The Prevalence and Radiologic Features of Renal Cancers Associated with FLCN, BAP1, SDH, and MET Germline Mutations

Abstract

Purpose

To investigate the prevalence of FLCN, BAP1, SDH, and MET mutations in an oncologic cohort and determine the prevalence, clinical features, and imaging features of renal cell carcinoma (RCC) associated with these mutations. Secondarily, to determine the prevalence of encountered benign renal lesions.

Materials and Methods

From 25 220 patients with cancer who prospectively underwent germline analysis with a panel of more than 70 cancer-predisposing genes from 2015 to 2021, patients with FLCN, BAP1, SDH, or MET mutations were retrospectively identified. Clinical records were reviewed for patient age, sex, race/ethnicity, and renal cancer diagnosis. If RCC was present, baseline CT and MRI examinations were independently assessed by two radiologists. Summary statistics were used to summarize continuous and categorical variables by mutation.

Results

A total of 79 of 25 220 (0.31%) patients had a germline mutation: FLCN, 17 of 25 220 (0.07%); BAP1, 22 of 25 220 (0.09%); SDH, 39 of 25 220 (0.15%); and MET, one of 25 220 (0.004%). Of these 79 patients, 18 (23%) were diagnosed with RCC (FLCN, four of 17 [24%]; BAP1, four of 22 [18%]; SDH, nine of 39 [23%]; MET, one of one [100%]). Most hereditary RCCs demonstrated ill-defined margins, central nonenhancing area (cystic or necrotic), heterogeneous enhancement, and various other CT and MR radiologic features, overlapping with the radiologic appearance of nonhereditary RCCs. The prevalence of other benign solid renal lesions (other than complex cysts) in patients was up to 11%.

Conclusion

FLCN, BAP1, SDH, and MET mutations were present in less than 1% of this oncologic cohort. Within the study sample size limits, imaging findings for hereditary RCC overlapped with those of nonhereditary RCC, and the prevalence of other associated benign solid renal lesions (other than complex cysts) was up to 11%.

Keywords: Familial Renal Cell Carcinoma, Birt-Hogg-Dubé Syndrome, Carcinoma, Renal Cell, Paragangliomas, Urinary, Kidney

© RSNA, 2024

See also commentary by Choyke in this issue.

Summary

Hereditary renal cell carcinoma associated with germline mutations in FLCN, BAP1, SDH, and MET genes was present in less than 1% of a large cohort of oncologic patients and radiologically overlapped with its nonhereditary counterpart.

Key Points

• ■ FLCN, BAP1, SDH, and MET germline mutations were present in less than 1% of an oncologic cohort of more than 25 000 patients.

• ■ The most prevalent renal cell carcinoma (RCC) histologic subtype for FLCN, BAP1, SDH, and MET mutations was unclassified RCC (three of four, 75%), clear cell RCC (three of four, 75%), SDH-deficient RCC (six of nine, 67%), and papillary RCC (one of one, 100%), respectively.

• ■ The radiologic features of hereditary RCC at CT and MRI in the 18 patients diagnosed with RCC overlapped with those of patients with nonhereditary RCC, and the prevalence of encountered benign renal lesions was up to 11% for oncocytomas and angiomyolipomas.

Introduction

Hereditary renal cell carcinoma (RCC) accounts for 5%–8% of all malignant renal tumors (1). To date, the National Comprehensive Cancer Network recognizes seven hereditary RCC syndromes (with their respective mutated genes): Von Hippel–Lindau syndrome (VHL), Birt-Hogg-Dubé syndrome (FLCN), tuberous sclerosis complex (TSC1-2), hereditary leiomyomatosis and RCC (FH), BAP1 tumor predisposition syndrome (BAP1), hereditary paraganglioma/pheochromocytoma syndrome (SDHAF2, SDHB, SDHC, and SDHD, henceforth together referred to as SDH), and hereditary papillary renal carcinoma (MET) (2). While the syndromes related to VHL and TSC1-2 mutations have been studied extensively, and a research group recently published about the syndrome related to FH mutation (3), the clinical and radiologic features of the remaining four syndromes related to FLCN, BAP1, SDH, and MET genetic mutations have not been systematically reported (4–6).

These four mutations are considered rare. FLCN mutation has an estimated prevalence of two cases per 1 000 000 people (7). It is mainly associated with hybrid oncocytic/chromophobe or chromophobe RCCs (8). It is also associated with some reported papillary and clear cell RCCs and some benign renal lesions, such as angiomyolipomas and oncocytomas (8). BAP1 mutation has an unknown prevalence in the general population (5). It is associated predominantly with clear cell RCC (9). The prevalence of SDH mutation in the general population has been reported to be two to eight cases per 1 000 000 people (10), and it is associated with SDH-deficient RCC (11). Finally, germline MET mutation has an estimated incidence of one in 10 000 000 people (12). Of note, unlike other hereditary RCC syndromes, hereditary papillary renal carcinoma (MET mutation) is limited to renal manifestations, typically multifocal type 1 papillary RCC (13).

The aim of this study was to investigate the prevalence of FLCN, BAP1, SDH, and MET mutations in an oncologic cohort and to determine the prevalence, clinical features, and imaging features of RCC in patients diagnosed with these syndromes. Secondarily, the aim was to determine the prevalence of benign renal lesions in these syndromes.

Materials and Methods

Ethical Approval and Patient Inclusion

This retrospective, single-institution observational study at a tertiary cancer center was Health Insurance Portability and Accountability Act compliant and approved by the institutional review board at Memorial Sloan Kettering Cancer Center, and the need for informed consent was waived. From January 1, 2015, to December 31, 2021, a total of 25 220 consecutive patients with cancer prospectively underwent germline analysis consisting of a panel of more than 70 cancer-predisposing genes at our institution. Patients were included in this retrospective study if they had a cancer diagnosis; had either germline pathogenic or likely pathogenic mutation in FLCN, BAP1, SDH, or MET; and underwent a baseline CT or MRI examination at diagnosis of RCC. The following patients were excluded from the study: (a) patients with germline pathogenic or likely pathogenic mutations other than the four included in this study (n = 25 141) and (b) patients with germline pathogenic or likely pathogenic mutations in MET, FLCN, BAP1, or SDH but without RCC (n = 61). Figure 1 represents the flow of patient inclusion into this study. None of the patients were related to each other. A prior study reported on five patients who were included in the current study (9). The prior study assessed clinical characteristics by mutation status, while the current study expands on this by having a larger patient cohort and including radiologic features.

Figure 1:

Flowchart of patient selection. RCC = renal cell carcinoma.

Clinicopathologic Data Collection

Electronic health records were reviewed by a radiology fellow in oncologic imaging (C.C.) and a radiology resident (M.S.) for clinicopathologic characteristics, including patient age, sex, race/ethnicity, and renal cancer diagnosis including histologic subtype.

Imaging Analysis

Two radiologists (C.C., a radiology fellow in oncologic imaging, and P.I.C.A., a fellowship-trained radiologist with 5 years of experience) independently reviewed the baseline imaging studies of all 79 patients with MET, FLCN, BAP1, or SDH mutations, checking for the presence of any renal lesion or mass and further analyzing those with a pathologic diagnosis (n = 16) or radiologic suspicion (n = 2) of RCC. Radiologic suspicion was defined following the guidelines of the Bosniak classification as a cystic mass with a solid component or a solid mass that enhanced after administration of an intravenous contrast agent, with the enhancement perceived visually or as a 20% or greater increase in attenuation at CT or a 15% or greater increase in intensity at MRI (14). Discrepant cases were resolved by consensus between the two radiologists, and readings from the fellowship-trained radiologist were used for the analysis.

RCC features that were reviewed included the largest axis, focality (unifocal or multifocal), margins (ill-defined or circumscribed), presence of cystic/necrotic component, and pattern of enhancement (homogeneous or heterogeneous). Features of local extension, such as involvement of the renal sinus fat and the hilar collecting system as well as renal vein invasion/ thrombosis, were recorded. CT studies were further evaluated for the presence of calcifications in renal tumors. MRI studies were further assessed for the presence of T1-hyperintense hemorrhage, intracellular lipid/microscopic fat, T2 homogeneity or heterogeneity, and diffusion restriction of the solid component of the renal tumor. In addition to RCC features, regional nodal and distant metastases at diagnosis were assessed based on the baseline imaging study at the time of RCC diagnosis as well as surgical pathology. The presence of associated benign renal lesions—such as oncocytomas, complex cysts, multicystic renal disease, and angiomyolipomas—was also recorded.

Of note, CT and MRI studies were performed at different institutions using different scanners and protocols. Of the 79 patients who had germline mutation and RCC, all patients underwent CT of the abdomen with intravenous contrast agent administered, 60 patients underwent MRI, and eight patients underwent gadolinium-enhanced MRI.

Statistical Analysis

Summary statistics, including medians, ranges, and percentages, were used to summarize continuous and categorical variables by mutation profile. The exact 95% CI was estimated for the proportion of patients with RCC in every mutation profile. The Kruskal-Wallis test or the Fisher exact test was used to test if any germline mutation groups were different from others on demographic and clinical variables. The MET mutation group was not included in the comparison because group size was too small. The exact Wilcoxon rank sum test was used to examine whether mass size was different in patients with RCC with or without distant metastasis at diagnosis. Considering the small number of patients with imaging features reported (n < 20), the κ statistic CI could not be estimated reliably; therefore, the percent concordance between two readers, with the 95% CI based on the exact binomial distribution, was summarized instead. P < .05 was considered statistically significant. All statistical analyses were performed in R (version 4.3.1; R Foundation for Statistical Computing) using the packages stats and gtsummary.

Results

Prevalence of Germline Mutations and RCC

A total of 79 of 25 220 (0.31%) patients had germline pathogenic or likely pathogenic mutations in the FLCN (n = 17, 0.07%), BAP1 (n = 22, 0.09%), SDH (n = 39, 0.15%), or MET (n = 1, 0.004%) gene. Of these 79 patients, 18 (23% [95% CI: 14%, 34%]) were diagnosed with RCC (FLCN: four of 17, 24% [95% CI: 7%, 50%]; BAP1: four of 22, 18% [95% CI: 5%, 40%]; SDH: nine of 39, 23% [95% CI: 11%, 39%]; and MET: one of one, 100% [95% CI: 3%,100%]), some at baseline imaging, which prompted genetic testing, and some at follow-up to assess for genetic predisposition. Demographic characteristics of patients with germline mutations and RCC, including patient age, sex, race/ethnicity, and renal cancer diagnosis, are summarized in Table 1.

Table 1:

Clinical Features by Mutation Type in All Patients

Clinical and Imaging Characteristics of Syndrome-associated RCC

Baseline clinical and imaging characteristics by germline mutation are summarized in Tables 2 and 3. Other noncancer features associated with the syndromes are reported in Table 4. The two readers evaluated the imaging characteristics with 100% concordance in all categories except enhancement pattern (85.7% [95% CI: 57.2%, 98.2%]) and renal vein thrombosis (93.3% [95% CI: 68.1%, 99.8%]).

Table 2:

Clinical Features by Mutation Type in Patients with RCC

Table 3:

Imaging Features by Mutation Type in Patients with Renal Cell Carcinoma

Table 4:

Other (Noncancer) Features Associated with Each Genetic Syndrome

Only three of 18 patients (17%) had distant metastases at diagnosis. Increased RCC tumor size at diagnosis was significantly associated with the presence of distant metastases at diagnosis (median RCC mass size was 3.4 cm [IQR, 2.1–6.4 cm] for those without distant metastases at diagnosis vs 10 cm [IQR, 8.7–11.2 cm] for those with distant metastases at diagnosis; P = .048).

FLCN-associated RCC

In the four patients with FLCN-associated RCC, the predominant histologic subtype was unclassified RCC (hybrid oncocytic/chromophobe; three of four, 75%), followed by clear cell RCC (one of four, 25%). The median largest dimension was 4.7 cm (IQR, 2.7–8.0 cm). Most patients (three of four, 75%) had unifocal tumors. Only one patient had regional nodal and distant metastases at diagnosis (one of four, 25%) (Table 2).

At baseline CT, all FLCN-associated RCC tumors (four of four, 100%) had ill-defined margins, while the majority had heterogeneous enhancement (three of four, 75%) and central nonenhancement (three of four, 75%); one (one of four, 25%) had internal calcifications. In the two patients who underwent MRI, one tumor had intrinsic T1 shortening secondary to hemorrhage and two had heterogeneous T2 signal intensity. No tumor had microscopic fat or restricted diffusion (Table 3).

The local extent was variable, with two of four tumors (50%) invading the renal sinus fat and one of four (25%) invading the renal collecting system/hilum. Renal vein thrombosis was observed in one patient (one of four, 25%). Additional lesions observed in these patients included complex/proteinaceous cysts (three of four, 75%). Figure 2 shows images in a patient with FLCN-associated RCC.

Figure 2:

Images in a 58-year-old female patient with bilateral FLCN-mutated renal cancer, nonmetastatic at diagnosis. (A) Axial contrast-enhanced CT image demonstrates well-defined and heterogeneously enhancing bilateral renal masses measuring 6.5 cm (right renal mass) and 10.7 cm (left renal mass) in the longest axis. The right renal mass extends into the renal sinus fat and hilar collecting system and invades the right renal vein and inferior vena cava (blue arrow). The left renal mass extends into the renal sinus fat, with internal necrotic/cystic components (white arrow). No calcifications were observed. (B) Coronal T2-weighted steady-state free precession MRI scan at diagnosis demonstrates T2 heterogeneous bilateral renal masses (arrow). (C) Axial diffusion-weighted MRI scan demonstrates restricted diffusion of the left renal mass.

BAP1-associated RCC

In the four patients with BAP1-associated RCC, the predominant histologic subtype was clear cell RCC (three of four, 75%), followed by papillary RCC (one of four, 25%). The median largest dimension was 7.3 cm (IQR, 4.4–8.9 cm). Most patients (three of four, 75%) had unifocal tumors. Only one patient (one of four, 25%) had regional nodal and distant metastases at diagnosis (Table 2).

At baseline CT, all BAP1-associated RCC tumors (four of four, 100%) had ill-defined margins, while the majority had heterogeneous enhancement (three of four, 75%) and central nonenhancement (three of four, 75%), and two (two of four, 50%) had internal calcifications. Among the two patients who underwent MRI, both had tumors with intrinsic T1 shortening secondary to hemorrhage and one had a tumor with heterogeneous T2 signal intensity. Additionally, both patients had tumors with microscopic fat and restricted diffusion (Table 3).

The local extent was variable, with two of four (50%) tumors invading the renal sinus fat and two of four (50%) invading the renal collecting system/hilum. Renal vein thrombosis was observed in one patient (one of four, 25%). Additional lesions observed in these patients included complex/proteinaceous cysts (two of four, 50%). Figure 3 shows images in a patient with BAP1-associated RCC.

Figure 3:

Images in a 62-year-old female patient with BAP1-mutated left renal cancer, metastatic to the liver and lungs at diagnosis. (A) Axial contrast-enhanced CT image demonstrates a well-circumscribed and heterogeneously enhancing mass measuring 7.3 cm in the longest axis in the left kidney, extending into the renal sinus and hilar collecting system. The mass had central necrotic/cystic components (arrow) and calcifications (not shown). (B, C) Additional axial contrast-enhanced CT images demonstrate hypervascular hepatic metastasis (arrow in B) and multiple solid lung nodules in both lungs consistent with metastases (arrows in C).

SDH-associated RCC

In the nine patients with SDH-associated RCC, the predominant histologic subtype was SDH-deficient RCC (six of nine, 67%), all involving SDHB genetic mutation, followed by clear cell RCC (one of nine, 11%), involving SDHAF2 mutation. Two lesions were not biopsied. The median largest dimension was 3.8 cm (IQR, 2.2–7.6 cm). Six patients (six of nine, 67%) had unifocal tumors. Only one patient (one of nine, 11%) had regional nodal and distant metastases at diagnosis (Table 2). With a median of 2 years (range, 1–5 years) of follow-up, three of nine (33.3%) patients developed metastatic disease.

At baseline CT, most SDH-associated RCC tumors had ill-defined margins (eight of nine, 89%), heterogeneous enhancement (six of nine, 67%), and central nonenhancement (seven of nine, 78%), and none had internal calcifications. In the three patients who underwent MRI, two tumors had intrinsic T1 shortening secondary to hemorrhage and heterogeneous T2 signal intensity. Additionally, only one tumor had microscopic fat, and only one tumor demonstrated restricted diffusion (Table 3).

The local extent was variable, with three of nine (33%) tumors invading the renal sinus fat and three of nine (33%) invading the renal collecting system/hilum. Renal vein thrombosis was not observed. Additional lesions observed in these patients included an oncocytoma (one of nine, 11%), complex/proteinaceous cysts (four of nine, 57%), and an angiomyolipoma (one of nine, 11%). Figures 4 and 5 show images in patients with SDH-associated RCC.

Figure 4:

Images in a 50-year-old male patient with SDHAF2-mutated renal cancer. (A) Axial contrast-enhanced CT image demonstrates a well-circumscribed left renal mass measuring 10.0 cm in the longest axis, heterogeneously enhancing with central necrotic/cystic component (arrow). (B) Coronal contrast-enhanced CT image demonstrates involvement of the renal sinus fat as well as extension into the hilar collecting system (arrow). (C) Axial contrast-enhanced CT image shows metastasis to the left adrenal gland that was present at diagnosis (arrow).

Figure 5:

Images in a 35-year-old female patient with SDHB-mutated left renal cancer. (A, B) Axial contrast-enhanced CT images demonstrate left upper pole (arrow in A) and lower pole (arrow in B) well-circumscribed masses measuring 1.9 cm and 1.7 cm in the longest axis, respectively, with necrotic/cystic component.

MET-associated RCC

For the single patient with a germline MET mutation, the histologic subtype was papillary RCC. The largest dimension was 6.4 cm. The tumor was unifocal. No nodal or distant metastasis was identified (Table 2).

At baseline CT, the tumor had ill-defined margins, heterogeneous enhancement, central nonenhancement, and no internal calcifications. At MRI, the tumor did not demonstrate intrinsic T1 shortening secondary to hemorrhage, heterogeneous T2 signal intensity, microscopic fat, or restricted diffusion (Table 3).

The tumor did not invade the renal sinus fat or collecting system/hilum. Renal vein thrombosis was not observed. Additional lesions observed included complex/proteinaceous cysts. Figure 6 shows images in the patient with MET-associated RCC.

Figure 6:

Images in a 68-year-old male patient with MET-mutated left renal cancer, nonmetastatic at diagnosis. (A) Coronal and (B) axial nonenhanced CT images demonstrate multiple cysts, some of which are hyperattenuating, in the left kidney, with a dominant mass measuring 3.5 × 3.5 cm (arrow) that has been slowly growing since prior studies. The patient underwent left radical nephrectomy, and pathologic examination showed papillary renal cell carcinoma. (C) Follow-up coronal contrast-enhanced CT image 2 years later demonstrates a growing mass with similar features in the contralateral kidney (arrow).

Discussion

To our knowledge, this is the largest study looking into the rare FLCN, BAP1, SDH, and MET mutations in an oncologic cohort. We found that the prevalence of such mutations was less than 1% even in an oncologic cohort, the spectrum of hereditary RCC imaging findings overlapped with those reported for nonhereditary RCC in the literature, and the prevalence of other benign solid renal lesions such as angiomyolipomas and oncocytomas (but not including complex cysts) was up to 11%.

The prevalence of FLCN, BAP1, SDH, and MET mutations in our oncologic cohort was considerably less than 1%, even though it is higher than that in the general population. While the prevalence of FLCN, SDH, and MET mutations has been studied in oncologic cohorts previously, our study is the first to our knowledge to report the prevalence of BAP1 mutation in an oncologic cohort. All four hereditary RCC syndromes are associated with an increased risk for RCC development. The prevalence of RCC in patients with FLCN mutation (24%) in our study is in concordance with previously reported prevalence values in the literature ranging from 15% (15) to 34% (16). Minimal data are available concerning the prevalence of RCC in patients with BAP1 mutation (6); in our study, 18% of patients with BAP1 mutation had RCC. Additionally, our study showed that the prevalence of RCC was 23% among patients with SDH mutations, which is higher than the prevalence of 10%–15% previously reported in literature (17,18). Finally, the risk of RCC development in patients with MET mutation is reported to be 25% (17); the one patient with MET mutation in our study had RCC.

Regarding the demographic characteristics of patients with RCC associated with FLCN, BAP1, SDH, and MET mutations in our oncologic cohort, patients with FLCN mutation in our study were found to develop RCC at an age comparable to the previously reported mean age of 50 years (15). However, patients with BAP1 mutation in our study developed RCC at a median age of 68 years, which is older than the age range of 47–50 years previously described in the literature (19). The age at diagnosis of RCC was the lowest for patients with SDH mutation, where RCC was detected in patients as young as 14 years, consistent with previously published studies (20,21). Finally, while RCC in patients with MET mutation has been detected at various ages, and as young as 30 years (13), the only patient with MET mutation and RCC in our study was 67 years old at the time of diagnosis.

The histologic subtypes of RCC encountered in the different hereditary RCC syndromes in our study were similar to those previously reported in the literature (6,8,9,22–24). Regarding other benign renal lesions, while angiomyolipomas and oncocytomas have been associated with FLCN mutation in the literature (8,25), none were detected in patients with FLCN mutation in our study. However, one patient with SDHB mutation was found to have both an angiomyolipoma and an oncocytoma. Regarding metastasis at diagnosis, the presence of regional nodal and distant metastases was found to correlate positively with RCC tumor size at diagnosis (P = .048). While metastasis at the time of RCC diagnosis has rarely been described in patients with FLCN mutation (13), it was observed in one patient (25%) with FLCN mutation in our study who had both regional nodal and distant metastases at diagnosis. In The Cancer Genome Atlas cohort, the rates of regional nodal and distant metastases at diagnosis in patients with BAP1 mutation and RCC were reported to be 45.8% and 16.2%, respectively (26). In our study, one of four patients (25%) with BAP1 mutation and RCC had both regional nodal and distant metastases. One of nine (11%) patients with SDH mutation and RCC was found to have nodal and distant metastases at diagnosis, which is a lower rate than the previously reported rate of 33% (4). The only patient in our study with MET mutation and RCC did not have metastases at diagnosis.

The radiologic features of RCC associated with FLCN, BAP1, SDH, and MET mutations in our oncologic cohort were similar to those of sporadic RCC, with most tumors demonstrating ill-defined margins, heterogeneous enhancement, and internal necrotic/cystic components. Tumors also had the potential to invade the renal sinus (BAP1, FLCN, and SDH mutations), hilar collecting system (BAP1, SDH, and FLCN mutations), and renal vein (BAP1 and FLCN mutations). None of the hereditary RCC syndromes were associated with additional imaging features distinguishing hereditary RCC from sporadic RCC.

Some clinical and radiologic features may still aid in raising the suspicion of hereditary RCC associated with these genetic mutations. Hereditary RCC tends to manifest at a younger age in comparison to nonhereditary RCC, particularly in RCC associated with SDH (20) and MET (13) mutations. Hereditary RCC can also coexist with other noncancer pathologies, such as fibrofolliculomas, lung cysts (15), and spontaneous pneumothoraces (27) when associated with FLCN mutation; other cancers such as uveal and cutaneous melanomas and mesotheliomas when associated with BAP1 mutation (13); and paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors when associated with SDH mutation (11). Last, hereditary RCCs can be multifocal at diagnosis, mainly when associated with FLCN (27) or MET (24) mutation. Nevertheless, and taking into consideration our small sample, we were not able to identify specific features of the renal mass itself that may aid in diagnosis.

The strengths of this study include its large oncologic cohort for the evaluation of sporadic syndromes, shedding light on four rare hereditary RCC syndromes that, to our knowledge, have not been previously systematically examined in an oncologic population.

The limitations of this study include the small number of individuals within each mutation group, limiting significant statistical association with clinical and imaging features. Studies with larger samples of patients with FLCN, BAP1, SDH, and MET mutations, likely multi-institutional, would be needed to confirm these findings.

In conclusion, the prevalence of FLCN, BAP1, SDH, and MET mutations was less than 1%, even in an oncologic cohort. These mutations should be suspected if RCC is present in younger patients, patients with RCC and other cancers or fibrofolliculomas or lung cysts, or patients with multifocal RCC. Nevertheless, with our sample size, we found no distinct radiologic features of hereditary renal cell carcinoma or significant association with other benign renal lesions.