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R E S E A R C H Open Access
Effects of sex hormones on survival of
peritoneal mesothelioma
Yeqian Huang
1
, Nayef A. Alzahrani
2,4
, Winston Liauw
3
and David L. Morris
4*
Abstract
Background: Previous studies have suggested the presence of steroid receptors as a favourable prognostic factor
in peritoneal mesothelioma (PM). This study aims to investigate possible hormonal effects on survival of PM.
Methods: This is a retrospective study of prospectively collected data of 52 consecutive patients with PM who
underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by the same
surgical team at St George Hospital in Sydney, Australia, between April 1996 and April 2013. Females were arbitrarily
divided into assumed premenopausal (<51 years old; n= 15) and assumed postmenopausal (≥51 years old, n= 9).
In each gender group, patients were furthered divided into three age groups (<40, 40–60, >60). A significant
statistical difference was defined as p< 0.05.
Results: Females with epithelial mesothelioma had a significantly higher survival than males (p= 0.023). They also
had a better overall median survival (>60 months) than males (43 months), although this difference was not
statistically significant (p= 0.098). Survival of postmenopausal females became similar to males after excluding
benign cystic mesothelioma.
Conclusions: The better survival in premenopausal females could probably be explained by higher levels of
oestradiol and progesterone. Also, our data suggests that higher rates of benign cystic mesothelioma in females
was not the key reason for the better survival in female patients, further supporting the hypothesis of hormonal
links with survival of PM. Therapeutic effects of sex steroid hormones on PM may be a valuable area to explore.
Keywords: Peritoneal mesothelioma, Hormone, Female, Survival
Background
Mesothelioma arises from serosal lining of the pleura,
peritoneum, pericardium or tunica vaginalis [1]. Histo-
logical appearance of mesothelioma ranges from a well-
differentiated cystic variant to a poorly differentiated
sarcomatoid variant [2]. The peritoneum is the second
most common site for mesothelioma, contributing one
third of all cases [3]. Common presentations of periton-
eal mesothelioma (PM) include increased abdominal
girth, abdominal pain, abdominal mass or ascites and
weight loss. Due to nonspecific symptoms, diagnosis is
often delayed [3, 4]. Systemic chemotherapy has shown
to have limited efficacy [5]. The current approach for
mesothelioma is a combined locoregional treatment
which consists of cytoreductive surgery (CRS) and
hyperthermic intraperitoneal chemotherapy (HIPEC) for
suitable patients. This approach has been shown to pro-
long the survival of PM and achieve a median survival of
up to 60 months [6].
There is a clear relationship between asbestos expos-
ure and mesothelioma. Higher incidence of asbestos-
related occupations among males has been suggested to
account for the higher risk of mesothelioma in males.
Nevertheless, mesothelioma also occurs in 20 % of pa-
tients without previous clearly identified asbestos expos-
ure, suggesting that other factors may be responsible for
the pathogenesis in this disease [7]. Female patients have
been consistently reported to have a better prognosis
than male patients in previous studies [4, 6, 8–11]. The
prognostic difference between sexes has suggested a pos-
sible hormonal link with the survival of this disease.
Also, a few histological studies have demonstrated the
* Correspondence: david.morris@unsw.edu.au
4
Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St
George Hospital, University of New South Wales, Level 3 Pitney Building,
Gray Street, Kogarah, Sydney, New South Wales 2217, Australia
Full list of author information is available at the end of the article
WORLD JOURNAL OF
SURGICAL ONCOLOGY
© 2015 Huang et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Huang et al. World Journal of Surgical Oncology (2015) 13:210
DOI 10.1186/s12957-015-0624-4
presence of sex steroid receptors in PM [3, 7, 12, 13].
Thus, the aim of this study was to assess hormonal ef-
fects on survival of PM.
Methods
Settings
This is a retrospective study of prospectively collected
data of 52 consecutive patients with PM who underwent
CRS and HIPEC by the same surgical team at St George
Hospital in Sydney, Australia, between April 1996 and
April 2013. All the clinical and treatment-related data
were collected and entered into a computerised database
in order to evaluate the survival outcomes of patients
with peritoneal mesothelioma. A signed informed con-
sent to use their clinical data for research purposes was
obtained from all patients prior to their surgery. This
study was ethically approved by South Eastern Sydney
Local Health District Human Research Ethics Committee,
New South Wales, Australia.
Patients
Patients had a good performance status (World Health
Organization Performance Status ≤2) and had a histo-
logical diagnosis of peritoneal mesothelioma. Histological
diagnosesinthisstudyincluded benign cystic mesotheli-
oma, epithelial mesothelioma, sarcomatoid mesothelioma
and biphasic mesothelioma (mixed epithelial and sarcoma-
toid variants). All patients were managed by a standard
treatment protocol which includes CRS and HIPEC. Suit-
ability to undergo CRS and perioperative intraperitoneal
chemotherapy (PIC) was evaluated during a regular weekly
meeting attended by a multidisciplinary team including
surgical oncologists, medical oncologists, radiologists, can-
cer care nurses and research staff. Survival differences be-
tween sexes were analysed. All patients were then further
divided into three groups for survival analysis including
premenopausal females, postmenopausal females and
males. Premenopause was defined as less than 51 years old
(n= 15) whereas postmenopause was defined as at least
51 years old (n= 9). Subgroup analysis compared survival
outcomes of different mesothelioma subtypes within
each gender group. Also, survival of three age groups
(i.e. aged less than 40, between 40 and 60 and greater
than 60 years old) was also compared within each gen-
der group (Females: <40 group n=7; 40–60 group n=
14; >60 group n= 3; Males: <40 group n=5; 40–60
group n= 16; >60 group n=7).
Preoperative management
All patients underwent standard preoperative investigations
which included physical examination, double contrast-
enhanced computed tomography scans of the chest, abdo-
menandpelvis,aswellaspositronemissiontomography.
CRS
A standardised treatment protocol combining CRS and
PIC was performed by the surgical team. An initial assess-
ment of the volume and extent of disease was recorded
using the peritoneal cancer index (PCI), as described by
Jacquet and Sugarbaker [14]. This assessment combines
thickness of lesion size (LS) (LS 0: no macroscopic tumour;
LS 1: tumour <0.5 cm; LS 2: tumour 0.5–5cm;andLS3:
tumour >5 cm) with tumour distribution (abdominopelvic
region 0–12) to quantify the extent of disease as a numer-
ical score (PCI 0–39). The aim of CRS was to remove all
macroscopic intraperitoneal and visceral tumour deposits.
CRS was performed using Sugarbaker’s technique [15].
All sites and volumes of residual disease following CRS
were recorded prospectively using the completeness of
cytoreductive (CC) score (CC0—no macroscopic residual
cancer remained; CC1—no nodule >2.5 mm in diameter
remained; CC2—nodules between 2.5 mm and 2.5 cm in
diameter remained; CC3—nodules >2.5 cm in diameter
remained) [14].
HIPEC
After CRS, but prior to intestinal anastomosis or repair of
seromuscular tears, HIPEC was performed by installation
of a heated chemoperfusate into the abdomen using the
coliseum technique. Cisplatin (100 mg/m
2
in 1000 ml nor-
mal saline) and mitomycin (12.5 mg/m
2
in 1000 ml nor-
mal saline) were given simultaneously over 90 min.
Statistical analysis
All statistical analyses were performed using IBM SPSS
for Windows version 22. Comparison of normally dis-
tributed variables was performed using analysis of vari-
ance (one-way ANOVA) test. Categorical variables were
analysed using chi-square test or Fisher’exact test where
appropriate. Median survival was calculated based on
the last time of contact or death in the unit of months.
Survival analysis was performed using the Kaplan-Meier
curves and log-rank test for comparison. A significant
difference was defined as pvalue less than 0.05.
Results
Descriptive characteristics
Table 1 demonstrates the background characteristics of
our patients with mesothelioma. There was a significant
statistical significance in terms of histological diagnosis
(p= 0.045). Of females, 29.1 % were diagnosed with the
benign cystic form of mesothelioma as compared to
3.7 % in males. More males (18.5 %) were diagnosed
with malignant biphasic mesothelioma as compared to
8.3 % in females. There was no statistical difference in
terms of age, mean PCI, CC score, transfusion units and
HIPEC between females and males.
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 2 of 7
Survival analysis—epithelial type of mesothelioma
Due to the small numbers of patients with sarcoma and
mixed variants, the statistical analysis of all histological
subtypes could not be performed. However, survival was
significantly higher in females with epithelial type of
mesothelioma (p= 0.023). As half of the female patients
with epithelial mesothelioma were still alive at the time
of analysis, median survival could not be calculated for
female patients. However, according to the survival
curve, the median survival in females with epithelial type
of mesothelioma was greater than 60 months as com-
pared to survival in males (median = 22.0 months, 95 %
confidence interval (CI) = 7.9–36.1) (Fig. 1)
Survival analysis—females vs. males
As more than 50 % of patients remained alive at the end
of this study, median survival of all females, premeno-
pausal and postmenopausal females was unable to be
calculated. It was shown that females had a better me-
dian survival (>60 months as shown in Fig. 2) than
males (median = 43.0 months, 95 % CI = 5.5–80.5), al-
though this difference did not reach a statistical signifi-
cance (p= 0.098).
Survival analysis—premenopausal females vs.
postmenopausal females vs. males
Figure 3 compares the survival curve including benign cys-
tic mesothelioma with the curve excluding benign cystic
mesothelioma. Two survival curves showed similar trends
in all three groups. However, survival of postmenopausal
females became more similar to males after excluding be-
nign mesothelioma. It also showed that premenopausal fe-
males have better survival then the other two groups.
However, there was no statistical significance in terms of
Table 1 Background characteristics
Female Male
Total n=52 p
N(%) 24 (46.2) 28 (53.8)
Age mean (SD) 46.8 (49.5) 51.8 (50.0) 0.147
Diagnosis n(%) 0.045
Benign cystic 7 (29.1) 1 (3.7)
Epithelial 14 (58.3) 21 (77.8)
Sarcomatoid 1 (4.2) 0 (0)
Biphasic 2 (8.3) 5 (18.5)
PCI mean (SD) 17 22 0.099
CC n(%) 0.117
0 17 (73.9) 13 (46.4)
1 6 (26.1) 14 (50.0)
2 0 1 (3.6)
300
Transfusion mean (SD) 4.75 (4.54) 7.21 (7.81) 0.180
HIPEC n(%) 0.872
Yes 22 (91.7) 26 (92.9)
No 2 (7.7) 2 (7.1)
Fig. 1 Survival curve for epithelial mesothelioma
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 3 of 7
median survival among premenopausal females, postmen-
opausal females and males (p= 0.253).
Subgroup survival analysis: <40 vs. 40–60 vs. >60
Since more than 50 % of patients remained alive at the
end of this study, median survival of females aged <40
and females aged between 40 and 60 was unable to be
calculated. The median survival of females aged >60 was
23 months (95 % CI could not be calculated). The sur-
vival curve showed that patients aged ≤60 have a better
median survival than those aged greater than 60 (Fig. 4).
However, such a difference did not reach a statistical sig-
nificance (p= 0.952).
Inthemalegroup,mediansurvivalofthoseagedless
than 40, between 40 and 60 and greater than 60 was
62 months (95 % CI could not be calculated),
43 months (95 % CI = 13.5–72.5) and 18 months (95 %
CI = 15.4–20.6), respectively. Although the difference
was not statistically significant (p= 0.486), the survival
graph showed a trend of improving survival in younger
male patients (Fig. 4).
Discussion
Mesothelioma is aggressive and fatal. The differential ex-
pression of hormonal receptors has been suggested to be
correlated with survival differences between sexes in PM
[3]. A recent study done by our group, Pillai et al. [7], in-
vestigated the role of oestrogen receptors in malignant
PM (MPM). They identified nuclear oestrogen receptor-
β(ER-β(n)) as a favourable prognostic factor in PM and
suggested that high level of oestradiol may explain the
survival difference in sexes, since ER-β(n) is oestradiol-
dependent [7]. Also, the study done by Horita et al. sug-
gested that progesterone induces apoptosis in malignant
mesothelioma cells. Our data is consistent with these
hormonal findings. We have seen a significantly better
survival in females with the epithelial type in this study.
Better survival outcomes in assumed premenopausal fe-
males and similar survival trends between postmeno-
pausal females and males shown in our study could be
explained by a high level of oestradiol and progesterone
in premenopausal patients (Fig. 3). Although we have
not measured sex hormones or their receptors in this
study, our finding is consistent with previous literature
in pleural mesothelioma [16, 17]. The study done by
Taioli et al. reviewed 14,228 patients with MPM and
showed less apparent difference in survival for females
over age 50 years. Wolf et al. studied 715 cases of pa-
tients with MPM and showed that young females are
disproportionately represented among long-term survi-
vors of MPM [18]. They suggested that hormonal status
may contribute to better survival in female patients
with MPM.
Our subgroup analysis findings suggest that females
have a better survival in the epithelial mesothelioma
group as compared with males. Given that epithelial
variant was suggested to be a favourable prognostic fac-
tor, such a significant difference may further suggest the
Fig. 2 Survival curve for males and females
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 4 of 7
key role of sex steroids and/or hormonal receptors in
the survival of PM. In addition, our findings also show
that younger patients have better survival in both gender
groups. This could be contributed by a high level of
oestradiol in females. Also, free and bioavailable oestradiol
levels decline significantly with ageing in males [19]. This
could contribute to the much higher survival in male
patients aged <40 as compared with those aged >60 (62
vs. 18 months, respectively). However, the evidence to
support these possible explanations is insufficient from
our data.
Overall survival was higher in females with PM than
males, which is consistent with previous studies [3, 5, 7–10].
A higher incidence of MPM in males was also demon-
strated. Nevertheless, our data suggests that higher rate of
benign cystic mesothelioma in females was not the key rea-
son for greater survival in female patients given similar sur-
vival curves shown in Fig. 3, supporting the hypothesis of a
hormonal link with the survival of PM.
Our study is the one of the few clinical studies that eval-
uated the link between sex steroid hormones and survival
of patients with PM. However, this is a retrospective study
Fig. 3 Survival—premenopausal females vs. postmenopausal females vs. males (aincludes benign cystic mesothelioma; bexcludes benign
cystic mesothelioma)
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 5 of 7
conducted at a single centre. Given that suitability of pa-
tients for peritonectomy was discussed during weekly
meetings and only selected patients were offered this com-
bined therapy, there was selection bias in this study. Also,
our study was limited by the small sample size due to the
low incidence of this disease. A similar study design could
potentially be applied for a greater population in order to
further explore the link between sex steroid hormones
and survival of PM.
Conclusions
In conclusion, oestrogen and progesterone may prolong
the survival of patients with PM. Therapeutic effects of
sex steroid hormones on PM may be a valuable area to
Fig. 4 Survival subgroup: <40 vs. 40–60 vs. >60
Huang et al. World Journal of Surgical Oncology (2015) 13:210 Page 6 of 7
explore. Potential topics for future research include the
survival outcomes of young females with and without
hysterectomy, as well as postmenopausal females on
hormonal replacement therapy.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
YH acquired and analysed the data, participated in the interpretation of the
data and drafted the manuscript. NAA participated in the interpretation of
the data and revised the manuscript. WL contributed to the conception and
design of this study. DLM contributed to the conception and design, revised
the draft critically and gave the final approval of the version to be published.
All authors read and approved the final manuscript.
Acknowledgements
The authors give their special thanks to Jing Zhao, MD, for maintaining the
peritonectomy database.
Author details
1
St George Clinical School, University of New South Wales, Sydney, New
South Wales, Australia.
2
College of Medicine, Imam Muhammad ibn Saud
Islamic University, Riyadh, Saudi Arabia.
3
Department of Medical Oncology, St
George Hospital, University of New South Wales, Sydney, New South Wales,
Australia.
4
Hepatobiliary and Surgical Oncology Unit, Department of Surgery,
St George Hospital, University of New South Wales, Level 3 Pitney Building,
Gray Street, Kogarah, Sydney, New South Wales 2217, Australia.
Received: 21 March 2015 Accepted: 11 June 2015
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