Ovarian cancer Flashcards
Life time risk of ovarian cancer?
1-1.5%, 3% if first degree relative.
Association with BRCA
3 main groups of ovarian ca? And what proportion of ovarian cancers do they account for?
Carcinomas (malignant epithelial cancers) - 90%
Malignant germ cell tumours - 2-5%
Potentially malignant sex cord-stromal tumours - 1-2%
(Borderline tumours)
Subtypes of carcinoma?
5 main subtypes (account for 98% carcinomas) High grade serous (HGSC) - 70% Endometroid - 10% Clear cell - 10% Mucinous - 3% Low grade serous (LGSC) - <5%
Characteristics of HGSC
Includes primary peritoneal and primary fallopian tube cancers
Evidence that >60% HGSC in BRCA patients originate from the fallopian tube (most commonly fimbrial end)
Commonly present as advanced disease - <10% confined to ovary at diagnosis
What are the 3 main embryological cell lines of malignant germ cell?
embryo (teratoma)
yolk sac (yolk sac, endodermal sinus tumour)
trophoblast (choriocarcinoma)
Risk factors for ovarian cancer?
Nulliparity
Infertility,
Obesity
Personal hx of BRCA (especially BRCA1) or colon cancer
Smoking
Use of perineal talc
HRT is also associatedwith a slightly raised risk.
FIGO stage 1 of ovarian cancer?
Stage 1 - tumour confined to ovaries 1a: Tumor confined to one ovary or fallopian tube, intact capsule, no tumor on surface, no tumor cells in ascites or washings 1B: Tumor involves both ovaries or fallopian tubes, otherwise like stage IA 1C: IC1: Intraoperative spill IC2: Capsule rupture before surgery or tumor on ovarian or fallopian tube surface IC3: Positive peritoneal washings or ascites
FIGO stage 2?
Stage 2: Tumor involves one or both ovaries or fallopian tubes with pelvic extension or primary peritoneal cancer
2a: Extension to or implant on uterus or fallopian tubes, or some combination thereof 2b: Extension to other pelvic intraperitoneal tissues
FIGO stage 3?
Stage 3: tumor involves one or both ovaries or fallopian tubes with involvement of the peritoneum outside the pelvis, metastasis to the retroperitoneal lymph nodes, or both.
3a: IIIA1(i): Metastasis of ≤ 10 mm to the retroperitoneal lymph nodes IIIA1(ii): Metastasis of > 10 mm to the retroperitoneal lymph nodes IIIA2: Microscopic, extrapelvic peritoneal involvement (above the brim) with or without involvement of retroperitoneal lymph nodes
3b: Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm with or without involvement of retroperitoneal lymph nodes (includes extension to capsule of liver or spleen)
3c: Macroscopic, extrapelvic, peritoneal metastasis > 2 cm with or without involvement of retroperitoneal lymph nodes (includes extension to capsule of liver or spleen)
FIGO stage 4?
Distant metastasis excluding peritoneal
4a: Pleural effusion with positive cytology
4b: Distant metastasis including
parenchymal metastasis to liver,
spleen, or extraabdominal organs
Presenting symptoms?
70-75% present with stage III/IV disease abdominal bloating non-specific abdominal/pelvic pain reduced appetite / indigestion / heart burn / nausea weight loss fatigue urinary frequency or obstruction altered bowel habit watery/bloody vaginal discharge palpable mass
First line investigations?
Pelvic USS
CA125, CEA, CA19-9
CA125 raised in 90% malignant ovarian tumours, but also raised by many benign conditions
Women under 40yrs germ cell tumours are more likely - require BHCG, AFP, LDH
Hormones produced by germ cell tumours?
Dysgerminoma: HCG, LDH
Immature teratoma: a-FP, LDH
Yolk sac tumour: a-FP, LDH
Choriocarcinoma: HCG
How to calculate RMI and what figures constitute low, moderate and high risk?
RMI = USS x M x CA125
USS: multilocular, bilateral, solid areas, ascites, metastases (0,1, 3)
M: post menopausal = 3, premenopausal = 1
RMI <25 low risk (<3%), 25-250 moderate risk (20%), >250 high risk (75%)
All women with RMI >250 require MDM referral
Investigations for staging?
CT CAP Histological diagnosis - necessary if considering neoadjuvant chemotherapy Ascitic fluid for cytology Needle biopsy Surgical staging Frozen section
What are the principles of management?
- Cytoreductive surgery (aim to reduce to no visible disease)
- 6 cycles platinum based chemotherapy
EITHER 3 cycles neoadjuvant chemo before surgery, then 3 cycles adjuvant chemo afterwards
OR cytoreductive surgery with 6 cycles adjuvant chemo afterwards
Summary of EORTC vs CHORUS trials
2 large RCTS comparing neoadjuvant chemo to initial debulking surgery
EORTC included biopsy proven stage IIIc/IV disease
CHORUS included stage IIIa,b,c/IV disease
Findings:
No significant difference in progression free survival or overall survival between those getting NACT vs surgery
Better outcomes when NACT used for stage IV
NACT may improve outcomes for poor surgical candidates (e.g. high ECOG score, multiple comorbidities)
Aims of cytoreductive surgery
Women with optimally resected tumour have on average a 20-month increased survival compared to suboptimal resection
Reduce tumour burden to optimise response to chemo
Reduce disease related symptoms
Reduces cytokines produced by tumour cells to improve immune competence
Options of cytoreductive surgery
TAH-BSO and washings Infracolic/gastrocolic omentectomy Retroperitoneal lymph node dissection Peritoneal disease resection Resection of rectosigmoid Resection of small bowel diaphragmatic stripping Splenectomy, hepatectomy, distal pancreatectomy, urological rescetion, abdominal wall
Which chemotherapy agents are used in platinum based therapy?
Side effects?
Carboplatin +/- paclitaxel (a taxane)
Carboplatin SE: N&V, hypersensitivity reaction, neutropenia, thrombocytopenia, nephrotoxity
Paclitaxel SE: Alopecia, N&V, arthralgia, myalgia, neurotoxicity, hypersensitivty, nephrotoxicity and neutropenia, neuropathy
Treatment pathway for stage 1 epithelial cell tumours
Stage 1-2a: TAH-BSO and comprehensive surgical treatment.
After surgery- if low grade stage 1A and 1B, chemotherapy may not be necessary. If high grade or >stage 1B then likely to require chemotherapy.
Conservative surgery aimed at maintaining fertility may be appropriate for very early disease (stage 1 grade 1 disease subsequently confirmed by histology and cytology)
Follow up and surveillance
Follow-up 3-4 monthly for first 2 years, then 6 monthly till 5 years
Pelvic exam and CA125 with each visit
CA125 good predictor of recurrence - rises 2-4 months before symptoms herald recurrence
BUT treatment started at initiation of rising CA125 vs awaiting symptoms does not increase overall survival (MRC/EORTC Trial 2010)
What is a borderline ovarian tumour?
Borderline tumour is a hyperplastic ovarian tumour without histological evidence of stromal invasion but with peritoneal implants. Although the implants can be invasive. Other histological criteria are nuclear atypia, stratification of the epithelium, formation of microscopic papillary projections.
Accounts for 10-15% of epithelial tumours.
Histological types of borderline ovarian tumour?
Histological types: serous (most common), mucinous, endometrioid, clear-cell and transitional-cell (or Brenner) tumours.
Prognostic factors for borderline ovarian tumours?
Age at diagnosis
FIGO staging (which is the same as ovarian cancer)
Residual disease at completion of primary surgery
Type of peritoneal implants
Presence of primary borderline tumour
Biomarker status (Ca 125)
What factors decrease the risk of ovarian cancer?
lactation COCP > 5yrs (0.5) 2 SVD (0.6) TL/hysterectomy (0.7) Vit A derivatives
What are the components of surgical staging?
Who should have surgical staging?
Surgical staging for patients with early disease or borderline tumours
peritoneal washings for cytology
exploration of all peritoneal surfaces (incl. Diaphragm, bowel serosa, Pouch of Douglas)
biopsy of any suspicious lesions
infracolic colectomy and peritoneal biopsies
Adequate sampling of pelvic and para-aortic lymph nodes
Malignant germ cell tumours- subtypes?
yolk sac tumour: second most common germ cell malignancy (25% of all tumours)
histo finding – Schiller-Duval body (isolated papillary projection lined with tumour cells surrounding a single central blood vessel). Most secreta AFP, only 5% bilateral
50% dysgerminomas (15% bilateral) –secrete LCD or HCG. Most common ovarian tumour diagnosed in pregnancy- sometimes discovered in patients with primary amenorrhoea – often associated with gonadal dysgenesis and gonadoblastoma
20% immature teratomas – rarely bilateral < 5%
8% mixed germ cell tumours – include at least 2 different germ cells (dysgerminomas & endodermal sinus tumours)
Rare: embryonal carcinoma – aggressive if pure; secrete estrogen (ass with precocious puberty or irregular bleeding) plus hCG and AFP
choriocarcinoma – in children – signs of precocious puberty; adults signs of ectopic
polyembryomas – usually mixed, often metastased at diagnosis
gonadoblastomas – usually diagnosed in work-up of abnormal genitalia, virilisation or primary amenorrhoea. Karyotyping – single X (45 XO) or mosaic (45 XO/46XY) – 80% phenotypic women, rest phenotypic men with hypospadias, cryptorchidism & internal female organs. Of women – half normal & half virilized with primary amenorrhoea or abnormal genitalia
Management of malignant germ cell tumours
Surgery
As most young, if no disease apparent outside affected ovary – unilateral salpingo-oophorectomy performed (leaving uterus & contralateral ovary)
Any suspicious lesions should be biopsied
Thorough staging procedure should be performed
Advanced disease – surgical cytoreduction performed
If stage 1A dysgerminoma or stage 1A grade 1 immature teratoma – surgery only
All other patients require adjuvant chemotherapy (currently = BEP (bleomycin, etoposide and cisplatin))
Survival malignant germ cell tumours
Most present early with disease limited to ovary
dysgerminomas have an excellent prognosis & most are cured
Stage 1A disease have > 95% 5yr survival
Even with advanced disease 5-yr survival rates of 85-90%
Patients with non-dysgerminomatous tumours in advanced stages have a 5 yr survival of 60-80%
Principles of ovarian conservation in TAH without known ovarian ca
- Oophorectomy without consent may consitute assault
- It is for the patient to make the decision based upon informed discussion which has been documented
- The benign disease may be better treated by including oophorectomy eg. endomteriosis, PID, unexpected pathology found at surgery
- Oophrectomy may be indicated where there are unwanted ovarian endocrine effects eg. PMS, hirsutism, mastalgia
The advantages of oophorectomy relate to: - the prevention of ovarian cancer; lifetime risk 1 in 70 of dieases; 1 in 100 of death, 60% of women presenting at a surgically incurable stage - the increase in these risks if there is a positive family history
- the avoidance of further surgery for subsequently developing ovarian pathology
The disadvantages of oophorectomy relate to: - the longer the use of HRT, the greater the increased risk of breast cancer and cardiovascular disease - the loss of libido, which may be difficult or impossible to treat
Comment critically on the objectives or surgical Mx of epithelial ovarian cancer.
Staging laparotomy is crucially important: - as a prognostic index for the individual - to influence subsequent Rx (whether adjunctive chemoRx is required in early stage disease, whether additional surgery is required after conservative surgery
- to provide data for use in clinical trials
Primary cytoreductive surgery is intended to: - improve tumour response to chemo- or radio-therapy - treat, prevent or delay complications caused by tumour masses eg. ascites, bowel obstruction
- enhance immunological competence - provide psychological benefit
The value of such surgery in improving survival rates is unproven.
Second-look procedures other than palliative surgery are controversial and their benefits uncertain eg. intervention cytoreductive surgery after chemotherapy, second-look laparotomy and secondary cytoreductive after recurrence of tumour.
Palliative surgery aims to improve quality of life but survival is often limited (eg. resection bypass or colostomy)
Critically appraise the morbidity of chemotherapeutic regimens for ovarian epithelial cancers and the measures which might be taken to minimise the side-effects of therapy.
Baseline tests may influence treament planning eg. FBC, renal function, ECG
Possible side-effects include: nausea and vomiting bone marrow suppression (particularly thrombocytopaenia), infection, Leukaemia, neuropathy
Cisplatin vs. carboplatin: Carboplatin drug of choice as less side effects, less neuropathy. Does cause thrombocytopaenia.
SE of paciltaxel as previous slide
Toxicity can be assessed by: monitoring FBC and differential WCC, and platelets, renal function and liver tests
The measure to minimise side-effects are: - sedation, effective anti-emetics prior to and during Rx, steroids and H2 antagonists
- fluid loading prior to treatment, overnight administration of cytotoxics agents
- limitation of Rx if no response after three pulses of therapy
- limitation of Rx to one year beyond which it is not helpful and the risk of leukaemia is incr.
- alopecia is prevented by selection of appropriate chemotherapy; other methods of prevention are not of proven efficacy - specilaised support and treatment in a cancer centre
Types of sex cord-stromal tumours
Arise from gonadal stroma surrounding oocytes including granulosa cells, thecal cells, sertoli cells, leydig cells and fibroblasts
Either from sex cord (sertoli or granulosa cell tumour)
Or stromal cells (fibroma, thecoma, leydig cell)
Or both (Sertoli-leydig)
Treatment of stage 2 and 3 epithelial cancers
Stage 2b-3b: start with debulking and staging surgery, aiming at complete resection.
After this then chemotherapy (typically 6 cycles) is required.
If advanced disease or the woman is too unwell for surgery then may need to start with 3 cycles of chemotherapy and then reassess and consider debulking at this stage. Normally then requires another 3 cycles of chemo after debulking/staging surgery.
Treatment of stage 4 epithelial cancers
Stage 3c-4: Start with neoadjuvant chemotherapy. Then decide if patient is fit for radical surgery and there is evidence that disease is not progressing. If so then aim for debulking. If not then for another 3 cycles of neoadjuvant chemotherapy. (Although may start with surgery)
Typical presentation of malignant germ cell tumours
Most germ cell tumours are diagnosed in young women in their teens or twenties
Often present with acute pain or palpable rapidly enlarging abdominal mass.
May also have abnormal vaginal bleeding plus abdo distension
BRCA genes
- 0.1-.08% of population but more common in women of Ashkenazi Jewish (Eastern European) descent
- BRCA genes act as tumour suppressor genes
- Oophorectomy protects against breast ca
- Need to know specifics of FHx of ovarian ca as risk of BRCA much higher if high grade serous vs mucinous BOT
Consider genetic testing in women with:
- a family history of breast and/or ovarian cancer,
a personal history of either cancer at a young age,
- Ashkenazi (eastern European) Jewish heritage
Offer genetic counselling
Screening if BRCA +ve
Monthly breast self-examination (BSE) beginning at age 18
Clinical breast examination two to four times annually beginning at age 25
Annual mammography beginning at age 25
Annual breast MRI
Twice yearly ovarian cancer screening with ultrasound and serum CA-125 levels beginning age 3
Prophylactic surgery in BRCA carriers
Risk reducing BSO recommended for women with BRCA1 at age <40 and age <45 for women with BRCA2. Discuss RRBSO after child bearing completed
Reduces risk of ovarian and breast ca (also recommend bilateral mastectomy)
Improves survival by 60-76%
Still carries a risk of primary peritoneal disease
If no personal hx of cancer can offer HRT until around 50
Genes linked to ovarian cancer:
BRCA 1 and BRCA 2
CDH1: mutation is linked to a raised risk of ovarian and breast cancer.
MLH1 and MLH2 gene: mutation is linked to a raised risk of both Lynch syndrome and ovarian cancer.
PALB2 gene
PTEN gene: mutation is linked to a raised risk of Cowden syndrome and ovarian cancer.
STK11gene: mutation is linked to a raised risk of Peutz-Jeghers syndrome and ovarian cancer.
TP53 gene: somatic mutation is present in almost half of all cases of ovarian cancer.
BRCA genes and risk of breast and ovarian cancer by age 70
- BRCA1: ovarian cancer of up to 63% and of breast cancer of up to 85%.
BRCA2: up to 27% ovarian and 84% breast respectively
Lynch syndrome cause
germline mutations in the DNA mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2)
Risk of malignancy with Lynch syndrome
Increased risk of early-onset cancer of multiple types,
including colorectal, endometrial, ovarian, gastric, small bowel, hepatobiliary, brain, ureteric and renal
pelvic cancers.
The lifetime risk for endometrial cancer is 40–60% compared with a risk of 3% in the general population.
For ovarian carcinoma, the lifetime risk is
10–12% compared with the general population risk of 1.4%.
How to assess families for potential Lynch syndrome
Families with Lynch syndrome are identified clinically using the Amsterdam criteria and the Bethesda
Guidelines
Risk reducing surgery for women with Lynch syndrome
Evidence lacking for endometrial surveilance
Offer TLH-BSO
Peutz-Jeghers syndrome
Germline mutations in the STK11 gene cause Peutz-Jeghers syndrome (PJS), an autosomal dominant
gastrointestinal polyposis disorder which confers an increased risk of breast, gastrointestinal and
gynaecological tumours. Patients with the condition manifest characteristic pigmented lesions on the
lips and buccal mucosa, which should prompt clinicians to consider the underlying diagnosis. Women
with PJS are at risk of developing sex cord stromal tumours with annular tubules of the ovary and
adenoma malignum of the cervix
