A 54-year-old female patient with no medical or family history presented to the urology department for evaluation of an incidentally detected left renal mass. Laboratory examination showed serum tumor markers of alpha-fetoprotein (AFP): 2.72 ng/mL [normal < 7.0 ng/mL], carcinoembryonic antigen (CEA), 1.8 ng/mL (normal < 5.2 ng/mL), carbohydrate antigen (CA) 19 − 9, 9.0 U/mL (normal < 34.0 U/mL), and CA 125, 28.4 U/mL (normal < 35.0 U/mL). A computed tomography (CT) scan of the abdomen was performed and revealed a left renal mass measuring 13×10 cm at maximum dimensions. The mass showed heterogeneous enhancement and irregular margins (Fig. 1A). The patient underwent an open radical nephrectomy for diagnosis and treatment.
Gross examination of the specimen revealed a tumor measuring 14.2x9.8 cm. Macroscopically, the tumor consisted of two components: a yellowish hard lesion (lesion 1) and a white-grayish soft lesion (lesion 2). The tumor had an irregular margin and revealed suspicious invasion into perinephric fat and adrenal tissue (Fig. 1B). Microscopically, the yellowish hard lesion (lesion 1) showed morphologic features typical of ChRCC (Fig. 1C). The white-grayish soft lesion (lesion 2) showed large cells with marked nuclear pleomorphism and bizarre mitotic figures (Fig. 1D). Tumor cells invaded into perinephric fat and the adrenal gland (Fig. 1E). In a limited area, there were some foci showing the transition between lesion 1 and lesion 2 (Fig. 1F). In lesion 1, immunohistochemical staining showed strong positivity for keratin 7 (KRT7) (Fig. 2A). Lesion 1 was also positive for Hale’s colloidal iron stain (Fig. 2B). Lesion 1 and lesion 2 showed opposing staining for KIT (CD117) and vimentin (Fig. 2C and 2D). KRT showed diffuse strong positivity in lesion 1 (right side, Fig. 2E) and focal positivity in lesion 2 (Fig. 2F). We performed targeted next-generation sequencing (NGS)-based genomic profiling for lesion 1 and lesion 2 using the NGS gene panel Oncomine® Comprehensive Assay Plus. The lesions shared an insertion-deletion (indel) variant; RNF46 (c.349_350delCGinsA, p.Arg117ThrfsTer41). Copy number analysis identified identical chromosomal loss in 1, 2, 6, 10, 13, 15, 17, 21, X in both lesions.
Based on the above findings, the pathological diagnosis confirmed the mass to be a ChRCC with sarcomatoid change. To evaluate the efficacy of immunotherapy, immunohistochemical staining for programmed cell death ligand 1 (PD-L1) was performed. Lesion 1 and lesion 2 showed opposing staining for PD-L1. PD-L1 was negative in the ChRCC component and more than 10% positive in the sarcomatoid area (Fig. 2G and 2H).
Although the two components shared some genetic changes, there were also significant differences. The sarcomatoid component exhibited distinct genetic features not seen in the ChRCC component. Copy number analysis confirmed chromosomal gains in 1, 2, 6, 10, 13, 15, 17, 21, X along with chromosomal loss in 1, 2, 6, 10, 13, 15, 17, 21, X in the ChRCC component (Fig. 3A and 3B). Additionally, several genomic alterations were identified: single nucleotide variants (SNV)/indel variants in TP53 (c.1176_1179delAGAC, p.Ter394IlefsTer27), TSC2 (c.1675G > A, p.Asp559Asn), NF1 (c.60 + 1G > A, p.?), and CDKN1B (c.384_385insAG, p.His129SerfsTer17) and a MET-CAPZA2 fusion mutation.
After diagnosis, the patient underwent chemotherapy with nivolumab and cabozantinib. Despite adjuvant treatment, the patient experienced tumor progression followed by multiple organ metastasis including lung, liver, bone, and lymph nodes. The patient’s condition deteriorated, and she died within one month.