|Year : 2022 | Volume
| Issue : 2 | Page : 116-122
Clinical and pathological patterns of non-epithelial malignant ovarian tumours in Western Saudi Arabia
Nisreen Mohammad Anfinan1, Eman S Shaldoom1, Hesham Sait1, Omar Baghlaf1, Ahmad Alwazzan1, Ahmed Mousa1, Maram Sait2, Bayan Alkhalili3, Khalid Sait1
1 Department of Obstetrics and Gynecology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
3 Faculty of Medicine, Ibin Sina Collage, Jeddah, Saudi Arabia
|Date of Submission||04-Nov-2021|
|Date of Acceptance||30-Nov-2021|
|Date of Web Publication||23-Apr-2022|
Nisreen Mohammad Anfinan
Professor and Consultant, Faculty of Medicine, King Abdulaziz University, P. O. Box 80215 Jeddah 21589
Source of Support: None, Conflict of Interest: None
Objective: To report a single-center experience in non-epithelial malignant ovarian tumours (NEMOT), by presenting different clinical and pathological characteristics, management and outcomes. Methods: We retrospectively reviewed electronic files of all female patients who underwent surgery for NEMOT at the Gynecology Department of King Abdulaziz University Hospital, Jeddah, Saudi Arabia, from July 2003 to July 2019. We collected baseline demographic, anthropomorphic and clinical data; pathological characteristics; management and follow-up data; and outcomes including residual disease, recurrence and last follow-up status (deceased or alive). Results: Thirty-three women were included; mean (standard deviation) age = 33.24 (17.72) years, range = 4, 86 years. Granulosa cell tumor was the most frequent subtype diagnosed in 17 (51.5%) patients, followed by germ cell tumours 13 (39.4%). The majority of patients were diagnosed at FIGO Stage I (22, 66.7%) and with tumor Grade 1 (23, 69.7%), while 8 (24.2%) were diagnosed with Grade 3 tumors. Granulosa cell and Sertoli-Leydig cell tumours were diagnosed at an older age (mean age = 39.30 vs. 23.92 years) compared to germ cell tumours, respectively (P = 0.012). Two-third of the patients benefited from conservative surgery including oophorectomy + staging, and 16 (48.5%) benefited from chemotherapy with bleomycin, etoposide and platinum being the most common protocol (13, 39.4%) for germ cell tumours. Postoperatively, only 2 (6.1%) patients had residual disease. Recurrence and mortality were reported in one and four patients, respectively, resulting in recurrence rate = 3.0% (95% confidence interval [CI] = 0.01%, 15.8%) and mortality rate = 12.1% (95% CI = 3.4%, 28.2%). Conclusions: The present series of NEMOT was predominated by sex cord-stromal cell tumors, which were diagnosed in patients with older age, while germ cell tumours were underrepresented. Although survival rates were comparable to those reported internationally, more consideration should be given to following up patients regarding fertility outcomes to provide a more comprehensive evaluation of treatment success and quality of care.
Keywords: Germ cell tumour, Malignant, Non-epithelial, Ovarian, Saudi Arabia, Sex cord-stromal cell tumour
|How to cite this article:|
Anfinan NM, Shaldoom ES, Sait H, Baghlaf O, Alwazzan A, Mousa A, Sait M, Alkhalili B, Sait K. Clinical and pathological patterns of non-epithelial malignant ovarian tumours in Western Saudi Arabia. Niger Postgrad Med J 2022;29:116-22
|How to cite this URL:|
Anfinan NM, Shaldoom ES, Sait H, Baghlaf O, Alwazzan A, Mousa A, Sait M, Alkhalili B, Sait K. Clinical and pathological patterns of non-epithelial malignant ovarian tumours in Western Saudi Arabia. Niger Postgrad Med J [serial online] 2022 [cited 2022 Jul 1];29:116-22. Available from: https://www.npmj.org/text.asp?2022/29/2/116/343737
| Introduction|| |
Non-epithelial malignant ovarian tumours (NEMOT) are uncommon types of neoplasms, which account for <15% of all ovary cancers. Depending on their histological and embryological origin, NEMOTs are categorised into malignant germ cell tumours (MGCT) and sex cord-stromal cell tumours (SCSTs), each having various histological subtypes.,,
MGCTs are a fraction of germ cell tumours, which share a common origin from the primitive germ cells of the male and female embryonic gonads, and are more frequently diagnosed at a younger age. In female, MGCTs represent <15% of germ cell tumours, which account for the second-largest group of ovary tumours.,, However, the proportion of malignant ovary germ cell tumours (MOGCT) among ovary malignancies differs across countries and regions. In Saudi Arabia, MOGCTs account for approximately 14% of overall ovarian tumours according to 1999–2008 data from the Saudi Cancer Registry. MGCT have the specificity to be pluripotent and give rise to a variety of tissue components and are characterised by their degree of maturity, as well as their production of serum tumours markers such as alpha-fetoprotein and human chorionic gonadotrophin, both characteristics being valuable in diagnosis, treatment indication and prognosis. Of the MOGCT subtypes, dysgerminoma is the most frequent, notably in Saudi Arabia, followed by immature teratomas and yolk sac tumours, subject to some variances across the world's regions and ethnicity.,,, Furthermore, there is a big discrepancy in the prevalence of each subtype as a function of age and gender, with a peak incidence in school-age children and young adolescents.,,,,,,
Similarly, SCSTs may be benign or malignant, and malignant ones account for nearly 8% of all ovarian malignant cancers, both in Saudi Arabia and worldwide, with granulosa cell tumours being the most common subtype., As their nomenclature implies, SCSTs arise from the sex cord and ovarian stroma, and are characterised by slow progression with relatively more aggressiveness compared to MOGCTs. They are more frequently observed at an older age, but can be observed at younger age with a more favorable prognosis.
The surgical management of NEMOT ideally involves conservative surgery including unilateral salpingo-oophorectomy and resection of all visible disease, with preservation of reproductive function by preserving the uterus and the contralateral ovary. Although this approach is generally possible in early and unilateral tumours, it may be also appropriate in some women with advanced disease, notably by debulking surgery by minimizing residual disease. Otherwise, bilateral salpingo-oophorectomy with or without hysterectomy may be necessary in bilateral and advanced disease, notably in case of highly invasive tumours or lymph node metastasis.,,,, Besides surgery, the advent of chemotherapy had significantly increased the therapeutic success of NEMOTs and improved both vital and functional prognosis in most patients, especially as a complement to fertility-sparing surgery to control the residual disease, notably in MOGCTs, thereby maximizing the chance of cure and allowing considering future pregnancies.,,, Such progress considerably improved survival outcomes of these malignancies enabling nearly 90% of 20-year specific survival and disease-free survival, both in Saudi Arabia and internationally.,,,
In this paper, we report a single-centre experience in NEMOT. We present the different pathological subtypes, management including surgical procedures and chemotherapy regimens, and patients' outcomes including relapse and mortality.
| Methods|| |
Design and settings
We retrospectively reviewed electronic files of all female patients who underwent a surgical procedure for NEMOT at the Gynecology Department of King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia, from July 2003 to July 2019. Patients with epithelial ovarian cancer were not included. The unit of biomedical human ethics research committee for KAUH approved the study protocol based on the international recommendations on human subject research and according to principles of the Helsinki declaration.
Data that was collected was divided into 4 types:
- Demographic data including age and marital status
- Baseline anthropomorphic and clinical data including height, weight with the calculation of the body mass index, parity and co-morbidities (hypertension, diabetes, etc.)
- Pathology data including pathological subtype and FIGO stage at diagnosis
- Management and follow-up data including type of procedure (oophorectomy + staging, TAH-BSO + debulking, or TAH-BSO + staging), adjuvant chemotherapy and protocol used (bleomycin + etoposide + cisplatin [BEP], residual disease, recurrence and location where applicable with time from surgery to recurrence, and last follow-up status (deceased or alive) with the calculation of the time from surgery to death.
Data processing methods
Data were entered and coded in Microsoft Excel. Statistical analysis was performed with the Statistical Package for the Social Sciences version 21.0 for Windows (SPSS Inc., Chicago, IL, USA). Descriptive statistics were used to present socio-demographic and baseline clinical data, tumour pathology characteristics and management and follow-up data. Categorical variables were presented as frequency and percentage, while numerical variables were summarised as mean ± standard deviation (SD) and range. Recurrence and mortality rates were calculated as a percentage out of the study sample with a 95% confidence interval (CI).
| Results|| |
Patients' demographic and clinical characteristics
During the study period, a total of 177 women were diagnosed with ovarian cancer, 144 (81.4%) of them were epithelial ovarian cancers and 33 (18.6%) were NEMOTs. By focusing on NEMOT patients, the mean (SD) age was 33.24 (17.72) years and the youngest patient was 4 years old, and 54.5% were married. Other clinical data showed that the majority of patients were overweight or obese (60.6%), and 6 (18.2%) and 4 (12.1%) had hypertension and diabetes, respectively [Table 1].
Granulosa cell tumour was the most frequent subtype diagnosed in 17 (51.5%) patients, followed by MGCTs 31 (39.4%), including dysgerminoma (4, 12.1%), yolk sac tumour (4, 12.1%) and immature teratoma (3, 9.1%). The majority of patients were diagnosed at FIGO Stage I (22, 66.7%) and with tumour Grade 1 (23, 69.7%), while 8 (24.2%) were diagnosed with Grade 3 tumours [Table 2]. Subgroup analysis showed that 85.0% of SCST were diagnosed at Stage I, versus 38.5% among MGCOTs, and the result was statistically significant (P = 0.009, Fisher's exact test).
Age distribution by histological origin and histopathological type is depicted in [Figure 1]. This showed older age with high variance for SCSTs (mean ± SD = 39.30 ± 20.02 years) compared to MGCTs (mean ± SD = 23.92 ± 6.91 years), and the difference was statistically significant (P = 0.012, independent t-test). Age distribution by subtype showed mean age for granulosa cell tumour (39.65 years), dysgerminoma (22.00 years), yolk sac tumour (23.75 years), immature teratoma (28.00 years) and mixed germ cell tumour (24.00 years), (P = 0.204, Kruskal–Wallis test).
|Figure 1: Age distribution by histological origin (a) and pathological sub-type (b) of non-epithelial malignant ovarian cancers Bars (error bars) represent the mean (standard deviation) of patients' age in the given tumor category.|
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Management and outcome
Management included surgery for all patients with oophorectomy + staging being the most common procedure (66.7%), and 16 (48.5%) of the patients benefited from adjuvant chemotherapy with BEP being the most common protocol (13, 39.4%). Management differed sensitively depending on the histological type with the majority MGCTs patients benefiting from oophorectomy + staging (92.3% versus 50.0%, P = 0.039) and chemotherapy (83.3% versus 30.0%) compared to SCST ones (these results are not presented in tables). Postoperatively, only two (6.1%) patients had residual disease. Recurrence and mortality were reported in one and four patients, respectively, resulting in recurrence rate = 3.0% (95% CI = 0.01%, 15.8%) and mortality rate = 12.1% (95% CI = 3.4%, 28.2%) [Table 3].
Clinical and pathological characteristics of deceased patients
Three out of the four deceased patients were old (59 years or older) and had comorbidities (hypertension and or diabetes); all 3 had granulosa germ cell tumour that was diagnosed at Stage I or II with tumour Grade 1 and underwent invasive surgery including TAH-BSO + debulking. These three elderly patients survived 43 months to 13 years after surgery, and one of them had a second surgery + chemotherapy for recurrence. The remainder mortality case was a younger patient (23 years old) with no comorbidity, who underwent conservative surgery + BEP chemotherapy for a Stage IIIC, Grade 3 malignant mixed germ cell tumour; she deceased 1 month after surgery from sepsis [Table 4].
| Discussion|| |
Summary of findings
In the present series of 33 patients treated and followed for NEMOT, less than half were children, adolescents or young adults (aged up to 26 years old). Granulosa cell tumours accounted for 51.5% (17/33) of the cases, was associated with older age and two-third of patients were diagnosed at an early stage (Stage I) with low tumour grade, while the fourth of them had grade 3 tumour at diagnosis. MGCOTs accounted for 39.4% of the cases and were diagnosed at younger patients, but relatively in later stage as 61.5% were diagnosed at Stage II or higher. The majority of MGCT patients benefited from conservative surgery including oophorectomy with staging, while half SCST patients underwent radical surgery including TAH-BSO. Chemotherapy was used in approximately 50% of the patients, more frequently among MGCT cases using BEP. Post-operative time was characterised with 87.9% survival rate and low recurrence rate (3.0%).
Most frequent pathological subtypes and comparison with other studies
Granulosa cell tumour was the most frequent sub-type of NEMOTs in the present study, followed by germ cell tumours including dysgerminoma and yolk sac tumour (also known as endodermal sinus tumour) both having the same frequency, while mixed germ cell tumour and immature teratoma as well as Sertoli-Leydig cell tumour were underrepresented. This is more or less consistent with reports from other local and international studies showing that dysgerminoma is the most frequent MOGCT subtype followed by immature teratoma, yolk sac tumours, and mixed germ cell tumours, with some differences across countries.,,, In a previous comparable series by Ezzat et al., in 1999, dysgerminoma was the most frequent type, representing 49% of MOGCT cases, followed by immature teratomas (27%), endodermal sinus tumours (15%) and mixed tumours (9%). Internationally, in Turkey, Italy, and Norway, dysgerminoma represented 32%–40% of MOGCT cases, while immature teratoma was the most frequent type in the United States,, and Korea. Furthermore, the frequencies of yolk sac tumour and mixed germ cell tumours varied between 10%–35% and 6.3%–31.9%, while more uncommon types including choriocarcinoma and embryonal carcinoma represented <2.5%.,,,,,,
Granulosa cell tumour
Granulosa cell tumours are considered rare tumours of the ovary, although they represent the most common type of SCSTs. They are characterised by a favorable prognosis and are associated with endometrial hyperplasia due to excess estrogen production by granulosa cells. There are two different forms of granulosa cell tumours: juvenile form, which is rare and occurs in prepubertal girls; and adult form, more common, occurring at an older age. Thus, are frequently diagnosed at an early stage and the most frequent presenting symptom is post-menopausal bleeding, in menopaused women, or menstrual irregularity and precocious pseudopuberty in premenopausal women and premenarchal girls, respectively; besides other signs such as abdominal pain, distention, ovarian mass, infertility or acute haemorrhagic presentation. The treatment of choice includes unilateral salpingo-oophorectomy with appropriate staging in women at childbearing age, and adjuvant chemotherapy using a combination of bleomycin, etoposide and cisplatin is highly recommended in advanced stages (II-IV) and poorly differentiated tumors. Relapse rate may reach 15%, where a second-line treatment is necessary, and radiotherapy may be indicated as adjuvant in primary treatment or after relapse.,,, In the present study, the majority of patients with granulosa cell tumours were diagnosed at an early stage, which probably explains the highly favorable prognosis.
Malignant ovary germ cell tumours
Although two-third MGCTs cases were diagnosed at Stage II or higher, in the present study, the majority were treated with conservative surgery with adjuvant chemotherapy. Unilateral salpingo-oophorectomy, where the contralateral ovary and the uterus are preserved, is considered the most suitable surgical treatment for women with MOGCT. With careful surgical staging in early staging, unilateral salpingo-oophorectomy is considered very valuable for selecting appropriate adjuvant therapy, while in the advanced one, the benefit of aggressively cytoreductive surgery is not well established, nor is removing both ovaries proved to improve the outcome. Therefore, the recommended protocol for MOGCT is surgery alone for surgically staged and histologically confirmed Stage IA tumours, pure dysgerminomas and low-grade immature teratomas. As previously mentioned, MOGCTs occur most often among women at reproductive age; therefore, an emphasis is made on fertility preservation. Fertility-sparing surgery aims at extracting the tumour without causing any damages that may lead to sterility. In the absence of randomised trials, fertility-sparing surgery is increasingly advocated as a safe approach, which demonstrated excellent survival after long-term follow-up and is being recommended in all patients regardless of stage or pathology.,
Furthermore, since these tumours are exquisitely chemo-sensitive, the introduction of effective combination chemotherapy leads to considerable improvements in the prognosis including survival as well as preservation of fertility by allowing fertility-sparing surgery in some advanced cases. The combination chemotherapy of vincristine, actinomycin and cyclophosphamide (VAC regimen) was reported to enable an 86% cure rate in Stage I non-dysgerminomatous forms. Yet, platinum-based regimens, such as BEP, are considered the treatment of choice and are used widely. For patients with the completely resected disease, the BEP is administrated for three cycles; while for patients with macroscopic residual disease, it is administrated for four cycles. For patients with immature teratoma and a growing teratoma syndrome, secondary cytoreductive surgery may have some benefits, yet its role remains controversial. Radiation therapy remains one of the treatment options for MOGCT, although it should be avoided as much as possible as it did not show benefit in terms of relapse reduction or survival.
Recurrence was reported in only one patient (recurrence rate =3.0%) while the mortality rate was 12.1% (four patients), and time from surgery to death was early (1 month post-operative) for the one deceased MGCT patient, who died of sepsis, probably a nosocomial infection. However, post-operative survival time was longer for the three deceased SCSTs patients, ranging between 3.5 and 13 years, and two of them died of renal failure. This is comparable to local data by Ezzat et al., who reported 89% of disease-free survival and 94% overall survival over the first two post-operative years, while 10-year overall and disease-free survival rates were 89% and 76%, respectively. Another study reported 3-year overall survival rates in MOGCTs (87.7%) and SCSTs (88.8%), denoting comparable outcomes. Furthermore, similar survival rates in MOGCT were reported in a number of international studies showing 5-year survival rates approaching 90% with no noticeable difference between the different subtypes; and this survival rate seems to be maintained in a plateau for a long time after treatment, up to 20 years, except in case of regional and distant metastasis where 10–20-year survival rate drops to approximately 60%.,,,
Furthermore, regarding fertility, which constitutes another dimension of the treatment objectives and outcomes, the few available studies showed encouraging fertility rates even following platinum-based chemotherapy regimens, with no noticeable adverse effects of pregnancy on tumour prognosis or fatal outcome. However, in concerned patients, fertility-sparing surgery should be tailored according to the patient's expectations and future fertility attempts should be carefully managed, eventually by proposing in vitro fertilisation in case of failed natural attempts.,,,
This study is limited by the small sample size and some missing clinical and pathological data including presenting symptoms and their duration, gross tumour size and lymph nodes invasiveness. Furthermore, follow-up data notably fertility outcomes were not available on patient records and would have provided valuable information about the functional prognosis of fertility-sparing surgery.
| Conclusions|| |
The present series of NEMOTs was predominated by SCSTs, notably granulosa cell tumour, which was diagnosed in patients with relatively older age, while MGCT sub-types including dysgerminoma, yolk sac tumour, mixed germ cell tumour and immature teratoma were underrepresented.
Despite sensitive variance in treatment protocol between SCST and MGCT cases, conservative surgery benefited two-third of the patients, and chemotherapy was used in half of the patients, more frequently using BEP. Analysis of outcomes showed a very low recurrence rate and high survival rate, which were comparable to those reported internationally; however, further survival analyses were not possible due to a lack of follow-up data.
We emphasise the importance of enhancing early detection, notably of MGCT in youngsters as they are diagnosed at a relatively late stage. In addition, more consideration should be given to following up patients regarding fertility outcomes to provide a more comprehensive evaluation of treatment success and quality of care that is provided to these patients, and to allow more ambitious objectives in future management plans.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]