Fumarate hydratase-deficient renal cell carcinoma

Highlights

1. FH-deficient RCC is an aggressive renal cancer subtype linked to HLRCC syndrome and FH gene mutations.
2. Common symptoms include flank pain, hematuria, and abdominal pain, often presenting with advanced disease.
3. Radiological features include large, unilateral, cystic tumors with infiltrative margins.
4. Pathological characteristics involve varied patterns and prominent eosinophilic nucleoli, driven by fumarate accumulation.
5. Treatment includes radical nephrectomy for localised cases and combination therapies like bevacizumab and erlotinib for metastatic disease.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common type of kidney cancer. It makes up about 90% of all kidney cancers. There are three main types: clear cell RCC (ccRCC), which is about more than 70-75% of cases; papillary RCC (pRCC), which is 10-15%; and chromophobe RCC (chRCC), which is around 5%. RCC cases are increasing globally, with an estimated 434,000 new cases and 155,000 deaths in 2022¹. This rise is mostly due to more people getting abdominal scans, which can find small kidney tumours early. Risk factors include obesity, smoking, and high blood pressure. Genetic research has found many mutations linked to RCC, helping us understand its development and find new treatments².

Fumarate hydratase (FH) deficiency is very important in a rare and aggressive type of RCC called FH-deficient RCC. It is related to hereditary leiomyomatosis, and renal cell carcinoma (HLRCC) syndrome caused by FH gene mutations. The FH enzyme is essential in the Krebs cycle. Without it, fumarate builds up in the body, which can lead to cancer through changes in genes and metabolism. FH-deficient RCC often shows up with advanced disease. Common symptoms are abdominal or flank pain, blood in the urine, and a palpable mass. This type of RCC usually affects younger adults, around 40-50 years old, and compared with women, it is slightly more prevalent in men^3–5. This review aims to provide a complete overview of FH-deficient RCC, focusing on its genetic, clinical, and pathological features to improve understanding and patient care.

Figure 1. Pathogenesis of FH-deficient RCC

Epidemiology

FH-deficient RCC commonly presents in middle-aged adults. In a study of 32 patients, the median age at presentation was 43 years, ranging from 18 to 69. The male-to-female ratio was approximately 2.2:1, indicating a higher prevalence in males. Specific data on the ethnic distribution of FH-deficient RCC is limited due to its rarity. However, as with many rare genetic syndromes, it is likely underreported across various populations. The hereditary nature suggests it can affect diverse ethnic groups without a clear predisposition⁶.

Clinical Presentation

FH-deficient RCC often presents with advanced or metastatic disease at diagnosis. Common symptoms include flank pain, hematuria, and abdominal pain. Patients may also have a personal or family history of uterine or cutaneous leiomyomas. This cancer subtype is aggressive, frequently showing a mix of histologic growth patterns and often presenting symptoms related to metastasis rather than a localised renal mass. Early and comprehensive diagnostic evaluation is crucial for effective management^4,6. Despite the aggressive nature and late presentation of FH-deficient RCC, there is a growing interest in identifying biomarkers for early diagnosis. One promising candidate is S-(2-succinyl)cysteine (2SC), which accumulates due to FH deficiency and can be detected through immunohistochemistry. However, the application of 2SC as a routine diagnostic marker requires further validation. Additionally, circulating tumour DNA (ctDNA) and metabolomic profiling are being explored as non-invasive tools for early detection, though these approaches are still in the experimental stages.

Radiological Features

FH-deficient RCC exhibits aggressive radiological features. On computed tomography (CT) and magnetic resonance imaging (MRI), these tumours are typically unilateral, large, and have infiltrative margins. In many cases, they frequently contain significant cystic components, constituting more than 75% of the tumour volume. Contrast-enhanced imaging reveals heterogeneous enhancement patterns, while MRI shows heterogeneous T2 signals and diffusion restriction in solid components, indicating high cellularity.

Commonly, these tumours invade the renal sinus fat and the hilar collecting system with renal vein thrombus. F-18-Fluorodeoxyglucosepositron emission tomography (FDG PET)/CT scans demonstrate high metabolic activity, reflecting the tumour's dependence on glycolysis, a distinguishing feature from other RCC subtypes. These detailed imaging characteristics aid in the early identification and aggressive management of FH-deficient RCC​^7,8.

Pathological Features

FH-deficient RCC typically displays a variety of architectural patterns, including papillary, tubular, solid, and microcystic formations. The tumours are generally unilateral and solitary, presenting with a gross appearance that ranges from light brown to whitish. Commonly, these tumours show infiltrative margins and often invade surrounding structures such as the renal sinus and perinephric fat. In some cases, sarcomatoid changes and rhabdoid features are present, contributing to the aggressive nature of the disease. A hallmark cytological feature is the presence of prominent, eosinophilic nucleoli surrounded by a clear halo resembling cytomegaloviral (CMV) inclusions​.

FH-deficient RCC is associated with HLRCC syndrome, characterised by mutations in the FH gene. These mutations lead to an accumulation of fumarate, which acts as an oncometabolite, promoting tumorigenesis. The tumours often present at an advanced stage, frequently with metastases to organs such as bones, lungs, liver, and lymph nodes. Microscopically, the tumours display a range of growth patterns, often mixed within the same tumour, and commonly exhibit necrosis and haemorrhage​.

Immunohistochemistry (IHC) plays a critical role in diagnosing FH-deficient RCC. Tumours typically show a loss of FH protein expression, confirmed by negative staining for FH on IHC. Additionally, detecting succinate proteins (S-(2-succinyl) cysteine, 2SC) using specific antibodies can be a robust biomarker for FH deficiency. These succinate proteins accumulate due to the loss of FH activity, and their presence is highly specific to FH-deficient tissues. IHC for 2SC has proven to be a sensitive and specific method for identifying FH-deficient RCC, even without direct genetic testing​^6,9–17.

These detailed morphological, pathological, and immunohistochemical features are crucial for accurately diagnosing and managing FH-deficient RCC, distinguishing it from other RCC subtypes.

Genomic and Molecular Features

FH-deficient RCC is characterised by mutations in the FH gene, which encodes the Krebs cycle enzyme fumarate hydratase. These mutations can be germline, leading to HLRCC syndrome, or somatic in sporadic cases. Germline FH mutations are found in approximately 70-90% of individuals with HLRCC, including missense, nonsense, frameshift, and splicing variants. Notably, FH mutations result in the loss of enzymatic activity, leading to the accumulation of fumarate, an oncometabolite that promotes tumorigenesis through various pathways​. The inactivation of FH in tumour cells results in a pseudohypoxic state by stabilising hypoxia-inducible factor 1-alpha (HIF-1α), which drives the transcription of genes involved in angiogenesis, glycolysis, and other pathways that support tumour growth. This metabolic shift is known as the Warburg effect, where cells rely heavily on glycolysis for energy production, even in the presence of oxygen. Accumulated fumarate can inhibit α-ketoglutarate-dependent dioxygenases, including those involved in histone and DNA demethylation, leading to epigenetic modifications that further drive cancer progression.

Molecular diagnostics for FH-deficient RCC include genetic testing for FH mutations and IHC staining for FH protein. Loss of FH protein expression in tumours is indicative of FH deficiency. Additionally, S-(2-succinyl) cysteine (2SC), a byproduct of fumarate accumulation, is a specific biomarker for FH-deficient tumours. These diagnostic tools are critical for identifying patients with FH-deficient RCC and guiding appropriate treatment strategies^11,18–24.

Recent studies have also shown that FH-deficient tumours exhibit upregulation of antioxidant response genes and suppression of the homologous recombination DNA repair pathway, making these cells vulnerable to specific therapeutic strategies, such as poly (ADP-ribose) polymerase (PARP) inhibitors.

FH-deficient RCC is characterised by a low somatic mutation burden but frequent somatic copy number alterations (SCNAs). Key SCNAs include losses at 1p, 8q, and 10p, and gains at 4p and 7q. FH mutations lead to epigenetic reprogramming, including a CpG island methylator phenotype (CIMP), contributing to tumorigenesis. These epigenetic alterations affect genes related to tumour suppression and DNA repair, offering potential therapeutic targets, such as immune checkpoint inhibitors and demethylating agents¹².

In summary, the genomic and molecular features of FH-deficient RCC underscore its unique pathogenesis driven by metabolic reprogramming and epigenetic alterations, providing distinct diagnostic and therapeutic opportunities.

Management of FH-Deficient RCC

The management of FH-deficient RCC often involves a multimodal approach, with radical nephrectomy being the standard for localised tumours due to their aggressive nature. Systemic therapies, including VEGF inhibitors and mTOR inhibitors, have shown varying degrees of efficacy in metastatic cases. Retrospective studies have demonstrated the potential benefit of antiangiogenic agents. Building on these findings, current prospective trials are exploring combinations of targeted therapies and immunotherapies, offering hope for more effective treatment strategies in the future.

For localised HLRCC-associated renal tumours, the National Comprehensive Cancer Network (NCCN) guidelines recommend total radical nephrectomy due to the aggressive nature of these tumours. Surveillance of renal tumours is generally not recommended. Patients with confirmed HLRCC should undergo annual MRI or CT scans of the abdomen with and without IV contrast starting at ages 8-10 years.

Srinivasan et al. conducted a phase II study investigating the combination of bevacizumab and erlotinib in patients with advanced HLRCC or sporadic pRCC. The study included subjects with histologically confirmed advanced HLRCC or sporadic pRCC, with a median age of 44 years. Participants were treated with bevacizumab (10 mg/kg every two weeks) and erlotinib (150 mg/day). The rationale for this combination is based on their complementary mechanisms: bevacizumab inhibits vascular endothelial growth factor (VEGF), thereby reducing tumour blood supply, while erlotinib targets epidermal growth factor receptor (EGFR), inhibiting tumour cell proliferation. The study reported an objective response rate (ORR) of 72% and a median progression-free survival (PFS) of 21.1 months, with the median overall survival (OS) not reached at the time of analysis. In this study, the ORR was specifically reported for patients with FH-deficient RCC. For the HLRCC group, the ORR was 72.1% (95% CI 57.2–83.4), whereas the sporadic group exhibited an ORR of 35% (95% CI 22.1–50.6). This distinction emphasises the varying response rates between hereditary and sporadic forms of this rare cancer subtype. Treatment-related adverse events (AEs) included hypertension (64%), proteinuria (36%), diarrhoea (34%), and rash (30%), with manageable grade 3-4 toxicities. This study, presented at the 2020 ASCO Annual Meeting, demonstrates the efficacy and manageable safety profile of the bevacizumab and erlotinib combination in treating advanced HLRCC​²⁵.

Building on the promising results from the Srinivasan et al. (ASCO 2020) study²⁵, a new phase II trial is evaluating the combination of bevacizumab, erlotinib, and atezolizumab in patients with advanced HLRCC-associated RCC or sporadic pRCC. This open-label, multicentre study includes adult and paediatric patients with histologically confirmed advanced HLRCC-associated or sporadic pRCC, aged ≥12 years, with an ECOG performance status ≤2. Patients with up to two prior VEGF-targeted therapies and no previous PD-1 or PD-L1 inhibitor treatment are eligible. The primary endpoint assesses the complete response rate according to RECIST 1.1, with secondary endpoints including safety, ORR, disease control rate (DCR), PFS, and OS. Key exploratory endpoints involve evaluating immunologic modulation²⁶. This study is currently ongoing (NCT04981509).

A retrospective study by Choi et al. analyzed the efficacy and safety of bevacizumab plus erlotinib in Korean patients with HLRCC-associated RCC²⁷. The study included 10 patients with confirmed FH germline mutations treated at three academic hospitals. The median age at diagnosis was 41 years, and the majority of patients had locally advanced or metastatic disease. Bevacizumab was administered at 10 mg/kg every two weeks and erlotinib at 150 mg/day. The ORR was 50%, with a median PFS of 13.3 months and a median OS of 14.1 months. AEs were generally manageable, though one patient experienced fatal gastrointestinal bleeding²⁷.

Also, there are case reports about the combination of bevacizumab and erlotinib. In one case report by Tomar et al., a 42-year-old female with FH-deficient RCC achieved extended remission using this combination. The patient, who presented with a large renal mass and multiple distant metastases, received 46 cycles of treatment over 23 months. Despite experiencing grade 3 acneiform rash and an episode of acute calculous cholecystitis, the patient's tumour showed significant regression on follow-up CT scans, and she maintained stable disease until the last follow-up²⁸.

Lucia Carril-Ajuria et al. conducted a retrospective study to evaluate the efficacy of different systemic therapies in patients with FH-deficient RCC²⁹. The study included 24 patients from multiple centres in France and Spain, with 21 patients receiving systemic therapy. The therapies evaluated included cabozantinib, sunitinib, other antiangiogenics (sorafenib, pazopanib, and axitinib), erlotinib-bevacizumab (E-B), mTOR inhibitors (mTORi), and immune checkpoint blockers (ICBs). The ORR were 50% for cabozantinib, 43% for sunitinib, 63% for other antiangiogenics, 30% for E-B, 0% for mTOR inhibitors, and 18% for ICBs. The median time-to-treatment failure (TTF) was significantly higher for antiangiogenics (11.6 months) compared to mTOR inhibitors (4.4 months) and ICBs (2.7 months). The study concluded that antiangiogenics might be superior to ICBs and mTOR inhibitors in treating FH-deficient RCC, suggesting a preference for these therapies in managing this aggressive cancer subtype²⁹.

In a study by Gleeson et al., the therapeutic responses of 32 patients with FH-deficient RCC were evaluated. The mTOR and VEGF inhibitor combination demonstrated the highest efficacy, with an ORR of 44% and a DCR of 77%. Monotherapies with VEGF and mTORi had lower ORRs of 20% and 0%, respectively, and ICBs had an ORR of 0% and a DCR of 38%. Among 27 evaluable patients, the median PFS was 8.7 months, with the mTORi/VEGF combination achieving the longest median PFS at 10.7 months. For OS, 28 patients were included, showing a median OS of 21.9 months. The mTORi/VEGF combination also led to the longest median OS of 33.0 months, compared to 30.0 months for ICBs, 13.2 months for VEGF monotherapy, and 8.2 months for mTORi monotherapy. These findings highlight the mTORi/VEGF combination as an effective treatment in extending PFS and OS for patients with FH-deficient RCC ³⁰.

Sotés et al. published another case report discussing the combination of pembrolizumab and axitinib in a patient with HLRCC. The patient, an 18-year-old male with advanced RCC, demonstrated a significant partial response after two months of therapy, with a reduction in the size of the retroperitoneal node and resolution of other metastatic lesions. This combination therapy resulted in an OS of 20 months and disease-free survival of 15 months, highlighting the potential efficacy of pembrolizumab and axitinib in managing this rare and aggressive cancer subtype³¹.

A recent phase II trial led by Ritesh R. Kotecha et al. evaluated the efficacy of talazoparib and avelumab in patients with genomically defined metastatic kidney cancer, specifically including those with FH-deficient RCC. The study included eight patients in the cohort for FH- or succinate dehydrogenase (SDH)-deficient RCC, four of whom had FH-deficient RCC. These patients had previously received at least one ICB or a VEGF inhibitor. The primary endpoint was the ORR by Immune Response Evaluation Criteria in Solid Tumors at four months. No objective responses were observed in the FH-deficient RCC cohort. Two patients achieved stable disease (SD) as the best response, with a median PFS of 1.2 months and a median OS of 8.6 months. The most common treatment-related AEs included fatigue (61%), anaemia (28%), and nausea (22%). Grade 3-4 AEs were reported, but no grade 5 events occurred¹⁸. This study highlights the challenges in treating FH-deficient RCC, indicating that while the combination of talazoparib and avelumab is tolerable, it does not provide significant clinical benefits in this patient population.

CONCLUSION AND DISCUSSION

This review has highlighted key aspects of FH-deficient RCC, an aggressive and rare subtype linked to HLRCC syndrome. The comprehensive analysis included epidemiological data, clinical presentation, radiological and pathological features, genomic and molecular characteristics, and various treatment responses. Significant findings include the unique metabolic reprogramming and epigenetic alterations due to FH deficiency, which drive the pathogenesis of this aggressive cancer.

FH deficiency results in the accumulation of fumarate, an oncometabolite, leading to metabolic and epigenetic changes that promote tumorigenesis. This unique pathogenic mechanism underscores the aggressive nature of FH-deficient RCC and its tendency to present at an advanced stage with a poor prognosis. Stabilising hypoxia-inducible factor 1-alpha (HIF-1α) due to FH inactivation leads to increased angiogenesis and glycolysis, highlighting potential therapeutic targets.

For localised HLRCC-associated renal tumours, the NCCN guidelines recommend total radical nephrectomy due to the aggressive nature of these tumours. Surveillance of renal tumours is generally not recommended. The combination of bevacizumab and erlotinib has shown promising results for metastatic disease. Other treatment strategies, such as mTOR/VEGF combinations, have also demonstrated efficacy, with a median OS of 33.0 months in evaluable patients. However, monotherapies and checkpoint inhibitors have shown limited success, underscoring the need for more effective treatment strategies.

Patients with confirmed HLRCC should undergo annual MRI or CT scans of the abdomen with and without IV contrast starting at ages 8-10 years. Follow-up for relapsed or stage IV disease includes physical exams every 6-16 weeks, laboratory evaluations per therapeutic requirements, and imaging every 6-16 weeks, adjusted based on disease progression and patient status.

While significant progress has been made in understanding and treating FH-deficient RCC, ongoing research and clinical trials are crucial to developing more effective and targeted therapies to improve patient outcomes. The rarity of this condition poses challenges in conducting large-scale clinical trials, highlighting the need for collaborative research efforts. Improving early detection through genetic screening and regular follow-up can potentially improve outcomes for patients with HLRCC.

Potential Areas for Future Research

Exploring novel therapeutic targets that exploit the metabolic vulnerabilities of FH-deficient tumours.Developing and testing combination therapies that can effectively manage this aggressive cancer subtype.Conducting large-scale, multicentre trials to validate the efficacy of promising treatments and improve patient outcomes.Further understanding of the molecular pathways involved in FH deficiency to identify additional biomarkers for early detection and targeted therapy.

CONFLICT OF INTEREST

Advisory boards: Yüksel Ürün has served on the advisory board for Abdi-İbrahim, Astellas, AstraZeneca, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen ilaç, Gilead, GSK, Janssen, Merck, MSD, Novartis, Pfizer, Roche. Travel, honoraria or consultation fees: Yüksel Ürün received honoraria or has served as a consultant for Abdi-İbrahim, Astellas, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen İlaç, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, Roche

FUNDING

No funding was received for this work.

ACKNOWLEDGEMENTS

I am grateful to Emre Yekedüz, MD for his critical review and graphic design.

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Posted on 17 October 202418 October 2024