Gynaecology cancer Flashcards
1
Q
Benefit of cervical screening programme?
A
o Number of women dying from cervical cancer has halved since programme introduced
2
Q
What does NHSCSP involve? Which three tests? When?
A
o Liquid based cytology (LBC)
Detect early abnormalities of cervix, which may lead to cancer
HPV and Chlamydia tested simultaneously
Dyskaryosis is based on nuclear enlargement, variation in size and shape of nuclei, hyperchromasia and reduced cytoplasm
o Human papilloma virus triage and test of cure
Women with borderline changes or low-grade dyskaryosis given a reflex high-risk HPV test
o Colposcopy
Diagnose cervical intraepithelial neoplasia (CIN) and differentiate high-grade lesions from low-grade abnormalities in women with abnormalities
3
Q
System for NHSCSP?
A
o First invitation at age 25
o Routine recall three-yearly between 25-49, then 5-yearly until 65
Women >65 only screened if not been screened since 50 or have had recent abnormal tests
o If HIV positive, annually
4
Q
Process of NHSCSP? What does each test result mean?
A
o Plastic speculum inserted vaginally to via squamocolumnar junction of cervix
LBC – brush rotated against squamocolumnar junction
Results available in 2 weeks
Negative
o Endocervical cells with normal nuclei seen
Inadequate
o Insufficient or unsuitable material sampled, unlabelled specimen or inadequate fixation on slide
Borderline
o Cells are seen with abnormal nuclei, but not indicative of dyskaryosis
Mild Dyskaryosis
o Cancer very unlikely
Moderate Dyskaryosis
o Pre-cancerous condition with intermediate probability of developing into cancer
Severe Dyskaryosis
o Carcinoma-in-situ
Glandular Neoplasia
o Suggestive of adenocarcinoma-in-situ, of cervix/endometrium
5
Q
Management of normal result on NHSCSP?
A
o Inform patient of result
o Recall as appropriate for screening rules
6
Q
Management of inadequate result on NHSCSP?
A
o Repeat sample immediately after treating infection (<3 months), as soon as convenient
o If three inadequate, advise assessment by colposcopy
7
Q
Management of borderline/mild dyskaryosis changes on NHSCSP?
A
o High-risk HPV testing (HPV triage)
Positive – referred for colposcopy
Negative – normal recall
8
Q
Management of moderate/severe dyskaryosis on NHSCSP?
A
o Colposcopy
Takes punch biopsies
9
Q
What does each CIN stage mean?
A
• CIN – histological diagnosis only made on biopsy
o CIN1 – lower 1/3 of epithelium
o CIN2 – lower 2/3 of epithelium
o CN3 – full thickness of epithelium
10
Q
Management of each stage of CIN?
A
- CIN1 – treatment or no treatment
* CIN2/3 – Excision to depth 8mm, LLETZ (large loop excision of transformation)
11
Q
If histologically confirmed, untreated CIN 1 - follow up?
A
o Follow up 12 months with cytology and HPV testing
If negative - normal recall
If positive – colposcopy
12
Q
Treated CGIN - follow up?
A
o Follow-up 6 months
Test of cure with/without colposcopy
If HPV pos or both neg – repeat 12 months - if then both neg – 3 year recall
13
Q
Test of cure follow up following treatment of CIN1/2/3
A
o 6-month test of cure
If negative – follow up test then normal recall
If positive – colposcopy
14
Q
What is the HPV vaccine programme?
A
o Girls (and now boys for 2019-20 cohort) aged 12–13 years human papillomavirus (HPV) vaccine as part of the Childhood Immunization Programme
15
Q
What vaccine is given in HPV? Schedule?
A
o Gardasil® quadrivalent vaccine (covering HPV types 16 and 18, and types 6 and 11 giving additional protection against genital warts)
o Two-dose schedule – given school Year 8 and then 6-24 months later
16
Q
How common is cervical cancer? Peak age?
A
- 3rd most common gynaecological cancer after uterus and ovary
- Most common cancer in women under 35
- Age peaks 25-34
17
Q
Define CIN?
A
• Cervical intraepithelial neoplasia (CIN) precursor lesion for carcinoma of the cervix
o CIN 1 – disease confined to lower third of epithelium
o CIN 2 – disease confined to lower and middle thirds of epithelium
o CIN 3 – affecting full thickness
18
Q
Define invasive cervical cancer?
A
o Breeches epithelial basement membrane
o If deepest part is <5mm from surface of epithelium – micro-invasive
o If it extends beyond 5mm or wider than 7mm – invasive carcinoma
19
Q
Histology of cervical cancer?
A
- Squamous cell = 70%
- Adenocarcinoma = 15%
- Mixed = 15%
- Neuroendocrine tumour, clear cell carcinoma, glassy cell carcinoma, sarcoma botryoides, lympohoma = <1%
20
Q
Spread of cervical cancer?
A
- Direct = Parametrium, vagina, bowel and bladder and then to the pelvic side wall.
- Lymphatic = parametrial nodes, internal, external and common illiac nodes, obturator nodes, pre-sacral and para-aortic nodes
- Ovarian spread is rare
- Haematological = liver and lungs
21
Q
Risk factors for CIN?
A
- Persistent HPV infection
- Multiple partners
- Smoking
- Immunocompromise (e.g. HIV, immunosuppressive agents)
- COCP
22
Q
Risk factors for cervical cancer?
A
- Exposure to HPV (early first sexual experience, multiple partners, non-barrier contraception)
- COCP
- High parity
- Smoking
- Immunosuppression (esp. HIV and transplant patients)
23
Q
Symptoms of cervical cancer?
A
• Cervical smear showing invasion (requires biopsy) • Incidental finding at treatment for CIN • Common symptoms o Post-coital bleeding (PCB) o Intermenstrual bleeding o Post-menopausal bleeding o Vaginal discharge - blood stained, offensive, serous • Late Symptoms • Painless haematuria • Urinary frequency • Weight loss • Bowel disturbance • Fistula • Pain
24
Q
Signs of cervical cancer?
A
o White or red patches on cervix
o Roughened hard cervix or ulcer +/- loss of fornices
o Fixed cervix if there is extension of the disease
• Death is commonly from uraemia due to ureteric obstruction.
25
Investigations in cervical cancer?
* Screening programme
| * Test for chlamydia – pre-menopausal
26
When to refer to gynaecology?
o Refer all women urgently to gynaecology if suspicious, persistent vaginal discharge not explained
o Postmenopausal
2-week gynaecology clinic if not on HRT and vaginal bleeding or persistent or unexplained vaginal bleeding after stopping HRT for 6 weeks
o Premanopausal
Gynaecology clinic if persistent intermenstrual bleeding, post-coital bleeding, blood-stained discharge
2-week if negative pelvic exam, not had smear, >3 months, new symptoms
27
Investigations performed in cervical cancer?
o Colposcopy
Cervix visualised, transformation zone is identified and painted with acetic acid, taken up by neoplastic cells
Aceto-white areas identify abnormal areas and enable punch biopsy to be taken to diagnose histologically
Punch biopsies for histology (not LLETZ in cancer)
Irregular cervical surface, abnormal vessels dense aceto-white changes.
o Bloods
FBC, U&Es, LFTs
o Fitness for surgery
CXR, U&E, FBC, IV pyelogram
28
Staging investigations in cervical cancer?
```
o CT abdomen and pelvis
o MRI pelvis
o EUA (bimanual vaginal examination, cystoscopy, hysteroscopy, PV/PR examination)
```
29
What is cervical FIGO stage - 0?
o 0 – no primary tumour
30
What is cervical FIGO stage - Tisb?
o Tisb – carcinoma in-situ (pre-invasive)
31
What is cervical FIGO stage - 1?
o 1 – confined to uterus
1A – Microscopic
• 1A1 – max 3mm depth and 7mm horizontal spread
• 1A2 – stromal invasion >3 to <5mm with <7mm spread
1B – Macroscopic 4cm or more
32
What is cervical FIGO stage - 2?
o 2 – Extended locally to upper 2/3 of vagina
2A – no parametrial invasion
2B – parametrial invasion
33
What is cervical FIGO stage - 3?
o 3 – Spread to lower 1/3 of vagina +/- hydronephrosis
3A – Not spread to pelvic wall
3B – Pelvic wall
34
What is cervical FIGO stage - 4?
o 4 – spread to blader or rectum
4A – bladder or rectum or beyond true pelvis
4B – distant metastases
35
Vaccination prevention of cervical cancer?
- Part of the NHS childhood vaccination programme – will include boys next academic year 2019/20
- Gardasil (Merck) – HPV 16, 18 + 6, 11 (used)
- Cervarix (GSK) – HPV 16, 18
36
Management of CIN? 1 & 2/3
- If dyskaryosis on smear test, refer for colposcopy
- CIN 1
o If HPV +ve offer 6-month colposcopy and LLETZ if persistent
LLETZ – large loop excision of transformation zone, dine under LA with loop diathermy
- CIN 2/3
o Excised with LLETZ, smear at 6 months with high-risk HPV testing
o If negative, return to 3-year smears
o If abnormal, repeat assessment with colposcopy
37
Management of Stage 1A1 (<3mm depth) Cervical cancer?
o Comb biopsy
| o Local excision (radical trachelectomy, cervicectomy) or hysterectomy
38
Management of Stage 1A2 (<5mm depth) & 1B1 (<4cm diameter) Cervical cancer?
o Lymphadenectomy and if node negative, proceed to Wertheim’s hysterectomy (TAH)
Excision of primary tumour with 1cm margin and en bloc resection of main pelvic lymph node areas
May involve – removing upper 1/3 of vagina and ligaments
39
Management of Stage 1B2 (>4cm diameter) & 2A Cervical cancer?
```
o Chemoradiotherapy (cisplatin)
Involves external beam and brachytherapy
o If negative lymph nodes, consider Wertheim’s hysterectomy
```
40
Management of Stage >2B Cervical cancer?
o Combination chemoradiotherapy (cisplatin)
| Involves external beam and brachytherapy
41
Management of Stage 4B Cervical cancer?
```
o Chemoradiotherapy (cisplatin)
Involves external beam and brachytherapy
o Palliative radiotherapy to control bleeding
```
42
Complications of Weirthem's hysterectomy and lymphadenopathy in cervical cancer?
- Bleeding
- Infection
- DVT/PE
- Ureteric fistula
- Bladder dysfunction
- Lymphoedema
- Lymphocysts
43
Complications of radiotherapy in cervical cancer?
- Acute bowel and bladder dysfunction (tenesmus, mucositis, bleeding)
- 5% late bowel and bladder dysfunction (ulceration, strictures, bleeding, fistula formation)
- Vaginal stenosis, shortening and dryness
44
Follow up of cervical cancer?
- Patients are reviewed at 6 weeks post treatment, every 3-4 months for 1-2 years, annually for a total of 5 years
45
Survival in cervical cancer?
- 90% survival in women under 40 years of age
- 1-year survival >80%
- 5-year survival >65%
46
Complications cervical cancer?
- Psychological distress (loss of income, pain, nausea, infertility)
- Guilt (if not gone to smear appt)
- Sexual problems (loss of libido, decreased capacity for orgasm, vaginal stenosis, vaginal bleeding, atrophic vaginitis)
o Lymphoedema
o Treatment complications (radiotherapy)
47
How common is endometrial cancer?
Most common gynaecological cancer
48
Pathology of endometrial cancer?
• Endometrial hyperplasia with atypia (but not without) is a premalignant condition
• Unopposed oestrogen leads to hyperplasia
Hyperplasia predisposes to cytological atypia
Atypical hyperplasia is precancerous and develops into invasive cancer over years.
49
Types of endometrial cancer?
- Adenocarcinomas (80%)
o Main types: oestrogen-dependent endometrioid (Type 1) and oestrogen-independent non-endometrioid (Type 2)
- Adenosquamous carcinoma
- Clear cell or papillary serous carcinoma
- Mixed mesodermal Mullerian tumours (MMMT)
50
Spread of endometrial cancer?
- Direct = through myometrium to the cervix and upper vagina. The ovaries may be involved and the fallopian tubes. Surface of bowel and liver.
- Lymphatic = to pelvic then para-aortic lymph nodes.
- Haematological = occurs late liver, lungs.
- Recurrence is most common at the vaginal vault, normally in the first three years.
51
Aetiology of endometrial cancer?
Endogenous:
Peripheral conversion in adipose tissue of androstenedione to oestrone.
Oestrogen-producing tumour (granulosa cell tumour)
PCOS or anovulatory cycles at menarche or during climacteric period (lack of progesterone as no luteal phase)
Exogenous:
Oestrogen only HRT
Tamoxifen (oestrogen agonist in the endometrial tissue)
52
Risk Factors of endometrial cancer?
```
o Obesity
o DM2
o Hypothyroidism
o HTN
o Nulliparity
o PCOS
o Early/Late menopause
o HNPCC (Lynch 2 syndrome)
o Breast cancer +/- Tamoxifen
o Oestrogen-only HRT
o Oestrogen-secreting ovarian tumours
```
53
Protective factors of endometrial cancer?
o Parity
| o COCP
54
Symptoms of endometrial cancer?
• Post-Menopausal Bleeding (PMB)
- 1 in 10 women with PMB will have endometrial cancer or atypical hyperplasia.
- Atypical hyperplasia = abnormalities of the cellular or glandular architecture (premalignant).
- Most common cause of PMB is vaginal atrophy.
o Reassure, lubricants, E2 creams
• Irregular menstrual cycle
• Heavy or irregular periods (premenopausal women)
• PV discharge and pyometra (pus in the uterine cavity)
55
GP investigations for endometrial cancer?
o Vulval, vagina and speculum examination
| o Bloods – FBC, U&Es, LFTs
56
When to refer for endometrial cancer secondary care input?
- Referral 2-week pathway
o >55 with PMB, consider if <55
o Direct access USS in >55 with:
Unexplained vaginal discharge – new, thrombocytosis, haematuria
Visible haematuria – low Hb, thrombocytosis, high glucose
57
Investigations in endometrial cancer? When are biopsies taken?
o Speculum and Bimanual to exclude other causes
o TVUS
<4mm endometrial thickness/echo (ET) = very low risk of endometrial pathology in postmenopausal women
• No need for endometrial sampling unless recurrent
>4mm
• Biopsies
o Blind outpatient sampling (e.g. pipelle, vabra)
o Hysteroscopy (under LA as outpatient, or GA as in patient)
58
Staging tests in endometrial cancer?
CT/MRI pelvis
| CXR to exclude lung spread
59
FIGO staging of endometrial cancer - Stage 1?
o Stage I – confined to body of uterus (corpus uteri)
1A – endometrium with <1/2 myometrium invaded
1B – invasion >1/2 myometrium
60
FIGO staging of endometrial cancer - Stage 2?
o Stage II - involving the cervix
61
FIGO staging of endometrial cancer - Stage 3?
o Stage III - spread outside the uterus, but not beyond pelvis
3A – Invasion of serosa or adnexa or positive peritoneal cytology
3B – vaginal or parametrial metastases
3C – Metastases to pelvic (1), para-aortic (2) or both
62
FIGO staging of endometrial cancer - Stage 4?
o Stage IV - with bowel, bladder or distant organ involvement
4A – bowel or bladder mucosa
4B – distant metastases
63
Grading of endometrial cacner?
o G1 = well differentiated 5% or less
o G2 = moderately differentiated 6-50%
o G3 = poorly differentiated or high risk cell type >50%
64
Maagement of Stage 1 endometrial cancer?
Total abdominal hysterectomy with bilateral salpingo-oophorectomy with peritoneal washings (TAH-BSO)
Adjuvant radiotherapy
65
Maagement of Stage 2 endometrial cancer?
Radical hysterectomy with systematic pelvic node clearance
Para-aortic lymphadenectomy
Adjuvant radiotherapy
66
Maagement of Stage 3/4 endometrial cancer?
Maximal de-bulking surgery
Palliation – high-dose progesterone and external beam radiotherapy
67
Other treatment used in endometrial cancer?
o Adjuvant radiotherapy used in low-grade disease with deep myometrial invasion and high-grade disease with superficial invasion
o Radiotherapy used in pelvic recurrence
68
Follow up in endometrial cancer?
- 6 weeks post-surgery
- Every 3-4 months for 2 years
- Annually to 5 years
69
Prognosis in endometrial cancer?
- 5-year survival 85% in Stage 1, 25% in Stage 4
70
How common is ovarian cancer? When is peak age? Risk?
* 2nd most common gynaecological cancer after uterus.
* Most common cause of gynaecological cancer death.
* Peak incidence = 75-84 years.
* Lifetime risk 2% in UK
71
Types of ovarian cancers?
- 90% are epithelial ovarian cancers (EOC).
- Three main groups of primary ovarian tumours:
o Epithelial – derived from Mullerian epithelium (>50)
Can be serous, endometrioid, clear cell, mucinous, Brenner
o Sex cord or stromal – derived from ovarian stroma, sex cord derivatives or both
Fibroma, fibrosarcoma, Sertoli-Leydig tumour, Granulosa tumours
o Germ cell – derived from ovarian germ cells (<30)
Dysgerminoma, endodermal sinus tumours, teratoma, choriocarcinoma, sarcoma
72
Spread of ovarian cancer?
- Transcolemic spread = pelvis and abdomen
- Lymphatic
- Haematological
73
Risk factors of ovarian cancer?
- Nulliparity
- Early menarche and/or late menopause
- Endometriosis
- HRT
- Difficulty conceiving
- BRCA 1 and BRCA 2 mutations
- HNPCC (Lynch II syndrome – bowel, ovarian and endometrial ca)
- Age, smoking, obesity
74
Protective factors of ovarian cancer?
- COCP
- Pregnancy
- Female sterilisation
75
Symptoms of ovarian cancer?
- Vague which may look like IBS or diverticular disease
- Most present at Stage 3
- Symptoms
o Abdominal distension (often described as persistent bloating).
o Abdominal pain.
o Weight loss, loss of appetite, early satiety
o Fatigue
o Urinary symptoms
o Change in bowel habit
o Vaginal bleeding
76
Signs of ovarian cancer?
```
o Fixed pelvic mass
o Ascites
o Omental mass
o Pleural effusion
o Supraclavicular lymph node enlargement
```
77
When to refer for clinical genetic counselling in ovarian cancer? Management if genetic component found?
Two primary cancers in one 1st or 2nd degree relative
Three 1st or 2nd degree relatives with breast/ovarian/stomach/endometrial cancers
Two 1st or 2nd degree relatives, one having ovarian cancer at any age and the other with breast cancer <50
Two 1st or 2nd degree relatives with ovarian cancer at any age
o If gene mutation identified, yearly TVS with Ca125
o Offer BSO if BRCA +ve
78
When to refer for suspected ovarian cancer?
- Refer urgently in any woman with ascites and/or pelvic or abdominal mass which is not fibroids
79
Primary care tests of ovarian cancer?
o Bloods – FBC, U&Es, LFTs (esp. albumin)
| o Tumour markers
80
What tumour markers tested for in ovarian cancer and what do they mean?
CA125
• Raised in 80% of epithelial cancers (serous, endometrioid).
• Also raised in endometriosis, PID, pregnancy, torsion, rupture, other cancers, HF
CEA (carcinoembryonic antigen)
• Raised in colorectal cancers, normal in ovarian cancer.
CA19.9
• Raised in mucinous tumours
AFP, hCG, LDH
• If woman <40
81
When to refer urgently in ovarian cancer?
o If Ca125 >35, TVUS and abdominal US
| If suggestive of cancer, refer urgently
82
Secondary care testing in ovarian cancer?
```
o Ca125, TVUS and abdominal US
o CT/MRI staging
o Work out RMI, >250 needs MDT review
o CXR
o Ascites or pleural effusion sampled and sent for cytology
```
83
FIGO staging of ovarian cancer - Stage 1?
o Stage I – ovaries only
1A – One ovary
1B – Both
1C – One or both ovaries with: capsule ruptured, on surface, malignant cells in ascites
84
FIGO staging of ovarian cancer - Stage 2?
o Stage II – beyond ovaries and confined to pelvis
2A - Extension +/- implants on uterus +/- Fallopian tubes
2B – Extension to +/- implants on other pelvic tissues
2C – Extension +/- implants with malignant cells in ascites washing
85
FIGO staging of ovarian cancer - Stage 3?
o Stage III – disease beyond pelvis, confined to abdomen (SI, omentum, peritoneum)
3A – Microscopic peritoneal mets
3B – Macroscopic peritoneal mets <2cm
3C – Peritoneal mets >2cm +/- regional lymph node met
86
FIGO staging of ovarian cancer - Stage 4?
o Stage IV - distant metastases
87
Management of ascites and pleural effusion in ovarian cancer?
- Drainage of massive tense ascites or a pleural effusion pre-operatively.
- For ascitic drainage use a small suprapubic catheter (e.g. Bonanno)
- Consider USS guidance, especially if bowel mets are suspected or previous abdominal surgery.
- Albumin may decrease following ascitic draining.
88
Management of ovarian cancer?
- Exploratory laparotomy for histological confirmation, staging and tumour debulking
o Total abdominal hysterectomy and bilateral salpingo-oophorectomy
Younger women can have more conservative surgery
o Omentectomy
o Para-aortic and pelvic lymph node sampling
o Peritoneal washings and biopsies
89
When is adjuvant chemo used in ovarian cancer?
o Everyone but low-grade stage 1A and 1B
| o Carboplatin with paclitaxel
90
Management of stage 3/4 ovarian cancer?
Add Neoadjuvant chemotherapy
91
Follow up of ovarian cancer?
* 6 weeks post-surgery.
* Every 3-4 months for 1-2 years.
* Annually to 5 years
* Ca125 often used to monitor
92
Prognosis of ovarian cancer?
- Stage 1>97%
| - Stage 4 50%
93
How common are vulval carcinomas?
- Vulval carcinomas are uncommon.
- Mostly occur in older women (~74 years)
- Labia majorum most common site
94
Types of vulval cancers?
o ~90% are squamous cell carcinomas.
o ~5% are primary vulval melanomas with basal cell, Bartholin’s gland carcinoma and rarely sarcomas accounting for the rest
95
Spread of vulval cancers?
o Usually locally, slow metastases to groin nodes and then pelvic nodes
o Local to vagina, urethra and anus
96
Risk factors of vulval cancers?
```
o Lichen sclerosis
o VIN.(vulval intraepithelial neoplasia)
o HPV
o Psoriasis
o Smoking
o Pagets Disease of vulva (adenocarcinoma in situ)
```
97
Symptoms and signs of vulval cancers?
- Lump
- Pain
- Irritation
- Bleeding
- Ulceration
- Pruritus
- Palpable groin lymph nodes – enlarged, hard, immobile
98
Diagnosis of vulval cancers?
o Examination and biopsy (wedge)
99
Other investigations used in vulval cancers?
```
o Colposcopy
o Cystoscopy
o Proctoscopy
o MRI (staging)/CT
o CXR (staging and preoperative)
```
100
FIGO staging of vulval cancers - Stage 1?
o 1 – confined to vulva
1A - <2cm in size, confined to vulva or perineum with stromal invasion <1mm, no nodal mets
1B - >2cm in size, confined to vulva or perineum with stromal invasion >1mm, no nodal mets
101
FIGO staging of vulval cancers - Stage 2?
o 2 – extension to adjacent perineal structures (lower 1/3 urethra, lower 1/3 lower vagina, anus) with negative nodes
102
FIGO staging of vulval cancers - Stage 3?
o 3 – with or without extension to adjacent perineal structures (lower 1/3 urethra, lower 1/3 lower vagina, anus) with positive inguino-femoral lymph nodes
3A – One LN >5mm
3B – Two or more LN mets >5mm
3C – positive with extracapsular spread
103
FIGO staging of vulval cancers - Stage 4?
o 4 – Invades regional (Upper 2/3 vagina, upper 2/3 urethra) or distant
4A – invading upper urethral +/- vaginal mucosa, bladder, rectal mucosa or fixed to pelvic bone, fixed or ulcered inguino-femoral LN
4B – distant mets including pelvic LN
104
When to refer for 2-week wait for vulval cancer?
o Women with unexplained vaginal lump, vulval bleeding or ulceration
o Women with pruritus or pain which has been treated and still persists
105
Surgical management of vulval cancer?
- Mainstay of treatment for curative intent and palliation.
- All patients with >1mm deep, triple incision surgery
o Wide local excision + ipsilateral groin node biopsy (lymphadectomy) + sample contralateral side
o If tumour <2cm width and <1mm deep, LN excision is not needed
106
Management of advanced vulval cancer?
o Radical vulvectomy (wide excision of vulva + removal of inguinal glands)
o Chemoradiotherapy used pre-op to shrink tumours
107
If unsuitable for surgery- management of vulval cancers?
- Chemoradiation used if unsuitable for surgery, to shrink tumours pre-operatively or for relapses
108
Prognosis of vulval cancers?
- 5-year survival >80% for lesions <2cm with no nodes, otherwise <50%
