Late retroperitoneal recurrence of adult-type ovarian granulosa cell tumors: Two case reports and literature review

Abstract

Adult-type ovarian granulosa cell tumors are rare low-grade malignancies characterized by late recurrence and atypical clinical manifestations. This study reports two cases of recurrent adult-type ovarian granulosa cell tumor with distinct timelines and anatomical sites, including one case with two postoperative recurrences. We analyze their imaging features, surgical management, histopathology, postoperative follow-up, and review relevant literature. These cases highlight the importance of long-term follow-up and raise awareness of rare recurrence sites, emphasizing the diagnostic value of imaging and the need for individualized surveillance strategies in adult-type ovarian granulosa cell tumor patients.

Introduction

Ovarian granulosa cell tumor (GCT) is a low-grade malignant neoplasm originating from the sex cord-stromal tissue, accounting for ∼2%–5% of all ovarian tumors. ¹ It exhibits unique biological behavior and a tendency for late recurrence. According to the World Health Organization (WHO) classification, GCT is divided into adult-type (AGCT, 95%) and juvenile-type (5%).^2,3 The recurrence of AGCT is closely related to its low-grade malignant potential, prolonged dormancy, and hormone-dependent growth. Microscopic residual disease may persist for years following initial surgery and reactivate under specific conditions, such as microenvironmental changes or FOXL2-driven genetic alterations. Histological features, including nuclear atypia, diffuse architectural patterns, and high mitotic activity, are associated with increased recurrence risk. Due to the indolent growth pattern of recurrent lesions and the absence of hormone-related or location-specific symptoms in many cases, early diagnosis is often delayed. In particular, lesions located in deep anatomical sites such as the retroperitoneum may remain asymptomatic until they reach a considerable size, and tumor markers typically remain within normal ranges, further complicating detection.^2,4 Recent studies have revealed heterogeneity in AGCT recurrence patterns. In addition to common pelvic recurrences, rare metastatic sites such as the retroperitoneal space, perihepatic region, and splenic hilum have also been reported. ⁵ Besides, given the unpredictable timing, sometimes decades after primary treatment, no standardized follow-up protocol has been established. Most guidelines recommend long-term, even lifelong, clinical and radiological surveillance, aiming to identify recurrence early and enable timely intervention. However, there is still no consensus regarding their imaging characteristics and treatment strategies.

Thus, our study described two cases of AGCT recurrence in the retroperitoneum at 9 and 15 years postoperatively, respectively. One case involved retroperitoneal recurrence occurring 15 years after initial surgery, while the other presented with recurrence along the ileal wall following two previous operations over a 9-year period. By highlighting the atypical sites and long latency periods, we aim to raise clinical awareness, improve diagnostic accuracy in imaging, and inform appropriate follow-up strategies for long-term survivors of AGCT. In addition, the reporting of this study conforms to CARE guidelines. ⁶

Case 1

The patient is a female in her early 60s with a history of total hysterectomy and bilateral oophorectomy performed at an outside hospital 15 years ago for an ovarian tumor, with postoperative pathology confirming malignancy.

The patient was admitted to the First Affiliated Hospital of Ningbo University (Waitan Campus) with a three-year history of intermittent right flank pain in 2018, which acutely intensified over 2 days. Physical examination revealed right costovertebral angle tenderness without palpable masses. Serum tumor markers (AFP, CEA, CA-125, CA-19-9, and CA-15-3) were within normal limits. As shown in Figure 1(A), abdominal CT demonstrated a retroperitoneal mass (48 × 59 mm) between the aorta and inferior vena cava, predominantly composed of soft tissue density (∼40 HU), interspersed with several roundish hyperdense foci (∼59 HU) and patchy hypodense areas (∼20 HU). Besides, smooth, well-defined margins were observed. Contrast-enhanced magnetic resonance imaging (MRI) revealed a heterogeneous retroperitoneal mass (45 × 53 × 65 mm) positioned between the abdominal aorta and inferior vena cava (IVC), predominantly right-sided. The lesion demonstrated mixed signals (T1 isointense/hypointense and T2 hyperintense/heterogeneous), suggesting hemorrhagic and cystic components, with thick internal septations and restricted diffusion. The mass was well-demarcated from the pancreas and major vessels, and was seen to compress the IVC. Dynamic contrast-enhanced images showed moderate peripheral and septal enhancement, without obvious lymphadenopathy around the lesion or in the indicated regions (Figure 1(B) to (H)). The patient underwent a retroperitoneal mass resection. Under general anesthesia, the encapsulated mass was observed to be densely adherent to the IVC, with significant venous compression. Intraoperatively, the tumor was found situated between the abdominal aorta and the inferior vena cava, with a well-defined capsule. The intestines were protected using moist gauze pads to maintain a clear surgical field. Blunt dissection combined with an ultrasonic scalpel was employed to sharply dissect the space between the tumor and the abdominal aorta, during which several small feeding arteries were identified and transected after hem-o-lock clipping. Dissection was then continued toward the IVC side, where the tumor capsule was densely adherent to the IVC, resulting in significant compression and difficult separation. Scissors were used for sharp dissection along the tumor capsule to gradually separate it from the IVC. Three collateral venous tributaries were identified, clipped with Hem-o-locks, and transected. Eventually, the tumor was completely dissected free from the IVC. In addition, the resected tumor was predominantly composed of yellow solid tissue, with localized areas of cystic degeneration and hemorrhage. The capsule on the surface of the tumor remained intact and unruptured. Immunohistochemical (IHC) staining demonstrated positivity for calretinin, inhibin-α, and focal CD99, weak positivity for Wilms tumor, partial SMA reactivity, while all other markers (CK7, CD10, EMA, melan-A, Ki-67, CKpan, S-100, CK5/6, D2-40, CgA, and Syn) were negative. Histologically, the tumor exhibited monomorphic small cells with uniform cytology, no significant mitotic activity, and absence of necrosis (as shown in Figure 2(A) to (E)). Based on morphological and IHC findings, the diagnosis was consistent with a GCT.

Figure 1.

Imaging characteristics and longitudinal follow-up of a retroperitoneal mass. (A) Non-contrast abdominal CT showed a heterogeneous density mass (arrows) between the abdominal aorta and inferior vena cava, containing multiple round hyperdense foci. (B) T2-weighted fat-suppressed MRI revealed hypointense nodules (white arrow) and small cystic hyperintense areas (red arrows). (C) T1-weighted fat-saturated sequence demonstrated hypointense septations (arrows). (D) DWI exhibited restricted diffusion within thick septa. (E–G) The contrast-enhanced CT images of (E) arterial phase, (F) portal venous phase (G) delayed phase demonstrated marked persistent enhancement of thick septa within the lesion. (H) The contrast-enhanced MRI images of the coronal plane (portal venous phase). (I) Postoperative contrast-enhanced CT at 24-month follow-up demonstrated clear anatomical structures in the surgical region with no evidence of recurrence.

Figure 2.

Histopathological and immunohistochemical features of the tumor with vascular invasion. (A) Hematoxylin and eosin (HE) staining (100 ×) demonstrated microfollicular structures (Call–Exner bodies) with eosinophilic material. (B) HE staining (400 ×) revealed tumor cells displaying nuclear grooves (arrows) and scant cytoplasm. (C) Calretinin immunohistochemistry showed diffuse cytoplasmic positivity. (D) Inhibin-α cytoplasmic expression. (E) Intravascular tumor thrombus (arrow).

The patient received a postoperative combination chemotherapy regimen consisting of bleomycin (15,000 units), etoposide (150 mg), and cisplatin (105 mg). Follow-up evaluations were conducted at 1, 6, 18, and 24 months after surgery. MRI and contrast-enhanced CT scans showed clear retroperitoneal and pelvic structures, with no evidence of residual or recurrent lesions. There was no significant lymphadenopathy, and no signs of metastasis were observed in the liver, spleen, or spine, indicating a good postoperative recovery (Figure 1(I)).

Case 2

The patient is a female in her late sixties with a past medical history of ovarian GCT. Nine years ago, she underwent a total hysterectomy with bilateral salpingo-oophorectomy for ovarian GCT, followed by no adjuvant chemotherapy or radiotherapy. Eight years ago, due to recurrence presenting as a pelvic mass, she underwent partial small bowel resection with end-to-end anastomosis, and postoperative pathology revealed recurrent GCT. Postoperative pathology confirmed a GCT located between the ileum and sigmoid colon. She received four cycles of chemotherapy following that surgery (in the first month after surgery, the patient underwent the first cycle of chemotherapy with bleomycin 15 mg, cisplatin 20 mg, and etoposide 100 mg. In the second, third, and fourth months postoperatively, the patient underwent three additional cycles of chemotherapy with bleomycin 15 mg, cisplatin 30 mg, and etoposide 150 mg).

The patient was admitted to the First Affiliated Hospital of Ningbo University (Waitan Campus) with a chief complaint of melena for over 40 days in 2021. Physical examination revealed an abdominal surgical scar with no significant tenderness or palpable mass. Laboratory tests indicated severe anemia (RBC 2.47 × 10¹²/L, Hb 70 g/L, and HCT 0.22). Tumor markers, including AFP, CEA, and the CA series, were all within normal limits. Imaging studies demonstrated a quasi-round, heterogeneous pelvic mass measuring 47 mm × 40 mm with a CT attenuation value of 34 HU. The mass showed indistinct borders with the adjacent small intestine but did not cause bowel obstruction. Contrast-enhanced CT revealed progressive enhancement across three phases (94, 105, and 110 HU), with no enhancement seen in the central hypodense area (Figure 3(A) to (D)). Under general anesthesia, the patient underwent adhesiolysis, segmental resection of the ileum, and ileo-ileal anastomosis. Intraoperative findings revealed a tumor (∼50 mm × 70 mm) located 40 cm proximal to the ileocecal valve, arising externally to the intestinal wall. The mass encased the small bowel in an Ω-shaped configuration, with a localized “fish lip-like” ulcer on the intestinal wall and a fish-flesh appearance on the cut surface. Immunohistochemistry supported the diagnosis of metastatic ovarian GCT: Calretinin and Inhibin α were positive, the Ki-67 proliferation index was ∼20%, while other markers, including CK7 and CD10, were negative. Final pathology confirmed metastatic GCT (45 mm × 40 mm × 30 mm). Moreover, the patient underwent adhesiolysis, ileal segmental resection, and ileo-ileal anastomosis under general anesthesia. Intraoperatively, no obvious metastases were seen in the liver or spleen; the tumor was located at the outer wall of the ileum about 40 cm from the ileocecal valve, where the bowel formed an Ω-shaped loop encasing the lesion. A 15-cm ileal segment was resected and bloc with the tumor, followed by side-to-side anastomosis. Grossly, the specimen showed a tumor of about 50 × 70 mm arising from the serosal side, with a fish-lip-like mucosal defect and a gray-white, fish-flesh-like cut surface. Both longitudinal and circumferential margins were negative, one mesenteric lymph node showed no tumor involvement, and local bowel wall changes were characterized by diverticulum-like structures with inflammatory alterations.

Figure 3.

Imaging features and follow-up evaluation of a pelvic soft tissue lesion. (A) Non-contrast CT scan demonstrated a well-defined soft tissue density lesion adjacent to the pelvic bowel loops. (B–D) Contrast-enhanced CT scans (arterial, portal venous, and delayed phases, respectively) revealed mild heterogeneous but progressive enhancement of the lesion. (E) Follow-up contrast-enhanced MRI performed 6 months postoperatively showed clear architecture of the surgical site with no evidence of recurrence or metastasis. (F) Contrast-enhanced CT performed 36 months after surgery showed no thickening of the bowel wall at the surgical site, with clear surrounding anatomical structures and no evidence of recurrence or metastasis.

Postoperatively, the patient received six cycles of combination chemotherapy consisting of paclitaxel (210 mg) + carboplatin (500 mg) + bevacizumab (400 mg). At the 6-month follow-up, contrast-enhanced pelvic MRI and contrast-enhanced abdominal CT revealed no definitive evidence of recurrence or metastasis in the pelvic surgical bed, abdominal cavity, retroperitoneum, liver, spleen, pancreas, or bilateral kidneys (Figure 3(E) and (F)).

Discussion

GCT of the ovary is a rare, low-grade malignant tumor originating from the ovarian sex cord-stromal tissue. It accounts for 2%–5% of all ovarian tumors and 70% of sex cord-stromal tumors. ¹ Surgical resection is the mainstay of treatment. The prognosis is generally favorable, but the tumor is characterized by late recurrence and metastasis^{. 7} Traditional histopathological evaluation plays a central role in diagnosis; however, it may be limited in predicting recurrence risk or distinguishing AGCT from other ovarian tumors with overlapping morphology. In such cases, emerging molecular markers, such as microRNA profiles, including mir-202-3p and mir-199a-5p, have shown promise in improving diagnostic accuracy. ⁸ Nonetheless, clinical symptoms of recurrence often remain nonspecific and are closely related to the location and size of the lesion. The symptoms of recurrent GCTs vary depending on the location and size of the recurrence. Some patients may be asymptomatic in the early stages and later present with non-specific symptoms such as abdominal pain or bloating as the tumor enlarges. In addition to nonspecific symptoms, AGCTs are typically hypervascular and prone to hemorrhage. In some cases, spontaneous rupture of the tumor can result in hemoperitoneum, presenting as an acute abdomen and necessitating emergency surgical intervention. This vascular-rich nature further complicates imaging interpretation and underscores the need for timely diagnosis. ⁹ In Case 1, the patient presented with right flank pain due to the tumor being located in the right retroperitoneum. In Case 2, the recurrent tumor was located outside the ileal wall without mucosal involvement, and the patient developed melena, which was considered to be caused by a diverticulum with inflammatory changes. The recurrence rate of adult-type GCT varies greatly and may be associated with factors such as initial tumor stage, lesion size, age at onset, extent of surgery, and residual tumor after surgery. ¹⁰ The interval between initial surgery and recurrence is often long and variable, with a median recurrence time of 5–10 years. ⁵ Some patients may experience multiple or multi-site recurrences, most commonly in the pelvis or through peritoneal dissemination, while distant metastases to the lungs, brain, liver, kidneys, or adrenal glands are relatively rare.^11,12 In addition to clinical and surgical variables, certain histopathological features have been associated with unfavorable outcomes. Poorly differentiated, diffuse, or sarcomatoid variants of AGCT demonstrate more aggressive behavior and higher recurrence rates. Moreover, nuclear atypia and increased mitotic activity have been proposed as independent predictors of recurrence, suggesting a need for closer postoperative monitoring in such cases. ¹³ In Case 1, the patient experienced recurrence in the posterior abdominal compartment 15 years after the first surgery. In Case 2, the first recurrence occurred between the ileum and sigmoid colon one year after initial surgery, and a second recurrence occurred 8 years later on the outer wall of the ileum. Both recurrences were confined to the pelvic cavity.

Due to the frequent atypical symptoms of recurrent ovarian GCTs, elevated serum levels of CA125 can serve as a biomarker for monitoring tumor recurrence and treatment response.^3,11–14 In the present study, serum CA125 tumor marker levels remained within normal limits in both cases. Therefore, imaging modalities such as CT and MRI play a critical role in evaluating potential recurrence in ovarian GCTs. Imaging findings of recurrent adult-type GCTs are similar to those of the primary tumors, most commonly appearing as solid, solid-cystic, or cystic masses, with solid masses being predominant and often showing multiple cystic changes.^14–16 Multiloculated cystic masses with hemorrhagic components are characteristic features on MRI. ¹⁴ The shape of the lesion varies and may appear round, oval, or lobulated. Most lesions have smooth margins and a well-defined capsule. When the tumor size is small, the lesion is mainly solid or even completely solid. As the tumor increases in size, cystic changes tend to become more pronounced, often multifocal, with internal hemorrhage visible. The cyst walls often show thick, coarse septa of variable thickness, most of which are relatively thick. On contrast-enhanced imaging, the solid components demonstrate persistent enhancement. In Case 1, the imaging features of the recurrent GCT in the retroperitoneum on CT and MRI were consistent with the literature. In Case 1, the recurrent ovarian GCT located in the retroperitoneum manifested on imaging as a retroperitoneal mass demonstrating heterogeneous attenuation, predominantly solid in composition, with internal cystic degeneration and hemorrhage, exhibiting a lobulated contour and well-circumscribed margins. In contrast enhancement images, there was persistent enhancement of the solid components and internal septations, consistent with findings reported in the studies. Due to the long interval between recurrence and initial diagnosis, patients often forget their previous diagnosis, which may make preoperative diagnosis challenging and lead to misdiagnosis. Differential diagnoses for Case 1 should include retroperitoneal solid tumors that are prone to hemorrhage and cystic degeneration, such as leiomyosarcoma and ganglioneuroma. Thus, in Case 2, the two recurrences were located outside the intestinal wall in the pelvic cavity. Due to incomplete imaging data from the first recurrence, the second recurrence presented as a solid mass growing outside the ileal wall with mild cystic changes and no obvious hemorrhage. In the absence of a known medical history, the differential diagnosis should include gastrointestinal stromal tumors and exophytic gastrointestinal adenocarcinomas. Mayur reported an extremely rare collision tumor of recurrent ovarian GCT and colonic adenocarcinoma. ¹⁷

Ovarian GCTs generally carry a favorable prognosis, with surgical resection serving as the cornerstone of clinical management. However, even in early-stage disease, occult recurrence rates range from 20% to 30%.^18,19 Postoperative adjuvant chemotherapy can improve outcomes for patients with recurrent tumors.^20–23 Studies indicate that patients with Stage I disease have a 5-year survival rate exceeding 90%. ²¹ For young patients with early-stage disease desiring fertility preservation, fertility-sparing surgery is a viable option. ²⁴ Patient age at diagnosis, tumor stage, and the treatment approach for recurrence are important predictors of survival in ovarian GCT patients.^5,24,25

Conclusion

This study indicates that the timing and sites of ovarian GCT recurrence are unpredictable. Therefore, long-term and regular follow-up, even lifelong in some cases, is required during and after treatment to enable timely detection of recurrence and allow appropriate therapeutic intervention. The clinical symptoms of recurrent ovarian GCTs are nonspecific, and there are no distinctive laboratory markers. Imaging examinations can identify the tumor's location, extent, local invasion, and signs of recurrence or distant metastasis, thereby guiding clinical management strategies and ultimately improving patient outcomes.