Renal cell carcinoma with FH gene deletion is a rare subtype of renal cell carcinoma (RCC). These tumors are usually metastatic at presentation and typically solitary and unilateral, unlike other familial RCC syndromes that are characterized by bilateral multifocal tumors (1). Many patients who presented with local or distant metastasis succumbed to the disease <5 years from the initial diagnosis (2). There had been few reports about ultrasonographic imaging of metastasis of renal cell carcinoma with FH gene deletion. This case reported one of the features of metastasis of renal cell carcinoma with FH gene deletion of a male patient 7 months after undergoing radical nephrectomy.

A 36-year-old man presented with a left lumbar mass of 1-month duration without obvious inducement 7 months after undergoing radical nephrectomy. The present study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of our hospital. In another hospital, the tumor in the left kidney was diagnosed as renal malignancy preoperatively, which was proved to be primary FH gene-deficient renal cell carcinoma after radical nephrectomy. Seven months after the operation, the patient came to our hospital because of multiple metastases in a large number of organs diagnosed by MRI, which were hard, mobilized poorly, and progressively enlarged. The tumor in the abdominal wall near the left waist was resected in our hospital, and targeted therapy and immunotherapy were performed postoperatively. The patient’s parents are alive, his brothers or sisters are in good health, and there is no family or genetic history.

Physical examination showed that the shape of the abdomen was normal and that there was no tenderness or rebound pain. During palpation of the waist of the left kidney area, a hard and poorly mobilized lump that was as big as an egg was found.

Clinical biochemical test (normal values are given in parentheses) showed that creatinine (68–108) was 151 μmol/L, estimated glomerular filtration rate (56–122) was 50.46 ml/min/1.73 m², cystatin-C (0.51–1.09) was 1.64 mg/L, uric acid (240–490) was 572 μmol/L, triglyceride (0.29–1.83) was 4.42 mmol/L, anion gap (12.0–20.0) was 22.2 mmol/L, and calcium (2.11–2.52) was 2.54 mmol/L.

Fumarate hydratase-deficient renal cell carcinoma (FH-d RCC) is a rare subtype of RCC associated with fumarate hydratase (FH) gene and hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. HLRCC syndrome is a rare autosomal dominant disorder related to germline mutations of FH gene, which increases the risk of developing skin leiomyoma, uterine leiomyoma, and renal cell carcinoma (5, 6). In the latest 2016 edition of WHO renal tumor classification, HLRCC-associated RCC is listed as a new independent subtype of RCC (7).

In humans, the FH protein is encoded by FH gene, which is located on the q-arm of chromosome 1 (8). FH gene participates in the mitochondrial tricarboxylic acid cycle (9). In tumor tissues, heterozygous deletion of FH gene locus often results in complete loss of FH function. The most immediate effect is the accumulation of intracellular fumarate, which at high concentrations directly alters various cellular signaling pathways (8). Pyruvate has difficulty completing the tricarboxylic acid cycle in the cell, and the process of oxidative phosphorylation and energy supply inside the mitochondria is correspondingly difficult to unfold, and the energy supply can only rely on anaerobic glycolysis, which in turn leads to pseudo-hypoxia. There is an inextricable relationship between tumor development and pseudo-hypoxia (10).

At present, most studies focus on clinicopathology, molecular analysis, treatments, and so on of FH-d RCC. Yang et al. (11) investigated the multidetector computed tomography (MDCT) features of FH-d RCC, and Nikolovski et al. (12) evaluated the imaging features of FH-d RCC on CT, MRI, and FDG PET. However, the clinical imaging findings of metastasis of FH-d RCC, such as imaging of ultrasound, are rarely involved in reports.

FH-d RCC is different from ordinary familial RCC. It is highly aggressive, prone to local progression and metastasizing, and has a poor prognosis (13, 14). Studies by Muller et al. and Pan et al. showed that the median survival for metastatic FH-d RCC was about 18 months (15, 16). In this case, the patient underwent radical nephrectomy because of FH-d RCC, and tumors have been recurring and metastasizing in multiple organs 7 months after the operation. By using axitinib for the targeted therapy (200 mg ivggt q21d) and sintilimab (5mg bid) for the immunotherapy, the basic conditions of the patient improved gradually. To date, the patient has undergone 14 months (a total of 18 cycles of sintilimab) of treatment with this regimen, and the patient was very satisfied with our treatment plans.

The imaging features of the tumor or metastasis are unclear as a result of scarcity. The metastases of recurring lesions were reported, which displayed features by ultrasonography. In this case, by grayscale ultrasound, the mass features a septum in the cystic component or patchy anechoic areas in the hypoechoic mass. Relatively circumscribed margin, relatively regular shape, and heterogeneous echo in the mass could provide some clues for the diagnosis. In color Doppler and power Doppler, tiny punctiform and linear blood flow signals may indicate some characteristics of blood supply in the tumor. In contrast-enhanced ultrasound, the features of tumor perfusion, in this case, are distinctive. Hyperenhancement of the whole lesion was observed in the arterial phase, which contradicts ultrasonographic findings in color Doppler and power Doppler. Meanwhile, the tumor detected heterogeneous enhancement with fireworks-like enhancement, which showed punctiform hyperenhancement firstly from the center of the mass and then spread outward like fireworks in spite of patchy anechoic areas, which should present non-enhancement normally.

FH-d RCC is an infrequent renal malignant tumor, which is difficult to diagnose before the operation, and multimodal ultrasonography for the disease is even rarer. In this case, multimodal ultrasonographic features of metastatic lesions were described in detail, including grayscale, color Doppler, power Doppler, and contrast-enhanced ultrasound. Regrettably, there is no multimodal ultrasonography for the primary foci of FH-d RCC in this case report, and more cases are needed to obtain a more comprehensive understanding of the disease.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by West China Hospital, Sichuan University. The patients/participants provided their written informed consent to participate in this study.

XZ, YZ, and YL contributed the part of ultrasound. PS, ZL, and HZ provided the clinical case. MZ, NC contributed the part of pathology. JY contributed the part of MRI. RH contributed the part of PET/CT. DC acted as corresponding author. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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