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Department of Obstetrics and Gynaecology, Queen's University, Kingston, Ontario, CanadaDivision of Gynaecologic Oncology, Queen's University, Kingston, Ontario, Canada
DICER1 mutation has been linked to development of Sertoli-Leydig cell tumor and cystic nephroma, among other neoplasms.
Case
We present a unique case of recurrent ovarian Sertoli-Leydig cell tumor in a pediatric patient with a known DICER1 mutation and history of cystic nephroma. She underwent surgical staging and adjuvant chemotherapy, and her recurrences have been treated with chemotherapy, whole-abdomen radiation therapy, and further surgical debulking.
Conclusion
This report adds to the small body of evidence about this rare but unexpectedly highly aggressive tumor, especially in the recurrent setting, and reminds the reader of the importance of cancer diagnosis in this population.
Sertoli-Leydig cell tumors (SLCTs) are sex-cord stromal tumors primarily affecting females in the second and third decade. These rare tumors comprise less than 0.5% of all primary ovarian neoplasms.
Patients typically present with abdominal pain and virilization features, including voice change, hirsutism, clitoromegaly, and amenorrhea. Most SLCTs are unilateral, well-differentiated tumors that follow a benign course; moderately to poorly differentiated SLCTs are associated with poorer survival.
Heterologous components, including cartilage, skeletal muscle, carcinoid, and mucinous intestinal epithelium, are reported in 20% of cases, most commonly in the moderately and poorly differentiated groups.
Germline mutation in DICER1 has been linked to the development of SLCTs, cystic nephroma (CN), pleuropulmonary blastoma, multinodular goiter, and other rare benign and malignant tumors in a multi-tumor syndrome coined DICER1 syndrome.
DICER1-related gynecologic malignancies are exceptionally rare and tend to follow an aggressive clinical course. We report the case of a patient with a DICER1 mutation who initially presented with CN and 12 years later developed SLCT.
Case
A 14-year-old premenarchal female presented to the emergency department with abdominal pain of 3 months duration. She reported urinary frequency and straining. Her voice had deepened in the preceding months. Past medical history included CN, diagnosed at age 16 months, for which she underwent radical left nephrectomy with retroperitoneal dissection. Although CN is considered a major indication for germline DICER1 genetic testing,
Clinical exam revealed a normally developed, thin female (body mass index 19 kg/m2) with a deep voice and minimal clitoromegaly (the clitoris was not measured, but it appeared slightly longer than expected with normal width), without other virilizing features. Tanner stage was IV. She was admitted to the Pediatrics service, and Adolescent Gynaecology and Gynaecologic Oncology were consulted.
Ultrasound, CT, and MRI demonstrated a large inhomogeneously enhancing solid-cystic mass without pelvic lymphadenopathy, free fluid, or metastatic disease (Fig. 1A-B). CA-125 (59 kU/L, normal 0-35 kU/L) and AFP (293 ug/L, normal 0-10 ug/L) were elevated. LDH, bHCG, inhibin, testosterone, and androstenedione were normal. FSH and LH were suppressed (both < 1 IU/L).
Fig. 1(A) Axial vibe sequence pre-gadolinium (top) enhancement demonstrates an inhomogeneous mass (arrows), mostly lower signal intensity than muscle, with small ill-marginated areas of scattered high signal as well as irregular and focal areas of more marked low signal. Post-gadolinium (bottom) imaging demonstrates areas of prominent inhomogeneous enhancement. Areas of lower signal intensity on the pre-enhanced study have become better defined due to enhancing adjacent tissue. (B) The sagittal T2 midline image shows a large inhomogeneous mass with irregular regions of both high and low signal intensity effacing/displacing the uterus and dome of bladder. (C) Gross of the surface of the resected left ovarian mass showing a smooth surface with intraoperative surface defect. (D) Cut surface of the mass presents a heterogenous appearance with solid and cystic components, as well as areas of hemorrhage and necrosis. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Midline laparotomy, left salpingo-oophorectomy, and omental biopsy were performed. Small-volume ascites was present. The mass capsule ruptured during exteriorization, draining a small amount of serous fluid inside the abdomen. There was no visible metastatic disease, and the right ovary was grossly normal.
Pathology showed a hemorrhagic tumor with necrosis replacing the ovary (16 cm × 14 cm × 9 cm) (Fig. 1C-D). Histology revealed a moderately differentiated SLCT with heterologous cartilage and skeletal muscle elements (Fig. 2). Peritoneal washings, omental biopsy, and fallopian tube were negative for malignancy. FIGO stage was IC1 based on intraoperative rupture. Both germline and tumor genetic testing detected a mutation in the DICER1 gene with 2 variants. Variant 1 (c.5439G>T) was a missense mutation (p.Glu1813Asp) and has been reported as a hotspot mutation in ovarian SLCTs,
Fig. 2Histologic features: (A) The tumor exhibits an admixture of spindle cells, retiform-like tubules (not shown), and (B) pink Leydig-like cells. The presence of heterologous components showing (C) cartilage differentiation and (D) skeletal muscle, manifesting as spindle-celled elements with striations (arrow head). Immunohistochemically, the tumor showed (D) patchy positivity for calretinin and (F) inhibin. The skeletal muscle elements were positive for muscle-specific actin (not shown).
Menarche occurred after the patient's discharge from the hospital. Her care was led by Pediatric Oncology, and advice was sought from an expert in SLCTs. Adjuvant chemotherapy consisting of 4 cycles of bleomycin, etoposide, and cisplatin (BEP) was recommended but declined by the patient and her family due to concerns about fertility and nephrotoxicity in the setting of her solitary kidney.
Three months later, she presented with severe abdominal pain. MRI and ultrasound demonstrated likely recurrence, with multiple intra-abdominal masses, the largest measuring 4.2 × 6.3 cm (Fig. 3A-B). The right ovary and uterus were normal. No metastatic disease was identified on chest CT. AFP, which was previously elevated, was normal. She underwent laparotomy, adhesiolysis, tumor debulking, and appendectomy for an abnormal-appearing appendix. Histology showed a poorly differentiated tumor with heterologous elements and myoblastic differentiation, with involvement of the appendiceal serosa (Fig. 3C-D). The patient and her parents agreed to adjuvant chemotherapy. Reproductive Endocrinology was consulted before commencing chemotherapy, with a plan to evaluate ovarian function following treatment completion.
Fig. 3(A) Follow-up coronal T2 study demonstrates a new midline intraperitoneal inhomogeneous mass (arrows), mostly high signal, with irregular and nodular regions of lower signal intensity. (B) Follow-up axial T1-weighted post-gadolinium image demonstrates the inhomogeneously enhancing mass with irregular areas of lower signal, similar in pattern to the original mass. (C) Histology demonstrates sheets and sweeping fascicles of spindle cells, some of which show (D) rhabdomyoblastic differentiation with cytoplasmic striations (arrow head). Immunohistochemical stains (not shown) showed focal positivity for calretinin and inhibin.
After cycle 2 of a planned 4 cycles of BEP, MRI demonstrated a 5.5 × 2.2 cm cystic and solid mass in the location of the previous left salpingo-oophorectomy, concerning for disease progression on treatment. Pediatric Oncology at the Hospital for Sick Children in Toronto was consulted in conjunction with the previously consulted SLCT expert. Paclitaxel, ifosfamide, and cisplatin (TIP) treatment was recommended (Alliance for Clinical Trials in Oncology A031102, arm A). All 3 cycles were delivered. After cycle 2, MRI demonstrated some disease regression. Planned second debulking surgery followed, which consisted of laparotomy, significant adhesiolysis, total hysterectomy, right salpingo-oophorectomy, right hemicolectomy, low anterior resection, small bowel resection, and primary anastomosis. Pathology demonstrated a metastatic poorly differentiated SLCT with an extensive heterologous component, consisting of rhabdomyosarcoma differentiation. She received 1 further cycle of TIP after surgery.
Thereafter, our patient received whole-abdomen radiation therapy of 2400 cGy, followed by 4 cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). Post-VIDE imaging demonstrated a right lower quadrant lesion (1.2 cm), confirmed as recurrent disease on PET CT. The patient felt she had maximized her chemotherapy tolerance and opted for a third tumor debulking surgery, which is currently being arranged.
Conclusion
DICER1 syndrome is autosomal dominant with a haplo-insufficient inheritance pattern. It is strongly associated with SLCTs. Abdominal and pelvic ultrasound every 6 to 12 months has been proposed as a screening modality, beginning at age 8.
No recommendations exist about surveillance imaging intervals when a malignancy has already been diagnosed. Our patient could have benefited from early and frequent imaging after surgery to detect her recurrence before she became symptomatic. This unique case adds to the literature as it reinforces the aggressive nature and poor prognosis associated with DICER1-related SLCTs and reminds the reader of the importance of genetic testing for pathogenic germline variants. Unfortunately, this genetically linked cancer mostly affects the pediatric population as the median age at diagnosis is 14.5 years.
Following initial surgical staging, our patient experienced disease progression on first-line BEP. She was subsequently treated with TIP and VIDE chemotherapy, whole-abdomen radiation therapy, and subsequent debulking surgeries. There is no consensus on management of SLCTs due to their rarity. Initial treatment for SLCT consists of complete surgical excision. Platinum-based chemotherapy is recommended for patients beyond stage I, moderately to poorly differentiated tumors, or tumors containing heterologous elements. The ideal chemotherapy regimen in the recurrent setting remains unknown. Whole-abdomen radiation therapy was warranted for local control in this circumstance and targeted radiosensitive tumor components, such as rhabdomyosarcoma. Our case has added more evidence of multiple treatment modalities in the recurrent setting of SLCT.
In summary, DICER1-related SLCT is exceptionally rare. Both CN and SLCT are major indications that should prompt DICER1 germline testing. Surveillance and screening recommendations have been published, although the ideal interval for gynecologic screening has not been identified. The oncologic course and prognosis of DICER1-related SLCT is unlike that of sporadic SLCT, which is generally favorable. Due to our patient's short intervals between disease recurrences, we have provided various treatment modalities for this otherwise poorly described cancer. We hope that this case report can serve as a reminder to the reader of the importance of genetic screening for disease prevention.
Consent
The patient described in this case report gave permission for her experience to be published.
Author contributions
All authors contributed to the creation of this manuscript. The manuscript was drafted by Authors 1 and 2, who share first authorship. Radiology figures and expertise were supplied by Author 3. Pathology figures and expertise were supplied by Author 4. Author 5 is the supervising author and provided gynecologic oncology expertise. All authors participated in the editing of the manuscript.
Conflict of Interest Statement
The authors report no proprietary or commercial interest in any concept discussed in this article.
References
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Relative frequency of primary ovarian neoplasms: a 10-year review.
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