Pathological diagnosis and therapeutic management of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma

Abstract

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an autosomal dominant disorder caused by germline loss-of-function mutations in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of highly aggressive renal cell carcinoma (RCC), often associated with poor prognosis. We report the case of a 31-year-old Japanese woman diagnosed with unresectable RCC with nodal and adrenal metastases. Histopathological analysis of a biopsy specimen suggested papillary RCC; however, cancer genome profiling revealed a presumed germline pathogenic variant in FH. Subsequent germline testing confirmed the FH mutation, establishing the diagnosis of HLRCC-associated RCC. Cascade genetic testing identified several asymptomatic relatives carrying the same germline FH variant. Immunohistochemistry (IHC) revealed unexpected positivity for FH and S-(2-succinyl) cysteine in tumor cells. Although FH loss is a hallmark of HLRCC-associated renal cell carcinoma, rare cases, such as this one, may exhibit retained FH expression on IHC. The patient was treated with a combination of lenvatinib and pembrolizumab, achieving a sustained partial response for 18 months following treatment initiation.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13691-025-00811-9.

Introduction

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an autosomal dominant disorder caused by germline loss-of-function mutations in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and a significantly increased risk of highly aggressive renal cell carcinoma (RCC), often associated with poor prognosis [1]. Detection of a germline FH variant is essential for a definitive diagnosis of HLRCC. Histologically, these tumors are initially identified as FH-deficient RCC. However, the diagnosis of HLRCC-associated RCC (HLRCC-RCC) typically requires an integrated assessment of pathological features in conjunction with clinical indicators, such as early age of onset, characteristic symptoms, and a positive family history. In most cases, histopathologic evaluation precedes the confirmation of a genetic diagnosis. Immunohistochemistry (IHC) for FH and S-(2-succinyl) cysteine (2SC) is recommended by the World Health Organization (WHO) to support the diagnosis [2]; however, such testing is not universally available in all clinical settings. This is likely attributable to the historically limited recognition of FH-deficient RCC and HLRCC. HLRCC generally presents at a young age, with a median age at diagnosis of 37 years, and the estimated cumulative risk of RCC is approximately 15% [3, 4]. The prognosis of HLRCC-RCC is extremely poor, with previous studies indicating a median overall survival of less than 68 months [1]. Considering this unfavorable prognosis, early and accurate diagnosis is critical. Although treatment options for metastatic RCC have improved substantially with the introduction of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), clinical evidence regarding their efficacy in HLRCC-RCC remains limited. We emphasize the diagnostic value of IHC and report the clinical efficacy of combined TKI and ICI therapy in a patient with HLRCC-RCC.

Case presentation

A 31-year-old Japanese woman was referred to our clinic with sudden-onset right-sided lumbago without any apparent precipitating factor. Her medical history was notable for untreated hypertension and uterine leiomyoma. There was no significant family history of cancer; however, her mother had undergone surgery for uterine leiomyoma. Contrast-enhanced computed tomography of the abdomen revealed a right RCC with a hemorrhagic cyst, as well as lymph-node and contralateral adrenal metastases (cT4N1M1) (Fig. 1). Following hospitalization, her symptoms improved with blood pressure management and bed rest. As the renal tumor was deemed unresectable, a percutaneous biopsy was performed to determine the histologic subtype. The initial pathological diagnosis suggested papillary RCC; however, a differential diagnosis of FH-deficient RCC remained a consideration. IHC staining for FH could not be performed due to the unavailability of FH antibody at our institution. Subsequent cancer genome profiling (FoundationOne® CDx) of the biopsy specimen identified a presumed germline pathogenic variant in the FH gene: c.1094G > A (p.Ser365Asn), with a variant allele frequency of 70.5%. Based on these findings, IHC was performed at an external specialized laboratory, revealing unexpected positivity for FH protein (ab9590; Abcam, Cambridge, UK) and strong positivity for 2SC (CRB2005017_2; Biosynth, Staad, Switzerland) (Fig. 2). Subsequently, the patient received genetic counseling and underwent targeted germline testing, which confirmed the presence of the FH c.1094G > A (p.Ser365Asn) variant. This led to a definitive diagnosis of HLRCC. Cascade genetic testing was conducted in her family, revealing that her mother and younger brother also carried the same germline FH variant (Fig. 3). Both are currently undergoing regular imaging surveillance for early detection of HLRCC-RCC.

Fig. 1.

Computed tomography before treatment. The right kidney contains a hemorrhagic cyst, and extensive metastases are present along the inferior vena cava and aorta

Fig. 2.

Histopathological features of right renal tumor biopsy. a Hematoxylin and eosin staining of the tumor. Tumor cells cover the surface of the papillary architecture and are multilayered in some areas. The nuclei of the tumor cells are darkly stained, and large nucleoli with halos are seen in some cells. The cytoplasm is acidophilic and vacuolated. No foam cells are present in the stroma. b Within the tumor, capillary endothelial cells are positive for fumarate hydratase staining. c S-(2-succinyl) cysteine is strongly positive in the cytoplasm and nucleus

Fig. 3.

Pedigrees. (E) indicates the blood relatives who underwent genetic testing. (E +) indicates FH germline variant c.1094G > A (p.Ser365Asn) positivity. HT hypertension, UL uterine leiomyoma

First-line treatment with a combination of lenvatinib and pembrolizumab was initiated for unresectable metastatic RCC. Lenvatinib was started at 10 mg/day and subsequently reduced to a maintenance dose of 8 mg/day due to Grade 1 hepatic dysfunction and Grade 2 hand-foot syndrome. No adverse events related to pembrolizumab were observed. At 18 months following treatment initiation, the combination therapy remains ongoing, with imaging demonstrating a sustained partial response and a tumor volume reduction of over 80% (Fig. 4). Cytoreductive nephrectomy is being considered upon achieving further tumor shrinkage.

Fig. 4.

Computed tomography. Eighteen months after the initiation of lenvatinib and pembrolizumab, the primary tumor and metastases around the inferior vena cava and aorta had markedly shrunk

Discussion

Our study emphasizes key diagnostic and therapeutic considerations in HLRCC-RCC; it serves as an instructive example of the diagnostic challenges posed by HLRCC-RCC and emphasizes the potential clinical benefit of combination therapy with a TKI and ICI.

A clear understanding of the distinction between HLRCC-RCC and FH-deficient RCC is essential, as confusion between the two terms persists. In the 2016 WHO classification, HLRCC-RCC—defined by diagnostic FH deficiency—was recognized as a distinct tumor entity [5]. Since then, several studies have identified FH deficiency in numerous cases previously labeled as “unclassified high-grade renal carcinomas,” “tubulocystic carcinoma with dedifferentiated foci,” “type 2 papillary carcinomas,” and “collecting duct carcinomas” [6–8]. Therefore, the term FH-deficient RCC is now preferred to describe renal tumors exhibiting compatible histomorphology, negative FH-IHC, positive 2SC-IHC, and pathogenic FH variants in the tumor, particularly when the clinical or family history of cutaneous or uterine leiomyomas is absent and germline testing has not been performed [9]. In other words, once FH-IHC negativity is confirmed, the appropriate diagnosis is FH-deficient RCC, rather than HLRCC. This distinction underscores that the presence of a germline FH mutation is essential for a definitive diagnosis of HLRCC. However, in our study, FH-IHC was unexpectedly positive despite the confirmed germline FH mutation. Notably, the c.1094G > A (p.Ser365Asn) variant was previously reported in a single case as pathogenic [10]. This missense variant affects the p.Ser365 residue of FH. Other variants that disrupt this residue have been classified as pathogenic [11–13]. This indicates that the residue is clinically important and that variants disrupting this residue are likely to cause disease. For these reasons, this variant is classified as pathogenic. The retained FH-IHC may reflect preservation of antigenicity despite the presence of an amino acid substitution that disrupts enzymatic function. This functional impairment was suggested by the marked accumulation of 2SC, supporting the diagnosis of FH-IHC-positive FH-deficient RCC. In addition, PolyPhen-2 [14], a bioinformatic tool that predicts the impact of amino acid substitutions based on protein 3D structure, yielded a high score for this variant, indicating structural and functional alteration of the FH protein (Supplementary Fig. 1). Several studies have documented retained FH-IHC staining in genetically confirmed HLRCC cases, indicating that the sensitivity of FH-IHC is not 100% [1, 2, 15, 16]. This observation is clinically significant, as reliance on FH-IHC alone may result in misdiagnosis. It is therefore imperative to emphasize that FH-IHC and 2SC-IHC should be performed in the pathological evaluation of suspected FH-deficient RCC or HLRCC-RCC, in accordance with WHO recommendations [17]. Had FH-IHC been available at our institution during the initial workup, this case might have been misclassified.

Reports indicate that the prevalence of cutaneous leiomyoma in patients with HLRCC exceeds 70% [1, 10, 18]. Although our patient underwent examination by a dermatologist, no cutaneous leiomyoma was identified. However, the presence of cutaneous leiomyoma is a clinically important clue leading to the diagnosis of HLRCC.

The prognosis of HLRCC-RCC is extremely poor, with a reported median overall survival of 18 months and death typically occurring within 6 years [1]. By contrast, in one study of patients with FH-deficient RCC, 39% of patients died of the disease and 26% showed disease progression after mean follow-up of 27 months [19]. Both FH-deficient RCC and HLRCC are highly malignant and active tumors. The clinical behavior of FH-deficient RCC and HLRCC are similar [19, 20]. Furthermore, it is entirely possible that past reports of FH-deficient RCC may have included cases of latent HLRCC. Therefore, we discuss herein the efficacy of drug therapy encompassing both FH-deficient RCC and HLRCC. Xu et al. [21] reported outcomes in 48 patients with FH-deficient RCC (including HLRCC-RCC) treated with TKIs and ICIs, observing a median treatment duration of 10–12 months and an objective response rate of 33%. They also demonstrated that the objective response rate was 8.8% with TKI monotherapy, indicating superior treatment outcomes with combination therapy including ICIs. The efficacy of combination therapy with bevacizumab and erlotinib for HLRCC-RCC has been reported in a recent phase 2 study [22] (Table 1). In Japan, the number of reported HLRCC cases has been gradually increasing, accompanied by growing evidence regarding treatment outcomes in metastatic disease [23–27] (Table 2). Notably, one case achieved complete response with the combination of ipilimumab and nivolumab [23]. This is particularly significant, as the efficacy of dual ICI therapy (ICI + ICI) in HLRCC-RCC had not been previously reported. A single-center study reported treatment outcomes of 10 patients with metastatic FH-deficient RCC treated with TKIs and ICIs. The mean and median follow-up durations were 12.6 and 17.3 months, respectively, with a 3-year overall survival rate of 63% [24]. Although this represents the largest cohort reported in the Japanese population to date, it is important to note that only 40% of the patients underwent genetic testing. Therefore, it remains unclear whether these findings in FH-deficient RCC can be directly extrapolated to HLRCC-RCC.

Table 1.

Summary of published cases of HLRCC-RCC and FH-deficient RCC treated with ICI and TKI combination

	RCC type	Treatment	N	Median duration of treatment (mo)	Best overall response, n (%)
					CR	PR	SD	PD
Xu et al. [21]	FH-deficient RCC	ICI/TKI combination	48	12	16 (33)	25 (52)	0 (0)
		Anti-PD1 + pazopanib	5	12	2 (40)	2 (40)	1 (20)
		Anti-PD1 + cabozantinib	15	12	6 (40)	8 (53)	1 (6)
		Anti-PD1 + lenvatinib	4	9.5	2 (50)	1 (25)	1 (25)
		Anti-PD1 + axitinib	24	11	6 (25)	14 (58)	4 (17)
		Bevacizumab + Erlotinib	20	8	6 (30)	9 (45)	5 (25)
Srinivasan et al. [22]	HLRCC	Bevacizumab + Erlotinib	43	19.3*	2 (5)	29 (67)	12 (28)	0 (0)

ICI immunocheckpoint inhibitor, TKI tyrosine kinase inhibitor, PR partial response, CR complete response, SD stable disease, PD progressive

^*Median duration of response (mo)

Table 2.

Summary of published cases of drug therapy for HLRCC in Japan

	TNM category	Treatment	Duration of treatment (mo)	Best overall response
Iribe et al. (2021) [23]	cT3aN0M0	Nivo + Ipi	24	CR
Yonese et al. (2020)	pT3aN2M1	CN → radiation (bone mets) → Axi → Nivo → Axi → Evero → Nivo	48	PR
Tsuboi et al. (2024) [26]	cT3aN0M0	Nivo + Ipi → Cabo → Axi → Nivo	27	PR
Nohara et al. (2024) [27]	pT3aN2M1	CN → Nivo + Cabo	6	No recurrence
Present case	cT4N1M1	Lenvatinib + pembrolizumab	18	PR

ICI immunocheckpoint inhibitor, TKI tyrosine kinase inhibitor, CN cytoreductive nephrectomy, Nivo nivolumab, Ipi ipilimumab, Axi axitinib, Evero everolimus, Cabo cabozantinib, CR complete response, PR partial response

In the future, blood relatives who test positive for a germline FH mutation will require regular surveillance for RCC. HLRCC-RCC is often associated with distant metastases, even when presenting as a solitary tumor of less than 3 cm. Additionally, because up to 50% of patients already have metastases at diagnosis, early detection of RCC through imaging is crucial [28]. Furthermore, HLRCC lesions exhibit high glycolysis, because fumarate hydrolase is a key enzyme in the citric acid cycle. Therefore, fluorodeoxyglucose positron emission tomography combined with computed tomography is very useful for staging of patients with HLRCC [29]. Several studies strongly recommend RCC screening in carriers of pathogenic FH variants [18, 30]. Considering reports of RCC onset as early as 8 years of age, annual magnetic resonance imaging surveillance is recommended—even in pediatric carriers—to facilitate early detection and timely surgical intervention [4, 31].

With increasing recognition of HLRCC in Japan, a growing number of patients and carriers are being identified. The diagnosis of HLRCC-RCC is critical for affected individuals and their at-risk relatives. In young patients with active RCC—particularly those diagnosed with papillary renal cell carcinoma, tubulocystic carcinoma with dedifferentiated features, or collecting duct carcinoma—HLRCC-RCC should be included in the differential diagnosis. When HLRCC is suspected, a detailed family history must be obtained. In facilities without the ability to measure FH and/or 2SC antibodies, consultation with a specialized renal cancer pathology facility and/or consideration of FH germline testing is recommended when FH-deficient RCC or HLRCC-RCC is suspected based on clinical and pathological evaluation.

In conclusion, we presented a rare case of HLRCC-RCC with positive FH-IHC staining. Although the presence of a germline FH mutation is essential for the definitive diagnosis of HLRCC, combining FH-IHC with 2SC-IHC is recommended to avoid diagnostic misinterpretation, as IHC is often used as a preliminary step prior to genetic testing. We demonstrated the clinical efficacy of combination therapy with lenvatinib and pembrolizumab in HLRCC-RCC. Continued accumulation of case reports is essential to establish clearer diagnostic and therapeutic strategies for this rare entity.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

FH

Fumarate hydratase

2SC

S-(2-succinyl) cysteine

HLRCC

Hereditary leiomyomatosis and renal cell carcinoma syndrome

RCC

Renal cell carcinoma

IHC

Immunohistochemistry

TKI

Tyrosine kinase inhibitor

ICI

Immune checkpoint inhibitor

WHO

World Health Organization

Data availability

The datasets generated and analyzed during the current study are not publicly available due to patient privacy restrictions but are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human rights

Informed consent for publication was obtained from the patient described in this report.