Mucinous Ovarian

Carcinoma
Professor Timothy Perren
Leeds Institute of Cancer Medicine & Pathology
St Jamess Institute of Oncology
University of Leeds and St Jamess University Hospital
Leeds UK
 Mucinous ovarian tumours
15% of all ovarian neoplasms
Continuum from benign borderline
malignant
benign mucinous cystadenoma 10-15%

mucinous tumours of low 67%

malignant potential (mucinous
borderline tumours)

invasive mucinous 4%
adenocarcinoma
tumours metastatic to the ovary
Mucinous Tumour - Ovary
Pseudomyxoma peritonei
Pseudomyxoma peritonei
Appendix
Mucinous Carcinoma

Primary Metastatic
Unilateral Bilateral
>10cm If Unilateral <10 cm

Seidman J.D. et al
Am J Surg Pathol
2003; 27: 985

The Leeds Teaching Hospitals

NHS Trust
 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- Unlikely More likely
abdominal spread
Multinodular growth Not usual Characteristic
pattern with intervening
normal parenchyma
Surface involvement Not usual (other than Characteristic
background
endometriosis)
Hilar involvement Absent/not typical Typical
Extensive vascular Not usual Favours metastasis
invasion

Singh, N; 2014
 Distinction between primary ovarian
carcinoma and metastases to the ovary (2)
Feature Primary Metastatic
Patterns specifically Associated benign, Beware phenomenon of
favouring primary or borderline and malignant maturation of ovarian
metastatic carcinoma appearing areas metastases may result
in similar gradation of
features
Complex papillary Signet ring carcinoma
architecture
Association with Pseudomyxoma
background changes peritoneii or ovarii;
such as endometriosis, Colloid carcinoma;
Brenner tumour, mature Infiltrative pattern of
cystic teratoma, Sertoli- small glands with
Leydig cell tumour, desmoplastic reaction;
adenofibroma Single cell infiltrate

Singh, N; 2014
 Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Decision tree for differential diagnosis of primary
ovarian versus metastatic carcinoma

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Immunohistochemistry profile
Marker Ovary Ovary Colorectal Appendix Pancreas & Stomach Cervix
intestinal Mullarian biliary
CK7 Usually Diffuse Negative Usually Usually Usually Diffuse
diffuse (except negative diffuse diffuse
rectal)
CK20 Usually Negative Diffuse Usually Usually Usually Usually
focal negative negative negative negative
CEA Focal or Negative Diffuse Diffuse Diffuse or Diffuse or Diffuse or
diffuse focal focal focal
CA19.9 Diffuse Negative or Diffuse Diffuse Diffuse Diffuse Diffuse
focal
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/ Diffuse Diffuse Diffuse Diffuse Negative in Diffuse Diffuse
SMAD4 50%
P16 Negative or Negative or Negative or Negative or Negative or Negative or Diffuse
focal focal focal focal focal focal
PAX8 Usually Positive Negative Negative Negative Negative Positive
negative
Beta- Sometimes Sometimes Positive Usually Variable Positive Variable
catenin pos pos positive
Singh, N; 2014
 Immunohistochemistry profile
Marker Ovary Ovary Colorectal Appendix Pancreas & Stomach Cervix
intestinal Mullarian biliary
CK7 Usually Diffuse Negative Usually Usually Usually Diffuse
diffuse (except negative diffuse diffuse
rectal)
CK20 Usually Negative Diffuse Usually Usually Usually Usually
focal negative negative negative negative
CEA Focal or Negative Diffuse Diffuse Diffuse or Diffuse or Diffuse or
diffuse focal focal focal
CA19.9 Diffuse Negative or Diffuse Diffuse Diffuse Diffuse Diffuse
focal
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/ Diffuse Diffuse Diffuse Diffuse Negative in Diffuse Diffuse
SMAD4 50%
P16 Negative or Negative or Negative or Negative or Negative or Negative or Diffuse
focal focal focal focal focal focal
PAX8 Usually Positive Negative Negative Negative Negative Positive
negative
Beta- Sometimes Sometimes Positive Usually Variable Positive Variable
catenin pos pos positive
Singh, N; 2014
 Immunohistochemistry profile
Marker Ovary Ovary Colorectal Appendix Pancreas & Stomach Cervix
intestinal Mullarian biliary
CK7 Usually Diffuse Negative Usually Usually Usually Diffuse
diffuse (except negative diffuse diffuse
rectal)
CK20 Usually Negative Diffuse Usually Usually Usually Usually
focal negative negative negative negative
CEA Focal or Negative Diffuse Diffuse Diffuse or Diffuse or Diffuse or
diffuse focal focal focal
CA19.9 Diffuse Negative or Diffuse Diffuse Diffuse Diffuse Diffuse
focal
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/ Diffuse Diffuse Diffuse Diffuse Negative in Diffuse Diffuse
SMAD4 50%
P16 Negative or Negative or Negative or Negative or Negative or Negative or Diffuse
focal focal focal focal focal focal
PAX8 Usually Positive Negative Negative Negative Negative Positive
negative
Beta- Sometimes Sometimes Positive Usually Variable Positive Variable
catenin pos pos positive
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 Results

Cases: 27 of 50 evaluable pts mEOC Control
with stage III/IV mEOC from (n=27) (n=54)
RMH 1992-2001 Prog on Rx 63%
Controls: 54 pts stage III/IV CR+PR 1+4 6 + 18
non-mEOC matched for date (measurable (26%) (65%)
disease)
of Dx and stage
First line treatment: Median 5.7 mos 14.1 mos
PFS
1/3rd all pts single agent platinum;
2/3rd platinum containing Median OS 12.0 mos 36.7 mos
combinations

Hess et al: J Clin Oncol 2004; 22(6): 1040-4

 Mucinous epithelial ovarian cancer: a
separate entity requiring specific treatment

PFS OS

Hess et al: J Clin Oncol 2004; 22(6): 1040-4

 P

Retrospective analysis of GOG182 Survival of primary mEOC

[ICON5] substantially worse than serous
54 of 3435 (1.5%) pts entered by Median OS 14 mos vs 42 mos
GOG classified as mucinous P < 0.001
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
Cancer 2011;117:55462
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)

Oxaliplatin & Carboplatin & Oxaliplatin &

Carboplatin & Paclitaxel Capecitabine Paclitaxel Capecitabine
6 x 21-day cycles 6 x 21-day cycles 6 x 21-day cycles 6 x 21-day cycles

Bevacizumab given Bevacizumab given

every 3 weeks for 5 every 3 weeks for 5 or
or 6* cycles 6* cycles

Clinical assessment every 6

weeks for 36 weeks
Telephone 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] [B] [C] [D]

Carboplatin & Paclitaxel Oxaliplatin & Carboplatin & Oxaliplatin &
6 x 21-day cycles Capecitabine Paclitaxel Capecitabine
6 x 21-day cycles 6 x 21-day cycles 6 x 21-day cycles
N=13
N=13 Bevacizumab given Bevacizumab given
every 3 weeks for 5 every 3 weeks for 5 or
or 6* cycles 6* cycles

N=11 N=13

Target Statistics [A&C] vs [B&D]

n=24 n=26
332 pts required to detect 5 month Carbo/Paclitaxel vs Oxaliplatin/Capecitabine
increase in median PFS:
oxaliplatin/capecitabine [B+D]
adding bevacizumab [C+D] [A&B] vs [C&D]
n=26 n=24
No Bevacizumab vs addition of Bevacizumab
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. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Molecular alterations in ovarian and
colorectal mucinous carcinomas

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Molecular alterations in ovarian and
colorectal mucinous carcinomas

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Molecular alterations in ovarian and
colorectal mucinous carcinomas

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Molecular alterations in ovarian and
colorectal mucinous carcinomas

Alterations in KRAS, BRAF or HER2 tend to be mutually exclusive

So
Alterations in MAPK 60% 40% 38%
(Ras/Raf/MEK/ERK)

Kelemen, L. E. and M. Kbel (2011) Lancet Oncology 12(11): 1071-1080.

 Molecular characterisation of mEOC supports
stratified approach with HER2 targeting
Cases from Mayo Clinic, Australian KRAS mutation:
Ovarian Cancer Study Group, 26/33 (79%) MBOT
Toronto PMH & General, Alberta 31/71 (44%) mEOC
Cancer Research biorepository HER2 amplification
11/176 (6%) MBOT
HER2 amplification & KRAS
29/154 (19%) mEOC
mutation status investigated in189 HER2 and KRAS mutation
mEOC & 199 mucinous BOT status both known in 74
HER2 investigated by IHC, with mucinous carcinomas
FISH & CISH as appropriate
KRAS mutation investigated by
Sanger Sequencing

Anglesio et al, J Pathol 2013; 229: 111120

 Prognostic significance of HER2
and HER2/KRAS expression
HER2 PFS

---- KRAS + HER2 +

---- KRAS + HER2
---- KRAS wt HER2 +
---- KRAS wt HER2 -

HER2 OS

Anglesio et al, J Pathol 2013; 229: 111120

 Potential treatment algorithm for
primary mucinous ovarian carcinoma

Anglesio et al, J Pathol 2013; 229: 111120

 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 First line Second line
phenotype

HER2+, KRAS wt Anti HER2 therapy Add anti EGFR

thrapy

HER2+, KRAS mut Anti HER2 therapy GI chemotherapy

(very rare) option or trial

KRAS mut, HER2- Gi chemotherapy or Gi chemotherapy or

trial 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