Investigating age and ethnicity as novel high-risk phenotypes in mucinous ovarian cancer: retrospective study in a multi-ethnic population

Abstract

Objectives
Primary mucinous ovarian carcinoma represents 3% of ovarian cancers and is typically diagnosed early, yielding favorable outcomes. This study aims to identify risk factors, focussing on the impact of age and ethnicity on survival from primary mucinous ovarian cancer.

Methods
A retrospective observational study of patients treated at Sandwell and West Birmingham Hospitals NHS Trust and University Hospital Coventry and Warwickshire. Patients included were women aged ≥16 years, with primary mucinous ovarian cancer confirmed by specialist gynecological histopathologist and tumor immunohistochemistry, including cytokeratin-7, cytokeratin-20, and CDX2. Statistical analyses were performed using R integrated development environment, with survival assessed by Cox proportional hazards models and Kaplan-Meier plots.

Results
A total of 163 patients were analyzed; median age at diagnosis was 58 years (range 16–92), 145 (89%) were International Federation of Gynecology and Obstetrics stage I and 43 (26%) patients had infiltrative invasion. Women aged ≤45 years were more likely to have infiltrative invasion (RR=1.38, 95% CI 0.78 to 2.46), with increased risk of death associated with infiltrative invasion (HR=2.29, 95% CI 1.37 to 5.83). Compared with White counterparts, South Asian women were more likely to undergo fertility-sparing surgery (RR=3.52, 95% CI 1.48 to 8.32), and have infiltrative invasion (RR=1.25, 95% CI 0.60 to 2.58). South Asian women undergoing fertility-sparing surgery had worse prognosis than those undergoing traditional staging surgery (HR=2.20, 95% CI 0.39 to 13.14). In FIGO stage I disease, 59% South Asian and 37% White women received adjuvant chemotherapy (p=0.06). South Asian women exhibited a worse overall prognosis than White women (HR=2.07, 95% CI 0.86 to 4.36), particularly pronounced in those aged ≤45 years (HR=8.75, 95% CI 1.22 to 76.38).

Conclusion
This study identified young age as a risk factor for diagnosis of infiltrative invasion. Fertility-sparing surgery in South Asian women is a risk factor for poorer prognosis. South Asian women exhibit poorer overall survival than their White counterparts.

Full text

1
OlaoyeT, etal. Int J Gynecol Cancer 2024;0:1–9. doi:10.1136/ijgc-2024-005332
Investigating age and ethnicity as novel
high- risk phenotypes in mucinous ovarian
cancer: retrospective study in a multi-
ethnicpopulation
Tejumola Olaoye ,1,2 Ayushi -,3 William Boyle,4 Anthony Williams,5 Raji Ganesan,5 Kamana Subba,6
Akanksha Goyal,7 Elaine Leung,2 Rahul Chowdhary,8 Jennifer Pascoe,8 Sarah Williams,8 Jason Yap,9
Janos Balega,1 Satyam Kumar,7 Kavita Singh,1 Sudha S Sundar 1,2
For numbered afliations see
end of article.
Correspondence to
Professor Sudha S Sundar, Pan-
Birmingham Gynaecological
Cancer Centre, Sandwell and
West Birmingham Hospitals
NHS Trust, Birmingham, UK; S.
S. Sundar@ bham. ac. uk
Received 25 January 2024
Accepted 24 April 2024
To cite: OlaoyeT, - A,
BoyleW, etal. Int J Gynecol
Cancer Published Online First:
[please include Day Month
Year]. doi:10.1136/ijgc-2024-
005332
Original research
© IGCS and ESGO 2024. Re- use
permitted under CC BY- NC. No
commercial re- use. Published
by BMJ.
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INTERNATIONAL JOURNAL OF
GYNECOLOGICAL CANCER
ABSTRACT
Objectives Primary mucinous ovarian carcinoma represents
3% of ovarian cancers and is typically diagnosed early, yielding
favorable outcomes. This study aims to identify risk factors,
focussing on the impact of age and ethnicity on survival from
primary mucinous ovarian cancer.
Methods A retrospective observational study of patients
treated at Sandwell and West Birmingham Hospitals NHS
Trust and University Hospital Coventry and Warwickshire.
Patients included were women aged ≥16 years, with primary
mucinous ovarian cancer conrmed by specialist gynecological
histopathologist and tumor immunohistochemistry, including
cytokeratin- 7, cytokeratin- 20, and CDX2. Statistical analyses
were performed using R integrated development environment,
with survival assessed by Cox proportional hazards models and
Kaplan- Meier plots.
Results A total of 163 patients were analyzed; median age
at diagnosis was 58 years (range 16–92), 145 (89%) were
International Federation of Gynecology and Obstetrics stage
I and 43 (26%) patients had inltrative invasion. Women
aged ≤45 years were more likely to have inltrative invasion
(RR=1.38, 95% CI 0.78 to 2.46), with increased risk of death
associated with inltrative invasion (HR=2.29, 95% CI 1.37 to
5.83). Compared with White counterparts, South Asian women
were more likely to undergo fertility- sparing surgery (RR=3.52,
95% CI 1.48 to 8.32), and have inltrative invasion (RR=1.25,
95% CI 0.60 to 2.58). South Asian women undergoing fertility-
sparing surgery had worse prognosis than those undergoing
traditional staging surgery (HR=2.20, 95% CI 0.39 to 13.14).
In FIGO stage I disease, 59% South Asian and 37% White
women received adjuvant chemotherapy (p=0.06). South Asian
women exhibited a worse overall prognosis than White women
(HR=2.07, 95% CI 0.86 to 4.36), particularly pronounced in
those aged ≤45 years (HR=8.75, 95% CI 1.22 to 76.38).
Conclusion This study identied young age as a risk factor
for diagnosis of inltrative invasion. Fertility- sparing surgery in
South Asian women is a risk factor for poorer prognosis. South
Asian women exhibit poorer overall survival than their White
counterparts.
INTRODUCTION
Primary mucinous ovarian carcinoma represents 3%
of all ovarian cancers. It is often diagnosed early, with
at least 80% presenting in International Federation of
Gynecology and Obstetrics (FIGO) stage I(), resulting
in a favorable prognosis. However, several diagnostic
challenges persist, specically differentiating primary
WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒Primary mucinous ovarian cancer is rare, with a
generally overall favorable prognosis due to early
diagnosis. In cases of advanced or recurrent dis-
ease the outcomes are very poor with poor response
to adjuvant chemotherapy. Currently known risk
factors for prognosis include inltrative invasion
tumors, advanced stage at diagnosis, and residual
disease following surgical treatment.
WHAT THIS STUDY ADDS
⇒This pilot study aimed to identify additional risk
factors for poor prognosis to allow for better risk
stratication of primary mucinous ovarian cancer.
This pilot study identied young age (≤45 years) as
a risk factor for inltrative invasion (RR=1.38); South
Asian ethnicity as a risk factor for poor prognosis
(HR=2.07); and fertility- sparing surgery as a risk
factor for poor prognosis (HR=2.74); however, these
ndings need conrmation in a larger study.
HOW THIS STUDY MIGHT AFFECT RESEARCH,
PRACTICE OR POLICY
⇒The ndings indicate an underlying biological
mechanism may drive the potentially elevated risk
of increased inltrative invasion in young women
and poor prognosis in South Asian women. These
pilot results need further conrmation in a larger
multicenter study. In future research, we will un-
dertake a larger validation study and investigate
the molecular landscape with genomic sequencing.
Finally, the study ndings underscore the need for
a re- evaluation of approach and risk stratication
when assessing young and, particularly South Asian,
patients. Surgical approach (fertility- sparing sur-
gery vs traditional staging surgery) should be con-
sidered carefully with thorough patient counseling,
alongside liberal referral to specialist gynecological
oncology services for at- risk patients while further
evidence is developed in this eld.

2OlaoyeT, etal. Int J Gynecol Cancer 2024;0:1–9. doi:10.1136/ijgc-2024-005332
Original research
mucinous ovarian cancer as distinct from metastases to the ovary
due to clinical, morphological, and immunohistochemical similar-
ities1 2. FIGO stage I disease achieves up to 90% 5- year overall
survival, whereas diseases complicated by ovarian metastases
may result in a life expectancy of <6 months.3 Consequently, diag-
nostic accuracy is critical. This diagnostic challenge has previously
contributed to over- diagnosis, impacting clinical practice and
research.4 5 Datasets lacking central pathology review and rigorous
immunohistochemistry may be unreliable to adequately explore
novel and known prognostic factors.
For those with a ‘true’ histological diagnosis of primary muci-
nous ovarian cancer, adverse clinical outcomes have been found to
be associated with extensive disease spread at surgery (advanced
FIGO stage), tumor with inltrative invasion pattern, and incom-
plete cytoreduction (residual disease)6–10 In our clinical practice,
we observed that young women of South Asian ethnicity with
early- stage disease appeared to have poorer survival outcomes
than their White counterparts. This study aims to identify novel risk
factors for poor outcome; specically assessing the impact of age
and ethnicity on primary mucinous ovarian cancer survival.
METHODS
Study Design
A retrospective observational study design was used, gath-
ering consecutive data between 2005 and 2023 from the cancer
registry of two neighboring gynecological cancer centers within the
West Midlands, United Kingdom: Pan- Birmingham Gynecological
Cancer Center and University Hospital Coventry and Warwickshire.
These hospitals serve a diverse population of 2.9 million people
(Figure1A), 50% of whom reside in areas within the bottom 2.5%
for deprivation.11 Study approval was obtained from the respective
institutional clinical effectiveness and service improvement depart-
ments. Information on demography, histology, treatment modality,
disease stage based on 1998 and 2014 FIGO classications12 13,
and clinical outcomes was abstracted from the 222 patients iden-
tied for review (Figure1B). Ethnicity was self- reported and based
on categories described by the Ofce of National Statistics ethnicity
categories.14 15
Initial diagnoses of primary mucinous ovarian cancer were made
by gynecology specialist histopathologists. Review of histopathology
reports was conducted by study authors under the supervision of
expert gynecological histopathologists following specic training
on the interpretation of morphological and immunohistochemical
ndings in primary mucinous ovarian cancer. Secondary report
review by an expert histopathologist was carried out in 46/222
(21%) cases; achieving 100% interpretation concordance. Patients
were included from prior to the WHO standardized reporting of
primary mucinous ovarian cancer histological invasion ‘inltrative’
or ‘expansile’16; in patients where information was insufcient to
designate invasion they were recorded as ‘not stated’.
Statistical analysis
Statistical analysis used version 4.3.0 of the R integrated devel-
opment environment.17 Descriptive statistics represented base-
line characteristics. Fisher's exact tests were used for categorical
comparisons. Relative risks comparisons based on ethnicity and
age were determined using generalized linear models of the bino-
mial family with log link. Survival analysis was conducted using Cox
proportional hazards models using Firth’s correction and Kaplan-
Meier plots for the respective exposure arms.
RESULTS
Overall characteristics
A total of 222 patients were identied from the database of the two
cancer centers. Overall, 59 patients did not match the histological
inclusion criteria; therefore, 163 patients were included in this study
(Figure 2). Within the study cohort 145 (89%) patients had FIGO
stage I, 4 (2%) FIGO stage II, and 14 (9%) FIGO stage III. Invasion
type was available for 144 (88%) of patients, with 43 (26%) inltra-
tive and 101 (62%) expansile invasion. Surgery was performed by
a gynecological oncologist in 116 (71%) patients, a gynecologist in
46 (28%) of patients and not attempted in 1 (1%) patient. Surgical
efforts were recorded as either traditional staging surgery, including
hysterectomy and bilateral salpingo- oophorectomy omental and
peritoneal biopsies (141, 86%); fertility- sparing staging surgery
with retention of uterus and contralateral ovary if appropriate along
side staging omental and peritoneal biopsies (19, 12%); and no
surgical treatment in cases of exploratory laparotomy/laparos-
copy or no surgery (5, 3%). Staging surgery excludes lymph node
assessment, as this practice is not routinely performed at either
Figure 1 Population and patient selection methods. (A)Description of population served by cancer centers involved in
this study including population size and ethnic composition.14 (B)Study inclusion criteria ensuring the selection of eligible
participants. *IMD Rank, index of multiple deprivation rank of all 317 local authority councils in England: rank 1=most deprived,
rank 317=least deprived.11 PMOC, primary mucinous ovarian cancer.

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OlaoyeT, etal. Int J Gynecol Cancer 2024;0:1–9. doi:10.1136/ijgc-2024-005332
Original research
of the participating sites.18 The median age at diagnosis was 58
years (range 16–92); 47 (29%) were ≤45 years old. There were 119
(73%) White, 19 (12%), South Asian, 5 (3%) other, and 20 (12%) not
recorded ethnicities included. Table1 summarizes the clinicopatho-
logical characteristics of our study population. In view of sample
numbers, ethnicity comparisons were between White and South
Asian patients only.
Impact of Recognized Risk Factors in Primary Mucinous
Ovarian Cancer
The 5- year overall survival was lower in all women diagnosed with
FIGO stage IC disease than in those with FIGO stage IA, at 80%
and 87%, respectively with univariate analysis showing a HR=2.29
(95% CI 1.01 to 5.55). Invasion type was not related to capsule
status at diagnosis; with 76% all FIGO stage IA and 72% of FIGO
stage IC being expansile invasion (p=0.74). Inltrative invasion
was associated with an increased risk of death; univariate analysis
showed a HR=2.88 (95% CI 1.37 to 5.83). The 5- year overall
survival of expansile invasion versus inltrative invasion was 87%
and 63%, respectively (p=0.003) as depicted in Figure3C.
Impact of Age on Primary Mucinous Ovarian Cancer
Outcomes
Women aged ≤45 years had surgery performed by a gynecologist
more frequently (57%) than women aged >45 (17%) p<0.0001. Age
at diagnosis did not affect the likelihood of tumor capsule rupture;
48% of women were diagnosed with FIGO stage IC primary muci-
nous ovarian cancer in both the ≤45 and >45 age groups (p=1.00,
RR=0.96 (95% CI 0.64, 1.43)). In women aged≤45 the 5- year overall
survival for FIGO stage IA was 100%, contrasting with 73% for FIGO
stage IC (p=0.040, HR=1.76 (95% CI 0.75 to 4.39)). Women aged
≤45 years were at an increased risk of diagnosis with inltrative
invasion than women >45 years old, 35% and 28%, respectively,
RR=1.38, (95% CI 0.78 to 2.46) (Figure4A). In women aged ≤45,
Figure 2 Consort diagram illustrating the process of case selection for study inclusion and ethnicity and groupings within
age categories. IHC, immunohistochemistry; SWBH, Sandwell and West Birmingham Hospitals; UHCW, University Hospital
Coventry and Warwickshire.

4OlaoyeT, etal. Int J Gynecol Cancer 2024;0:1–9. doi:10.1136/ijgc-2024-005332
Original research
the 5- year overall survival of expansile invasion versus inltra-
tive invasion was 95% and 37% respectively p<0.002, HR=2.29
(95% CI 1.01 to 5.55). Overall, women ≤45 years had better 5- year
overall survival; 83% vs 79% in the >45 years age group (p=0.049),
HR=0.55 (95% CI 0.20 to 1.28). For every year older than 16 at the
time of diagnosis, there was a cumulative increase in the risk of
death, with a HR of 1.03 (95% CI 1.01 to 1.05).
Impact of Fertility Sparing Surgery on Oncologic Outcomes
Nineteen women underwent fertility- sparing surgery; there was
no signicant difference in rates of inltrative invasion for those
undergoing fertility- sparing surgery compared with those under-
going traditional staging surgery; 8 (47%) and 5 (22%), respec-
tively (p=0.32). In women aged ≤45 years undergoing fertility-
sparing surgery, 10 (59%) were diagnosed with FIGO stage IA
primary mucinous ovarian cancer compared with 10 (44%) women
aged ≤45 years undergoing traditional staging surgery (p=0.78).
In women aged ≤45 years there was no difference in the likeli-
hood of receiving adjuvant chemotherapy; in those undergoing
fertility- sparing surgery 6 (32%) received adjuvant chemotherapy
compared with 9 (39%) of those who underwent traditional staging
surgery (p=0.73). Univariate analysis indicated an increased risk
of death in women undergoing fertility- sparing surgery with HR of
2.74 (95% CI 1.26 to 5.26) (see Figure4C).
Impact of Ethnicity on Oncologic Outcomes
South Asian ethnicity women were at greater risk of being diag-
nosed with primary mucinous ovarian cancer aged ≤45 years old
than their White counterparts, RR=2.09 (95% CI 1.23 to 3.54)
(Figure 4B); with median age of 44 and 60, respectively. South
Asian women exhibited no signicant difference in 5- year overall
survival based on age (≤45: 45%, >45: 67%; p=0.49). White
women demonstrated better outcomes when diagnosed at age ≤45
years compared with those diagnosed at age >45 years, 91% vs
80% 5 year overall survival respectively (p=0.010) (Figure3B).
South Asian women were operated on by a specialist gyneco-
logical oncologist less frequently than White women (44% vs 78%,
p=0.007). A higher proportion of South Asian women were diag-
nosed at FIGO stage IC in comparison with White ethnicity women:
68% (n=13) vs 38% (n=45) (p=0.039, RR=1.73 (95% CI 1.23 to
2.43)). In FIGO stage I disease, 10 (59%) South Asian women and
38 (37%) White women received adjuvant chemotherapy (p=0.06).
South Asian ethnicity women opted for fertility- sparing surgery in
greater proportions than White ethnicity women 6 (32%) and 11 (9%),
respectively (p=0.012). Women of South Asian ethnicity undergoing
fertility- sparing surgery had worse 5- year overall survival rates of
28% compared with 79% in traditional staging surgery (p=0.031;
Figure 3D). In White ethnicity women undergoing fertility- sparing
surgery the 5- year overall survival was 88% vs 85% in traditional
Table 1 Clinical characteristics of all patients with validated primary mucinous ovarian cancer
Characteristics (n=163) All ethnicities, N (%)/median (IQR) South Asian (n=19) White (n=119)
Stage at diagnosis
1A 76 (47%) 5 (26%) 58 (49%)
1B 1 (1%) 0 (0%) 1 (1%)
1C 68 (42%) 13 (68%) 45 (38%)
2 4 (2%) 0 (0%) 3 (3%)
3 14 (9%) 1 (5%) 12 (10%)
Invasion type
Inltrative 43 (26%) 6 (32%) 28 (24%)
Expansile 101 (62%) 12 (63%) 77 (64%)
Not available 19 (12%) 1 (5%) 14 (12%)
Surgeon
Gynecological oncologist 116 (71%) 8 (42%) 93 (78%)
Gynecologist 46 (28%) 10 (53%) 26 (22%)
No surgical attempt 1 (1%) 1 (5%) 0 (0%)
Surgery type
Fertility- sparing surgery 19 (12%) 6 (32%) 10 (8%)
Traditional staging surgery 139 (85%) 12 (63%) 106 (89%)
No surgical treatment 5 (3%) 1 (5%) 3 (3%)
Adjuvant chemotherapy
Yes 66 (40%) 11 (58%) 49 (41%)
No 97 (60%) 8 (42%) 70 (59%)
Survival
5- Year overall survival 136 (79%) 13 (59%) 101 (83%)
Median survival (IQR) 75 (31, 132) 46 (17, 72) 89 (35,138)

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staging surgery (p=0.38). Univariate analysis of fertility- sparing
surgery in South Asian women demonstrated an increased risk of
death HR of 2.20 (95% CI 0.39 to 13.14) (Figure4C).
An increased risk of inltrative invasion was identied in South
Asian women, RR=1.25 (95% CI 0.60 to 2.58). Inltrative invasion
was identied in 6 (32%) South Asian women versus 22 (18%) in
White women. This observed trend persisted in women aged ≤45
years; inltrative disease was diagnosed in 5 (50%) South Asian
women versus 6 (20%) White women.
The 5- year overall survival for the entire study population was
83%, with a notable difference between South Asian and White
women. The 5- year overall survival was 59% in South Asian
women and 83%, in white women (HR=2.07 95% CI 0.86 to 4.36).
This disparity was greater in women aged ≤45 years, with 5- year
overall survival in South Asian women being 45% vs 91% in White
ethnicity women (p=0.006) (Figure3A). Young South Asian women
were shown to be at particular risk, with univariate analysis of the
interaction being HR=of 8.75 (95% CI 1.22 to 76.38) (Figure4C).
DISCUSSION
Summary of the Main results
Our study has revealed differences in survival outcomes in women
of South Asian and White ethnicity. In each postulated risk expo-
sure, young age, inltrative invasion, capsule rupture, and fertility-
sparing surgery, South Asian women consistently fared worse than
their White counterparts.
Figure 3 Kaplan- Meier survival analysis plots of overall survival in primary mucinous ovarian cancer comparing South Asian
and White ethnicity women. (A)Kaplan- Meier plot depicting 5- year overall survival in women diagnosed with primary mucinous
ovarian cancer at age ≤45 years stratied by ethnicity; South Asian vs White ethnicity. (B)Kaplan- Meier plot depicting the
overall survival in White ethnicity women diagnosed with primary mucinous ovarian cancer stratied by age at diagnosis:
≤45 years vs >45 years. (C)Kaplan- Meier plot depicting overall survival in women diagnosed with primary mucinous ovarian
cancer stratied by invasion type: expansile vs inltrative invasion. (D)Kaplan- Meier plot depicting 5- year overall survival in
South Asian women diagnosed with primary mucinous ovarian cancer stratied by surgery type at diagnosis: fertility sparing vs
traditional staging surgery (FSS vs TSS).

6OlaoyeT, etal. Int J Gynecol Cancer 2024;0:1–9. doi:10.1136/ijgc-2024-005332
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Results in the Context of Published Literature
This study identied an increased risk of inltrative invasion in all
women aged ≤45 years. Inltrative invasion is associated with a
signicant increased risk of death in this age group, with no differ-
ential impact based on ethnicity. Overall, age ≤45 years exhibited a
protective effect in terms of mortality; however, South Asian women
aged ≤45 years did not share this protective advantage. It is note-
worthy that South Asian women were more likely to receive a diag-
nosis of primary mucinous ovarian cancer at age ≤45 years.
The overall risk of extensive disease spread (FIGO stage III/
IV) at diagnosis remained low, with progression of disease stage
correlating with a decline in overall survival consistently across all
ethnicity groups.19 FIGO stage IC was identied as a predictor of
lower 5- year overall survival compared with FIGO stage IA. South
Asian women were more like to be diagnosed with FIGO stage IC
than their White counterparts; importantly surgery type/age at diag-
nosis is not related to this increased risk. Fertility- sparing surgery
was associated with an increased risk of death within this cohort.
The nding of increased risk associated with fertility- sparing
surgery had a differential impact within the cohort. South Asian
ethnicity women experienced worse outcomes following fertility-
sparing surgery compared with traditional staging surgery; this was
not the case in White women.
This study corroborated ndings that inltrative invasion was
associated with poorer prognosis than expansile invasion.20 Not
only were young women more likely to be diagnosed with inltra-
tive invasion, but the impact of inltrative invasion also appeared to
be more detrimental in this subgroup. South Asian women demon-
strated a trend of increased risk of inltrative invasion, and this
subgroup exhibited the poorest 5- year overall survival.
The rarity of primary mucinous ovarian cancer and the challenge
in distinguishing it from metastases to the ovary pose a signi-
cant challenge in acquiring sufcient large- volume data regarding
its outcomes. Following central pathology review, up to 50–70%
of cases are reclassied as metastasis to the ovary.4 5 Up to 38%
of metastatic ovarian tumors will precede the detection of the
true primary tumor,21therefore, creating a dataset of this size of
validated cases contributes signicantly to the body of literature
regarding primary mucinous ovarian cancer and its outcomes.
We have demonstrated for the rst time that South Asian ethnicity,
and young age are prognostic factors in primary mucinous ovarian
cancer. Our study’s ndings have corresponded with previously
published data reporting high risk of recurrence and death asso-
ciated with inltrative invasion, with apparent FIGO stage I inl-
trative invasion carrying a substantial risk of recurrence (40–52%)
and death (33%).21 In apparent FIGO stage I tumors with inltrative
invasion, 17–30% exhibit lymph node metastasis7 22 23 suggesting
that occult metastasis may contribute to the adverse outcomes
associated with this disease. Our study has also corroborated more
advanced stage at diagnosis as a poor prognostic indicator.5 6 24–26
Figure 4 Risk analysis comparing outcomes based on age and ethnicity. (A)Relative risk (RR) forest plot comparing key
prognostic risk factors in primary mucinous ovarian cancer between women aged ≤45 and women >45 years. The forest plot
illustrates the relative risk in the two age groups; the risk of death, diagnosis if South Asian, diagnosis with FIGO stage 1C
disease, diagnosis with FIGO stage 3/4 disease, inltrative invasion, and fertility- sparing surgery. Each square represents
the point estimate of relative risk with the horizontal line indicating the 95% CI. (B)Relative risk (RR) forest plot comparing
key prognostic risk factors in primary mucinous ovarian cancer between South Asian and White ethnicity women. The forest
plot illustrates the relative risk in the two ethnic groups; the risk of death, diagnosis at age ≤45 years, diagnosis with FIGO
stage 1C disease, diagnosis with FIGO stage 3/4 disease, inltrative invasion, and fertility- sparing surgery. Each square
represents the point estimate of relative risk with the horizontal line indicating the 95% CI. (C)Table describing median survival,
univariate and multivariable analyses of hazard ratios (HRs) with 95% condence intervals in primary mucinous ovarian cancer.
Exposures included in multivariable analyses identiers: age, ethnicity, stage, invasion type, and surgery type. *Age assessed
as a continuous variable with hazard reported for each additional year at age of diagnosis beginning at age 16 years. FIGO,
International Federation of Gynecology and Obstetrics.

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Variations in incidence of ovarian tumors based on ethnic origin
has been broadly reported within the literature.27–29 Biological
mechanisms linked to ethnic variations in cancer incidence are
already understood—for instance, clear cell ovarian carcinoma
is associated with endometriosis, both clear cell ovarian carci-
noma and endometriosis are more frequently diagnosed in East
Asia.27 28 Variations in outcome based on ethnicity have previously
been reported30 31 32 ; Qi et al demonstrated that Black ethnicity
women have a relative risk of death in primary mucinous ovarian
cancer of 2.22 compared with White women.33
Overall, young age (≤45 years) exhibited a protective effect for
mortality, consistent with ndings in the literature33 34; however,
the differential outcome noted in the South Asian ethnicity
subgroup is a novel nding. It has been widely regarded that
fertility- sparing surgery is safe in early- stage primary mucinous
ovarian cancer,35 5 36 a notion we sought to validate in this study.
Contrary to expectations, our ndings do not corroborate this
assumption. Notably, while we did not observe a specic impact
on 5- year overall survival in White women, a prognostic impact
was identied in South Asian women. This difference is notable
and underscores the emergence of a clinically signicant risk
factor in this population.
Strengths and Weaknesses
This is a consecutive dataset from two neighboring cancer centers
which serve a population of 2.9 million people and provide tertiary
referral care for eight district general hospital gynecology units. All
diagnoses of primary mucinous ovarian cancer are made within
regional multidisciplinary team meetings, with extensive expert
histopathology input. Long- term robust clinical follow- up data are
available and allow insight into survival. Analyzing this large data-
base has allowed for novel factors to be investigated—if validated
in other studies, this will have signicant clinical implications.
Despite this being a large dataset for this disease, the numbers
are small as primary mucinous ovarian cancer is rare. Given the
very small numbers (three Black, two other ethnicity) we were
unable to investigate other ethnicities. In this cohort we were only
able to identify the ethnicity in 88% of patients based on hospital
recorded demographic data. It is important to note this is in keeping
with national ethnicity reporting in healthcare; within NHS digital
Hospital Episode Statistics (HES) 82% of patients have ethnicity
recorded.37
The evaluation of invasion type was achieved in only 88% of
cases owing to insufcient information in certain cases, rendering
it impossible to complete the assessment based on the original
histological report. The primary objective of this research was
to investigate whether age and/or ethnicity could serve as prog-
nostic indicators in patients with primary mucinous ovarian cancer.
Initially, univariate analysis was conducted to address this specic
question. However, given the available data and the potential for a
broader evaluation, we also sought to assess the additional prog-
nostic value of ethnicity and/or age while adjusting for established
prognostic risk factors; consequently, a multivariable analysis was
performed. It is important to note that the relatively small number
of cases in this series resulted in wide condence intervals, high-
lighting the inherent limitations of this type of assessment within
this dataset.
Implications for Practice and Future Research
South Asian women appear to have poorer survival outcomes than
their White ethnicity counterparts. A distinct underlying biological
mechanism may drive the suggested elevated risk; this requires
further investigation. We plan to perform genomic analyses of
primary mucinous ovarian cancer tumors using next- generation
sequencing to gain further understanding of the molecular land-
scape of the disease. Clarifying variations in biology related to vari-
ations in outcome will give greater opportunity to identify signicant
drivers of poor outcomes and potentially identify points of access
for targeted treatment.
Both young women and South Asian women are more likely to
have surgery performed by a non- specialist gynecological oncol-
ogist and are at increased risk of inltrative invasion, which has
implications for survival. The study ndings underscore the need for
a re- evaluation of approach and risk stratication when assessing
young, and particularly, South Asian patients. Currently, it is difcult
to establish the relative impacts of disease biology and surgical
treatment provider in determining the poor overall survival expe-
rienced by South Asian women. The presence of two known risk
factors for poor outcome, inltrative invasion and surgery by non-
specialist gynecologists38, renders this assessment challenging.
Surgical approach (fertility- sparing surgery vs traditional staging
surgery) should be considered very carefully with thorough patient
counseling, alongside liberal referral to specialist gynecological
oncology services for at- risk patients while further evidence is
developed in this eld.
Conclusion
In conclusion, this study identied South Asian ethnicity and
fertility- sparing surgery in specic subgroups as novel risk factors.
South Asian women, particularly those aged ≤45 years, exhibit an
overall poorer prognosis than their White counterparts. Intriguingly,
young age is associated with the higher- risk inltrative phenotype.
Despite the challenges posed by the rarity of primary mucinous
ovarian cancer, the rigorous validation of cases provides robust
insights. Going forward, a larger multicenter study will investi-
gate these ndings, allowing for deeper exploration of variations
in outcomes. Genomic analyses aim to identify distinct biological
mechanisms, offering opportunities for targeted treatments. This
study marks a crucial step toward understanding the complexities
of primary mucinous cancer and improving tailored interventions.
Author afliations
1Pan- Birmingham Gynaecological Cancer Centre, Sandwell and West Birmingham
Hospitals NHS Trust, Birmingham, UK
2Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham,
UK
3Clinical Development Services Agency, Translational Health Science and
Technology Institute, Faridabad, Haryana, India
4Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
5Department of Cellular Pathology, Birmingham Women's and Children's NHS
Foundation Trust, Birmingham, UK
6Department of Obstetrics and Gynaecology, Birmingham Women's and Children's
NHS Foundation Trust, Birmingham, UK
7University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
8University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
9University of Birmingham, Birmingham, UK
X Tejumola Olaoye @TejumolaOlaoye1, Kamana Subba @holyhauri, Elaine Leung
@elaineleung and Sudha S Sundar @sundar_sudha

8OlaoyeT, etal. Int J Gynecol Cancer 2024;0:1–9. doi:10.1136/ijgc-2024-005332
Original research
Acknowledgements This research was supported in part by the International
Centre for Theoretical Sciences (ICTS) for participating in the program - Machine
Learning for Health and Disease (code: ICTS/mlhd2023/7) and the Birmingham
Women's Health Global Research Programme. We extend our gratitude to Professor
Richard Riley for his invaluable assistance with the statistical analyses, particularly
in prognostic evaluations in rare cancers.
Contributors Guarantor of integrity of the entire study: SSS. Study concepts and
design: TO, SSS. Literature research: TO. Clinical studies: TO, SSS, KSu, KSi, SK, AG,
EL, JY, JB, RG, AW, WB, RC. Data analysis: TO. Statistical analysis: TO, A. Manuscript
preparation: TO, A. SSS. Manuscript editing: TO, SSS, KS, AW, JB, JY, EL. Manuscript
review: TO, A, WB, AW, RG, KSu, AG, EL, RC, JP, SW, JY, JB, SK, KSi, and SSS.
Funding The authors have not declared a specic grant for this research from any
funding agency in the public, commercial or not- for- prot sectors.
Competing interests None declared.
Patient consent for publication Not applicable.
Ethics approval This study involves human participants and was approved by
Sandwell and West Birmingham NHS Trust Clinical Effectiveness Department,
University Hospitals Coventry and Warwickshire Clinical Audit and Effectiveness
Department. Aggregated anonymized clinical data held within departmental cancer
registries were used as the basis of the study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. To
minimize the unnecessary dissemination of patient clinical information, data will be
provided in an anonymized form only for specic requests.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, an indication of whether changes were made, and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iDs
TejumolaOlaoye http://orcid.org/0009-0001-8598-906X
Sudha SSundar http://orcid.org/0000-0002-5843-3015
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