Keywords
borderline ovarian tumors - implants - low malignant potential - predictors - progression
to invasive carcinoma - recurrence - reproductive outcome
Anupama Rajanbabu, MD, MRCOG
Introduction
Borderline ovarian tumors (BOTs), first described by Taylor in 1929, qualified as
tumors of low malignant potential, have a better prognosis with excellent survival
in contrast to ovarian cancers.[1] They comprise a subset of all epithelial ovarian neoplasms, accounting for 10 to
20%, and are characterized by atypical cellular proliferation and nuclear atypia without
destructive stromal invasion.[1]
[2]
The epidemiological shift that makes them distinct is the presentation in younger
women at an earlier stage.[3]
[4] Choosing the optimum treatment for these patients can be a challenge as they will
be desirous of fertility.
Long-term surveillance is recommended for borderline neoplasms as there can be late
recurrences even after 10 years, and there is a rare chance of malignant transformation.[5]
[6] The 5 and 10-year survival rates for stage I, II, and III disease are 99 and 97%,
98 and 90%, and 96 and 88%, respectively.[5]
[6] Recurrences in patients with BOTs were subclassified into two types: (1) borderline-type
recurrence and (2) invasive-type recurrence (progression to invasive carcinoma).[7] Factors such as the presence of micropapillary patterns and stromal microinvasion
in serous BOTs (SBOTs), presence of intraepithelial carcinoma in mucinous lesions,
and use of cystectomy in mucinous BOTs are considered controversial, and their effect
on recurrence is yet to be established. Besides, the International Federation of Gynecology
and Obstetrics (FIGO) higher stage, incomplete surgical staging, presence of residual
tumor, and fertility preservation strategy were recently confirmed to be independent
prognostic factors for recurrence of disease in a cohort study on BOT.[8]
Herein, we present the results of a retrospective study conducted to evaluate the
clinicopathological characteristics and high-risk factors affecting the relapse in
patients with BOTs.
Methods
This retrospective study was conducted at Amrita Institute of Medical Sciences, Kochi,
South India, after approval by the Institutional Scientific Committee. All consecutive
patients with pathologically confirmed BOTs who were treated at the institution between
January 2010 and December 2017 were included in the study. Data were obtained from
electronic medical records. Patients who did not receive primary treatment or did
not come for follow-up for at least 6 months were excluded from the analysis. Demographics,
preoperative imaging and clinicopathological finding, tumor markers, and treatment
details were collected.
Surgical approach was classified as open, laparoscopic, or robotic. The surgical treatment
was also divided for evaluation as (1) conservative (any patient with bilateral cystectomy,
unilateral salpingo-oophorectomy with contralateral cystectomy for bilateral ovarian
neoplasm, or unilateral cystectomy), (2) staging surgery (bilateral salpingo-oophorectomy
with or without hysterectomy, with omentectomy, peritoneal washing cytology, peritoneal
biopsies, and appendectomy [in mucinous tumor types]), and (3) fertility-sparing surgery
(defined as conservation of the uterus and at least a portion of one ovary). The completeness
of the surgical staging was evaluated according to the FIGO guidelines. For patients
with fertility preservation, surgical staging was considered comprehensive when, apart
from the reproductive organs, the same surgical steps as described for staging surgery
were performed.
The current World Health Organization criteria were strictly adhered to for the diagnosis
of BOTs by the pathologists. Extraovarian implants were divided histologically into
noninvasive and invasive implants characterized by the absence or presence of destructive
stromal invasion into the underlying tissue, respectively.
After completion of the primary treatment, during the first 2 years, patients were
examined every 3 months, every 6 months during the next 3 years, and thereafter yearly.
Posttreatment surveillance included physical examination, assessment of tumor markers,
and imaging studies. Recurrence was defined as the detection of the same tumor cell
histology after an apparently complete surgical resection.
Overall survival (OS) was calculated from the date of surgery to the date of disease-related
death or last contact. Progression-free survival was defined as the date of surgery
to the date of recurrence.
The whole study group was compared (1) based on histology of borderline neoplasm,
(2) conservative surgery versus comprehensive staging surgery versus fertility-sparing
surgery, (3) tumor recurrence rate, and (4) progression to invasive carcinoma rate,
and thereby mortality rates were analyzed. The outcomes were correlated with age,
FIGO stage, surgical approach (open or minimally invasive surgery), surgical radicality,
operating surgeon (nononcosurgeon vs. oncosurgeon), type of peritoneal implants (invasive
versus noninvasive), and histological type. Reproductive outcome was also assessed
separately.
Statistical Analysis
Collected data were analyzed by the statistical software IBM SPSS statistics (version
20.0, IBM Corp., Armonk, New York, United States), and qualitative and quantitative
data were analyzed using the chi-square test and Student’s t-test, respectively. Progression-free survival and OS were analyzed using the Kaplan–Meier
method, and time-to-event outcome was compared with log-rank test; p < 0.05 was considered statistically significant. For association of categorical variables,
the chi-square test was used. Survival analysis with the recurrence pattern was performed
using the Kaplan–Meier analysis approach with log-rank test to look into their significance.
Results
A total of 1,060 patients presented with epithelial ovarian tumor between January
2010 and June 2017. Of the, 110 (10.4%) patients were identified with BOTs. Of the
110 patients, 7 did not satisfy the eligibility criteria and were excluded from the
study. A total of 103 patients were included in the study group, having a median follow-up
of 46 months (range: 23–130 months). [Table 1] presents the demographic details of the study cohort. The median age of the study
population was 41 years, with 43.7% < 40 years of age. The most common presentation
was mass per abdomen in 46% followed by pain abdomen in 34% of the patients, and 20%
were asymptomatic and detected incidentally on ultrasonography. The young patients
who were desirous of fertility were 43.7%. Around 17.5% of the women had ascites on
presentation. Tumor was unilateral in 87 (84.5%) patients, whereas it was bilateral
in the remaining 16 (15.5%) patients. Cancer antigen 125 (CA-125) was elevated beyond
35 IU/mL in 26% of the patients, and of them, 18% had a value > 100 IU/mL. Carcinoembryonic
antigen was elevated in 7.8% of the patients among all mucinous borderline neoplasm.
The histopathological features are given in [Table 2].
Table 1
Demographic details of the study population
|
Patient characteristics
|
n = 103
|
|
Median (years) (range)
|
41 (14–80)
|
|
Parity, n (%)
|
|
|
Nulliparous
|
35 (34)
|
|
Muciparous
|
68 (66)
|
|
Evaluation for infertility
|
13 (12.6)
|
|
Menopausal state, n (%)
|
|
|
Premenopausal
|
64 (64)
|
|
Postmenopausal
|
36 (36)
|
|
Stage, n (%)
|
|
|
IA
|
72 (69.9)
|
|
IB
|
7 (6.8)
|
|
IC
|
16 (15.5)
|
|
II
|
4 (3.9)
|
|
IIIB
|
1 (1)
|
|
IIIC
|
3 (2.9)
|
Table 2
Histopathological classification in the study population (n = 103)
|
Serous
|
Mucinous
|
Endometrioid
|
|
Number of cases (n = 103), n (%)
|
57 (55.3)
|
45 (43.7)
|
1 (1)
|
|
Median age
|
38
|
44
|
47
|
|
Bilateral, n (%)
|
14 (29.5)
|
2 (4.5)
|
0
|
|
Invasive implant
|
3
|
4
|
0
|
|
Micropapillary
|
8
|
0
|
0
|
|
Microinvasion
|
6
|
7
|
0
|
|
Intraepithelial carcinoma
|
2
|
4
|
0
|
Among patients managed surgically, open approach (75.7%) was preferred over laparoscopy
and robotic approaches, accounting to 21.4 and 2.9%, respectively. Almost 31.1% had
conservative surgery such as unilateral or bilateral cystectomy, 51.5% had complete
peritoneal staging surgery, and 17.5% had fertility-preserving surgery ([Table 3]). Around 41.7% of the patients were operated by nononcosurgeons and referred to
our hospital, 43.7% were operated by combined nononcosurgeon and oncosurgeon, and
14.6% were operated by an oncosurgeon. All tumors were staged as per the FIGO staging
criteria 2014.
Table 3
Clinicopathological characteristics in relation to borderline ovarian tumor recurrences
|
Clinicopathological characteristics
|
Total cases (n)
|
Recurrence (%)
|
p-Value
|
|
Abbreviation: MIS, minimally invasive surgery.
|
|
Age (years)
|
|
<40
|
45
|
9 (20)
|
0.168
|
|
>40
|
58
|
6 (10.3)
|
|
|
Stage
|
|
IA, B
|
79
|
9 (11.4)
|
0.154
|
|
IC
|
16
|
5 (31.2)
|
|
|
IIB
|
4
|
1 (25)
|
|
|
III above
|
4
|
0
|
|
|
Histology
|
|
Serous
|
57
|
7 (12.3)
|
0.676
|
|
Mucinous
|
45
|
8 (17.8)
|
|
|
Endometrioid
|
1
|
0
|
|
|
Operating surgeon
|
|
Nononcosurgeon
|
44
|
7 (15.9)
|
0.783
|
|
Oncosurgeon
|
59
|
8 (13.6)
|
|
|
Surgery approach
|
|
Open
|
77
|
9 (11.7)
|
0.099
|
|
MIS
|
26
|
6 (23.122)
|
|
|
Surgical intervention
|
|
Conservative surgery
|
32
|
9 (28.1)
|
0.007
|
|
Staging surgery
|
53
|
3 (5.7)
|
|
|
Fertility-preserving surgery
|
18
|
3 (16.7)
|
|
Of the 103 patients, 98 are alive after median of 46 months of follow-up. Fifteen
(14.6%) recurrences were recorded. Almost 5.82% had malignant transformation at recurrence.
Six patients had died, of which five (4.9%) deaths were specific to disease (had malignant
transformation at recurrence). Looking at the relation of age with recurrences, nine
(20%) patients who experienced recurrences were <40 years of age (p = 0.16). Three of six malignant transformations were in patients above the age of
40 years.
Looking at the relationship with stage, 9 (11.4%) recurrences were in stage IA, 5
(31.2%) in stage IC, and 25% in stage IIB1 disease. In 15 of 103 recurrences, nine
were in stage I and five women who progressed to malignancy were from stage I. Younger
patients with recurrences were predominantly in the early stage I (88.3% in stage
I). Looking at the relationship with histology, mucinous histology was significant
for recurrences. Malignant histology was also higher in the mucinous variety. Recurrences
in serous papillary histology were 7/57 (12.3%) and that in mucinous variety were
8/45 (17.8%), of which 4 were mucinous endocervical and 4 mucinous intestinal.
The type of surgery performed was found to be a significant factor affecting the recurrences
([Table 3]). Completing the surgical staging reduced the chance of recurrences in BOT. Focusing
on six patients who underwent malignant transformation, observation was made that
all underwent initially conservative surgery. The type of surgery or surgeon did not
seem to affect the number of recurrences in BOT.
Extraovarian implants were found in 10.67% (11/103) of the patients. Seven patients
had invasive implants and four patients had noninvasive implants. Only one patient
had recurrence among patients with invasive implants, and she was alive till the end
of the study period. Among all patients recurred with invasive implants, none progressed
to malignancy. Five patients with invasive implants received six cycles of adjuvant
chemotherapy. Difference in survival for extraovarian invasive versus noninvasive
implants was not statistically significant (95 vs. 102 months, respectively; p = 0.53).
Thirteen patients conceived during the follow-up period, of which one had a miscarriage.
Looking at the relationship of recurrences with histology, 17.8% (8/45) had a mucinous
BOT, 12.3% (7/57) were serous micropapillary. Of the five cancer-related deaths, four
were in women with mucinous tumors (4/45–8.9%) and one serous papillary with microinvasion
(1/57–1.8%), who succumbed to death. In our study, micropapillary pattern showed no
significance in recurrence. Outcome in women with mucinous tumors looks clinically
worse compared with serous tumors, but the difference was not statistically significant
(p = 0.676).
Complete staging surgery was found to have a better DFS outcome in comparison with
fertility-sparing surgery and conservative surgery (103 vs. 97 vs. 71 months, respectively)
([Fig. 1]). No difference was found in the OS with 113 versus 121 versus 125 months for complete
staging surgery, fertility-sparing surgery, and conservative surgery, respectively
([Fig. 2]).
Fig. 1 Kaplan–Meier plot: survival probability by the type of surgery with conservative
surgery (c), comprehensive staging (s), and fertility-sparing surgery (sf) statistically
significant.
Fig. 2 Kaplan–Meier plot: overall survival of the surgical intervention group.
Discussion
BOT is an intermediate form of neoplasia, between benign and malignant. In our retrospective
analysis of the clinicopathological characteristics and predictors of recurrence in
BOT, staging surgery was seen as the single most important factor affecting recurrence.
It was observed that no patient with borderline type of recurrence died of the disease,
and disease-related death was observed only in patients with progression to invasive
carcinoma similar to other studies.[7] Identification of patients with high-risk factors (i.e., advanced stage, old age,
micropapillary and microinvasion, mucinous histology, ascites, type of surgical approach,
adequate staging or fertility-preserving surgery, and residual disease) is essential
for offering more selective therapeutic strategies or monitoring to prevent progression
to invasive carcinoma.
[Table 4] compares our recurrences to published studies. The Arbeitsgemeinschaft Gynaekologische
Onkologie (AGO) ROBOT study reveals that recurrence was significantly more frequent
in patients <40 years, and relapse was usually in residual ovarian tissue.[6] In our analysis, there was no difference in survival by age.[7] In this analysis, advanced FIGO stage was not an independent risk factor. Some studies[8]
[9] concluded that advanced FIGO stage was a significant risk factor for disease-specific
mortality as well as for recurrence and progression to invasive carcinoma. More recurrences
were seen in stage I, and all five deaths (cancer related) that had progressed to
invasive and lethal consequence were in FIGO stage I A/C. Contrary to our observations,
Camatte et al[10] reported that the absence of a staging procedure in patients with an “apparent stage
I” BOT does not modify survival. Similar to our observation, clinical audit at the
University of Cape Town found that 5.6% of early-stage disease had died of cancer,
similar to our study.[11]
Table 4
Published studies comparing recurrence percentage with other study analysis
|
Recurrence
|
Total, n (%)
|
|
Walter H Gotieb et al (1998)
|
82 (4.87)
|
|
Zanetta G et al (2001)
|
339 (12.3)
|
|
Lazarou A et al (2014)
|
151 (16.8)
|
|
Present study
|
103 (14.6)
|
In our study, the risk of progression to invasive carcinoma was 5.8%. This rate was
similar to three previous studies.[8]
[12]
[13] Morice et al[14] reported a 2 to 3% progression rate in their study. Song et al[7] reported that SBOTs seemed to be more prone to progression to invasive carcinoma
(5.5 vs 2%; p = 0.104), the progression rate was 3.3%, and the independent risk factors for progression
were advanced FIGO stage, age 65 years or older, and the presence of microinvasion
also related to OS.[7] Contrary to that, in our study, mucinous histology (5/6 in 103 women) was more prone
to malignant transformation, whereas the histological type did not significantly differ
between the mucinous and serous histologies for recurrences. Koskas et al[15] report that the 10-year cumulative risk of recurrence in the form of invasive carcinoma
was 13% with mucinous BOT and concluded that, unlike SBOT, mucinous BOT does not appear
to be such a “safe” disease.
In terms of histology, 43.7% had a mucinous BOT and 55.3% were serous papillary; this
differs from most international data where SBOT occurred more frequently.[16] Of the five deaths, all five were in women with mucinous tumors.
To preserve fertility potential, Morice et al[14] conducted a review looking at the results of epithelial malignant and BOTs and proposed
that conservative management could be performed in patients with BOT[16] and also concluded that this management would not affect survival in these patients.
There is a place for conservative management in younger women who have not completed
their childbearing,[17] and it appears safe to carry out conservative surgery as long as they do not have
an invasive implant as well. Our study also shows that fertility-preserving staging
is an acceptable option in women desirous of future pregnancy. All cancer-related
deaths were recorded in 103 BOT-affected women who underwent conservative surgery
without adequate staging. The patients who underwent complete staging surgery had
the best DFS, whereas OS did not seem to differ in conservative versus fertility-sparing
versus complete staging groups. du Bois et al showed that higher stage, incomplete
staging, tumor residuals, and organ preservation were all independent prognostic factors
for disease recurrence.[5]
Adjuvant chemotherapy is currently not believed to play a role in the treatment of
BOTs. Of 103 women, five with invasive implants received six cycles of adjuvant chemotherapy
in the form of platinum-based regimens. Chemotherapy was mainly indicated in patients
with advanced-stage disease.[18]
Our study is one of the few studies to determine the predictors for recurrence of
BOTs.[18] Our observation with BOT is that they have a good OS. We looked into several factors
that were reported to affect the outcome but found that the type of surgery was the
only factor that significantly influenced the chance of having a recurrence. Fertility-sparing
surgery is an acceptable option for a woman who is desirous of pregnancy.
Nevertheless, the results have to be cautiously interpreted as this is a single-institution
retrospective study. Future prospective multicentric studies are needed, as most of
the current studies on BOT have been conducted retrospectively.
BOTs may have a very long natural history and can recur up to 20 years after initial
diagnosis; therefore, long-term evaluation is required to elucidate better the natural
history. Follow-up should also occur for a long time as relapses may occur 15 years
after surgery, and in our analysis, one recurrence was after 11 years, and the same
patient succumbed to death as it was a disseminated disease. Close monitoring is advised
for women treated with conservative surgery because of the high rate of relapse. Fertility-sparing
approach can be done for younger patients after thorough consultation.
Conclusions
Complete staging surgery is an important prognostic factor for DFS in BOT. However,
fertility-sparing surgery is also an acceptable option for the management of BOT in
a younger patient. This analysis highlights the importance of complete comprehensive
staging surgery of BOT even when fertility is preserved.
