Background: Adult and juvenile granulosa cell tumors of the ovary are rare functional sex-cord-stromal ovarian neoplasms characterized by low malignant potential and late relapse. Evidence-based management options for primary and recurrent juvenile (JGCT) and adult (AGCT) granulosa cell tumors are limited and treatment options have not been standardized. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may be an option to treat these women effectively.
Methods: Systematic literature review using PubMed and the Cochrane Central Register of Controlled Trials.
Results: No reports of HIPEC among women with a first diagnosis of AGCT were identified. We identified 5 reports on the safety and therapeutic efficacy of CRS and HIPEC in 19 patients with recurrent AGCT and one patient with JGCT. The pooled rate of complete cytoreduction was 95 % (18/19) with 16 % (3/19) severe morbidity and no procedure-related mortality. The median time of follow-up was 30 (range, 3 to 72) months, during which 6/19 (31 %) patients experienced a recurrence and two patients (10 %) died of the disease.
Conclusion: CRS and HIPEC are a safe and potentially effective treatment option for selected women with recurrent AGCT limited to the abdomen.
Sex-cord-stromal tumors are rare ovarian neoplasms accounting for less than 5 % of ovarian malignant tumors . Granulosa cell tumors (GCT) are the most common type of ovarian sex-cord-stromal tumors. This entity is divided based on the age at the time of diagnosis and also based on morphological differences into the common adult granulosa cell tumor (AGCT) and the less frequent juvenile granulosa cell tumor (JGCT) [2–4]. In addition to morphological variations, these two tumor types differ regarding their prognosis as well as their clinical course. In addition, AGCT and JGCT are further divided into well and moderately differentiated tumors. Regarding their gross appearance, AGCT are mostly solid, encapsulated tumors with a yellow-to gray cut surface. There is also a cystic variant of AGCT resembling cystadenocarcinoma.
Well differentiated AGCT have a large inter- and intratumoral variety of growth patterns ranging from macro- to microfollicular, trabecular, insular, solid or diffuse. The microfollicular pattern is the most common growth pattern and is accompanied by Call-Exner bodies in 30 % of cases . Call-Exner bodies are rosette-like arranged granulosa cells surrounding central eosinophilic material or shrunken nuclei. Around a third of AGCT are poorly differentiated with undulating parallel or gyriform rows of granulosa cells in a single file and diffuse sarcomatoid-like pattern characterized by a monotonous appearance . An important tool to differentiate AGCT from adenocarcinomas, carcinoids, or poorly differentiated carcinomas is the nuclear appearance of granulosa tumor cells. Typically, they are pale and uniform with an oval to irregular shape with longitudinal, grooved (,coffee-bean-like’) nuclei. In contrast to this appearance, undifferentiated carcinomas have hyperchromatic, ungrooved nuclei with intense anisokaryosis . In addition, the mitotic count is helpful in distinguishing these two entities with undifferentiated carcinomas showing more mitoses than AGCT . Immunohistochemistry is another commonly used tool to identify and characterize AGCT. For example, AGCT typically express alpha-inhibin and calretinin . Other markers described to be expressed by AGCT are CD99, CAM 5.2, AE1/AE3, CD10, S100, WT-1, smooth muscle actin, and desmin. The lack of CK7 and EMA expression is considered a diagnostic criterion for AGCT, whereas these markers are typically expressed in endometrioid ovarian cancer cells . In a study of 52 morphologically and immunhistochemically unequivocal cases of AGCT, Kommoss et al. demonstrated that molecular testing of FOXL2 might help to confirm the diagnosis .
Clinically, AGCT are often detected at an early stage and affected women show features of hyperestrogenism with breast pain, menorrhagia, and metrorrhagia. Other presenting symptoms are nonspecific such as abdominal pain and swelling. AGCT often follow an indolent course and are characterized by a low malignant potential and late relapses [1, 2]. Although AGCT has a favorable prognosis with overall survival rates of 87 % and 76 % after 5 and 10 years, respectively. , there is a subset of patients with biologically aggressive tumors developing recurrence and ultimately leading to death. Typically, these recurrences develop late and have been described up to 19 years after the initial diagnosis [12–14]. There have been efforts to characterize recurrent AGCTs and to identify prognostic markers associated with recurrence. For example, in a retrospective cohort study of 156 cases of AGCT with 8 recurrences, Ud et al. found that a tumor size of >5 cm, a diffuse histologic pattern, and a high mitotic count were predictive of recurrence . Others identified initial tumor stage, tumor size, degree of cellular atypia, and mitotic index as predictors of tumor recurrence . In addition, subcellular characteristics such as loss of ER-beta expression, high proliferating cell nuclear antigen (PCNA) expression, and aneuploidy have also been described as those features characterizing the subgroup of AGCT with poor outcome [15, 16].
Surgery is the mainstay of treatment for the initial management of women with AGCT with the goal of complete tumor resection [1, 2]. Despite a high rate of tumor recurrence, there is no established role for adjuvant chemotherapy or adjuvant hormone therapy [1, 2, 12–15]. Based on the rarity of the disease and due the absence of comparative trials, there is no consensus on the optimal management of women with recurrent AGCT, which occurs in around a third of patients. For example, in a large retrospective series of 160 FIGO stage I AGCTs, Wilson et al. observed recurrent disease in 32 % (51/160) of cases over a follow-up period of 7 years . The median time to relapse was 12 years underscoring the typical biological behavior of AGCT with late relapse. Due to the rarity of AGCT, treatment options for recurrent disease have not been rigorously tested in clinical trials. Therefore, evidence-based management options for recurrent AGCT are limited and treatment options have not been standardized. In a systematic review of the Cochrane Collaboration covering the literature until 2014, no comparative trial in women with recurrent AGCT was identified . However, in retrospective single-center and multi-center cohort studies, a variety of treatment options have been described, among them systemic chemotherapy, surgery, radiation, and hormonal treatment [17–19].
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a form of local intraperitoneal chemotherapy based on experimental evidence suggesting an enhanced anti-tumor effect of chemotherapeutic compounds at an elevated temperature >40 °C . Several studies have convincingly shown that hyperthermia can increase both tumor penetration of cisplatin  as well as DNA crosslinking . In addition to hyperthermia, HIPEC theoretically offers a number of further advantages, among them a homogenous distribution within the abdomen, no interval between cytoreduction and chemotherapy, high concentrations of chemotherapy in the intraperitoneal compartment with low systemic exposure . On the other hand, HIPEC requires intraoperative perfusion machines, elaborate logistics, and a high degree of organizational effort. In addition, the morbidity and mortality associated with CRS and HIPEC are considerable. For example, Voron et al. reported a 2.5 % mortality rate and a major morbidity rate of 30 % in a series of 204 patients treated with CRS and HIPEC .
Based on the safety and efficacy of CRS and HIPEC in cancer entities such as colon cancer, gastric cancer, and mesothelioma, CRS and HIPEC have been used in women with recurrent AGCT. For example, Al-Badawi et al. performed CRS and HIPEC with cisplatin (50 mg/m²) and doxorubicin (15 mg/m²) in the abdominopelvic cavity for 90 min at 41.0–42.2 °C . The procedure was successful in all 6 patients with grade 2, 3, and 4 morbidities in 2, 1, and 1 cases, respectively. These data demonstrate that CRS followed by HIPEC is feasible in women with recurrent AGCT.
The aim of the present study was to perform a systematic literature review on primary and recurrent AGCT cases treated with CRS and HIPEC and to assess the safety and efficacy of this approach. For this purpose, we systematically searched the PubMed library and the Cochrane Central Register of Controlled Trials to identify all clinical trials reporting on the safety and efficacy of CRS and HIPEC in women with AGCT.
We performed a systematic literature search of the PubMed library and the Cochrane Central Register of Controlled Trials. No citation in the Cochrane Central Register of Controlled Trials was identified using the search term, HIPEC and granulosa cell tumor’. With the search terms, HIPEC’ and, granulosa cell tumor’ and using the search details: “HIPEC[All Fields] AND (“granulosa cell tumour”[All Fields] OR “granulosa cell tumor”[MeSH Terms] OR (“granulosa”[All Fields] AND “cell”[All Fields] AND “tumor”[All Fields]) OR “granulosa cell tumor”[All Fields] (search date 03-03-2016), we identified 4 PubMed citations [24–27]. All citations were retrieved in full and analyzed. A cross reference search of these articles identified no additional citation. One article in press describing a case of AGCT treated with CRS and HIPEC was identified by personal communication . All five articles described women with recurrent JGCT and AGCT. No report on CRS and HIPEC in women with a first diagnosis of GCT was identified. In the next step, data from all five articles containing reports on patients with JGCT or AGCT treated with CRS and HIPEC were extracted and analyzed. Figure 1 shows a flow diagram of the search algorithm used for this study.
Based on a systematic literature search of the PubMed library and the Cochrane Central Register of Controlled Trials, we identified 5 articles [24–28] containing data of 19 patients with recurrent AGCT and two patients with recurrent JGCT treated with CRS and HIPEC. Information on all of these cases was available for analysis. Data on disease location, histology, study type, toxicity, and disease outcomes of these patients were extracted and analyzed. Table 1 summarizes these findings. The pooled rate of complete cytoreduction was 95 % (18/19) with 16 % (3/19) of the patients experiencing severe morbidity and no procedure-related mortality. The median time of follow-up was 30 (range, 3 to 72) months, during which 6/19 (31 %) patients experienced a recurrence and two patients (10 %) died of the disease. Figure 2 shows microscopic images of adult granulosa cell tumors of the ovary with expression of inhibin, CD99, and CD56.
|Author||Year||HIPEC regimen||Number of patients (JGCT/AGCT)||Complete/partial cytoreduction||Follow up, months||Severe morbidity/mortality, n||Outcomes (recurrence/death), n|
|Al-Badawi et al.||2014||Cisplatin (50 mg/m2), Doxorubicin (15 mg/m2) for 90 min||6 (0/6)||5/1||40, 32, 27, 24, 20, 16||2 (Lung atelectasis)/0||0/0|
|Gouy et al.||2013||Oxaliplatin (360 mg/m2), Irinotecan (360 mg/m2) for 30 min||7 (1/6)||7/0||44, 32, 31, 56, 32, 25, 39||1 (Lymphcyst)/0||5/0|
|Canbay et al.||2012||Cisplatin (100 mg/m2) for 40 min||4 (0/4)||4/0||12, 72, -, -||0/0||0/1|
|Hayes-Jordan et al.||2015||Cisplatin (100 mg/m2) for 90 min||1 (1/0)||1/0||12||0/0||1/1|
|Dogan et al.||2016||Cisplatin (75 mg/m2), Doxorubicin (15 mg/m2) for 60 min||1 (0/1)||1/0||3||0/0||0/0|
|Pooled analysis||–||–||19 (2/17)||95 % (18/19)/5 % (1/19)||30 (Min 3, Max 72)||16 % (3/19)/0 % (0/19)||31 % (6/19)/10 % (2/19)|
Al-Badawi et al. performed CRS and HIPEC in 6 patients. Five patients had disease in the abdomen and pelvis and one patient in the abdomen only. Complete cytoreduction (CCR0) was achieved in five patients, one patient had a CCR1 resection. After surgery, HIPEC with cisplatin (50 mg/m²) and doxorubicin (15 mg/m²) in the abdominopelvic cavity for 90 min at 41.0–42.2 °C  using a closed technique with two inflow and two outflow drains was successfully performed in all six patients. All patients were cared for in the intensice care unit for 1 to 3 days. Procedure-related toxicity was observed in 5 patients with grade 1, 2, 3, and 4 morbidities according to the Clavien-Dindo classification observed in 2, 2, 1, and 1 cases, respectively. No grade 5 morbidity occurred. Specifically, two patients developed lung atelectasis, which was managed by mere chest physiotherapy. One patient developed urinary tract infection and another patient developed pneumonia all managed by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration. One patient developed pulmonary embolism requiring intensive care-unit management. Four chemo-naïve patients received adjuvant chemotherapy whereas the remaining two previously chemo-exposed patients received no adjuvant therapy. All patients were alive and disease-free without proof of recurrence at 40, 32, 27, 24, 20, and 16 months.
Gouy et al. published the largest series of women with GCT treated with CRS and HIPEC. They treated six patients with recurrent AGCT and one patient with recurrent JGCT . In contrast to Al-Badawi et al. they used a different chemotherapy regimen consisting of oxaliplatin (460 mg/m2) or oxaliplatin (360 mg/m2) and irinotecan (360 mg/m2) heated up to 41–43 °C for 30 min. They used an open technique with manual manipulation of the intra-abdominal contents to prevent stasis of the heated perfusate. In addition, all patients received intravenous 5-fluorouracil (400 mg/m2) with leucovorin (20 mg/m2) during CRS and before starting HIPEC. The location of the recurrence was exclusively the pelvis in 2 cases and both the pelvis and abdomen in 5 cases. Complete cytoreduction (CCR0) was achieved in all 7 patients. CRS and HIPEC was well tolerated with grade 2 and grade 3 morbidities according to the Clavien and Dindo classification observed in 6 and 1 patients, respectively. Specifically, one patient developed a lymphocyst which required percutaneous drainage twice. Six patients experienced extra-abdominal complications including infection of the central catheter (1 case), a urinary infection (2 cases), transient grade 4 hematologic toxicity (1 case) and transient confusional syndrome (1 case). One grade 3 lymphocyst occurred and the patient underwent percutaneous drainage twice. No grade 4 morbidity or procedure-related mortality occurred. During a median follow-up of 32 months (range, 25–56 months), 3 patients experienced a relapse with peritoneal carcinomatosis and 2 patients relapsed with liver metastases.
Canbay et al. reported a series of 4 patients with recurrent AGCT. The median length of disease free survival after primary treatment was 4.7 (range, 1 to 9) years in these patients. All of them were treated with CRS including peritonectomy and HIPEC using 100 mg cisplatin for 40 min at 43 °C . In this series, no complication and no in-hospitalization mortality were observed. The median length of stay in hospital was 13 (range, 12–21) days. Within a median follow-up of 4 (range, 1–6) years, 1 patient died and the other 3 patients were alive without disease progression.
Hayes-Jordan et al. applied CRS and HIPEC to pediatric girls with diffuse peritoneal disease using 100 mg/m2 of cisplatin for 90 min in a closed abdominal technique . All patients had also received neoadjuvant chemotherapy prior to HIPEC. All patients had disease limited to the abdominal cavity. Among a pediatric population of 101 children undergoing CRS and HIPEC, 8 had ovarian primary tumors and multifocal peritoneal disease. Among these, there was one case of a JGCT. The other tumors were yolk sac tumors (n=3), Sertoli-Leydig cell tumor (n=1), PNET of the ovary (n=1), choriocarcinoma (n=1), and adenocarcinoma (n=1). In the whole study population of 8 children, there were no perioperative deaths. Surgical complications occurred in two patients including two wound infections, one urinary tract infection, and one enterocutaneous fistula. Six patients had no complications. The patient with the enterocutaneous fistula had JGCT with multiple recurrences over a period of 8 years prior to HIPEC and had undergone high-dose total abdominal radiation and at the time of surgery had a “frozen abdomen”.
Three of these 8 patients had a recurrence and died of their disease. Among them was the patient with JGCT, who died 12 months after the intervention. The remaining 5 patients were disease-free 2 to 6 years after the intervention. Therefore, overall survival and relapse-free survival in this cohort was 64 % and 62 %, respectively.
Dogan et al. reported the case of a 60-year-old woman with recurrent AGCT initially diagnosed 19 years ago . After initial surgery 1996, the patient underwent four additional surgical interventions for recurrent disease in 2005 (abdominal wall), 2009 (abdominal wall), 2010 (paravesical), and 2011 (paravesical). In 2011, she underwent pelvic irradiation with 50.5 Gray. In 2015, another recurrence was diagnosed based on an increase of serum inhibin and a tumor seen on CT scan in the right upper abdomen. At laparotomy, the tumor was located attached to the terminal ileum and the ascending colon. There was no peritoneal carcinomatosis and no disease in the pelvis or upper abdomen. The patient underwent cytoreductive surgery (CRS) including a right hemicolectomy, resection of the terminal ileum, a side-to-side (functionally end-to-end) ileotransversostomy, and a subtotal peritonectomy. A complete cytoreduction with no visible residual tumor (CCR0) was achieved. Surgery was immediately followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin 75 mg/m2 and doxorubicin 15 mg/m2 using a closed technique. The duration of HIPEC was 1 hour with an intraabdominal temperature maintained at 41 °C. No postoperative complication occurred and the patient was discharged on postoperative day 6. Subsequently, antihormonal treatment with anastrozole 1.5 mg per day was prescribed. With a follow-up of three months, the patient was reported to be well and alive.
In this literature review, we summarize the clinical evidence on the safety and efficacy of CRS and HIPEC in women with recurrent GCT. Based on clinical reports of 17 patients with AGCT and two patients with JGCT, we found that CRS and HIPEC in these patients had a rate of complete cytoreduction of 95 % with 16 % (3/19) of the patients experiencing severe procedure-related morbidity. No peri- or postoperative mortality was observed among these patients. During a median follow-up of 30 months, 6/19 (31 %) patients experienced a recurrence and two patients (10 %) died of the disease. Based on these data, we conclude that CRS and HIPEC in selected women with recurrent GCT limited to the abdomen is feasible and may be an effective treatment option.
Surgery is the mainstay of treatment in women with a primary diagnosis of GCT. However, the optimal management of recurrent AGCT as well as recurrent JGCT is less clear. Many treatment options for women with recurrent GCT have been advocated, among them systemic chemotherapy, hormonal therapy, radiotherapy, and debulking surgery. For example, in a literature review of 15 studies with 224 patients, van Meurs et al. assessed the response rate to chemotherapy among women with residual or recurrent inoperable AGCT. They calculated a total response rate (including complete and partial responses) of 50 % (95 % confidence interval, 44–57 %). Strict criteria of response, however, were not uniformly applied in the analyzed studies . Hormone therapy is also used in women with recurrent GCT. Van Meurs et al. analyzed 22 women with measurable recurrence or residual disease treated with hormonal treatment, ie tamoxifen or aromatase inhibitors . The pooled objective response rate, defined as complete response or partial response, was 18 % (4/22). In one patient (4 %) a complete response and in three (14 %) a partial response was described. Fourteen patients (64 %) had stable disease. In the series of Wilson et al., surgery was the main therapeutic modality at relapse, but 86 % of patients additionally received non-surgical treatments with a clinical benefit rate of 43 % for chemotherapy, 61 % for hormonal therapy and 86 % for radiation . Whatever the treatment of recurrent disease, the duration of the disease-free interval since the initial operation seems to be an important determinant of the patient’s prognosis. For example, in a multicenter, retrospective cohort study of 44 patients with recurrent AGCT, disease-free interval after the initial operation was the only independent predictor of overall survival, regardless of treatment, suggesting that the natural behavior of the tumor is a critical factor for patients with recurrent AGCT .
HIPEC alone or in combination with debulking surgery has only been described in a few cases. Specifically, we found reports on 19 women, who have undergone CRS and HIPEC. In this patient collective, the rate of complete cytoreduction was high with 95 %, whereas the incidence of severe procedure-associated morbidity was acceptable with 16 % of patients affected. Given the fact that all reported patients had undergone multiple therapies before CRS and HIPEC was performed, the efficacy results with 63 % of the women being disease-free at 30 months of follow-up, are acceptable. Although several different HIPEC regimens were used, all contained a platinum compound. This is reasonable since AGCT is a platinum-sensitive malignancy [2–6] and HIPEC is – in essence – a local dose-escalation strategy in supposedly chemotherapy-resistant disease.
CRS followed by HIPEC is an aggressive strategy and therefore, caution should be exerted with offering this management to patients, especially in the absence of randomized trials establishing the efficacy of CRS and HIPEC in this indication. On the other hand, recurrent GCT is a rare event and it is unlikely that comparative trials will be available in the future. Thus, the best available evidence must be used to guide treatment in women with rare disease such as this one. However, based on the results of this systematic literature review, CRS and HIPEC should be limited to women with recurrent AGCT limited to the abdomen, because most studies report on this patient collective. Prior abdominal radiotherapy seems to be a contraindication as exemplified by one patient with frozen abdomen who developed enterocutaneous fistulas and ultimately dies after CRS and HIPEC.
Another important aspect of HIPEC is the choice of cytotoxic drugs. Al-Badawi et al. and Dogan et al. used cisplatin (50 mg/m² and 75 mg/m², respectively) and doxorubicin (15 mg/m²), Canbay et al. and Hayes-Jordan et al. used 100 mg/m2 of cisplatin, whereas Gouy et al. used a different chemotherapy regimen consisting of oxaliplatin (460 mg/m2) or oxaliplatin (360 mg/m2) and irinotecan (360 mg/m2). This heterogeneity clearly demonstrates that there is no standardized chemotherapy regimen for HIPEC in women with AGCT. Whereas both cisplatin and doxorubicin are active drugs in ovarian cancer, oxaliplatin and irinotecan – as used in Gouy’s study – seems an odd choice for an ovarian malignancy. However, in their manuscript, the authors do not comment on the reasons why they have chosen these particular drugs . Based on our literature search, no formal phase I trial to establish the optimal dosage of any given chemotherapy regimen has been performed. Clearly, the choice of all of these drugs and drug combinations is empirical. Based on the results of a comprehensive systematic review of the literature by the Cochrane Database, there is no evidence-based chemotherapy regimen for women with AGCT . A study that may be able to provide answers to the question of which chemotherapeutic regimen should be selected for management of AGCT is an ongoing, randomized, phase 2 study, led by the Gynaecological Oncology Group to compare the efficacy of carboplatin and paclitaxel versus a combination of bleomycin, etoposide and cisplatin .
In summary, AGCT is a rare entity characterized by high rates of recurrence and repeated surgical interventions. Due to the rarity of this disease, there is no consensus regarding the optimal therapy of recurrent AGCT. Thus, it is important to identify additional safe and effective treatment strategies. Based on our case report and the data reported in the literature we suggest that women with recurrent AGCT and disease localized to the abdomen, CRS and HIPEC may be offered, given that the patient is clinically fit enough to tolerate a procedure associated with considerable morbidity.
CRS and HIPEC are a potential treatment option for selected women with recurrent AGCT limited to the abdomen.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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