Fumarate hydratase-deficient renal cell carcinoma with sarcomatoid features: a case report

Introduction

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and highly aggressive subtype of renal cell carcinoma (RCC), resulting from germline or somatic mutations in the FH gene. FH-RCC can be associated with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), a genetic disorder caused by germline mutations in the FH gene, which is characterized by cutaneous and uterine smooth muscle tumors as well as renal malignancies (1,2). Sarcomatoid renal cell carcinoma (SRCC) can develop in any type of RCC, with sarcomatoid differentiation being a dedifferentiated pattern of tumor growth. The greater the proportion of sarcomatoid components, the lower the tumor’s degree of differentiation, which is associated with a more aggressive and treatment-resistant clinical course (3). The co-occurrence of FH gene loss and sarcomatoid differentiation in RCC is extremely rare. In this case, we present a patient who presented with persistent lower back pain. Routine blood biochemical markers and renal function were normal, and there were no elevated tumor markers. Further investigation through positron emission tomography-computed tomography (PET-CT), bone metastatic lesion biopsy, and renal biopsy led to the diagnosis of sarcomatoid RCC with widespread bone metastases. Genetic testing confirmed a heterozygous germline missense mutation (p.N188I) in exon 5 of the FH gene. After six months of systemic therapy with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), the activity of multiple bone metastases was suppressed, which allowed for the patient to undergo a renal tumor debulking procedure. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-25-40/rc).

Case presentation

A 36-year-old male patient was admitted for the management of persistent lower back pain lasting for 5 months. Enhanced computed tomography (CT) imaging revealed a mass in the lower pole of the left kidney with multiple bone metastases (Figure 1). Positron emission tomography-computed tomography (PET-CT) performed in December 2023 showed a 43 mm × 32 mm mass in the lower pole of the left kidney, accompanied by a soft tissue mass in the right first rib. Extensive bone metastases were identified, including lesions in the right first rib, bilateral sixth ribs, T2 vertebral body, T4 right transverse process, T11 accessory, T12–L4 vertebrae, L5 accessory, left ischium, bilateral iliac bones, right femoral head, and the upper segments of both femora. A biopsy of an L3 lesion was performed, with immunohistochemistry (IHC) staining revealing positivity for CK (pan), CK8/18, Vimentin, Pax8, INI-1, partial positivity for CD138, and negativity for Desmin, S-100, CD21, CD45, TTF-1, CK7, CK20, CD10, GATA3, S100P, SSTR2. The Ki-67 index was 80%, p53 was 3+, and PDL1 was expressed in 10% of the cells, EBER by ISH was negative. A left kidney biopsy showed poorly differentiated renal carcinoma, with a predominant sarcomatoid pattern (95%) (Figure 2). IHC analysis was positive for CK (pan), Vimentin, and Pax8, with partial positivity for GATA3 and negativity for CK7, CD10, NKX3.1, and Ki-67 (80%). High-throughput sequencing of the tumor tissue identified a heterozygous germline missense mutation (p.N188I) in exon 5 of the FH gene. The patient’s blood biochemical indicators and tumor markers were normal, with no documented history of cutaneous leiomyoma. His father had a history of early lung cancer surgery 2 years ago, and he denied a family history of genetic diseases. Based on the above features, the patient was diagnosed with sarcomatoid renal carcinoma of the left kidney [cT1bN1M1, stage IV, American Joint Committee on Cancer (AJCC) 8th edition]. Given the extensive destruction of thoracic and lumbar vertebral metastases accompanied by severe lower back pain and impending paraplegia risk, we first performed percutaneous vertebroplasty (PVP) at T12 and L3 to stabilize the spine. Subsequently, the patient developed right upper limb numbness and signs of neurocompression, prompting stereotactic body radiotherapy (SBRT) targeting the right first rib metastasis [prescription dose: 30 Gy in 3 fractions to the planning target volume (PTV)]. Following these interventions, the patient regained normal ambulation, and neurocompression symptoms resolved. A systemic treatment regimen was initiated, comprising ipilimumab (100 mg) + nivolumab (360 mg) + axitinib (5 mg twice daily), combined with denosumab (administered every 28 days) for bone protection. After two alternating cycles of nivolumab plus ipilimumab, maintenance therapy with nivolumab and axitinib was continued (every 21 days). Treatment-related adverse events included mild rash, trace proteinuria, and manageable hypertension. Serial CT evaluations demonstrated a marked reduction in the left renal mass (Figure 1). By June 2024, PET-CT revealed complete suppression of metabolic activity in most bone metastases, with residual activity persisting in the left femoral greater trochanter and right iliac bone. These sites subsequently underwent SBRT (30 Gy/3 fractions). Following radiotherapy, percutaneous cryoablation of the renal tumor combined with renal artery chemoembolization was performed to address the primary lesion. The patient continued immunotherapy and targeted therapy, with no evidence of local or systemic recurrence during follow-up. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Longitudinal imaging evaluation of a renal mass before and after targeted therapy. (A) Axial contrast-enhanced CT showed a heterogeneous enhancement of the renal mass in the lower pole of the left kidney and combined vertebral destruction. (B) After ICI and TKI treatments, the left kidney mass has shrunk. (C) Coronal sections showing an abnormally dense lesion in left renal mass. (D) After ICIs and TKIs treatments, the kidney mass has shrunk significantly. The red arrows indicate the critical lesion area. CT, computed tomography; ICI, immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor.

Figure 2 Hematoxylin and eosin staining. (A) Pathological image of left kidney biopsy under 100× magnification; (B) L3 lesion biopsy under 400× showing the tumor cells are short spindle-shaped, arranged in fascicles and irregular patterns, with focal epithelioid features.

Discussion

FH-RCC is a rare and aggressive malignancy defined by the World Health Organization (WHO) in 2022. The incidence is low, at approximately 1 in 100,000, and untreated patients typically survive less than 13 months (4). FH is located on chromosome 1q43, and its encoded enzyme, fumarate hydratase, is crucial in the tricarboxylic acid (TCA) cycle. A defect in this gene causes the accumulation of fumarate, which inhibits prolyl hydroxylase and leads to continuous activation of hypoxia-inducible factors (HIFs), promoting tumor growth and metastasis (5-7). FH-RCC is highly invasive, with most patients presenting with distant metastases to the bones, lungs, adrenal glands, liver, or lymph nodes (8). FH-RCC is strongly associated with IHC markers FH and S-(2-succino)-cysteine (2SC), typically characterized by loss of FH expression and/or positive 2SC staining. However, genetic testing remains the diagnostic gold standard for confirmation (9).

Currently, there is no established standard treatment for FH-RCC. Sequencing of 19 FH-RCC genomes and transcriptomes revealed high immunogenicity in both primary and metastatic lesions, suggesting that patients might benefit from ICIs (10). Further research with single-cell sequencing of patients undergoing ICI therapy showed that patients with germline mutations performed better in PFS compared to those with somatic mutations. while combining ICI with TKIs resulted in improved overall response rates and disease control compared to TKI monotherapy (11). FH-RCC also exhibits activated angiogenesis signaling, and while anti-angiogenic monotherapy has limited efficacy, the use of ICI combined with TKI may result in longer PFS (12). Therefore, a combination of targeted therapy, anti-angiogenesis therapy, and immunotherapy may become the standard of care for these patients. For patients with inherent immune escape or resistance, therapies targeting other immune checkpoints, such as TIM-3, TIGIT, and BTLA, or drugs inhibiting proliferation and cell cycle regulation, could represent future therapeutic directions (13,14).

SRCC is a unique histologic subtype of RCC, characterized by high levels of undifferentiated sarcomatoid components, with median overall survival (mOS) ranging from 6 to 13 months median progression-free survival (mPFS) from 3.5 to 5.8 months (15). In the case presented, most of the renal biopsies showed sarcomatoid features. The emergence of ICIs has greatly impacted the treatment and prognosis of SRCC. Clinical trials, such as Checkmate-214 and 016, demonstrated improved mPFS, complete response rate (CRR), partial response rate (PRR), and mOS with nivolumab and ipilimumab compared to sunitinib. Additionally (16-18), KEYNOTE-426 showed better outcomes with pembrolizumab combined with axitinib compared to sunitinib for advanced RCC (19).

Based on the molecular and pathological characteristics of this case, combination therapy with ICI and TKI is likely to provide therapeutic benefits. However, surgical resection remains the preferred treatment for early-stage RCC. SBRT has demonstrated efficacy in treating oligometastatic or locally progressive lesions. However, in advanced RCC with multiple bone metastases, the optimal timing for local treatment remains difficult to determine. The patient in this case tolerated a series of treatments well and basically met expectations. The mutation of the FH gene and the sarcomatoid differentiation observed in this patient led to widespread bone metastasis at the time of diagnosis. The combination of ICI and TKI could serve as a potential conversion therapy. Nonetheless, this study represents a single case report, and further clinical trials are needed to explore and validate the timing and significance of primary tumor debulking surgery.

Conclusions

Currently, there is no standard treatment regimen for advanced RCC with FH gene deletion and sarcomatoid differentiation. However, the combination of ICIs and TKIs may offer significant benefits to these patients, providing an opportunity for local tumor debulking surgery and potentially serving as a translational therapeutic approach. We advocate for an individualized, multidisciplinary approach to the management of such cases, involving the expertise of urologic surgery, oncology, radiation therapy, interventional radiology, and pathology. This collaborative strategy, which integrates systemic therapies with local treatments for metastatic tumors (such as surgery, SBRT, and ablation), can help develop an optimal treatment plan for patients with advanced metastatic RCC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-25-40/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-25-40/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-25-40/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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