Current Oncology · 9 authors, 1 centre
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This case report describes the first pediatric patient with a germline NF2 mutation who developed renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), a rare and aggressive kidney cancer. The patient achieved a complete response to platinum-based chemotherapy, which is unusual for this typically fatal disease. This finding suggests that SMARCB1-deficient malignancies should be considered in NF2 patients presenting with tumors outside the usual spectrum.
**Background:** Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder caused by mutations in the NF2 gene on chromosome 22q11.2, encoding the tumor suppressor merlin. It predisposes to central nervous system tumors such as schwannomas, meningiomas, and ependymomas. Renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) is a rare, aggressive renal cancer characterized by loss of SMARCB1 (INI-1) protein expression, typically occurring in young individuals with sickle hemoglobinopathies. The SMARCB1 gene is also located on chromosome 22q11.2, centromeric to NF2. This case presents the first pediatric patient with a germline NF2 mutation who developed RCCU-MP, suggesting a potential 4-hit mechanism involving both NF2 and SMARCB1.
**Methods:** This is a single case report of a Hispanic female with a known germline NF2 mutation (c.-854-??46+??deletion) who presented at age 15 with a right renal mass. Diagnostic workup included CT, MRI, PET scans, and two renal biopsies. Immunohistochemistry was performed on biopsy tissue. Hemoglobin electrophoresis ruled out sickle cell trait or disease. Next-generation sequencing (NGS) of the tumor was performed on 134 genes for somatic mutations and 47 genes for copy number variations. The patient was treated with a chemotherapy regimen of cisplatin 70 mg/m² on day 1, gemcitabine 1000 mg/m² on days 1, 8, and 15, and paclitaxel 80 mg/m² on days 1, 8, and 15, followed by right nephrectomy and retroperitoneal lymph node sampling.
**Key Results:** The renal mass measured 8.1 × 5.4 × 8.7 cm on MRI, with retroperitoneal lymphadenopathy (largest node 4.1 × 2 cm) and bilateral pulmonary nodules. Biopsy showed high-grade tumor with discohesive rhabdoid cells, positive for pankeratin and PAX8, and negative for CK7, CK20, GATA3, CDX2, TTF1, CAIX, ERG, S100, CD34, CD30, SMA, desmin, OCT3/4, and CD163. SMARCB1/INI-1 was lost by immunohistochemistry (lymphocytes served as positive internal control). Hemoglobin electrophoresis was negative for sickle hemoglobinopathies. NGS of the tumor did not identify somatic mutations or copy number variants in NF2 or other genes. After 2 cycles of chemotherapy, the renal mass decreased to 6.9 × 6.6 cm, and lymph nodes and pulmonary nodules decreased in size. After 4 cycles, nephrectomy and lymph node sampling showed no viable tumor. The patient completed 6 cycles total (with carboplatin 400 mg/m² substituted for cisplatin due to renal function decline), and end-of-therapy PET/CT and MRI showed no evidence of disease. She developed chronic kidney disease stage 2/3a, hypertension, hearing loss, and multiple infections during treatment.
**Clinical Implications:** This is the first reported case of pediatric RCCU-MP in a patient with a germline NF2 mutation. The patient achieved a complete response to platinum-based chemotherapy, which is notable given the median survival of 13 months and 29% response rate for RMC/RCCU-MP. The close proximity of NF2 and SMARCB1 on chromosome 22q11.2 suggests a potential 4-hit mechanism (germline NF2 mutation plus somatic alterations in both genes) as a possible etiology. Clinicians should consider SMARCB1-deficient malignancies (RMC/RCCU-MP, atypical teratoid rhabdoid tumor, malignant rhabdoid tumor) in NF2 patients presenting with tumors outside the usual spectrum, and pathological evaluation should include SMARCB1 immunohistochemistry.