This patient was a 26-year-old man with a 1-month history of intermittent back pain. He went to a hospital because he had asymptomatic gross hematuria. He consulted our hospital because a left renal tumor had been detected by echography and computed tomography (CT). CT revealed a 72-mm tumor at the upper pole of the left kidney, well-circumscribed, that was slightly enhanced heterogeneously in the corticomedullary phase and excretory phase but showed no strong enhancement in the corticomedullary, as is usually observed in clear cell RCC. In addition, multiple osteolytic changes were confirmed in bone (Fig. 1).
A CT-guided biopsy was performed on the left renal tumor, and osteoplastic changes of the second lumbar spine were noted. The left kidney tumor biopsy specimen showed bland tubular structures with focal clear cells, oncocytic changes, and cytoplasmic vacuolation accompanied by necrosis and spindle cells. The stroma had basophilic to eosinophilic mucin, aggregates of plasmacytes, and hyalinization. An immunohistochemical analysis revealed that tumor cells were diffusely positive for CK7, AMACR, and AE1/AE3. The histology and immunohistochemical profile were consistent with MTSCC of the kidney (Fig. 2). The bone biopsy specimen show massive coagulation necrosis with bland tubular structures with focal oncocytic changes, accompanied by spindle cells. These features were similar to those of left renal malignant tumor (Fig. 3). He was diagnosed with MTSCC of the kidney with bone metastases (cT2aN0M1) and an ‘intermediate risk’ according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (he had two prognostic factors [anemia and <1 year since the diagnosis]).
Combination therapy (once every 3 weeks, intravenously) of nivolumab (240 mg/body) and ipilimumab (1 mg/kg) was administered as the first‑line therapy. At the same time, 120 mg of denosumab was subcutaneously injected every 4 weeks, and palliative radiotherapy was also performed for bone metastases to control the bone pain in the first cervical vertebra and second lumbar vertebra. After 4 cycles of the combination of nivolumab plus ipilimumab, CT revealed that the non-enhanced area was increased in the left renal tumor, and sclerotic changes had appeared in the bone metastases. Nivolumab monotherapy (once every 2 weeks, 240 mg/body) was subsequently continued. He developed immune-related adverse events (irAEs) after four courses of nivolumab (diarrhea, Grade 3). CT showed no thickening of the intestinal tract. However, colonoscopy showed a slightly edematous mucosa and poor vascular visibility, and a colon biopsy showed colonic mucosa with mild chronic inflammatory infiltration. The diarrhea improved immediately after prednisolone was started at 1 mg/kg/day to control the AEs. Subsequently, nivolumab was restarted, and CT to evaluate the therapeutic effect after eight courses revealed that the left renal tumor had shrunk slightly, and the non-enhanced area was even further increased, as were the osteosclerosis changes in the bone metastases (Fig. 4). Therefore, the patient underwent cytoreductive nephrectomy (laparoscopic radical nephrectomy) after nine courses.
He resumed nivolumab treatment 2 weeks later after surgery and has been receiving nivolumab (480 mg/body) and denosumab every 4 weeks. At present, the observation period is quite short at 12 months, but no progressive disease or irAEs has been observed.
Grossly, the tumor at the left kidney was mostly necrotic with hemorrhaging and white-toned solid parts (Fig. 5). Histologically, the sections showed biphasic proliferation of a papillary or tubular pattern with atypical epithelial cells and clear or eosinophilic cytoplasm as well as diffuse proliferation of atypical spindle-shaped cells, accompanied by inflammatory cell infiltration and necrosis. Nucleoli were prominent and easily visualized at low-power magnification, showing an International Society of Urological Pathology grade was 3. Mucin was observed in the interstitium of the tumor on alcian blue staining (Fig. 6). An immunohistochemical analysis revealed that the tumor cells of the tubular/spindle components were positive for AE1/AE3(+/+), EMA(+/+), vimentin(+/+), PAX8(+/+), AMACR(+/+) in the resected specimen after nivolumab plus ipilimumab.
In addition, the biopsy of the pretreatment renal tumor and bone metastasis and the resected specimen after nivolumab plus ipilimumab was evaluated by immunostaining of programmed cell death ligand 1 (PD-L1), cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), CD4, and CD8. The PDL-1 expression was higher in the spindle components than in the tubular components, but CD4- and CD8-positve T cells showed greater infiltration in the tubular components than in the spindle components (Fig. 7, 8). Furthermore, CD-4- and CD-8-positive T cells in both components of the resected specimen showed greater infiltration than they had at the pretreatment biopsy of the renal tumor and bone metastases (Fig. 2, 3). There was no marked difference in the CTLA-4 expression between the spindle and tubular components in the resected specimen (Fig. 7, 8).
The nonsense variant S562* in the FBXW7 gene was reported. The tumor mutation burden was 2.52 mutations per megabase, and microsatellite instability was absent.