GONC Flashcards
Incidence of adnexal masses
Up to 10% of women will have some form of surgery for an ovarian mass during their lifetime
Pre-menopausal
- Almost all are benign and resolve in 2-3 menstrual cycles
- 0.1-0.3% of cysts are malignant
Post-menopausal:
Incidence of cysts is 5-17%
Incidence of ovarian cancer
Lifetime risk 1.5%
Mean age 61y
23% of gynae cancers are ovarian, but makes up 47% of deaths from gynae cancers
80% of cases present stage 2, 3, 4
Overall 5y survival 42%
Frozen section
Literature rates variable in terms of accuracy - 56-86%
Compared with final histological diagnosis
- Sensitivity 65-100%
- Specificity >99%
Factors that lower sensitivity
- Large neoplasm (>8cm)
- Mucinous tumours
- Borderline tumours
Adnexal torsion - aetiology
25% of adnexal torsions occur in children
- Only 50% a/w a mass
Dermoid most common aetiology - up to 10% of dermoids undergo torsion.
=/> 5cm –> risk of torsion
Cause:
- Postulated that occurs where there is an unusually long ovarian pedicle with a moderately large cyst
- No evidence more common in pregnancy
Disruption of venous return occurs but arterial supply is largely maintained
- That’s what causes congestion and oedema
USS findings of torsion
Sensitivity 46-75%
Ovary may be rounded, enlarged and have a heterogeneous appearance compared with the contralateral ovary due to oedema, engorgement, and/or haemorrhage
Ovary may be located anterior to the uterus, rather than in the normal lateral or posterior position
Multiple small follicles (string of pearls, peripheralisation of follicles) - due to displacement by oedema
Mass may be present
Doppler flow may be:
- Present / normal - Due to incomplete occlusion, intermittent torsion, collateral blood supply
- Decreased
- Absent
- Assess contralateral ovary doppler flow to compare
Whirlpool sign - round hyperechoic structure with concentric hypoechoic stripes or a tubular structure with internal heterogeneous echoes - Twisting of the vascular pedicle
Management of adnexal torsion
Surgical evaluation
- Ovarian necrosis is rare
- The vast majority of torsed ovaries can and should be salvaged, unless malignancy is suspected
- Studies had found that many patients (even those with black or blue ovary) retain ovarian function following detorsion - USS f/u - rate of follicular development >80%
Time (up to 36h) is more important than appearance
If premenopausal, benefits of ovarian conservation appear to outweigh theoretical risks
Post-menopausal, or suspicious looking –> USO
No high quality data to support oophoropexy
Cyst rupture / haemorrhage timing
Usually days 20-26 of cycle
Recurrent cyst rupture / haemorrhage can be prevented by ovulation suppression (e.g. COCP) - but won’t treat current cyst
Management of premenopausal simple cysts
Functional or simple ovarian cysts <50mm usually resolve over 2-3 menstrual cycles
50-70mm - yearly USS f/u
>70mm - consider further imaging (MRI) or surgical intervention
- Due to difficulties in examining the entire cyst adequately at time of USS
Recurrence rates after laparoscopic needle aspiration of simple cysts range from 53-84%
Complications of dermoid cysts
Avoid rupture as cannot exclude malignancy
Chemical peritonitis due to spillage occurs in less than 0.2% of cases
If spillage occurs, meticulous peritoneal lavage should be performed with warmed fluid
Post-menopausal - conservative management of cysts
Cystic lesions smaller than 1cm are clinically inconsequential
- At the discretion of the reporting clinician whether or not to describe them in the imaging report
Asymptomatic, simple, unilateral, unilocular ovarian cysts, <5cm
- Low risk of malignancy (<1%)
If normal Ca125, repeat evaluation in 4-6 months, if stable then discharge after 1y of follow if stable or reduces with normal Ca125
Post-menopausal - surgical management of cysts
Assess:
- Comorbidities
- Nutritional status
- Functional status
Indications:
- Symptomatic simple cyst
- Suspicious or persistent complex mass
Consider laparoscopy if:
- RMI <200
- Surgeon with suitable experience
Procedure: BSO
Avoid intraperitoneal spillage
Consider laparotomy if:
- RMI >200
- CT findings, clinical assessment or findings as laparoscopy require a full laparotomy and staging procedure
Work up of post-menopausal / complex cyst
Symptoms suggestive of malignancy?
- Protective factors - parity, COCP use
FHx of ovarian, bowel or breast cancer
Exam - ascites? LN?
Tumour markers
- Ca125 - should not be used in isolation to determine if a cyst is malignant, not specific
- Ca199, CEA = epithelial tumour markers
If under 40y - LDH, aFP, hCG
DON’T FORGET TO EXCLUDE PREGNANCY
Imaging
- USS first line
- MRI if need further cyst characterisation
- CT if RMI >200
Assess:
- Comorbidities
- Nutritional status
- Functional status
RMI
Menopausal status (M)
- 1 = premenopausal
- 3 = postmenopausal
Presence / absence of suspicious ultrasound features (U) 1 point for each of the following: - Multilocular cysts - Solid areas - Metastases - Ascites - Bilateral lesions U = 0 for ultrasound score of 0 U = 1 for score of 1 U = 3 for a score of 2-5
Serum Ca125 in IU/ml
RMI = U x M x CA-125
RMI I score >200
- 78% sensitivity and 87% specificity for cancer
- If post-menopausal, PPV 96% for malignancy
IOTA simple rules
- Benign features
Unilocular cyst Solid components present but <7mm Acoustic shadows Smooth multilocular lesion with largest diameter <10cm No blood flow
IOTA simple rules
- Malignant features
Irregular solid lesions
Ascites (fluid above the top of the uterus)
=/>4 papillary structures
Irregular multilocular-solid tumour with largest diameter >10cm
Abundant blood flow
Utility of IOTA simple rules
Sensitivity 95%, specificity 91%
25% of unclassifiable lesions can be sent for second opinion or have ADNEX model applied
Ovarian torsion in pregnant women
Most common cyst to affect pregnant women is a dermoid cyst
Torsion most commonly occurs in the first trimester or post-partum
Tumour markers for specific ovarian cancer types
Epithelial CA125 CEA Ca19-9 HE4
Germ cell
LDH
aFP
B-hCG
Sex cord stromal E2 FSH Inhibin Testosterone
CA125
Sensitive but not specific
Elevated in 80% of non-mucinous ovarian cancers
Elevated in only 50% stage I cancers
In premenopausal women, can be elevated if:
- Taken when menstruating
- Active endometriosis
- Pregnancy
- Infection
Better predictive value in post-menopausal women
CA 19-9
Non-specific Elevated in - Mucinous borderline tumours - Pancreatic - Gastric
Ovarian cancer
- 76% of mucinous carcinomas of the ovary
- 27% of serous carcinomas of the ovary
CEA
Elevated in
- Metastatic bowel cancer
- Mucinous borderline tumours
- Other cancers - lung, breast, liver, pancreas, thyroid, stomach
- Non cancerous conditions - e.g. UC, smoking
Elevated 37% of mucinous carcinomas of the ovary
Outline FIGO staging for ovarian cancer
I - Tumour confirmed to ovaries or fallopian tubes
- A - one ovary, capsule intact
- B - both ovaries, capsule intact
- C1 - surgical spill
- C2 - capsule rupture before surgery
- C3 - positive washings
II - pelvic extension
- A - uterus or tube or ovary
- B - other pelvic structures
III - spread to peritoneum outside of pelvis or retroperitoneal LN
- A1 - LN (i or ii)
- A2 - micro peritoneal mets
- B - macro peritoneal mets
- C - capsule of liver or spleen
IV - distant mets (excluding peritoneal mets)
- A - pleural effusion
- B parenchymal mets and mets beyond abdomen
Risk factors for ovarian cancer
Increasing age - Incidence increases rapidly after menopause Nulliparity (2x increased risk) Infertility Use of perineal talc Obesity HRT BRCA Lynch syndrome FHx of ovarian cancer
Protective factors for ovarian cancer
COCP - If on for >5y then reduce risk of ovarian or endometrial cancer by 50%
Breastfeeding - Cumulative total of 18 months –> reduced risk 1.5
Sterilisation / tubal ligation
Hysterectomy
First pregnancy at an early age
Early menopause
Typical ovarian tumour type based on age
Women <20y
- Germ cell tumours
30s and 40s
- Borderline tumours
> 50y
- Epithelial tumours
Screening for ovarian cancer
Currently no evidence to support general population or high-risk group screening
Studies using Ca125, USS and pelvic exam do not have an acceptable level of sensitivity and specificity
Low prevalence of disease and lack of high quality screening methods make it more likely to obtain false positive results –> unnecessary interventions
Types of ovarian cancer
90% epithelial
Malignant GCT 3%
Sex cord stromal cell tumours 1-2%
5% metastatic
Types of epithelial ovarian cancer
High grade serous - 70% Endometrioid 10% Clear cell - 10% Mucinous 5% Low grade serous - 5%
Staging laparotomy for ovarian cancer
If pre-op suspicion is of malignancy, laparotomy should be performed
If no visible or palpable evidence of metastasis, perform the following to ensure adequate staging
1. Careful evaluation of all peritoneal surfaces
2. Retrieval of any peritoneal fluid or ascites - if none, washings should be performed
3. Infracolic omentectomy
4. +/- Selective lymphadenectomy of the pelvic and para-aortic LNs (No role for standard lymphadenectomy)
5. Biopsy or resection of any suspicious lesions, masses or adhesions
6. Random peritoneal biopsies of normal surfaces
7. TAH + BSO in most cases
8. Appendectomy for mucinous tumours
Consider frozen section
Pathophysiology of epithelial cancers
HGSC - 60-80% arise from fimbrial ends, P53 / BRCA associated mutations. Typically aggressive
Endometrioid and clear cell - arise from endometriosis
LGSC - Typically younger age women than HGSC, Not a/w BRCA1/2
- Characterised by a relatively indolent behaviour and resistance to cytotoxic chemotherapy
Mucinous carcinoma - A/w obesity and smoking. Need to exclude a GI primary.
Cystic tumours with mucin secreting epithelium. Grow every large. 10% bilateral
Confined to ovary in 95-98%
Spread of ovarian cancer
Peritoneum, including omentum and pelvic and abdominal viscera - Includes diaphragmatic and liver surfaces
Primarily through lymphatic and LN drainage - Para-aortic - External iliac - Common iliac - Hypogastric - Lateral sacral - Occasionally to the inguinal Peritoneal surfaces --> diaphragmatic lymphatics and hence to the major venous vessels above the diaphragm
Haematogenous spread is rare
Diagnostic work up before MDM for ovarian cancer
Imaging - CT CAP - CXR can screen for pleural effusions - +/- PET Serum Ca125 If <40y, germ cell tumours more common - bHCG, AFP, LDH FHx - enquire about reproductive, breast or colon cancer
Definitive pathological diagnosis from tissue sample if suspect advanced
- Biopsy (ascites, LN)
Principles of treatment for ovarian cancer
Nutritional assessment
Optimise co-morbidities
Anaesthetic review
Genetics if HGSC
Primary surgery via midline laparotomy, by GONC
- staging
- High correlation between optimal cytoreduction (debulking) and survival
Neoadjuvant chemotherapy - Surgery deferred until after 3 cycles of chemotherapy, then interval debulking surgery, then followed by further 3 cycles.
- c.f. primary surgery - median overall survival similar, more likely to achieve optimal debulking, less likely to die within 28 days of surgery and had fewer post-op complications
vs. Adjuvant chemotherapy (given post-op)
Chemotherapy for epithelial ovarian cancer
Low chemosensitivity - LGSC, mucinous, CC
Evidence that all patients other than stage 1 grade 1 may benefit from chemotherapy
Standard: paclitaxel (taxane agent), followed by carboplatin (platinum-based)
- 6 cycles
Side effects paclitaxel
- alopecia
- neurotoxicity
- arthralgia
Side effects of carboplatin
- nephrotoxicity
- thrombocytopenia
Both have
- n/v
- neutropenia
- hypersensitivity reaction
Almost 80% of women with advanced stage disease who respond to first line chemotherapy relapse
What are PARP inhibitors?
Patients with BRCA (germline and somatic) have the greatest benefit
Frontline maintenance - for recurrence
Follow up after ovarian cancer treatment
Every 3-4 months in the first 2y
6 monthly to year 5 of treatment
Then annual
General clinical exam including pelvic exam
Serum Ca125
- Studies show no change to survival benefit compared to monitoring symptoms
Symptoms suggestive of recurrence –> imaging (usually CT)
Family history of ovarian cancer
Hereditary factors are implicated in ~20% of ovarian, fallopian tube and peritoneal cancers
Approx 3-fold increase in relative risk to all first-degree relatives
If first degree relative with epithelial ovarian cancer (EOC) and no known genetic susceptibility, lifetime risk of EOC is 2-3%
If 2 relatives –> 8% (provided BRCA1/2 excluded)
About BRCA
Autosomal dominant pattern of inheritance
Both are tumour suppressor genes that play a role in DNA repair
Ashkenazi Jewish - 1 in 40
General population: 1 in 400
“60, 40, 40, 20” for breast and ovarian cancer risk for BRCA1/2
> 15% of women with HGSC have BRCA1/2 mutation
BRCA management
Screen for in women with HGSC <70y
Full pedigree analysis and genetics referral
ACOG recommend TVS and Ca125 every 6 months for screening
- TVS and Ca 125 - associated with high false positive rates and show no proven benefit
Risk-reducing BSO once childbearing is complete
- BRCA1: between 35-40y
- BRCA2: between 40-45y
Obtaining RRBSO by the recommended age may reduce the risk of breast cancer
Risk reduction up to 95% for gynae cancer
Risk of diagnosing occult tubal cancer - up to 6% of women undergoing RRBSO
Residual lifetime risk of primary peritoneal cancer (1-2%)
Use of HRT is generally consider safe - provided no personal Hx of breast cancer, or medical contraindications
COCP reduces ovarian cancer risk of BRCA1, although significantly less effective than RRBSO
Offer BS if declines BSO
Lynch syndrome
Lynch syndrome accounts for ~3% of all endometrial cancers
50% of women with Lynch syndrome will present with a gynae cancer as their primary cancer
Germline mutation in one of the DNA MMR genes
Autosomal dominant
Associated with cancer of the:
- Colon
- Stomach
- Ovary - Lifetime risk 10-20% (EC or CCC)
- Endometrium - Lifetime risk up to 60%
- Prostate
- Pancreas
- Gallbladder
- Brain
- Skin
- Ureter
Discuss prophylactic hysterectomy and RR BSO once completed childbearing
PSEUDOMYXOMA
Syndrome rather than pathological term
Widespread deposit of mucin within the intra-abdominal cavity
Primary appendiceal lesion
Occasionally ovarian and other GIT sites
Krukenburg tumour
40% of metastatic cancer to the ovaries
Primary tumour in stomach, less commonly colon or appendix
Mucin filled signet ring cells on histology
Poor prognosis - most die within 1y
Primary sites of mets to ovary
Breast
Lower reproductive tract sites - cervix, uterine
GIT - bowel, gastric (stomach most common), pancreatic
Lymphoma
Aetiology of germ cell tumours
15-20% of all ovarian tumours
3% of all ovarian cancers
Benign or malignant (1/3)
Arise from primordial germ cells derived of the embryonal gonad
Undergo defective meiosis
Classified according to the type of cell that is produced
RISK FACTORS Higher in African, Asian, Hispanic Gonadal dysgenesis Abnormal karyotype Median age: 16-20y - Rare after 3rd decade No identifiable genetic link
Which germ cells cause with GCT
DIFFERENTIATED
Trophoblast –> choriocarcinoma (<1%) - HCG
Yolk sac –> yolk sac tumour (20%) - aFP
Embryo –> teratomas 20% (mature and immature)
Whole blastocyst –> embryonal carcinoma (<5%)
UNDIFFERENTIATED
Dysgerminoma (45%) - LDH
Clinical presentation of GCT
Tend to present more acutely than epithelial ovarian cancer
Rapidly enlarging mass
Acute severe lower abdominal pain due to tumour rupture, haemorrhage or torsion
Urinary symptoms - e.g. dysuria, frequency
Rectal symptoms
Menstrual irregularities
Positive pregnancy test
Investigation of GCT
aFP, hCG, LDH, Ca125
Karyotype in all premenarchal girls because these tumours can arise in dysgenetic gonads
Adnexal masses that require surgical exploration:
- > /=2cm in premenarchal girls
- Complex masses >/=8cm in premenopausal patients
Doppler USS and contrast-enhanced MRI of pelvis to look for adnexal masses and assess ease of operability
Contrast-enhanced CT / MRI to evaluate abdomen / solid organs
CXR - GCT can metastasise to the lungs or mediastinum
MRI brain with contrast - If any woman with disease spread above the diaphragm or if otherwise clinically indicated
Management of GCT
Fertility-preserving surgery via midline incision
- Unilateral salpingo-oophorectomy
- Surgical staging with omental and multiple peritoneal biopsies, peritoneal washings, biopsy of suspicious LN
- Biopsy of contra-lateral normal appearing ovary not recommended
Advanced stage disease - extensive surgery may delay chemotherapy administration, therefore chemotherapy is recommended as the primary treatment in the presence of metastatic disease
Very chemosensitive BEP chemotherapy - Bleomycin - Etoposide - Cisplatin (P for platinum) Offer for IB, recommend for IC + IA - chemo if recurrence (a/w 90% cure)
Most aggressive are endodermal sinus tumour and choriocarcinoma, but with combination chemotherapy are highly curable
Dysgerminomas are exquisitely radiosensitive, but no longer forms a part of routine treatment algorithms due to long-term toxicities and effects
Fertility for GCT post-treatment
Previous publications have reported a successful pregnancy rate of 75% in those wishing to conceive following chemotherapy for GCTs
No reports of an increased congenital abnormality rate following chemotherapy
Follow up of GCT
Using close surveillance, chemotherapy is utilised only for those who relapse without compromising survival (IA +/- IB)
Risk of relapse is relatively low
- If relapses, can then salvage with curative chemotherapy
Surveillance (10y total)
- Tumour markers every 2 weeks for 6/12
- Monthly for 6/12
- 3 monthly spacing up to 6 monthly
CXR on alternate visits
MRI every third visit
Advise against pregnancy during the first 2y
Aetiology of SCST
10% of ovarian neoplasms in childhood and adolescents are SCST Cells that give risk to tumours: - Granulosa cell - Theca cell - Sertoli cell - Leydig cell - Fibroblast
Granulosa cell tumour - accounts for 70%
Management of SCST
Most SCST are stage 1 at diagnosis, therefore curable with surgery alone
Surgery: Fertility preserving - USO + washings + omental biopsy + careful inspection of contralateral ovary and all peritoneal surfaces
Granulosa cell tumours - types
Two types:
Juvenile (5%)
- High estrogen production
- Typically develops before puberty and presents with precocious puberty
Adult types (95%)
- May present with PMB
- Usually present in middle-aged and older women (median 50-54y)
- Excess estrogen –> endometrial hyperplasia (25-50%) or carcinoma (5-10%)
Granulosa cell tumours - investigation and management
Tumour markers:
- Inhibin B
- AMH
- CA 125
No evidence that adjuvant CT or RT improves results of surgery alone for stage I disease
Stage at diagnosis - most important prognostic factor
If elevated inhibin B and/or AMH at initial diagnosis, can use as reliable markers during f/u
About fibroma
SCST
Benign
Most common
Originate from spindle cells, producing collagen
Meigs syndrome - Fibroma + ascites +/- pleural effusion, due to VEGF
About thecoma
Post-menopausal Originate from spindle and theca cells Benign Produce excess estrogen - endometrial hyperplasia in 15% - carcinoma in 20-25%
About Sertoli-Leydig cells
3rd and 4th decades of life
Benign or malignant
Sertoli cells –> oestrogen
Leydig cells –> androgens
Clinical virilisation
Management: USO
Or TAH + BSO + staging if family complete
70-90% 5y survival for malignant disease
Define borderline tumours
Heterogeneous group of lesions defined histologically by atypical epithelial proliferation without stromal invasion
Behaviour that is intermediate between benign cystadenomas and invasive carcinomas
Extensive sectioning of the tumour is necessary to rule out invasive cancer
Invasive cancers that arise in borderline tumours are often indolent and generally have a low response to platinum-based chemotherapy
Spontaneous regression of peritoneal implants has been observed
Incidence of BOT
1.8 to 5.5 per 100,000 women per year
Median age 45-48y
- 1/3 of borderline ovarian tumours are diagnosed in women <40y
75% are stage I at diagnosis
Histology of BOT
Serous 45-60%
Mucinous 30-50%
Seromucinous, endometrioid, clear cell, Brenner (transitional cell) 5-10%
Investigations of BOT
Typical USS features Multi-loculated ○ 30% of serous ○ 40% of mucinous Solid / cystic, internal papillations ○ 78% of serous ○ 40% of mucinous Thickened septae Bilateral
CA125 - similar to epithelial ovarian cancer
- elevated in 80-90% advanced serous borderline tumours
Management of BOT
Advise woman not a cancer
MDT
- Review pathology with expert pathologist
- GONC, radiologist, med onc
Complete staging vs. conservative surgery - should be individualised
Completion surgery when fertility preservation no longer required is controversial
Laparoscopy vs. laparotomy
- Laparoscopy a/w increased chance of cyst rupture and under staging
- Despite this, no difference in survival rates or treatment plan
No adjuvant therapy recommended as no change to survival rates (regardless of stage)
Surgical options for BOT
Complete staging- TAH + BSO + peritoneal washings + omentectomy + resection of mets
PROS - Detection of advanced stage disease
Upstaging not uncommon after initial non-staging procedure
Detection of occult invasion
Better information for prognostic counselling
CONS - Premature surgical menopause (1/3 <40y). Infertility. Procedure with higher surgical morbidity
Conservative treatment - conserve >1 ovary to preserve fertility, avoid premature menopause
Cystectomy - 10-30% recurrence vs. oophorectomy - ~1% recurrence.
PROS - Disease has a good prognosis. Recurrence does not affect survival (for USO vs, full staging)
CONS - Will require second procedure if missed occult invasion on frozen section
Prognosis of BOT
Favourable prognosis a/w:
- Early stage
- Serous histology
- Younger age at diagnosis
Causes of death usually complications of disease (e.g. SBO) or complications of therapy - rarely malignant transformation
Follow up of BOT
USS every 6 months +/- CA125 if elevated at diagnosis
Total 10-15y surveillence
Consider completion surgery when family complete
Features of BOT associated with increased risk of recurrence
Conservative surgery (cystectomy) - recurrence rate of 15-50%
- But survival unchanged
Micropapillary features of serous BOT
- A/w increased likelihood of both invasive peritoneal implants and recurrence
Mucinous prognostic factors
- Extra-ovarian tumour
- Pseudomyxoma peritoneii
Counselling of fertility with BOT
50% will become spontaneously pregnancy after conservative surgery
Increased risk of infertility - reduced ovarian reserve, adhesions
Large number of women already suffering from infertility before diagnosis
Evidence to guide management of adnexa at benign hysterectomy
Postmenopausal ovaries are physiologically active, continue to produce oestradiol (at low levels) and testosterone. Modelling study, 2005 - “women <65y clearly benefit from ovarian conservation, and at no age is there a clear benefit from prophylactic oophorectomy”
Nurses’ Health Study - Median f/u 24y
Bilateral oophorectomy at time of hysterectomy for benign disease a/w:
- Decreased risk of breast and ovarian cancer
- Increased risk of all-cause mortality, and fatal and non-fatal CHD
At no age was oophorectomy a/w increased survival
Oophorectomy not associated with decreased survival in women >55y at the time of hysterectomy + oophorectomy
Potential risks of oophorectomy at time of hysterectomy for benign disease
Increased mortality due to coronary heart disease
Increased morbidity and mortality due to osteoporosis related fracture
Increased risk of cognitive dysfunction, including dementia
Increased risk of depressive and anxiety symptoms
In premenopausal women:
- More severe and prolonged vasomotor symptoms than those seen following natural menopause
- Reduction in libido and sexual dysfunction
With the exception of osteoporosis related fracture, it is unclear whether the incidence and severity of the above conditions are ameliorated by oestrogen replacement therapy
Removal of the tubes at time of hysterectomy for benign disease
Growing evidence that high-grade serous tumours of ovary and peritoneal surface epithelium may originate in the fallopian tubes
Removal does not appear to increase surgical complications or impact ovarian function
No population based data to quantify the risk-benefit profile
Endometrial hyperplasia definition
and incidence
Irregular proliferation of glands of irregular size and shape, with an increase in the gland to stroma ratio when compared with proliferative endometrium
Incidence age dependent
- 1.3% in women <40y
- Post-menopausal with AUB - 8-15%
Risk factors for endometrial hyperplasia
Obesity - Peripheral aromatisation of fat tissue - androgens converted to oestrogen PCOS / anovulation Nulliparity Unopposed oestrogen - Oestrogen stimulating tumours (e.g. ovarian granulosa cell neoplasm) - Oestrogen therapy Tamoxifen Peri- and post-menopausal age groups FHx of breast, colon, or endometrial cancer Age >45y Late menopause Diabetes HTN
COCP and Mirena are protective
Compared histology of endometrial hyperplasia with and without atypica
Increase in gland to stroma ratio, variation in size and shape of glands
WITH ATYPIA
Nuclear atypia and hyperplasia
More related to cytological features rather than architectural criteria
Management of hyperplasia without atypia
Address reversible factors - Weight loss - Metformin Progesterone resolution rates up to 96% LNG-IUS = first-line - Higher disease regression rate - More favourable bleeding profile - Fewer adverse effects
Continuous oral progesterone
- MPA 10-20mg/day
- Norethisterone 10-15mg/day
Resample at 6/12 and 12/12
At least 2 negative biopsies prior to discharge
If high risk, annual sampling and f/u
Consider hysterectomy if no regression, progression to atypia, relapse or high risk of progression (on tamoxifen, FHx
Compare progression and concomitant cancer risk of endometrial hyperplasia with and without atypica
and spontaneous regression rates
Hyperplasia without atypia
- <5% over 20y
- <1% of concomitant cancer
- 80% regression
Hyperplasia with atypia
- 30% over 20y
- 22-43% of concomitant cancer
- <30% regression
Management of hyperplasia with atypia
Address reversible factors
Standard management if not desiring fertility and medically feasible: hysterectomy +/- BSO
Premenopausal - maybe BSO, individualise
- Warn about possibility of second procedure pending final histology
Fertility sparing:
- MDT review
- Need to rule out invasive Ca or co-existing ovarian Ca
- 5-fold reduction in risk of progression with progestogen Rx
- Regression rates up to 86% with LNG-IUS (1st line). Takes 3-10 months (mean 6 months)
- Relapse rates variable (approx 25%)
- LBR 26%
Resample 6 months, then 12 months
On completion of family, consider completion hysterectomy
Malignancy risk 11% long term with cessation of treatment
Endometrial cancer
- incidence
- aetiology
Up to 1 in 45
Higher in high income countries because fat and inactive
Majority are diagnosed early
Spread of endometrial cancer
Direct spread - Through the fallopian tubes onto the ovaries the peritoneal cavity
Most common route - myometrial and eventually serosal involvement
To parametrial, vaginal, pelvic and para-aortic nodes
Primary modality of distant metastatic spread
Haematogenous spread to liver, lungs, CNS, bone (rare)
Risk factors for endometrial cancer
Hyperplasia Obesity (34% attributed to obesity) Older age - Peak incidence 60-79y Unopposed oestrogen Tamoxifen (RR 2-3) Nulliparous (35-40% of endometrial cancers occur in women who are nulliparous) Early menarche Late menopause PCOS Diabetes Genetic syndrome - Lynch syndrome - Cowden syndrome FHx of ovarian, breast or colon cancer
Protective factors for endometrial cancer
OCP and smoking are protective
Physical activity
High coffee drinkers
Investigations for endometrial cancer
Endometrial thickness on US (post-menopausal)
- =4mm - risk of malignancy is <0.5%, >99% NPV
- > 10mm - risk of malignancy is 10-20%
PIPELLE
- Failure rate: ~7%
- Inadequate samples 13-15%
- Potentially >90% sensitivity for endometrial Ca if good sample
HYST D&C
- PPV 100%, NPV 99.5%
What is type 1 endometrial cancer?
Grade 1 and 2 endometroid carcinoma
Most common
May arise from complex atypical hyperplasia
Linked to excess estrogen (unopposed by progesterone)
Usually diagnosed early
Relatively good prognosis
What is type 2 endometrial cancer?
Grade 3 endometrioid tumours, non-endometrioid tumours
- Typically serous cancers (molecular pathogenesis driven by p53 mutation)
Develop from atrophic endometrium
Less hormone sensitive
Diagnosed later, generally more aggressive
FIGO staging - endometrial cancer
I - confined to uterus
- A <50% myometrial invasion
- B >/=50%
II - invades cervical stroma
III - local or regional spread
- A - serosa or adnexa
- B vaginal or parametrial
- C1 - pelvic LN
- C2 - para-aortic LN
IV - invasion of bladder, bowel, distant sites
- A bladder or bowel
- B - distant mets (incl abdominal mets, inguinal LN)
Imaging for pre-op staging
Endometrial Cancer
Australia tend to do CT abdo pelvis, NZ MRI
- MRI no medicare funded in Australia
- MRI is less accessible
- Similar in detection of nodal metastases and extrauterine spread
MRI - Optimal method for assessing degree of myometrial invasion in endometrioid tumours
CXR
+/- Ca125 (associated with advanced stage, peritoneal involvement, ovarian mets)
Prognostic factors with endometrial cancer
Grade of tumour (G3 - poorly differentiated) Depth of invasion (myometrial) Histologic subtype - non-endometroid histology (papillary serous and clear cell) LVSI (lympho-vascular space invasion) Cervical stromal involvement Increasing age (>65y) Stage (>IB) Tumour extension beyond fundus Tumour >2cm Positive peritoneal cytology Comorbidities
Principles of treatment of endometrial cancer
Surgical Conservative - For surgically unfit - Desiring fertility Medical - Can consider up front in some scenarios Palliative
Surgical management of endometrial cancer
Standard primary treatment is surgery
Complete staging may confer some benefit but no evidence of survival advantage
Hysterectomy + BSO
- Tubes and ovaries may contain micro-metastases therefore recommend removal +/- peritoneal washings
+/- Move to sentinel node rather than extensive lymphadenectomy (unless high risk features)
Sentinel LN - NPV 99.6%
Full surgical staging is not required for low risk tumours - grade 1-2, stage IA - can be operated on by general gynae (TLH+BSO)
Risks of pelvic lymphadenectomy
for endometrial cancer
Intraoperative
- Vessel injury
- Nerve damage (obturator, genitofemoral)
- VTE
Post-op
- Lymphocele 20% (symptomatic in 6%)
- Lymphoedema (1.5-28%) but 60% report affect on ADLs
- Infection
Radiotherapy for endometrial cancer
Stage I-II disease - reduces pelvic recurrence with no change in survival
Indications:
- To treat recurrence
- Palliative setting - bleeding
- Rx in non-surgically resectable disease
- Stage I disease - if patients have high-intermediate risk factors then vaginal brachytherapy, >2 of: age >60y, deep myometrial invasion, grade 3, serous or CC, LVSI
- stage II + disease
Hormonal therapy in endometrial cancer
Progesterone Indications: - Fertility sparing treatment desired - Inoperable (co-morbidities) - Recurrent disease
LNG IUS or oral progesterone 100mg bd
Response rate: 50-95%
Recurrence rates: up to 66%
Pregnancy outcomes similar to those of atypical hyperplasia
Treat underlying co-morbidities
- bariatric surgery
Prognosis of endometrial cancer
Overall cure rate 75-80% Recurrence - Classically at the vault - 75% within 12 months Treatment of recurrence: - If no previous RT, then pelvic RT appropriate - If prior radiation with isolated central pelvic recurrence with no evidence of LN involvement - consider exenterative surgery - Hormonal Rx - Chemotherapy
Follow up of endometrial cancer
Role of f/u is controversial
- Unlikely to find recurrence in absence of symptoms
75% of recurrences symptomatic
NCCN guidelines:
- Physical exam every 3-6 months for 2-3y, then 6 monthly or annually
- Imaging as clinically indicated
- Patient education - Symptoms of recurrence
- Treatment of recurrence - MDT
Hormone replacement therapy
Theoretical risk of stimulating the tumour cells
- Evidence is unclear about this risk
Treat on individual basis depending on the symptoms and prognostic risk factors
Consider alternative treatments
What is tamoxifen?
Selective estrogen receptor modulator (SERM)
- Anti-oestrogen effects in the breast
- Oestrogenic effects in other tissues including blood (VTE risk), bone and endometrium
Indications for tamoxifen:
- ER positive breast cancer
- Risk reduction in pre-menopausal women with a high inherited risk of breast cancer
Gynae effects of tamoxifen
Oestrogen-like changes in the vaginal epithelium of some patients
Stimulation of endometriosis –> worsening Sx
Stimulation of growth of benign fibroids
ENDOMETRIUM Benign cystic hyperplasia Increased incidence of: - Benign endometrial polyps - Endometrial proliferation - Hyperplasia If endometrial pathology prior to starting tamoxifen, statistically significantly higher risk of developing lesions at 2y compared to patients without Increased risk of endometrial adenocarcinoma in post-menopausal women (RR = 4.01) only
Can induce ovulation
May be teratogenic
Management of women on tamoxifen
Routine screening with TVS or endometrial biopsy is not recommended
No clear evidence that LNG-IUS prevents endometrial cancer in those with breast cancer on tamoxifen
Investigate if symptomatic
Uterine sarcoma
Arise from the myometrium or the connective tissue elements of the endometrium
<10% of cancers of the uterine corpus
Often behave aggressively
Risk factors of uterine sarcoma
Age (usually >40y) - Mean age of diagnosis: 60y Menopausal status African American ethnic background Current or prior tamoxifen exposure Hx of pelvic irradiation Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome Survivors of childhood retinoblastoma
Types of uterine sarcoma
Endometrial stromal sarcoma - low grade, best prognosis
Adenosarcoma - low grade
Undifferentiated endometrial sarcoma - high grade
Leiomyosarcoma - high grade
Prognostic factors of uterine sarcoma
Tumour stage = most important
High grade tumour
Adnexal spread
LN metastasis
Management of uterine sarcoma
TAH + BSO
Pelvic and/or para-aortic lymphadenectomy
- Mainly indicated in carcinosarcoma
- Not in leiomyosarcoma or undifferentiated sarcoma
Adjuvant pelvic RT
- Reduces risk of local recurrence but has little influence on overall survival rates
Leiomyosarcoma aetiology
Incidence of 0.02-0.3%
Malignant transformation occurs in <1% of fibroids
Approx 1/3 of uterine sarcomas
Arises from the smooth muscle of the uterine wall
Leiomyomas do not appear to be the precursor to leiomyosarcomas
Clinical features of leiomyosarcoma
Rapidly expanding mass
PMB or variants of AUB (if premenopausal)
Ascites
Lymphadenopathy
Evidence of secondary spread
No established tumour markers for LMS, but may be an elevation in LDH related to increased cell turnover
Typically large (>10cm)
Prognosis of leiomyosarcomas
Often behave aggressively
Have a poorer prognosis than EAC
70% of stage I and II tumours recur
- Often in the form of distant mets
Acute radiation side effects
Urinary
- Radiation cystitis - irritative voiding symptoms and bladder spasms
GI
- Enteritis / colitis - nausea and vomiting, watery diarrhoea, cramping, urgency
- Proctitis - rectal discomfort, tenesmus
Vaginal
- Ulceration
- Erythema
- Discharge
- Infection
Skin
- Erythema
- Moist desquamation
Late radiation (>3 months) side effects
Urinary
- Bladder fibrosis, reduced capacity, haematuria, ulceration, pain
- UV and VV fistula
GI
- Chronic enteropathy - chronic diarrhoea and malabsorption
- Fibrosis - dysmotility or obstruction / ileus
- Ulcerations
Vaginal
- Sexual dysfunction
- Stenosis
- Vaginismus
- Adhesions
Ovaries - Early menopause
Bone and bone marrow - Insufficiency fractures
Skin
- Fibrosis
- Hyperpigmentation
- Telangiectasia
Breast cancer background
Lifetime risk 1 in 9
15% diagnosed before age of 45y
Effect of pregnancy on breast cancer
Pregnancy itself does not appear to worsen prognosis for women diagnosed in pregnancy
However, pregnancy-associated breast Ca occurs in a younger population who may have features that carry a higher risk of metastases
Diagnosis of breast cancer
If presents with breast lump during pregnancy, refer to breast specialist team
Diagnosis can be difficult when pregnant or lactating
USS first line for discrete lump
Tissue diagnosis through US-guided biopsy for histology
- Cytology (FNA) inconclusive in pregnancy due to proliferative changes
Staging for metastases is conducted only if there is high clinical suspicion
- CXR
- Liver USS
- Gadolinium-enhanced MRI - limited safety evidence, therefore avoid in pregnancy
- Bone scanning and pelvic CT are not recommended in pregnancy
Tumour markers not helpful
Management of breast cancer in pregnancy
MDT Consider TOP Surgical treatment - Including loco-regional clearance - Can be done in all trimesters Radiotherapy - Contraindicated until delivery
Chemotherapy
- Contraindicated in first trimester
- Safe from second trimester
- Tamoxifen and trastuzumab are contraindicated in pregnancy
Most women can go to full term and have a normal or induced delivery
Following Rx, can breastfeed from the unaffected breast
May depend on surgery and whether major ducts have been excised
- No evidence breastfeeding increases the risk of recurrence
RT –> fibrosis - makes lactation unlikely
Not advised while on chemotherapy
Non-hormonal contraception
Fertility after breast cancer
Chemotherapy induced gonadotoxicity may cause permanent amenorrhoea with complete loss of germ cells, transient amenorrhoea, menstrual irregularity and subfertility
Dependent on specific agents used, cumulative dose, women’s age
Tamoxifen - can cause menstrual irregularity but doesn’t appear to affect fertility
Planning pregnancy after breast cancer
MDT input
Long-term survival after breast cancer is not adversely affected by pregnancy
Stop tamoxifen for at least 3/12 prior to trying to conceive
- If ER + disease, tamoxifen is usually given for 5 years
Most women should wait at least 2y after treatment before conceiving - as this is when the risk of cancer recurrence is highest
Outcome of pregnancy
- May be an increased risk of miscarriage
No evidence of increase in congenital malformations or stillbirth
About HPV - pathogenesis
Double stranded DNA virus
single ring genome
Starts with sexual activity, introduces viral particles
Virus infects the parabasal cells of metaplasia epithelium (via microabrasions)
Then enters the cytoplasm, where hard to detect
At some point HPV DNA enters nucleus –> low grade squamous changes
Koilocyte - characteristic cells of HPV infection, occurs when HPV enters cell and replicates. At the end of the life cycle, cells lyse, releases infective particles into genital tract
In 10-20% HPV genomes integrates into host genome –> HG changes
E6 and E7 proteins (viral oncogenes) are over-expressed –> inactivation of p53 and pRB (growth regulatory proteins) –> uncontrolled cell division and no apoptosis
HPV methods that evade the immune system
Viral lifecycle takes place entirely within epithelium
No viraemia
No cell death
No inflammation
Local immunosuppression caused by viral proteins
Infection rates with HPV
~70-80% of sexually active women worldwide become infected at some stage of their life
- in 80% - infection will be transient, asymptomatic and resolve spontaneously
- in 10% will develop cervical dysplasia
10-20y latency between HPV infection and development of cervical cancer
HPV vaccination make up and benefit
Made from Virus Like Proteins (VPL) - Does not contain live, attenuated or killed viruses, therefore are not infectious IM infection Induces antibody response Do not treat existing lesions
Gardasil 9 - contains HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58
- Potentially prevents 90% of cervical cancers
- Trials demonstrated 95-100% efficacy against HPV types in the vaccine
75% decline in HSIL in young women since introduction of vaccine (Victoria)
59% reduction in genital warts
Some studies that show if vaccinate women who were previously unvaccinated, after their treatment for CIN/HPV, significantly reduce their risk of recurrence
High risk HPV and cancers implicated
Cervix (99.7%)
- Types 16 and 18 account for ~71% of cervical cancers (16 >18)
- 31, 33, 45, 52 and 58 - account for ~19%
- Non-oncogenic types 6 and 11 cause genital warts
Vulva, vagina (40%)
Anus (90%) - HPV 16
Penis
Some head and neck cancers
Safety of HPV vaccine
OK when breastfeeding
Not recommended during pregnancy (note no adverse effects reported)
Anaphylaxis rate: 1-3 in every million doses
No other serious responses have been identified
Minor adverse reactions - injection site reactions, fever, headaches, dizziness, muscle pain
Immune response may be smaller in the immunocompromised patient
Effectiveness is optimal when given <15y and prior to onset of sex
Vaccine schedule in NZ
Registered for use in females 9-45y and males 9-26y
Funded for males and females 9-26y (inclusive)
9-14 get 2 dose schedule (0 and 5-13 months)
15-26y get 3 dose schedule (0, 2, and 6 months)
Benefits and negatives of primary HPV screening
Higher sensitivity and NPV (99%)
Allows extended screening intervals
Expected to have cost reductions long term
Thought to result in 30% reduction in incidence of cervical cancer over time (more sensitive and detects higher grade lesions earlier)
Initially result in increase colposcopy by 36% but will be reduced by 7% due to HPV vaccine
6% increase in treatments for CIN2 in unvaccinated population, decrease for those that are vaccinated
Australia screening program
5 yearly HPV screening with reflex liquid-based cytology
25-74y
Exit test age 70-74
Primary HPV test with partial HPV genotyping and reflex liquid based cytology triage
Self-testing
- For under-screened or never-screened women
- Facilitated by a medical or nurse practitioner
If hrHPV –> colp
If oncogenic HPV that isn’t 16 or 18, conventional smear
- if normal smear or LSIL, repeat HPV in 1/12
- if HSIL –> colp
NZ screening program
3 yearly
If ‘first ever’ or >5y since the previous test, second test 12 months later
25-69 for any person who is sexually active
Liquid based cytology
If unsatisfactory, repeat after 4-6 weeks
- If 3 consecutive –> colp
- If post-menopausal, PN or breastfeeding, give Ovestin nightly for 2-3 weeks prior to repeating cytology
NZ
Management of LSIL / ASC-US
If no abnormal cytology within the last 5y and 25-29, repeat in 12 months
If at 12 months:
- Negative - repeat in 12 months, then return to 3y
- If abnormal - refer colp
- Don’t test HPV as positivity rate is too high in this age group
If prev abn cytology in last 5y, refer straight to colp
> 30y then reflex hrHPV test added
- If negative - repeat cytology in 12 months
- If positive - refer colp
Colp assessment of ASC-US / LSIL
Satisfactory and normal
- Refer back to smear taker for 2 annual cytology tests
Satisfactory and abnormal –> target biopsy. Histologically confirmed LSIL - refer back to smear taker for two annual smears
Unsatisfactory
- Review cytology - if concerned LG, repeat colp, cytology and hrHPV in 12 months
Colp assessment of ASC-H/HSIL
Satisfactory and abnormal colp –> targeted biopsy
- If CIN 1 - MDM review
- If HSIL on biopsy –> Rx
Satisfactory and normal colp / negative biopsy:
Review cytology - If confirms HG, repeat colp + cytology within 3 months
- normal, repeat at 12/12
- LSIL –> MDM
- HSIL –> Rx
HPV testing should be used to assist with the management of people with discordant results
Unsatisfactory colp
- Review cytology - if confirms ASC-H/HSIL - type 3 excision is recommended. Otherwise MDM.
If colp shows no abnormality, need careful inspection and colposcopy of the entire lower genital tract
F/u after HSIL treatment
Ensure HPV + cytology co-testing at 6 and 18 months post-treatment
If negative x2, they can return to 3 yearly screening
If positive, then re-refer to colp
Glandular abnormalities on smear
Refer any one with glandular abnormalities on cytology for colp
AIS on smear –> type 3 excision to exclude cancer
Colp
Hysteroscopy D&C
Type 3 excision
Even when margins clear, AIS risk of recurrence up to 20%
Pregnancy and cervical screening
Can be taken at any time during pregnancy
Particularly if never screened, overdue, abnormal screening history
After delivery, delay screening until 3/12 PP to allow the pregnancy-associated changes to resolve
If screening PN and/or breastfeeding, PV oestrogen cream nightly for 2-3 weeks is recommended
Colp is safe
Unlikely that biopsy or Rx would be undertaken during pregnancy
Risk of progression of HSIL to invasive cancer during pregnancy is low
Biopsy if invasion suspected
- If not suspected, delay until after delivery
Endometrial cells on smear
Normal endometrial cells in cervical cytology
- Pre-menopausal - If asymptomatic, no further evaluation is recommended
- > 40y - rarely can be a/w endometrial pathology. If symptoms –> investigation. Correlate with symptoms and histology specimens where possible
Atypical endometrial cells- at any age, refer to gynae
Cervical screening in immune deficiency
Normal cytology
- Annual screening and indefinite
Abnormal cytology
- Refer for colp, even for LSIL
Evaluate whole of lower genital tract
Treatment of the cervix should be excisional methods
F/u should include colposcopy + cytology
DES in utero exposure
Diethylstilboestrol prior to 18/40 –> increased risk of clear cell adenocarcinoma of the vagina and cervix, and some increased risk of HSIL and cervical cancer
Normal cytology
- Offer annual screening and colp
- Continue indefinitely
Abnormal cytology - Refer colp
Who to screen post hysterectomy (NZ, RANZCOG)
Subtotal hyst, HSIL regular screening
Do single screen if no screening if 5y prior to hyst
LSIL in past 5y, or LSIL in specimen - 2 vault smears 12 months apart, then stop
Surveillance under/guided by GONC if hyst for malignancy
Colposcopy
- definition
- sensitivity
Subjective method of examining the cervix with a low power microscope to identify areas of pre-invasive disease in asymptomatic women with abnormal cervical screening
Limitations (colp vs. 4 quadrant biopsy)
- Sensitivity 81% for CIN2
- 91% for CIN3
- 100% for cancer
Anatomy of cervix for colp
Ectocervix (intravaginal)
- Lined by squamous epithelium
Endocervical canal
- Lined by columnar epithelium
The squamocolumnar junction (SCJ) = - the junction between the two
When the cervix grows (influence of oestrogen - puberty, pregnancy), the cervix elongates and everts slightly, pushing columnar epithelium into the acidic vaginal environment
- Columnar epithelium replaced by squamous (metaplasia)
- When columnar epithelium extends to the ectocervix, it forms an ectropion
- New SCJ forms close to the ectocervix
- Following menopause, moves towards and into the cervical canal - may be invisible on visual examination
Transformation zone (TZ) = the area between the original SCJ and the current SCJ - Almost all CIN and carcinoma develops in the TZ
Types for transformation zone
Type 1 - Completely on the ectocervix and visible to colposcopic assessment
Type 2 - Partially extending into the endocervical canal, but completely visible to colposcopic assessment
Type 3 - Partially or completely extending into the endocervical canal, and not completely visible to colposcopic assessment
Features of the TZ to assess
Surface contour - flat = normal
- Micropapillary, hyperkeratosis, ulcerated
Vascular pattern - abnormal vessels - appear to stop and start (punctation), variable calibre (mosaic)
Acetic acid 5% changes - dehydrates cells and reversibly coagulates the nuclear proteins
- More rapidly dividing = more nuclear protein / nuclear activity = more white
Topography - describe lesions and TZ, how many quadrants, use clock face to describe location
Iodine uptake - stains deeply brown in mature squamous epithelium containing glycogen, dysplastic epithelium contains little to no glycogen so does NOT take up iodine
Columnar epithelium does not stain at all
HSIL cytological changes
Enlarged pleiomorphic nuclei - irregular in size and shape
Relatively reduced cytoplasm (halo cells)
- Increased nucleus : cytoplasm ratio
Large irregular cells
Irregular chromatin formation with clumping
HSIL histological changes
Increased nuclear material
Reduction in cellular differentiation
Increased mitotic figures
Involves entire thickness of epithelium but does not breach basement membrane
LSIL
Changes in lower third of epithelium
Reason for treatment of CIN3
Progression to cervical cancer 30-50% at 30y
Reduces 0.7% with treatment
Goals of HSIL Rx
Aim is to remove, or destroy, a cone shaped block of tissue, down to a minimum depth of 6mm, aiming to remove the entire TZ
6mm is the depth to which cervical glands (and therefore potential dysplastic cells) may extend
Most surgeons aim for 8mm
Principles of / criteria for ablation treatment
Adequate colp exam with pathologic / colposcopic diagnosis agreement
Must have a fully visible TZ / entire lesion can be visualised
Must have no evidence of invasive disease or glandular disease (on cytology, colposcopy or histology)
Must have biopsies taken
Usually for women who want to have children
Any recurrence after ablative treatment should be treated by excision
Post-op advice for LLETZ/cone
Minimal pain
Blood-stained vaginal discharge for 2-3 weeks
Some short term disturbance of menstrual periods (variable)
No intercourse, tampons for 4-6 weeks
No swimming for 2-4 weeks
Follow up
Pregnancy implications of cervical Rx
Excision > ablative treatment methods are a/w a small but real increase in long-term adverse obstetric outcomes
Excision depth >10mm –> significantly increased risk
However PTL is increased in women with untreated CIN
If younger, uncompleted family - laser
If older, completed family - LLETZ
Indications for cone biopsy
TZ if not fully visible
Suspicion of invasive disease or glandular disease (on cytology, histology or colposcopy)
Cytological evidence of high grade disease but no evidence of this on colposcopy / biopsy
Cervical cancer
- lifetime risk
Lifetime risk <1 in 250
- And falling
90% of cases in LMIC
- 18x higher mortality than high income countries
HPV found in virtually all cases of squamous cell cervical cancer
Most glandular lesions also contain HPV
70% are squamous lesions
20% are adenocarcinomas
Risk factors for cervical cancer
HPV types Early onset of sexual activity Multiple sexual partners Family Hx COCP Diethylstilbestrol (in utero exposure) HIV Low SES, remote access, being indigenous Under screening
SCC
- smoking
- parity
- younger age at first giving birth
FIGO staging of cervical cancer
I - confirm to cervix
- A - microscopic disease
- A1 stromal invasion <3mm
- A2 3-5mm
- B1 <2cm
- B2 2-4cm
- B3 >4cm
II -
A - upper 2/3 of vagina without parametrial (1 <4cm, 2 >4mcm)
B - with parametrial involvement
III
- A lower 1/3 of vagina
- B pelvic wall, hydronephrosis or non-functioning kidney
- C 1. pelvic LN, 2. para-aortic LN
IV -
- A - growth to bladder or rectum
- B - distant organs
Changes to FIGO cervical cancer (2018)
Previously clinical staging preferred to surgical staging as accessible in LMIC
Allow use of any imaging modality and/or pathological findings
No recommendations for routine investigations, which are to be decided on the basis of clinical findings and standard of care
MRI is superior to CT and clinical exam in determining the size, site and extent of cervical tumours
No imaging for microinvasive disease
PET-CT - More accurate than CT and MRI for nodal mets >10mm
Recommend FIGO exam for staging (cervical cancer)
- Colposcopy of the cervix
- EUA
- Endocervical curettage
- Hysteroscopy
- Cystoscopy
- Proctoscopy
Prognostic factors for cervical cancer
Overall 5-yr survival is 68%
- LVSI is a poor prognostic factor
- Age and performance status of the individual patient
- Tumour type
- Size of tumour (tumour volume)
- Metastases to pelvic or para-aortic nodes
Recurrence - survival closely related to tumour size and LN involvement
Surgery vs. chemoradiotherapy for cervical cancer
Surgery
- Preserves sexual function, although vagina may be shortened
- Conserves ovarian function (if patient doesn’t opt for removal)
- Treatment short with hospital stay ~1/52
- Few long-term problems
- May require radiotherapy post-op pending histology
Chemo-radiotherapy
- Low immediate risk
- Avoids major surgery
- Prolonged Rx (6 weeks)
- Sexual function difficult, dilators may help
- Loss of ovarian function
- N/v with CT
- Long-term bowel and bladder problems including fistula formation (uncommon, but may be difficult to treat)
Management based on stage of cervical cancer
IA1 - diagnosed on cone
- If completed fam, simple hyst
- If LVSI +/- LN
IA2 - type 2 rad hyst + pelvic LN
- if desires fertility, cone or rad trachelectomy + pelvic LN
IB1 - type C rad hyst + pelvic LN
- if <2cm and want fertility, rad trach
- If surgical margins close, or LN involved, consider adjuvant RT
IB2 / IIA1 - Surgical or RT can be chosen as the primary treatment depending on other patient factors and local resources
IB3 / IIA2 - Concurrent platinum-based chemoradiation = preferred Rx
- Surgery not encouraged as first line
IIB - IV A - Concurrent chemoradiation
IVB - chemotherapy
Recurrence of cervical cancer
Most recurrences are within 3y
Prognosis is poor - Most patients die from progressive disease with uraemia being the most common terminal event
Most common site of recurrence = pelvis
- Potentially curable - if isolated, no pelvic side wall recurrence, <3cm
- If follows surgery, usually treat with radical chemoradiation
- If isolated central pelvic recurrence, consider pelvic exenteration
Following radiotherapy, it is often difficult to perform anything other than a total exenteration in recurrent disease
PET-CT scan - most sensitive non-invasive test to determine sites of distant disease
Follow up of cervical cancer
Stage IA
- Smears q3/12 for 2y, then q6/12 for 3y
- Normal at 5y –> routine screening
Routine f/u visits:
- Every 3-4 months for the first 2-3 years
- Then 6 monthly until 5y
- Then annual for life
Consider HRT if <50y and lost ovarian function
VIN usual type
VIN warty type
- Surface is undulating or spiking –> condylomatous appearance
- Marked cellular proliferation with numerous mitotic figures and abnormal maturation
VIN basaloid type
- Thickened epithelium with a relatively flat, smooth surface
- Atypical immature parabasal type cells with numerous mitotic figures and enlarged hyperchromatic nuclei
VIN mixed
Typically occurs in younger, premenopausal women
Risk factors
- HPV infection
- Smoking
- Immunodeficiency
Multifocal VIN and multicentric VIN are most often associated with HPV 16, 18, and 31
Risk of progression of HSIL is 9-16% if untreated (3% in treated cases)
Differentiated variant (dVIN)
<5% of preneoplastic lesions of the vulva
Usually occur in postmenopausal women
Usually unifocal and unicentric
Often a/w lichen sclerosis (not HPV)
Progresses in 30%
Commonly found adjacent to keratinising squamous cell carcinoma or in patients with a Hx of vulvar cancer
Appearance:
- Epithelium is thickened and parakeratotic with elongated and anastomising rete ridges
- Abnormal cells are confined to the parabasal and basal portion of the rete pegs with little or no atypia above the basal or parabasal layers
- Basal cells usually stain positively for p53
Clinical presentation of VIN
Pruritis - most common complaint Visible lesion Palpable abnormality Perineal pain or burning Dysuria 50% asymptomatic
Investigation of VIN
Tissue biopsy
Colposcopy
Inspection and palpation of the vulva and groin for masses, ulceration or colour changes
- Most VIN lesions are multifocal and located in the non hairy part of the vulva
Management principles of VIN
prevent development of invasive vulvar cancer and relieve symptoms, while preserving normal vulvar anatomy and function
Individualise Rx
Options:
- WLE - Laser ablation - Topical Rx
Wide local excision for VIN
Advantages: occult invasive SCC present in many women, especially >50y
Preferred Rx for dVIN as unifocal nature and high malignant potential
1cm margins
Excision can be performed with knife, electrosurgery, or CO2 laser
Laser ablation of VIN
Useful if multifocal disease, especially multiple small lesions
Disadvantages
- Tissue is ablated, therefore liberal colposcopy directed biopsies required to rule out invasive cancer
Colposcopy used to control the depth of tissue destruction to <1mm
- Ablates intraepithelial lesion and allows for rapid healing
- 1mm - sufficient for hair free epithelial
- 3mm required for hairy areas because the hair root sheath tends to extend as deep as 2.5mm and significant risk of harbouring VIN
Superficial laser vaporisation may offer cosmetic advantages
Deep results in destruction of the skin appendage - Leads to hypertrophic scar formation, negating cosmetic advantages over excisional surgery
Medical Rx of VIN
Aimed at preserving anatomy, useful in younger patients
Careful colp exam with biopsies to exclude invasive disease
Imiquimod (Aldara)
- Topical immune response modifier
- Antiviral and antitumour effects mediated through the stimulation of local cytokine production and cell-mediated immunity
- Appears to be effective therapy for HGIL - need more data
PAGET’S DISEASE OF THE VULVA
Unusual kind of skin cancer that arises from glandular cells
Rare
Lesions may appear as eczematoid with a scaly surface but vague margins
Or may be sharply bordered with a red and velvety texture with areas and islands of hyperkeratosis
Vulval adenocarcinoma may be present in 4-8%
Achieving clear margins is difficult
Recurrence: 50% or more
Vulval cancer aetiology
0.3% lifetime risk
Mean age 65y
Keratinising SCC
- Differentiated vulvar intraepithelial neoplasia
- Usually occurs in a background of lichen sclerosus
Warty / basaloid SCC
- High risk HPV - particularly 16, 18, 31, 33
- 25-30% of all vulvar SCC
- Precursor: HSIL or usual type VIN
Vulval cancer histopath
Squamous carcinomas 90% Malignant melanoma 3% Basal cell carcinoma 2-4% Adenocarcinoma <1% Verrucous carcinoma <1% Sarcomas 1-2%
Pre-op work up for vulval cancer
Biopsy including area of skin where there is a transition from normal to abnormal epithelium
- Keyes biopsy instrument (3 or 4mm)
- Depth >1mm
Presence or absence of enlarged groin LN
If HPV related aetiology suspected, perform colposcopy of cervix and vagina
FBC, U&E, LFTs
Consider HIV screening
Pre-op imaging
- CT AP or MRI - for LN or distant mets
- USS groin
- CXR or CT for chest imaging
Prognostic factors of vulval cancer
Inguinofemoral LN metastases
- Most important factor determining survival
- negative –> 92% 5y survival
- positive nodes –> varies, 30-75%
FIGO stage
Histological grade of the tumour
Depth of invasion - Most important factor for predicting nodal involvement
- 1-2mm –> positive nodes in 8%
- 3-5mm –> 30%
Age and performance status of the patient
Centrally localised tumours have a worse prognosis than lateral tumours
- Propensity to metastasise to both groins
FIGO staging of vulva
I - tumour confined to vulva
A - <2cm size, stromal invasion <1mm
B - >2cm, or >1mm
II - extension to 1/3 lower vagina, urethra or anus
III - positive inguinofemoral LN
A and B related to number and size of LN
C - extracapcular spread of LN mets
IV - 2/3 upper vagina, urethra or distant mets
Surgical treatment of vulval cancer
Mainstay of Rx
Tumour-free margin of >8mm in the fixed histopathological specimen (2cm macro)
Stage IA - WLE alone
Otherwise radical WLE with groin LN dissection (sentinel or lymphectomy)
- triple incision technique to reduce morbidity
Radical WLE is as effective as radical vulvectomy in preventing local recurrence, but substantially decreases the psychosexual morbidity of treatment
Indications for sentinel nodes in vulval cancer
Radio-labelled technetium and blue dye
Unifocal tumours confined to the vulva
<4cm in diameter
Stromal invasion >1mm
Clinically negative groin nodes
If ipsilateral sentinel LN is not detected, complete lymphadenectomy should be done
If positive sentinel LN, then bilateral inguinofemoral lymphadenectomy is recommended
Disadvantages
- False negative rate up to 4%
- If false negative associated with 90% mortality
- If positive, need repeat procedure for full LN dissection
Complications of groin lymphadenectomy
Wound dehiscence Infection Lymphocyst formation Lymphoedema 30% Immobility Prolonged hospitalisation
Radiation for vulval cancer
Adjuvant radiotherapy a/w improved survival in patients who have >1 or grossly positive LN
Indications for adjuvant RT to the pelvic and groin:
- Presence of extracapsular spread in the involved groin node
- 2+ positive groin nodes
Radiation fields should include LNs in:
- Inguinofemoral
- External and internal iliac
Shown to improve survival if positive margins
If node positive, shown to benefit from chemo in addition to R
Advanced (III or IV) vulval cancer treatment
Treatment decisions depend on patient wishes and performance status
Ultra-radical surgery
- Radical vulval excision with partial or total exenteration and groin lymphadenectomy with plastic reconstruction
- Post-op mortality 0-20%
Pre-op RT and CT may shrink the tumour to allow less destructive surgery
- Combination Rx is a/w significantly more morbidity than either Rx alone
Primary RT +/- CT
Palliative treatment
REcurrence of vulval cancer
Up to 1/3
Vulva is the commonest site of recurrence (70%)
- many “recurrent” vulvar cancers are probably new tumours
If small local vulval recurrence –> WLE, better prognosis
- Or consider RT
Groin recurrence –> surgery or RT
- Poorer prognosis
Pelvic recurrence –> chemo RT
Follow up of vulval cancer
No evidence for best schedule
Clinical exam of vulva and groin No evidence for routine imaging European society of gynae onc: - 3-4 monthly for first 2y - 6 monthly for years 3 and 4 - Annual thereafter
