Complete reduction surgery of a huge recurrent adult granulosa cell tumor after neoadjuvant chemotherapy

Abstract

Adult granulosa cell tumors are rare, accounting for only 3–5% of all ovarian tumors. Adult granulosa cell tumors have late recurrences, for which complete resection is an effective option. We report a patient who underwent complete resection of a huge recurrent adult granulosa cell tumor after neoadjuvant chemotherapy. A 72-year-old woman underwent primary surgery for an adult granulosa cell tumor 19 years earlier. A huge recurrent tumor, 11 × 10 cm in size, was noted to elevate the hepatic hilum, inferior vena cava, and right renal vein. The recurrent tumor was too large to resect, thus paclitaxel and carboplatin were administered as neoadjuvant chemotherapy. The tumor shrank to 6 × 5 cm after 6 cycles of chemotherapy, then complete tumor extirpation with resection of the right kidney and temporary scission of inferior vena cava was performed. The patient was alive and well without evidence of a recurrence 1 y postoperatively. Paclitaxel and carboplatin, as neoadjuvant chemotherapy, might be an effective treatment option to achieve complete reduction surgery. This is the first report demonstrating the effectiveness of paclitaxel and carboplatin for huge recurrent adult granulosa cell tumor.

Introduction

Adult granulosa cell tumors (AGCTs) only account for 3–5% of all ovarian tumors, but are the most common malignant sex cord-stromal tumors [1]. AGCTs recur in 20%-30% of patients, and late recurrences also occur [2]. AGCTs were previously classified as ovarian borderline tumors, but are now classified as low-grade malignant ovarian tumor [3]. Chemotherapy, radiotherapy, or surgery is selected for recurrent AGCTs; however, surgery has been reported to prolong survival if recurrent tumors are resectable [4].

We have cared for a patient with an AGCT recurrence 19 years after the primary surgery. Complete tumor extirpation combined with resection of the right kidney and temporary scission of the inferior vena cava (IVC) was performed after paclitaxel and carboplatin as neoadjuvant chemotherapy.

Case report

A 72-year-old gravida 2 para 2 was diagnosed with an ovarian malignancy and underwent an abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, pelvic lymph node dissection and para-aortic lymph node biopsy at 52 years of age. The tumor was 29 × 22 cm in size. Approximately 8300 ml of ascites was suctioned from the abdomen intraoperatively. The serum estradiol level was 528 pg/ml; the serum CA-125 level was not determined. Pathologic evaluation of the tumor specimen showed uniform tumor cell proliferation with insular (Fig. 1A) and microfollicular patterns (Fig. 1B), Call-Exner bodies (Fig. 1C), and nuclear grooves (Fig. 1D). Immunohistochemical analysis showed the tumor cells to be positive for inhibin, vimentin, S100, and AE1/AE3. Peritoneal cytologic analysis of ascites was negative, and pelvic and para-aortic lymph node showed no metastases. The final diagnosis was stage Ia AGCT (FIGO, 1988). No adjuvant therapy was administered postoperatively. The patient was followed for 3 y after initial surgery without a recurrence, then lost to follow-up care.

Fig. 1.

A-F. Pathologic findings of the primary specimen. A The tumor is composed of uniform tumor cell proliferation with insular B and microfollicular patterns, C Call-Exner bodies, and D nuclear groovesPathologic findings of the recurrent specimen. E The resected specimen was similar to the primary AGCT. F Immunohistochemical staining was positive for inhibin. A × 40; B × 40; C × 200; D × 1000; E × 200; F × 400

Nineteen years after the primary surgery, an incidental retroperitoneal tumor was demonstrated on a CT scan obtained elsewhere for unknown indications, and she was referred to our hospital for further evaluation. The tumor was 11 × 10 cm in diameter and was shown to elevate the hepatic hilum, inferior vena cava (IVC), and right renal vein (Fig. 2A). The serum estradiol level was 37.6 pg/ml, thus an AGCT late recurrence was suspected. A CT-guided tumor biopsy was performed, which confirmed an AGCT recurrence. A PET-CT examination of the tumor showed high uptake with an SUVmax of 10.7, but no abnormal FDG uptake in other anatomic sites. Complete reduction surgery of the solitary recurrent tumor was our preferred treatment; however, the tumor was too huge to excise because IVC was compressed at the border between the lower surface of the liver and the tumor, removal from IVC was expected to be difficult. We judged that the complete reduction surgery at this time carried the risk of intraoperative death due to excessive bleeding. Therefore, neoadjuvant chemotherapy consisting of paclitaxel and carboplatin (PC) was administered to shrink the recurrent tumor. Specifically, paclitaxel (175 mg/m²) and carboplatin (AUC = 6) were administered every 3 weeks. The tumor diameter was 6 × 5 cm after 6 courses of PC (Fig. 2B). The serum estradiol level was 12.3 pg/ml after chemotherapy. Reduction surgery was tried with a general surgeon assisting, because IVC on the underside of the liver had expanded, removing from IVC was considered to be possible.

Fig. 2.

A-B. A Computed tomography. The recurrent tumor occupied the retroperitoneal space, elevating the hepatic hilum and inferior vena cava. B The recurrent tumor shrunk after 6 courses of the PC regimen

No ascites was present at the time of laparotomy. Because complete detachment of the tumor and IVC was difficult (Fig. 3A), the operative field was developed by severing the IVC at the confluence of the left and right renal veins, and the IVC on the peripheral side with an automatic suture device (Fig. 3B). The cranial, caudal, and dorsal aspects of the tumor were easily dissected while viewing the dorsal aspect of the IVC (Fig. 3C), but it was difficult to dissect the tumor from the aorta and right renal hilus. Because the right renal artery and vein adhered to the tumor at the right renal hilum, detachment was difficult and persistent bleeding occurred. Therefore, the decision was made intraoperatively to resect both the right kidney and tumor, after which the IVC was reconstructed with an end-to-end anastomosis using 5–0 Prolene^® (Fig. 3D). Complete resection of the recurrent tumor was achieved. The operative time was 12 h 54 min and the blood loss was 700 g. The pathologic findings of the resected specimen were similar to the primary AGCT (Fig. 1E). Immunohistochemical staining was positive for inhibin (Fig. 1F). Thus, the diagnosis of an AGCT recurrence was confirmed. All surgical margins were tumor-free. The patient was alive and well for 1 y after reduction surgery without evidence of a recurrence or the need for adjuvant chemotherapy.

Fig. 3.

A-D. Intraoperative findings. A Complete adhesion of the tumor and the IVC. B The operative field was created by cutting the IVC. C The tumor was easily dissected while viewing the dorsal side of the IVC. D The IVC was reconstructed with an end-to-end anastomosis

Discussion

This is the first report that has demonstrated the PC regimen is effective as neoadjuvant chemotherapy for a huge recurrent AGCT. Moreover, complete resection of the recurrent tumor was achieved with temporary transection of the IVC.

It is well-known that AGCTs have late recurrences. Herein we provided details of a patient in whom an AGCT recurred 19 years after the primary surgery. Lee et al. [5] reported that 8 of 35 AGCTs recurred with a median time-to-relapse of 75 months (range 55–137 months) during a median follow-up duration of 177 months (range 8–212 months). Thus, continuous long-term follow-up of patients with AGCTs is essential. Based on a literature review of 41 stage I recurrent AGCTs, it was concluded that recurrences occur between 6 and 156 months (median = 58 months), of which 20 recurred after 60 months [6]. East et al. [7] reported that a 73-year-old woman who had undergone surgery for a granulosa cell tumor in her early 30 s had a recurrence 40 years later, which is the longest reported interval between primary surgery and a recurrence based on a PubMed search. The patient reported herein also had a late recurrence, recurring 228 months after the primary surgery.

Several risk factors for AGCT recurrences have been described. The presence of residual tumors after surgery may significantly affect the recurrence rate; however, the FIGO stage is an important prognostic factor for AGCT [5]. Plett et al. [8] reported that only early-stage disease is significantly associated with improved progression-free survival. The estimated 5-year progression-free survival in FIGO stages IA/B, IC, and II–IV disease was 94.7%, 72.8%, and 74.3%, respectively (p = 0.008, hazard ratio [HR] = 5.09; and p = 0.008, HR = 5.62) [8]. In a systematic review of 11 studies, tumor stage was significantly associated with overall survival, with an HR of 3.052 for stage III and 2.734 for stage IV tumors (p = 0.037) [9]. In contrast, Alhusaini et al. [10] reported that the presence of ascites and an elevated preoperative CA-125 level were associated with a higher risk of recurrence. Moreover, tumor diameter and age are also risk factors. Hines et al. [11] concluded that unfavorable prognostic factors include bilaterality, tumor size > 15 cm, age > 40 years, a high mitotic count, tumor rupture, and lymphatic space invasion. The serum CA-125 level in the current case was not determined before the primary surgery, but there was a large ascites volume (2900 ml) at the time of primary surgery, the tumor diameter was 29 cm, and the patient was 52 years old. Even though there were many risk factors for recurrence, the FIGO stage was only IA.

There are several treatment strategies for recurrent AGCTs, such as debulking surgery, chemotherapy, radiotherapy, and hormonal therapy. Without a treatment strategy proven to be most effective, physicians are confronted with many treatment options. Indeed, complete debulking surgery may contribute to prolonging survival. Sehouli et al. [12] reported that the 10-year survival rate after an AGCT recurrence was 56.8%, and residual tumor disease was associated with a poor prognosis (p < 0.001). The MITO-9 retrospective study showed that optimal debulking surgery is a good prognostic factor, not only at the time of diagnosis, but even at the time of recurrence [4]. Our case had no residual lesions at the time of primary and second surgeries; thus, a favorable prognosis might be anticipated in the future.

There have been no reports involving cytotoxic neoadjuvant chemotherapy for recurrent AGCTs, but some effective chemotherapy regimens have been reported. Bleomycin, etoposide, and cisplatin (BEP) is effective for AGCT [13]. Fourteen of 38 patients (37%) had negative findings at second-look laparotomy and a median survival of 24.4 months for 6 complete responders [13]. Taxanes are also effective for AGCTs. Brown et al. [14] reported that there was no difference in overall survival (BEP, 97.2 months and taxane, not reached [52 + months]; p = 0.994) and progression-free survival (BEP, 46.1 months and taxane, not reached [52 + months]; p = 0.213) between BEP- and taxane-treated patients. The response rate for 30 patients treated with a taxane + cisplatin for recurrent measurable disease was 42% (complete response, 4; partial response, 9) and the median progression-free interval for all 30 patients was 16.8 months [14, 15]. The BEP regimen has been shown to cause severe toxicity and the PC regimen is a commonly used for gynecologic malignancies, thus we chose the PC regimen for our patient. The tumor was reduced from 11 to 6 cm after 6 courses of the PC regimen, and a complete resection was performed for a recurrent huge AGCT. PC, as a neoadjuvant chemotherapy regimen, might be an effective treatment option to achieve complete reduction surgery for a huge recurrent AGCT.

Funding

This research was supported by Japan Society for the Promotion of Science

Data availability

The data that support the findings of this case report are available from the corresponding author, upon reasonable request.

Declarations

Conflict of interest

No author has any potential conflict of interest.

Ethical approval

The authors declare that this study conformed with the Declaration of Helsinki.

Informed cosent

Informed consent was obtained from this patient.