in CA125 to precede symptomatic relapse by a median of 4.5 months (range 0.5–29.5 months).
-No difference in OS between received chemotherapy for rising CA125 or until were symptomatic

Question 19

EOC recurrent disease treatment

Answer 19

-Value of surgery not established in RCT
-Could be offered in
=total macroscopic tumour clearance achievable
=long treatment free interval
=good performance status

-Ongoing trials
=DESKTOP III
=GOG 213

-Palliative surgery

Question 20

Platinum sensitive recurrent EOC treatments

Answer 20

-Treatment-free interval >6 moths after achieving a complete response following completion of first-line therapy
-Response rates 27-33%
-Combination therapy improves PFS and OS
=carboplatin / paclitaxel, carboplatin / liposomal doxorubicin, carboplatin / gemcitabine

Question 21

Platinum resistant recurrent EOC treatments

Answer 21

-Treatment-free interval of <6months after first-line therapy
-Single agent non-platinum agents
-Short lived responses 10-25%
-Addition of bevacizumab shown to increase PFS (3 mths)but not OS

Question 22

Other medical treatments for EOC!

Answer 22

-PARP inhibitor (Olaparib) - BRCA
=PARP enzymes involved in DNA repair
=Improved PFS in patients with relapsed, platinum-sensitive, high-grade serous ovarian carcinoma. Maintenance therapy.
=If they have had 3 or more courses of platinum- based chemotherapy
=Cure

-HRD Status
=Niraparib
=Maintenance – until toxicity or recurrence

Question 23

Epidemiology of vulval cancer

Answer 23

-Rare
-1000/yr in UK
-Mortality 1.3/100 000
-Predominantly disease of older women
=Usually >65
=< 50 uncommon
=Incidence in 40-49 group increasing (2 fold in 30 yrs)

Question 24

Predisposing factors in vulval cancer

Answer 24

-Vulval Intraepithelial neoplasia (VIN)
=Usual type
==Warty/basaloid/mixed
==HPV related
==Younger women
==May be multifocal
==Includes VIN2/3
=Differentiated type
==Seen in context of lichen sclerosis
==Older women
==Usually not HPV related
==High grade lesion

-Risk of progression
=VIN (highly variable in literature 7-8%)
=Lichen sclerosis (4% not clear if reduced by treatment)

Question 25

HPV infection in vulval cancer

Answer 25

-HPV infection varies 15-79% in vulval cancers
=HPV 16 (18/31/33/45)
=Vaccination – reduction in incidence of VIN in young women

-Viral Oncoprotein
=E6/E7: cell immortalization through p53 degradation (E6) and inactivation of retinoblastoma tumour suppressor gene product (E7)

Question 26

Presentation of vulval cancer

Answer 26

-Mass/Ulcer
-Pain
-Bleeding
-Burning
-Itch
-Discharge
-Diagnosis often delayed

Question 27

Histological subtypes of vulval cancer

Answer 27

-SCC (90%)
-Melanoma (5%)
-Bartholin’s gland tumour (2-3%)
-Adenocarcinoma (<1%)
-Verrucous carcinoma (<1%)
-Sarcoma (1-2%)

Question 28

Diagnosis of vulval cancer

Answer 28

-Biopsy
=Representative biopsy of the tumour including area of epithelium with transition of normal to abnormal tissue.
=In very small lesions – a wide local excision biopsy with margins of at least 1cm may be possible (Clinical photography)

Question 29

Prognosis of vulval cancer

Answer 29

FIGO stage
1= 79% 5 year survival
2= 59%
3= 43%
4= 13%

Question 30

Management of early stage vulval cancer

Answer 30

-<2cm in diameter and depth of invasion (DOI) <1mm(stage 1a)
=WLE only

->2cm diameter, DOI >1mm
=Removal of primary tumour Groin node dissection
=’Triple incision technique’ vulvectomy

-Which nodes?
=<1cm from midline (bilateral)
=At least 1cm from midlines (unilateral/ other side removed if positive)

Question 31

Surgical considerations in management of vulval cancer

Answer 31

-Histological margin
=8mm
=Up to 50% recurrence
=Take measured margin of15mm in all planes
-Plastic surgery involvement for closure
-Adjacent structures
=Distal 1cm of urethra can be resected without significant impact on continence

-Morbidity in co-morbid population
=wound breakdown/ wound infection/deep vein thrombosis and pulmonary embolism/ pressure sores/ introital stenosis/ urinary incontinence/Rectocele/ faecal incontinence/inguinal lymphocyst/ Lymphoedema/Hernia
=psychosexual complication

Question 32

Management of sentinel lymph nodes in vulval cancer

Answer 32

-Injection of technetium-99 and/or Patent Blue dye
=Unifocal cancers <2cm in diameter
=Negative predictive value 89-100%
=Full nodal dissection in cases of positive nodes including deep and superficial inguinal nodes
=Groin node recurrence carries high mortality

Question 33

Surgery in advanced vulval cancer

Answer 33

-Primary Tumour
=Same principles as early stage disease
=Larger lesions may involve adjacent structures: Consider radiotherapy preoperatively to shrink tumour and salvage sphincters

-Clinically Suspicious Nodes
=Surgery remains cornerstone of management
=Fixed/ulcerated nodes surgery and/or radiotherapy

Question 34

Radiotherapy in vulval cancer

Answer 34

-Primary treatment
=Sphincter preservation
=Histologically proven groin node involvement
=Women not fit for surgery

-Adjuvant treatment
=close margins options: RT/ re-excision/ surveillance with surgical salvage

Question 35

Chemotherapy in vulval cancer

Answer 35

-Only small series in literature
-NACT
=Variable response
-Adjuvant
=?feasible strategy in patients with multiple lymph node mets

Question 36

Recurrent vulval cancer

Answer 36

-Recurrence rates 15-33%
=Vulva – 70%
==Surgery
==Radiotherapy
=Groins -24%
==Radiotherapy

Question 37

What is Lynch syndrome?

Answer 37

-Lynch syndrome is a genetic disease of autosomal dominant inheritance that causes an increased risk of bowel cancer. It also increases the risk of developing womb (endometrial) and ovarian cancer.
-Current guidelines recommend that women with Lynch syndrome are offered annual TVS, hysteroscopy and endometrial biopsy after the age of 35 years

Question 38

Incidence of endometrial cancer

Answer 38

-Endometrial cancer (EC) is the fourth most common cancer in women in the UK and the most common gynaecological malignancy.
-In the UK, there are over 9000 new cases each year and the incidence has risen by 57% since the early1990s. This is attributed to the ageing population, a growing prevalence of obesity and declining rates of hysterectomy for benign disease

Question 39

Aetiology of endometrial cancer

Answer 39

-Endometrial cancer is the most common gynaecological malignancy.

=obesity
=unopposed estrogen
=polycystic ovary syndrome- Endometrial hyperplasia
=Nulliparity
=Early menarche, late menopause
=Tamoxifen following breast cancer (cornerstone, x3-6 as weak oestrogenic effect on endometrium)/ FH breast cancer
=HRT use
=Lynch Syndrome

Question 40

Clinical presentation of endometrial cancer

Answer 40

-Post menopausal bleeding
-Unscheduled bleeding on HRT at any time after 6months of starting HRT.
-Vaginal discharge (less common) – Blood stained, watery or purulent

Question 41

Investigations in endometrial cancer

Answer 41

-Transvaginal/transabdominal Ultrasound Scan (endometrium less than 3mm unlikely)
-Endometrial biopsy
-Dilation and Curettage
-Outpatient Hysteroscopy
=Occasionally inpatient if endometrial cavity cannot be visualised on outpatient hysteroscopy

Question 42

Diagnosis of endometrial cancer

Answer 42

Histology confirmation of Endometrial cancer (usually adenocarcinoma)
Imaging for extent of disease/metastasis. CT Thorax (pulmonary metastasis), abdomen, MRI or CT of pelvis

Question 43

Management of endometrial cancer

Answer 43

-Discuss management at oncology multidisciplinary meeting.
-Assess risk factors for surgery- co morbidities, morbid Obesity
-Mirena coil or palliative radiotherapy

-Radiotherapy; Rarely given as primary treatment unless advanced stage or medically unfit. Given post-operatively dependant on stage. Would be vaginal brachytherapy +/- External Beam radiotherapy
-Chemotherapy given in combination with radiotherapy for intermediate-high and high risk tumour types only
Hormonal - (High dose progestins, Letrazole) for those medically / surgically unfit
-Immunotherapy (Pembrolizumab) for advanced stage disease not amenable to surgery or radiotherapy

-Laparoscopic Total hysterectomy and bilateral salpingo-oophorectomy. Pelvic washings for cytology.
-If the pipelle biopsy comes back with a high-grade pathology, an omentectomy is also performed
-Lymphadenectomy is sometimes performed, if such invasion is suspected
-Radical radiotherapy in higher stages of cancer or it may be used as an adjuvant
-Chemotherapy – Doxorubicin, and cisplatin

Question 44

Prognosis of endometrial cancer

Answer 44

-Unlike ovarian cancer, endometrial cancer often presents at an early stage when there is a possibility of curative treatment by hysterectomy; early, accurate and timely diagnosis is therefore important.
-Patients are seen within 2 weeks of referral even with a single episode of PMB

-Stage 1 - 95% Confined to the uterus
-Stage 2 - 65% Extending to the cervix
-Stage 3 - 40% Serosa, ovaries fallopian tubes and lymph nodes
-Stage 4 - 10% bowel, bladder and distant metastasis

Question 45

When is radiotherapy used as an adjuvant in endometrial cancer?

Answer 45

-The tumour invades the myometrium deeply
-Poorly differentiated high grade disease
-Adenosquamous, clear cell or papillary serous carcinoma
-Positive pelvic lymph nodes

-Local radiotherapy to the vault of the vagina (brachytherapy) may prevent recurrence developing in this area .If the disease is widespread, chemotherapy may be considered. The drugs most helpful in this situation are cisplatinum and doxorubicin