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Mucinous Ovarian
Carcinoma
Professor Timothy Perren
Leeds Institute of Cancer Medicine & Pathology
St James’s Institute of Oncology
University of Leeds and St James’s University Hospital
Leeds UK
Mucinous ovarian tumours
Continuum from benign borderline
malignant
benign mucinous cystadenoma ≈ 10-15%
mucinous tumours of low
malignant potential (mucinous
borderline tumours)
≈ 67%
invasive mucinous
adenocarcinoma
≈ 4%
tumours metastatic to the ovary
15% of all ovarian neoplasms
Mucinous Tumour - Ovary
Pseudomyxoma peritonei
Pseudomyxoma peritonei
Appendix
• Metastatic
– Bilateral
– If Unilateral <10 cm
• Primary
– Unilateral
– >10cm
Seidman J.D. et al
Am J Surg Pathol
2003; 27: 985
The Leeds Teaching Hospitals
NHS Trust
Mucinous Carcinoma
Mucinous carcinoma
MC rarely bilateral
Usually present as Stage Ia
Grade 1 or 2 treated by surgical resection and no
adjuvant chemotherapy
Recurrent or metastatic MC associated with poor
prognosis
Unusual sites for mets (lung/bone)
Mucinous carcinoma (show reduced mucin cf
borderline mucinous tumours)
Most of “intestinal type”
“endocervical (Mullarian type)” rare
Distinction between primary ovarian
carcinoma and metastases to the ovary (1)
Feature Primary Metastatic
Laterality Unilateral Bilateral
Size Max diameter > 12 cm Max diameter < 10 cm
Extensive intra-
abdominal spread
Unlikely More likely
Multinodular growth
pattern with intervening
normal parenchyma
Not usual Characteristic
Surface involvement Not usual (other than
background
endometriosis)
Characteristic
Hilar involvement Absent/not typical Typical
Extensive vascular
invasion
Not usual Favours metastasis
Singh, N; 2014
Distinction between primary ovarian
carcinoma and metastases to the ovary (2)
Feature Primary Metastatic
Patterns specifically
favouring primary or
metastatic carcinoma
Associated benign,
borderline and malignant
appearing areas
Beware phenomenon of
“maturation of ovarian
metastases – may result
in similar gradation of
features
Complex papillary
architecture
Signet ring carcinoma
Association with
background changes
such as endometriosis,
Brenner tumour, mature
cystic teratoma, Sertoli-
Leydig cell tumour,
adenofibroma
Pseudomyxoma
peritoneii or ovarii;
Colloid carcinoma;
Infiltrative pattern of
small glands with
desmoplastic reaction;
Single cell infiltrate
Singh, N; 2014
Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Immunohistochemistry profileMarker Ovary
intestinal
Ovary
Mullarian
Colorectal Appendix Pancreas &
biliary
Stomach Cervix
CK7 Usually
diffuse
Diffuse Negative
(except
rectal)
Usually
negative
Usually
diffuse
Usually
diffuse
Diffuse
CK20 Usually
focal
Negative Diffuse Usually
negative
Usually
negative
Usually
negative
Usually
negative
CEA Focal or
diffuse
Negative Diffuse Diffuse Diffuse or
focal
Diffuse or
focal
Diffuse or
focal
CA19.9 Diffuse Negative or
focal
Diffuse Diffuse Diffuse Diffuse Diffuse
CDX2 Focal Negative Diffuse Diffuse Focal Focal Negative or
focal
CA125 Negative Diffuse Negative Negative Negative Negative Diffuse
ER Negative Diffuse Negative Negative Negative Negative Negative or
focal
DPC4/
SMAD4
Diffuse Diffuse Diffuse Diffuse Negative in
50%
Diffuse Diffuse
P16 Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Diffuse
PAX8 Usually
negative
Positive Negative Negative Negative Negative Positive
Beta-
catenin
Sometimes
pos
Sometimes
pos
Positive Usually
positive
Variable Positive Variable
Singh, N; 2014
Immunohistochemistry profileMarker Ovary
intestinal
Ovary
Mullarian
Colorectal Appendix Pancreas &
biliary
Stomach Cervix
CK7 Usually
diffuse
Diffuse Negative
(except
rectal)
Usually
negative
Usually
diffuse
Usually
diffuse
Diffuse
CK20 Usually
focal
Negative Diffuse Usually
negative
Usually
negative
Usually
negative
Usually
negative
CEA Focal or
diffuse
Negative Diffuse Diffuse Diffuse or
focal
Diffuse or
focal
Diffuse or
focal
CA19.9 Diffuse Negative or
focal
Diffuse Diffuse Diffuse Diffuse Diffuse
CDX2 Focal Negative Diffuse Diffuse Focal Focal Negative or
focal
CA125 Negative Diffuse Negative Negative Negative Negative Diffuse
ER Negative Diffuse Negative Negative Negative Negative Negative or
focal
DPC4/
SMAD4
Diffuse Diffuse Diffuse Diffuse Negative in
50%
Diffuse Diffuse
P16 Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Diffuse
PAX8 Usually
negative
Positive Negative Negative Negative Negative Positive
Beta-
catenin
Sometimes
pos
Sometimes
pos
Positive Usually
positive
Variable Positive Variable
Singh, N; 2014
Immunohistochemistry profileMarker Ovary
intestinal
Ovary
Mullarian
Colorectal Appendix Pancreas &
biliary
Stomach Cervix
CK7 Usually
diffuse
Diffuse Negative
(except
rectal)
Usually
negative
Usually
diffuse
Usually
diffuse
Diffuse
CK20 Usually
focal
Negative Diffuse Usually
negative
Usually
negative
Usually
negative
Usually
negative
CEA Focal or
diffuse
Negative Diffuse Diffuse Diffuse or
focal
Diffuse or
focal
Diffuse or
focal
CA19.9 Diffuse Negative or
focal
Diffuse Diffuse Diffuse Diffuse Diffuse
CDX2 Focal Negative Diffuse Diffuse Focal Focal Negative or
focal
CA125 Negative Diffuse Negative Negative Negative Negative Diffuse
ER Negative Diffuse Negative Negative Negative Negative Negative or
focal
DPC4/
SMAD4
Diffuse Diffuse Diffuse Diffuse Negative in
50%
Diffuse Diffuse
P16 Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Negative or
focal
Diffuse
PAX8 Usually
negative
Positive Negative Negative Negative Negative Positive
Beta-
catenin
Sometimes
pos
Sometimes
pos
Positive Usually
positive
Variable Positive Variable
Singh, N; 2014
Falling incidence of primary mucinous
ovarian carcinoma diagnosis
• better recognition of the clinical importance of making the
distinction
– stage I mucinous ovarian carcinoma has an excellent prognosis
– metastasis from upper GI / pancreatic primary very poor prognosis
– treatment quite different
• better histological distinction between metastases to the
ovary and primary mucinous ovarian carcinoma
– pattern recognition
– cytokeratin and other immunohistochemical staining
• better preoperative work-up with imaging, and tumour
markers coupled with MDT discussion
Mucinous epithelial ovarian cancer: a
separate entity requiring specific treatment
Patients & methods
• Cases: 27 of 50 evaluable pts
with stage III/IV mEOC from
RMH 1992-2001
• Controls: 54 pts stage III/IV
non-mEOC matched for date
of Dx and stage
• First line treatment:
– 1/3rd all pts single agent platinum;
– 2/3rd platinum containing
combinations
Results
mEOC
(n=27)
Control
(n=54)
Prog on Rx 63%
CR+PR (measurable
disease)
1 + 4
(26%)
6 + 18
(65%)
Median
PFS
5.7 mos 14.1 mos
Median OS 12.0 mos 36.7 mos
Hess et al: J Clin Oncol 2004; 22(6): 1040-4
Mucinous epithelial ovarian cancer: a
separate entity requiring specific treatment
Hess et al: J Clin Oncol 2004; 22(6): 1040-4
PFS OS
P
Retrospective analysis of GOG182
[ICON5]
• 54 of 3435 (1.5%) pts entered by
GOG classified as mucinous
carcinoma
• 10 had insufficient material for
review or not mucinous
• 44 reviewed independently by 3
pathologists according to 2
classification systems (no IHC)
• 16 to 18% judged primary mEOC
• 57 to 63% judged metastatic
• No difference in OS between
primary and metastatic mucinous
Survival of primary mEOC
substantially worse than serous
• Median OS 14 mos vs 42 mos
P < 0.001
Cancer 2011;117:554–62
Mucinous ovarian carcinoma responds
poorly to platinum based chemotherapy
Harrison et al; Int J Gynecol Cancer 2008: 209-214
Mucinous ovarian carcinoma may
respond preferentially to oxaliplatin & 5FU
• mEOC cell lines ‒ MN-1, OMC-1, RMUG-L, RMUG-S, TU-OM-1
• All resistant to platinum & Paclitaxel
• All sensitive to oxaliplatin & FU with additive or synergistic effect
• In a xenograft model treatment with oxaliplatin & FU increased survival over PBS or either drug alone
Sato et al; Cancer Science 2009 March, 100 (3) 546-551
A GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/-bevacizumab compared with oxaliplatin and capecitabine +/- bevacizumab as first line chemotherapy in patients with mucinous
Epithelial Ovarian Cancer (mEOC)
[GOG241]
Cancer Research UK & UCL Cancer Trials Centre
mEOC [GOG 0241]
Trial Design – 2x2 Factorial
Randomise (332 patients – 83 patients in each arm)
Carboplatin & Paclitaxel 6 x 21-day cycles
Oxaliplatin & Capecitabine 6 x 21-day cycles
Carboplatin & Paclitaxel 6 x 21-day cycles
Bevacizumab given every 3 weeks for 5 or 6* cycles
Oxaliplatin &Capecitabine6 x 21-day cycles
Bevacizumab given every 3 weeks for 5 or 6* cycles
Clinical assessment every 6 weeks for 36 weeksTelephone call between visits
Bevacizumab given every 3 weeks for 12 cycles
Clinical assessment every 6 weeks for 36 weeks
Follow-up
mEOC Trial Timelines and
Recruitment• MHRA approval – September
2008
• MREC approval – October 2008
• Launch meeting – 6th Feb 2009
• Start date December 2009
• Trial stopped early (2013) due to poor accrual
• 50 pts recruited
• Median follow up 23 months
• 31 progressions/deaths
mEOC (GOG 0241)Recruitment
Aim to randomise (332 patients – 83 patients in each arm)Recruitment – 50 pts [End 09 to Early 2013]
[A]Carboplatin & Paclitaxel 6 x 21-day cycles
N=13
[B]Oxaliplatin & Capecitabine 6 x 21-day cycles
N=13
[C]Carboplatin & Paclitaxel 6 x 21-day cycles
Bevacizumab given every 3 weeks for 5 or 6* cycles
N=11
[D]Oxaliplatin &Capecitabine6 x 21-day cycles
Bevacizumab given every 3 weeks for 5 or 6* cycles
N=13
[A&C] vs [B&D]n=24 n=26Carbo/Paclitaxel vs Oxaliplatin/Capecitabine
[A&B] vs [C&D]
n=26 n=24
No Bevacizumab vs addition of Bevacizumab
Target Statistics
332 pts required to detect 5 month
increase in median PFS:
• oxaliplatin/capecitabine [B+D]
• adding bevacizumab [C+D]
Abstract submitted to ASCO 2015
Gore et al
mEOC• Data submitted to ASCO 2015
• Specialist pathology review n = 36
− 19 were considered to not have primary
mEOC
− (many metastatic disease)
• Setting up & conducting this international trial
was challenging in this rare group
• Correctly assigning histological diagnosis was
difficult.
• Primary mEOC is rare so different approaches
are needed to evaluate new therapies.
A dualistic approach to the
classification of ovarian carcinoma
Kurman RJ, Shih IM: Hum Pathol 2011, 42:918-931
Ovarian Cancer Genotyping
• EORTC GCG and EORTC GCG Translational Research Group
• 262 high risk stage I and stage II-IV from University Hospitals
Leuven and EORTC 55971
• Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA,
PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY
– Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant
– Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant
– Mucinous subtypes significantly more KRAS mutations than all
nonmucinous tumours (50% vs 4%, P < 0.001)– PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and
endometrioid carcinoma (20%) and were frequently associated with endometriosis
– Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than high-
grade serous tumours (0.6%)
– Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%)
• KRAS or PIK3CA mutation did not correlate with progression-free
survival or overall survival
Despierre et al (2014). Int J Gynecol Cancer 24(3): 468-477.
Ovarian Cancer Genotyping
• EORTC GCG and EORTC GCG Translational Research Group
• 262 high risk stage I and stage II-IV from University Hospitals
Leuven and EORTC 55971
• Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA,
PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY
– Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant
– Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant
– Mucinous subtypes significantly more KRAS mutations than all
nonmucinous tumours (50% vs 4%, P < 0.001)– PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and
endometrioid carcinoma (20%) and were frequently associated with endometriosis
– Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than high-
grade serous tumours (0.6%)
– Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%)
• KRAS or PIK3CA mutation did not correlate with progression-free
survival or overall survival
Despierre et al (2014). Int J Gynecol Cancer 24(3): 468-477.
Ovarian Cancer Genotyping
• EORTC GCG and EORTC GCG Translational Research Group
• 262 high risk stage I and stage II-IV from University Hospitals
Leuven and EORTC 55971
• Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA,
PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY
– Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant
– Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant
– Mucinous subtypes significantly more KRAS mutations than all
nonmucinous tumours (50% vs 4%, P < 0.001)– PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and
endometrioid carcinoma (20%) and were frequently associated with endometriosis
– Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than high-
grade serous tumours (0.6%)
– Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%)
• KRAS or PIK3CA mutation did not correlate with progression-free
survival or overall survival
Despierre et al (2014). Int J Gynecol Cancer 24(3): 468-477.
Ovarian Cancer Genotyping
• EORTC GCG and EORTC GCG Translational Research Group
• 262 high risk stage I and stage II-IV from University Hospitals
Leuven and EORTC 55971
• Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA,
PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY
– Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant
– Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant
– Mucinous subtypes significantly more KRAS mutations than all
nonmucinous tumours (50% vs 4%, P < 0.001)– PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and
endometrioid carcinoma (20%) and were frequently associated with endometriosis
– Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than high-
grade serous tumours (0.6%)
– Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%)
• KRAS or PIK3CA mutation did not correlate with progression-free
survival or overall survival
Despierre et al (2014). Int J Gynecol Cancer 24(3): 468-477.
Molecular alterations in ovarian and
colorectal mucinous carcinomas
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Molecular alterations in ovarian and
colorectal mucinous carcinomas
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Molecular alterations in ovarian and
colorectal mucinous carcinomas
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Molecular alterations in ovarian and
colorectal mucinous carcinomas
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Molecular alterations in ovarian and
colorectal mucinous carcinomas
Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.
Alterations in KRAS, BRAF or HER2 tend to be mutually exclusive
So
Alterations in MAPK 60% 40% 38%
(Ras/Raf/MEK/ERK)
Molecular characterisation of mEOC supports
stratified approach with HER2 targeting
• Cases from Mayo Clinic, Australian
Ovarian Cancer Study Group,
Toronto PMH & General, Alberta
Cancer Research biorepository
• HER2 amplification & KRAS
mutation status investigated in189
mEOC & 199 mucinous BOT
• HER2 investigated by IHC, with
FISH & CISH as appropriate
• KRAS mutation investigated by
Sanger Sequencing
Anglesio et al, J Pathol 2013; 229: 111–120
• KRAS mutation:• 26/33 (79%) MBOT
• 31/71 (44%) mEOC
• HER2 amplification• 11/176 (6%) MBOT
• 29/154 (19%) mEOC
• HER2 and KRAS mutation
status both known in 74
mucinous carcinomas
Prognostic significance of HER2
and HER2/KRAS expression
HER2 PFS
HER2 OS
---- KRAS + HER2 +
---- KRAS + HER2 –
---- KRAS wt HER2 +
---- KRAS wt HER2 -
Anglesio et al, J Pathol 2013; 229: 111–120
Potential treatment algorithm for
primary mucinous ovarian carcinoma
Anglesio et al, J Pathol 2013; 229: 111–120
Cetuximab in mucinous ovarian
cancer cell lines• EGFR & KRAS mutation status investigated in 5
ovarian cell lines
– MN-1, OMC-1, RMUG-L, RMUG-S, MCAS
– EGFR expressed in all but MN-1
– KRAS at codon 12 only in MCAS
• Evaluated in vivo & in vitro effects of cetuximab
– inhibited RMUG-L & OMC-1 growth in vitro
– completely blocked RMUG-L tumour in vivo
– no effect on MCAS in vitro & only partial growth reduction in vitro
Sato et al 2012, Oncology Reports; 27: 1336-1340
HER2 targeting in mucinous
ovarian carcinoma• HER2 status investigated in
– 33 mEOC & 16 mBOTs
– 5 cases of documented recurrence with tissue avail
– 3 prospectively documented HER2 pos recurrent
mEOC
• HER2 amplification observed in
– 6/33 (18%) mEOC
– 3/16 (19%) mBOT
• 1/3 HER2 amplified recurent mEOC had
dramatic response to trastuzumab
McAlpine J et al. BMC Cancer 2009; 9(1): 433
Possible approaches to management of metastatic
or recurrent mucinous ovarian carcinoma
Molecular
phenotype
First line Second line
HER2+, KRAS wt Anti HER2 therapy Add anti EGFR
thrapy
HER2+, KRAS mut
(very rare)
Anti HER2 therapy GI chemotherapy
option or trial
KRAS mut, HER2- Gi chemotherapy or
trial
Gi chemotherapy or
trial
HER2-, KRAS wt Anti EGFR therapy Gi chemotherapy or
trial
P53 gene mutation ? Platinum based
chemotherapy
Adapted from Anglesio et al J Patho, 2013; 229: 111-120
Potential new approaches for
mucinous ovarian carcinoma• Anti HER2 therapy:
– Trastuzumab, MGAH22, lapatinib, TDM-1,
• Anti EGFR therapy for KRAS wt
– cetuximab, panitumumab
• KRAS mut
– Targeting Src and Tubulin in Mucinous Ovarian Carcinoma: Liu T et al; Clin
Cancer Res 2013; 19(23): 6532-43
– Phase 1 selumetanib + MK-2206: Durable response in 1 of 2 low grade ovarian
with RAS mutation. Tolcher 2014
• Chemotherapy
– phase II Japanese study of women with advanced or recurrent are undergoing
treatment with oxaliplatin and S1, an orally active drug combining tegafur,
gimeracil, oteracil
Mucinous ovarian carcinoma
conclusions• Probably the most challenging subtype of ovarian cancer
due to its rarity and diagnostic difficulty
• Large phase disease orientated 3 trials seem unlikely to
succeed (mEOC)
• Would a broader study enroling patients with advanced
stage mucinous tumours involving the ovary whether
primary or secondary be more likely to succeed?
• ?Adaptive trial design platform study with a series of single
arms or randomised phase 2 trials defined by molecular
phenotype. Clinical & translational endpoints
• Monitoring & reporting strategy: SMART [Shared Access
Medicine an Approach to Rare Tumours]
– http://www.smartcancerproject.com
• Broad international cooperation
Thank you
Acknowledgments:
Dr Nafisa Wilkinson for histology slides and guidance