Rare Gynae Tumours

Prof Marcia Hall

Mount Vernon Cancer Centre

Classification• Epithelial serous ovarian cancer 60% (clear cell, ovary carcinosarcoma,

mucinous)• Low grade serous ovarian 10% (of 60%)

• Sex cord stromal tumours 2-5%– Granulosa Cell– Sertoli +/- Leydig

• Germ cell tumours 25% (mostly dermoids)• Others - 5%

• Sarcomas• Squamous cell carcinoma• Neuroendocrine

• Struma ovarii• Borderline tumours

Mixed Mullerian Tumours Carcinosarcoma of Ovary

• 10% of all ovarian epithelial carcinomas.

• both carcinomatous and sarcomatous components

• occur in low parity postmenopausal woman.

• Same staging as for epithelial ovarian cancers

• Postop adjuvant chemo same as epithelial OC

• Prognosis poorer.

Some debate now that these are just very undifferentiated epithelial OC – very limited information on MMMT alone treatments

Low grade serous ovary cancer +/- mixed HG/LG SOC

• Average age 43y (younger)

• Median survival 83 months (vs 57-65 months in HG)

• 60% associated with tumours of low malignant potential

• More frequent b-raf, k-ras and PTEN mutations 30-50% (vs 20% in HG) and only rare p53 (vs>80% in HG)

– Benign cystadenomas, LMP tumors, and mucinous adenocarcinomas have similar gene expression

Sex-cord stromal tumours

• Granulosa Cell

– Adult 95%

– Juvenile 5%

• Sertoli – Leydig Cell

• Sex-cord of mixed or unclassified origin

• Steroid cell tumours

Granulosa Cell Tumour

• Juvenile

• Adult –

– 60-95% stage 1 but 5% will recur median time to relapse 4-6 years

– adverse features:

• size (<7cm unlikely to recur)

• tumour rupture

• stage

• age >40 years

• bilaterality

• mitotic activity, atypia, ploidy

Coffee bean like cells – Cal-Exner body

Recent paper from Korea describing laparoscopic surgery

For most patients with non-epithelial ovarian tumours

that appeared to be stage 1A radiologically. All successful

6 omentectomies performed out of 28 patients

Granulosa Cell Tumour

Management granulosa cell tumours

Stage 1A

•Higher Risk Stage 1*

•Stage > 1

Recurrent disease:

Pelvic / intra-abdominal

Recurrent disease:

distant

•TAH/BSO + staging

•Fertility-sparing surgery + staging in young patients

•Hysteroscopy and curettage to exclude hyperplasia (55%)

or carcinoma (4-20%)

•Adjuvant treatment not indicated

•TAH/BSO/staging surgery (no nodes)

•Fertility-sparing surgery + staging in selected cases

•Hysteroscopy and curettage to exclude hyperplasia (55%)

or carcinoma (4-20%)

•No adjuvant treatment

•Secondary / tertiary debulking surgery where feasible

•Postoperative therapy based upon previous treatments:

Hormones

- Platinum-based chemotherapy

(63-80% response but short-lived)

- Radiation treatment for

localized disease has been reported

Platinum-based chemotherapy

Hormones (PARAGON study)

Granulosa cell tumor in a 60-year-old woman with postmenopausal bleeding.

Shanbhogue A K P et al. Radiographics 2010;30:903-919

Granulosa Cell Tumour

• Follow up

– Stage 1A – if TAH / BSO could consider discharge as long patient aware of 5% chance recurrence eve 20-30 years later.

– Advanced / recurrent disease: 3-12 monthly depending on inhibin levels and disease position and symptoms

– Tend to offer surgery where at all possible

Serum inhibin

• Secreted by granulosa cells of ovary

• Inhibits FSH secretion

• Secreted during menstrual cycle and pregnancy

• Elevated in almost all with granulosa cell tumour

• Elevated in 18/22 with mucinous ovarian adenocarcinomas

PARAGON trial 2018

• Granulosa Cell Tumours frequently express hormone receptors (ER / PR)

• Response rates to hormonal therapy ~ 70% (pooled literature)

• Phase II single arm study of arimidex in 41 pts granulosa cell tumours of ovary: 80% clinical benefit rate but only 4 pts (9.8%) had PR on RECIST. 53% still on arimidex at 6 months.

– Hence RaNGO study

Sertoli Leydig cell tumour group

• <0.5% ovarian neoplasms

• Mean age: ~ 25 y (2-75y)

• 1/3 virilised, some have oestrogenic manifestations 50% no endocrine problems

• >95% stage 1

– If young and radiologically stage 1 – fertility sparing surgery appropriate

– Otherwise full staging

Staging of sertoli leydig cell tumours

Young / Scully 1985

Brown 2009

Zaloudek 1984

Young 1984

Bhat 2013 Roth 1981

Stage 1 202 (97.6%)

13 (40.6%) 62(97%) 13 (100%) 13 (86.7%) 34 (100%)

Stage 1A 193 (93.2%)

0 62 (97%) 13 10 (66.7%) 0

Stage 1B 3 (1.4%) 0 0 0 0 0

Stage Ic 6 (2.9%) 0 0 0 3 (20.0%) 0

Stage II 3 (1.4%) 2 (6.3%) 0 0 0 0

Stage III 2 (1.0%) 1 (3.1%) 2 (3%) 0 0 0

Stage IV 0 0 0 0 0 0

unstaged 0 16 (50%) 0 0 2 (13.3%) 0

Total 207 32 64 13 15 34

Incidence of differentiation in sertoli leydig cell tumours

Young and Scully 1985

Roth 1981 Young 1984 Bhat 2013

Well differentiated

23 (11.1%) 8 (23.5%) 1 (7.7%) 5 (33.3%)

Intermediate 144 (69.6%) 15 (44.1%) 12 (92.3%) 6 (40.9%)

Poorly 40 (19.3%) 11 (32.4%) 0 4 (26.7%)

Heterologous elements

46 (22.2%) 6 (17.7%) 2 (15.4%) 1 (6.7%)

Further therapy for SLCT

• No randomised trials of adjuvant therapies in poorly differentiated or more advanced stage tumours. Descriptions of BEP, CAP, PVB etc

• Malignant SLCT tend to occur early so if no recurrence within first 2-3 years unlikely to recur (<10% after five years according to largest study – Young and Scully)

Familial syndromes associated with stromal ovarian tumors include

– Peutz–Jeghers syndrome, which consists of hamartomatous polyposis (mutation in the STK11 gene, 21% lifetime risk)

– Gorlin syndrome (mutation in PTCH, 20% lifetime risk)

Identified molecular alterations in rare gynae tumoursMOL. ALTERATIONS RARE GYNAECOLOGICAL TUMOURS

FOXL2 Sex-cord stromal tumours (adult granulosa cell tumours)

DICER-1 Sex cord stromal tumours (sertoli-Leydig, juvenile granulosa cell tumour)

K-RAS Low grade serous, mucinous, borderline

BRAF Low grade serous, mucinous, ?borderline

P13KCA Clear cell cancers, carcinosarcoma

PTEN Endometrioid, mucinous, clear cell cancers

HER2 Mucinous?

BRCA 1/2 Serous / endometrioid high grade tubal cancer, undifferentiated, carcinosarcoma

p53 Serous high grade tubal cancer, undifferentiated, carcinosarcoma, clear cell cancers

t(7:17)(p15;q21) Endometrial Stromal Sarcoma

ARID1A Clear cell carcinoma

B catenin Endometrioid

YHMEA FAM21/22 High grade uterine stromal sarcoma

Germ Cell tumours account for 30% of all ovarian tumours but overall only 3% ovarian malignancies:

• Dysgerminoma 1%

• Yolk sac tumour *

• Embryonal carcinoma *

• Polyembryoma *

• Choriocarcinoma *

• Teratoma 98.5%

– Mature 95.0%

– Immature 1.3%– Secondary malignant transformation

Malignant GCT Subtype Frequency Blood markers

Dysgeminoma 35-45% LDH, hCG

Endodermal sinus tumour (yolk sac)

20% AFP(commonly)

rarely α1antitrypsine

Teratoma (+/-mature)

20% Immature: AFP LDH Ca125

Embryonal carcinoma

rare AFP and hCG

Polyembryoma rare AFP and hCG

Choriocarcinoma Very rare hCG

Polyembryoma Rare AFP and hCG

Mixed GCT 10-20% Dependent on cells

Stage at presentationCharing Cross and MVCC 1997-

2003• Stage Number (%)

• IA 36 (24)

• IC/M 23 (15)

• II 25 (17)

• III 27 (18)

• IV 22 (15)

• ? But >IC/M 16 (11)

Investigations

• Tumour markers: BHCG, AFP, CA125

• US / CT thorax / abdo/pelvis

• MRI pelvis

If lung metastases do MRI brain

Could consider FDG PET

Optimal surgical managment

• If stage 1 will need careful fertility sparing surgical staging – especially if considering surveillance

– Do NOT biopsy contralateral ovary if looks normal but do node sampling and peritoneal biopsies as well as washings

• If clearly metastatic can treat on markers and imaging alone – biopsy ideal though

Evidence for fertility sparing surgery

Number 5 year survival (%) Relapses (%)

Malkasian 1964 27 83 41

Assadourian 1969 46 91 22

Gordon 1981 72 94 19a

De Palo 1982 11 100 0

Peccatori 1995 8 100 13

Bower 1996 9 100 56b

a– 9/14 recurrences in contralateral ovary

b– 2/5 recurrences in contralateral ovary

Good outcomes for chemotherapy for stage 1 ovarian GCT but how

many really needed it?• VAC 83% sustained remission

• BEP >98% sustained remission

ONLY need TWO cycles if used as adjuvant – 3 for rising markers (Cullen JCO 1996)

• Carboplatin >97% sustained remission

– for seminoma / dysgerminoma (Oliver, Lancet 2005)

Adjuvant vs surveillanceadvantages

• Immediate treatment

• Reduces risk of relapse to <2%

• Follow up less important

• Reduces anxiety about relapse and inadequate staging

Adjuvant vs surveillancedisadvantages

• Toxic therapy

• Unnecessary in >75%

• Survival no better than close surveillance

• Late effects – hips BP, second malignancies

What is Surveillance?Tumour markers (HCG, AFP,

CA125), US every 3rd visit,

First year

Second year

Third year

Fourth year

Subsequent years

Clinical examination

First year

Second year

Third year

Fourth year

Years 5-10

CT abdo pelvis baseline then 3 and 12 months

2-4 weekly

Two monthly

Three monthly

Four monthly

Six monthly

Monthly

Two monthly

Three monthly

Four monthly

Six – 12 monthly

Survival following surveillance for ovarian GCT 1981-2003

• 11 of 37 patients relapsed (30%)

– 2/9 (22%) dysgerminoma

– 8/22 (36%) teratoma

Deaths: 1 x chemoresistant disease

1 x PE

1 x melanoma 10y after dysgerminoma

Overall disease specific survival 94%

(Patterson Int J Gyn Oncol 2007)

Tumour marker plots

Patients with ovarian GCT

Advanced ovarian GCT

Fig 3

Murugaesu et al

Stage IC / IM n =23

Stage II n = 25

Stage III n = 27

Stage IV n = 22

Time since diagnosis (years)

97 patients treated at CXH & Mount Vernon; worse prognosis with

advanced stage (p=0.03)

Squamous CC ovary in association with dermoids

• Malignant transformation of the squamous component of the mature cystic teratoma (dermoid) is rare but increases with age <1-2% median age 24y (range:14mo-58y)

• ‘malignant’ dermoids are generally larger (14.8cm versus 13.8cm)

• Histological risk factors mirror those seen in cutaneous SCC eg grade, depth of invasion, presence LVSI , capsular involvement

• SCC ‘ovary’ can also arise in background of endometriosis

Squamous CC ovary in association with dermoids (ii)

• Survival: Stage 1 76% 5y survival, Stage II 34% 5y OS, Stage III 21% 5y OS and Stage IV 0% (Chen 2008)

• No consensus on adjuvant chemotherapy • Chen et al suggest a benefit for those with Stage III /IV

disease but this is not public consensus• Similarly radiation not thought to be helpful

• Awaiting biological characterization to improve treatment strategies

Ovarian carcinoids• Rare 0.5-1.7% all carcinoid tumours arise in

gynaecological tract

– Primary - range from high grade aggressive eg. small cell cancers to relatively indolent (low Ki67) well-differentiated NETs (Il buono)

– Several histologies: insular, trabecular, strumal and mucinous (or goblet cell ), mixed exocrine/endocrine +/- adenocarcinoma (MANEC) - check not metastatic from GI primary (Il brutto)

– Often associated with dermoid, ipsilateral, bilateral or appear in other ovary to dermoid. Many found incidentally – can offer fertility sparing surgery with FU.

Functioning / metastatic carcinoids

• Functioning carcinoids more likely to be >10cm. Trabecular carcinoids are never functional

• May show positive scintigraphy for somatostatin receptors

• Chromogranins A and B may be useful in metastatic disease – better than urinary 5HIAA

• Treatment with somatostatin analogues, chemoembolization or hepatic artery embolization successful in 67%, chemotherapy in <30%

Malignant Struma Ovarii

• Rare type of mature teratoma with thyroid tissue being predominant (>50%)

• Usually managed as ovarian mass likely malignant –surgical removal +/- staging

• Actually only contains malignant change in 0.1-0.3% when may need thyroglobulin FU and / or treatment with I131

Small cell ca ovary hypercalcaemic subtype (i) (SCCOHT distinct to SCLC) – rhabdoid tumour

• <1% ovarian cancers, very aggressive, poor prognosis, median age 28y, non-smokers

• Hypercalcaemia in ~70%, only 20-25% stage 1

• If operable -standard staging surgery but biopsy only is adequate for obviously bulky Stage III/IV

• Platinum and etoposide (historical)

• NACT possible but no firm data

• Best prognostic indicator is stage -Stage 1A only <40% long term survivors other good features include <40y, normal calcium preoperatively, tumour size <10cm and absence of large cells histologically

Il Cattivo

Small cell ca ovary hypercalcaemic subtype (ii)desmoplastic small round cell tumour - rhabdoid• Inactivation / biallelic mutation or loss of

SMARCA4 (encoding BRG1 protein, member of SWI/SNF chromatin remodelling complex) are frequent in SCCOHT. BRG1 IHC may help with diagnosis and genomic profiling may help with treatment options

– Heterozygous gSMARCA4 is associated with rhabdoid tumour predisposition so patients with SCCOHT should be considered for referral for genetics assessment

Brenner Tumours

• Rare epithelial tumors that account for 1%-2% of all ovarian neoplasms.

– Benign – in 98%

– Borderline – 1%

– Proliferative / malignant neoplasms <1%

Mucinous ovarian cancer

• 5-10% ovarian cancer but majority Stage 1A

– 67% of these are reported borderline or of ‘low malignant potential’ – not strictly benign

– Others secondary to eg GI primary site

– Very rare true mucinous invasive primary ~2.4%

• Stage 1A 90% 5y OS (cf HG SOC Stage 1A 76%)

• Most common 20-40y, 18cm median size and 79% are unilateral

• Kras over-expressed in 42-59%, p53 generally wild type, HER2+ in 18%

• Poor response to chemotherapy – carbo/taxol perhaps better than GI type chemo -oxali/cape

Gore et al. J Clin Oncol 33, 2015 (suppl; abstr 5528)

Krukenberg tumours

• Gastric cancers

• Bowel cancers

• Breast cancers

– Lobular ca breast

• Melanoma

Endometrial Stromal Sarcomas (i)

• Accounts for 20% uterine sarcoma

• Median age 50y, 60% Stage 1A or in a polyp

• Obesity, early menarche, diabetes, tamoxifen all risk factors

• Difficult to diagnose radiologically – similar to fibroids – TAH is adequate, but morcellation is risky – can leave ovaries in younger patients

• Lymph nodes involved in 7-9% (where no node obviously enlarged)

Endometrial Stromal Sarcomas (ii)• Molecularly ESS related to chromosomal translocation

(t7:17,p15;q21) resulting in juxtaposition of 2 zinc finger genes in 50%. 3 further fusion genes have also been found: JAZF1/PHF1, EPC1/PHF1 and YWHAE-FAM22, the latter being associated with higher grade features and a poorer prognosis

• Outcomes good – 90% 5 year for all stages, 77% 10 y OS. Relapse often late 8-11y for Stage I

• ~100% ER/PR+,adjuvant hormones

reduces risk of relapse

• Surgery and hormones mainstay

therapy for relapse eg progestins

GnHRA, AIs effective in ~80%

Leiomyosarcoma (i)

• Most common type of uterine sarcoma, mostly incidental finding. Ovarian LMS very rare treat same as uterus

• Treatment TAH – NO MORCELLATION

• 5y OS Stage I- 76%, Stage II – 60%

Stage III – 45%, Stage IV – 29%

• Risk factors – Li-Fraumeni (germline p53 mutation), prior childhood cancers esp. retinoblastoma, radiation exposure, obesity, diabetes and tamoxifen

• Multiple somatic chromosomal anomalies –genotyping might help with treatment options

Leiomyosarcoma (ii)• Risk of relapse, even if confined to uterus initially,

>50%

• No adjuvant therapy has been shown to protect

• Resection of metastatic disease may improve OS, esp if long DFS and oligometastatic

• Other metastatic therapy:

• Doxorubicin 60mg/m2 q21d (19% ORR), gemcitabine 1000mg/m2 + docetaxel (27% ORR when given 2nd

line to dox, 36% if first-line). Trabectidin + dox ORR 57%

• Hormones can also be used in leiomyosarcoma although whether these really slow disease is uncertain as mostly used in indolent LMS anyway.

Rare

Neoplasias of

Gynaecological

Origin

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Study summary

• RaNGO: sample study of specified raregynaecological cancers to facilitate in-depthstudies of their clinical and biologicalbehaviours leading to a greater understandingof mechanisms of disease progression andresponse to treatment, possibly alsoapplicable to common tumours

Primary Tumour Site Tumour Type

Ovary Malignant Germ Cell tumour eg: embryonal, yolk sac, dysgerminoma, choriocarcinoma, malignant mixed germ cell tumour, immature teratoma, teratoma with secondary malignant transformation

Granulosa Cell Tumours

Potentially malignant non-granulosa cell sex cord stromal tumours eg: Sertoli, Sertoli-Leydig, Leydig and steroid cell tumour;, microcystic stromal tumours, sex-cord tumours with annular tubules (SCTAT) Malignant rhabdoid tumours (previously hypercalcaemic small cell cancer ovary)

Adnexa Female adnexal tumour of Wolffian origin (FATWO)

Uterus Endometrial stromal sarcoma, low and high gradeUndifferentiated uterine sarcomaLeiomyosarcomaSmooth muscle tumour of uncertain malignant potential (STUMP)Uterine tumour resembling ovarian sex-cord tumour (UTROSCT)

Cervix Neuro-endocrine tumours (all subtypes)Unusual morphological subtypes of cervical adenocarcinoma (mesonephric, clear cell, gastric - type, serous, carcinosarcoma,)Adenoid basal and adenoid cystic carcinoma

Amendment in progress

to add:

mucinous OC >Stage 1

low grade serous OC

vulva cancer >Stage 1B

Serous borderline >Stage 2

Primary endpoints

To obtain tumour samples and blood from all women in

UK with specified rare gynaecological neoplasms – at

diagnosis and any / all relapses.

Tissue samples:

• sequenced – to identify key genomic alterations

• stored for future transcriptomic analysis

Blood samples:

• to identify circulating tumour cells

• cell-free DNA (where applicable)

Secondary Endpoints

• To ensure clinical details collected aligns accurately with details available in registries e.g. ENCORE, Welsh, Scottish and Northern Irish National Cancer Registries.

• To compile anonymous, accurate confirmation of incidence and outcome (PFS, OS) of RaNGO with patient consent for publication purposes.

• Compile accurate information about treatments and adverse events of RaNGO with patient consent for publication purposes.

• Compile register of the location of tissue samples of raNGO available with appropriate consent for other future translational research.