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. Author manuscript; available in PMC: 2022 Mar 11.
Published in final edited form as: Clin Imaging. 2020 Jun 9;68:14–19. doi: 10.1016/j.clinimag.2020.06.010

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome: Spectrum of imaging findings

Anna K Paschall a,b,1, Moozhan Nikpanah a,1, Faraz Farhadi a, Elizabeth C Jones a, Paul G Wakim c, Andrew J Dwyer a, Rabindra Gautam d, Maria J Merino e, Ramaprasad Srinivasan d, W Marston Linehan d, Ashkan A Malayeri a,*
PMCID: PMC8916163  NIHMSID: NIHMS1780963  PMID: 32562921

Abstract

Purpose:

To retrospectively investigate the radiological presentations of HLRCC-associated renal tumors to facilitate accurate lesion characterization and compare these presentations with simple cysts and characteristics of other subtypes of renal cell carcinoma (RCC) as reported in the literature.

Methods:

The MRI and CT imaging characteristics of 39 pathologically confirmed lesions from 30 patients (20 male, 10 female) with HLRCC syndrome were evaluated by two radiologists. Patients had an average age at diagnosis of 43.8 ± 13.1 years. Lesion characteristics including laterality, homogeneity, diameter (cm), nodularity, septations, T1 and T2 signal intensity, enhancement, and restricted diffusion were recorded. Imaging characteristics of the lesions were further compared to characteristics of benign simple cysts surgically removed at the same time point.

Results:

The examined lesions had a mean diameter of 5.06 ± 3.80 cm, an average growth rate of 2.91 × 10−3 cm/day and an estimated annual growth rate of 1.06 cm/year. 50% of lesions demonstrated nodularity, 65% were mostly T2-hyperintense, 83% demonstrated restricted diffusion in solid portions of the lesions, and 65% had well-defined margins. 76% of patients demonstrated extra-renal manifestations, 53% lymphadenopathy, and 43% distant metastasis.

Conclusions:

Our analysis confirmed that while HLRCC-associated renal lesions demonstrate diversity in imaging presentations, the majority are unilateral and solitary, T2-hyperintense, heterogeneous with well-defined margins, and frequently demonstrate restricted diffusion and nodularity.

Keywords: Genitourinary, HLRCC, RCC, Papillary RCC, MRI, CT

1. Introduction

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by an autosomal dominant germline mutation in the fumarate hydratase (FH) gene (1q42.2), a tumor suppressor gene [1–5]. Mutation to the FH gene results in deficiencies in aerobic metabolism through the tricarboxylic acid cycle (TCA), resulting in a transition to aerobic glycolysis, commonly referred to as the Warburg Effect [4]. Additionally, these mutations to the FH gene result in an increase in cellular levels of fumarate, stabilizing hypoxia-inducible factors (HIF), downstream leading to increased transcription of genes influencing cancer development and metabolic activity, such as GLUT1 [4]. Carriers of the mutation are at increased risk of developing benign renal cysts and early-onset papillary type II renal cell carcinoma (RCC) [1,2,6]. Patients with HLRCC syndrome also frequently exhibit benign cutaneous and uterine leiomyomas [1,4,6]. Individuals with HLRCC syndrome have an estimated overall lifetime RCC risk of 15% [1]. In contrast to many other hereditary RCC syndromes, in which lesions demonstrate a multiple, bilateral presentation, HLRCC-associated lesions have traditionally been reported as unilateral [1,2,6,7]. Furthermore, HLRCC-associated lesions are very aggressive and highly metastatic, frequently metastasizing when under 1 cm in diameter [4,7].

Given the aggressive nature of HLRCC-associated lesions, serial imaging studies in patients with known mutations is recommended to enable early detection and resection of RCC via partial or radical nephrectomy. Radiofrequency ablation and other minimally invasive techniques are not recommended for lesions suspected or confirmed to be HLRCC-associated due to their highly aggressive nature and tendency to metastasize early in the disease course [8–10]. Current guidelines suggest genetic testing of children with possible FH mutations at age 8 and if positive, continued annual screening, as renal tumors have been noted in children as young as 10 years of age [1].

HLRCC-associated lesions of papillary type II RCC (pRCC type II) should not be confused with papillary type I lesions (pRCC type I), commonly seen in hereditary papillary RCC (HPRCC). Histopathologically, HLRCC-associated renal tumors are characterized by high-grade cells with large pseudo-stratified nuclei and or- angiophilic nucleoli surrounded by a clear halo with eosinophilic cytoplasm [2,6,11]. In comparison, pRCC type I lesions demonstrate papillae covered in single layer of small cells with low-grade nuclei with little cytoplasm [11,12]. The two subtypes of pRCC are also distinct in their imaging presentation (Table 1).

Table 1.

Lesion characteristics of imaging presentations of HLRCC-associated renal cell carcinoma (RCC) from our data compared to three common subtypes of RCC and benign oncocytomas from the literature.

PRCC II
 PRCC I
 CHRCC
 CCRCC
 Oncocytoma
Current study (HLRCC-associated) Other studies
No. of lesions 63% single 93.6% single [15] 100% single [15] 96.8% single [15] 85.7% single [16]
Laterality 48% R, 52% L 47.1% R, 52.9% L [13] 56.6% R, 39.8% L [15] 42.9% R, 57.1% L [13] 34.3% R, 65.6% L [15] 44.7% R, 52.2% L [15] 53.8% R, 46.2% L [17]
Diameter (cm) 5.06 ± 3.80 6.0 [14], 4.7 ± 3.5 [13] 5 ± 3.9 [15] 6.08 ± 3.09 [18], 3.5 [14], 2.9 ± 1.9 [13] 7 ± 4.5 [15] 7.40 ± 3.66 [18] 5.8 ± 3.4 [15] 4.83 ± 2.00 [18] 3.47 ± 1.20 [18], 5.31 ± 1.73 [16]
Growth rate (cm/year) 1.06 0.15 [19] 0.15 [19] 0.37 [19] 0.86 [20] 0.52 [21]
Well-defined margins 65% 52.9–100% [13,14] 87–95.2% [13–15] 84.4% [15] 45.9% [15] 45% [22]
Homogeneity 17% 0% [14] 9–67.8% [14,15,18] 25–50% [15,18,23] 7.1%–8.6% [15,18] 45–66.7% [18,22,23]
Consistency
Solid 42% 63.6–77% [15,18] 78.1–87.5% [15,18] 45.9–77.1% [15,18] 100% [18]
Cystic 37% 5.7–18.2% [15,18] 0% [15,18] 2.9–6.8% [15,18] 0% [18]
Mixed 22% 17.3–18.2% [15,18] 12.5–21.9% [15,18] 20–47.3% [15,18] 0% [18]
Septations 33% 33–45.5% [15,18] 0–71.4% [15,18] 25.4–64.7% [15,18] 0% [18]
Nodularity 50% 8.3% [15] 0% [15] 9.8% [15] N/A
T1 signal intensity
Hypointense 37% 16.7% [14] N/A N/A N/A 73% [22]
Isointense 37% 50% [14] N/A N/A N/A 27% [22]
Hyperintense 26% 33.3% [14] N/A N/A N/A 0% [22]
T2 signal intensity
Hypointense 26% 47.1–66.7% [13,14] 71.4–91% [13,15] 0% [15] 7.4% [15] 17% [22]
Isointense 9% 6.67% [14] 0% [15] 40% [15] 2.9% [15] 33–50% [22,24]
Hyperintense 65% 20% [14] 9% [15] 40–60% [15,24] 89.6% [15] 50% [22]
Enhancement > 15 HU (CT) N/A 100% [14] 98.4–100% [14,15] 100% [15] 73.9% [15] N/A
Organ metastases 43% 0% [14] 0–18.2% [12,14,15,18] 0–14.3% [15,18] 3.8–26.9% [12,15] 33.3% [18]
Lymph node involvement 53% 22–33% [14] 2.3–13% [12,14,15] 3.1–24.1% [15,23] 8.5–8.6% [12,15] 3.6% [23]
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HLRCC: Hereditary leiomyomatosis and renal cell carcinoma, PRCC II: Papillary type II renal cell carcinoma, PRCC I: Papillary type I renal cell carcinoma, CHRCC: Chromophobe renal cell carcinoma, CCRCC: Clear cell renal cell carcinoma.

The aim of this study is to describe the range of CT and MR appearances of HLRCC-associated lesions compared to other common subtypes of RCC (i.e. clear cell, chromophobe, and papillary type I), benign oncocytomas, and pathology proven simple cysts at the same time point to facilitate accurate diagnosis and timely intervention for these highly aggressive renal lesions. The radiologic appearance of RCC lesions in these patients is highly variable and while there has been some characterization of the spectrum of imaging findings, by greatly increasing the patient cohort examined and utilizing multiple imaging modalities, this report will strengthen our understanding and expand the characteristics that can be utilized to accurately identify these aggressive lesions in individuals at risk for HLRCC-associated renal tumors undergoing annual surveillance [13,14].

2. Methods

2.1. Image analysis

This study was a retrospective review of CT and MR studies. Two independent radiologists reviewed the images of 30 patients with 39 histologically-confirmed HLRCC-associated renal lesions that were surgically resected after contrast-enhanced CT and/or MR: 35/39 (90%) lesions on CT and 29/39 (79%) lesions on MR; 21/39 (54%) lesions were reviewed on both CT and MR. Furthermore, 15/28 (54%) CT scans and 20/23 (87%) of MR scans were contrast enhanced, with only two patients lacking contrast on all scans. All patients provided informed consent on institutional review board approved protocol (NCI-03-C-0066) at National Institutes of Health (Bethesda, MD). To be included in our study, patients had to have pathology proven papillary type II HLRCC-associated lesions, with at least one CT or MRI before surgery or biopsy. Imaging studies were obtained from December 2002 through December 2015. The tumors were assessed for laterality, diameter (cm), presence of nodularity (presence of solid component within a predominantly cystic mass) and septations, presence of cystic components, percent enhancement, homogeneity, margin definition, and growth rate. The growth rate (cm/year) was calculated from long axis diameter (D) at two time points (t1 and t0) using the following formula:

GR=Dt1−Dt0t1−t0

Lesions were also analyzed for T1 and T2 signal intensity and presence of restricted diffusion on MR. Furthermore, patient history was examined to ascertain reason for initial imaging, presence of cutaneous and/or uterine leiomyomas, sex, age at diagnosis, and time between imaging and surgery. Full pathology reports were used to confirm diagnosis prior to analysis and record the presence or absence of simple cysts removed at the same surgical time point. Nodal and distal metastases were also assessed. In cases of discrepancy between radiologists on characterization of parameters, a third radiologist was consulted as a “tie-breaker”. For calculation of percent enhancement, the degree of the cystic portion of lesion, determined by T2 signal hyperintensity or lack of enhancement on MRI and low attenuation or lack of enhancement (< 20 HU) on CT, was estimated by the reader. Lesions were defined as predominantly cystic if the solid enhancing component represented < 25% of the lesion, mixed if the solid enhancing component represented 25–75% of the lesion, and predominantly solid if the solid enhancing component represented > 75% of the lesion. The absence or presence of lymph node involvement and distant metastasis was recorded for each patient. Location of involvement was determined through a review of the entirety of patient imaging. The same imaging parameters were recorded for pathology proven simple cysts at the same time point. All scans were reviewed by fellowship trained body radiologists with > 40 years (AD) and 27 years (EJ) experience and reviewed for consensus by a fellowship trained abdominal radiologist with 4 years (AAM) of experience.

2.2. Image parameters

CT Scans were acquired on a variety of scanners, patients were scanned on either: GE (Lightspeed (Ultra, QX/I, VCT, Pro 16), Discovery CT750 HD), Siemens (Definition, Biograph 128, Emotion Duo, Somatom Definition AS (+), Sensation (16, 64), Somatom Force), Toshiba (Aquilion), or Philips (Brilliance 64). All scans had KVP of 120 (range 100–130). Furthermore, the mA range of NIH scans was 40–543, while the external scans ranged from 10 to 721. All scans had a slice width ranging from 2 to 7.5 mm. MR Scans were acquired on GE (Genesis Signa 1.5 T, Signa Excite 1.5 T, Discovery MR750 3.0 T, Signa HDxt 1.5 T), Philips (Achieva (1.5 T, 3.0 T)), Siemens (Verio 3.0 T, Symphony 1.5 T, Biograph 3.0 T, Aera 1.5 T, Avanto 1.5 T). All patients had T2-weighted fast spin echo based sequences, GRE based in/out phase T1-weighted scans with pre- and post-contrast, DWI and ADC imaging (0, 50, 500 and 800).

2.3. Statistical analysis

To reduce the influence of possible bias introduced through within-patient correlations, as our cohort consisted of 39 lesions from 30 patients, weighted percentages were calculated. As such, imaging characteristics of each lesion in a patient with two lesions was given half of the weight contribution toward final analysis. Statistical analysis was performed using R Statistical Software (RStudio: Integrated Development Environment for R, v1.0.44, Boston, MA).

3. Results

In 30 patients, a total of 39 histologically-confirmed HLRCC-associated renal lesions were reviewed. We had 20 male patients and 10 female patients. The lesions of 19/30 (61%) patients were the initial presentation, 7/30 (26%) patients demonstrated lesions following partial or radical nephrectomies, and 4/30 (13%) patients demonstrated lesions while being followed for routine imaging. Laterality and diameter (cm), and prevalence of consistency, nodularity, septations, homogeneity, and well-defined margins of our patient cohort compared to three common subtypes of RCC and benign oncocytomas from the literature is reported in Table 1 [12–24]. The majority of patients (19/30) presented with single lesions (63%), of the patients demonstrating multiple lesions, 5 of the 9 (56%) patients demonstrated bilateral lesions. With regard to enhancement, 11/30 (37%) lesions demonstrated < 25% enhancement, 3.5/30 (12%) demonstrated 25–50% enhancement, 3/30 (10%) had 50–75% enhancement, 6.5/30 (22%) had > 75% enhancement, and 6/30 (20%) had an enhancement level of 100%. The diversity in imaging presentations of lesions in our cohort is demonstrated in Figs. 1 and 2.

Fig. 1.

Fig. 1.

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A 40-year-old male with HLRCC syndrome showing a left renal mass with septations and nodularity on T2-WI (A). The areas of nodularity demonstrated restricted diffusion on ADC map (B). Mild enhancement within the areas of nodularity is shown on pre and post contrast images (C and D).

Fig. 2.

Fig. 2.

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A 58-year-old male presenting with HLRCC syndrome. Images show a septated mass with nodularity in the upper pole of the left kidney on T2-WI (A). An area of nodularity within the mass (arrow) with mild enhancement lower than the cortex identified (B and C).

24 patients were initially imaged due to a family history of an FH mutation or history suggestive of HLRCC syndrome (history of early uterine fibroids or cutaneous leiomyomas). Extra-renal manifestations were recorded for 25 patients (83%). Of these patients, 19/25 patients (76%) were positive for extra-renal presentations, with 17 out of the 25 (68%) patients presenting with pathologically confirmed cutaneous leiomyomas. Uterine fibroids were present in all female patients. Average age at pathology proven diagnosis was 43.8 ± 13.1 years. Average days between imaging and surgery or biopsy were 86.31 ± 105.05 days. Growth rate was analyzed for 17 lesions, which demonstrated an average growth rate of 2.91 × 10−3 cm/day, and an estimated annual growth rate of 1.06 cm/year.

In our examination of lymph node involvement and distant metastasis, we examined lesions with regards to those smaller and larger than 3 cm. The overall prevalence of lymph node involvement and distant metastasis are provided in Table 1. The distribution of distant metastases in our cohort is presented in Table 2. 24 of the 39 lesions were > 3 cm in size. Of the lesions > 3 cm 14.5/18.5 (78%) demonstrated lymph node involvement and 10.5/18.5 (57%) had distant metastasis. Of the lesions < 3 cm, 1.5/11.5 (13%) demonstrated lymph node involvement and 2.5/11.5 (22%) had distant metastasis. The majority of patients with metastasis were de novo patients (12/14, 86%), with one patient (1/14, 7%) being followed annually and one patient (1/14, 7%) being followed post nephrectomy. Of the patients with lesions only < 3 cm (n = 10), no patients demonstrated both lymph node involvement and distant metastasis. Amongst patients with lesions both less than and > 3 cm, 1/3 (67%) demonstrated both lymph node involvement and distant metastasis. Lastly, amongst patients with lesions only > 3 cm, 10/17 (59%) demonstrated both lymph node involvement and distant metastasis.

Table 2.

Distribution of distant metastasis amongst cohort.

Number of metastases Location of metastasis No. patients (%)
Single site Retroperitoneum 1/4 (25%)
Adrenal gland 1/4 (25%)
Mediastinum 1/4 (25%)
Bone 1/4 (25%)
Multiple sites Retroperitoneum 7/9 (78%)
Liver 6/9 (67%)
Bone 5/9 (56%)
Mediastinum 4/9 (44%)
Pelvis 3/9 (33%)
Lung 2/9 (22%)
Adrenal gland 2/9 (22%)
Spleen 1/9 (11%)
Breast 1/9 (11%)
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3.1. MR specific characteristics

The distribution of T1 and T2 signal intensity of lesions within our cohort is provided in Table 1. 15/23 (65%) of the MR patients had diffusion-weighted images performed. Of the 15 reported patients, 12.5 (83%) lesions demonstrated restricted diffusion.

3.2. Comparison to simple cysts reported at same time point

Upon complete analysis of pathology reports for each patient, we recorded that 6 of the 30 reported patients (20%, 11 cysts) had benign cysts removed at the same surgical time point as the excision of the HLRCC-associated lesion. However, the cysts of 2 patients were excluded because they were too small to measure and characterize. After exclusions, 5 cysts were examined in 4 patients. These cysts had an average size of 1.4 ± 1.3 cm. All cysts demonstrated 0% enhancement and lacked nodularity, and only 1 cyst 0.5/5 (12.5%) had septations. All cysts were homogeneous with well-defined margins, hypointense on T1 imaging, hyperintense on T2 imaging, and no lesions demonstrated restricted diffusion.

4. Discussion

This review of 30 patients with 39 pathologically-confirmed HLRCC-associated renal lesions demonstrates the diversity present in the radiological appearance of HLRCC-associated lesions. However, several characteristics are present in high percentages in the study population. It is our aim that these common characteristics can be utilized in order to more accurately identify lesions requiring biopsy and immediate surgical intervention, thus improving the current 5 year survival rate of 30% [25]. The diversity in presentation highlights the difficulty in accurately predicting the malignant potential of seemingly benign lesions. In patients with known FH gene mutations, serial imaging provides the only method to predict when a potentially benign lesion has transformed to a malignant lesion with metastatic potential.

Our analysis indicated no difference in laterality and confirmed that HLRCC-associated renal lesions are predominantly singular, and therefore, unilateral. With regards to enhancement and consistency, the lesions demonstrated a wide variety of features. While the papillary type II lesions demonstrated a similar percentage of septations (33%) as ccRCC and pRCC type I lesions, the type II lesions demonstrated a much higher rate of cyst with nodularity (50%) than other subtypes. The majority of lesions wereheterogeneous (83%) and had well-defined margins (65%). Our findings regarding heterogeneity were consistent with the findings of Yamada et al., which reported that papillary type II lesions are more heterogeneous than the pRCC type I lesions [26]. Furthermore, while the majority of the HLRCC-associated lesions had well-defined margins (67%), our findings were consistent with previous reports of HLRCC-associated lesions having poorer margin definition than papillary type I lesions [26]. Furthermore, in the study by Doshi et al., use of the features of margin distinction and heterogeneous enhancement performed high, with an area under the receiver operating characteristic curve (AUC) value of 0.822 for differentiation of pRCC type I and pRCC type II, indicating that these features may be useful for correctly differentiating HLRCC-associated lesions [13].

Moreover, a large portion of our patient cohort had lesions with restricted diffusion (83%), which could prove useful for differentiation of cysts and potentially malignant lesions. While no trend was seen in T1 signal intensity, the majority of lesions (65%) were T2-hyperintense, confirming the findings by Yamada et al. and Egbert et al., who found that pRCC type I lesions are consistently T2-hypointense, while pRCC type II lesions are consistently T2-hyperintense [14,26]. With regards to metastasis, our results were aligned with the previous clinical reports that patients with pRCC type II lesions are more likely to develop lymphadenopathy and metastatic disease than patients with other RCC subtypes [12,13]. In congruence with the literature, the majority of metastases of HLRCC-associated renal lesions in our cohort were to retroperitoneal lymph nodes, liver, bone, and mediastinal sites [5,27]. While rare cases of brain metastases have been previously reported in the literature for other subtypes of RCC, no case of brain metastases was found in our cohort. This finding is consistent with previous publications [5,27,28].

Our study had limitations. We reviewed the images of patients who were already deemed surgical candidates for likely malignant lesions, so it is unknown what percentage of seemingly benign renal cysts could be HLRCC-associated. Our study is also limited by the small patient population and varying quality of images obtained from 2002 to 2015. However, the characterization of the radiological characteristics of lesions, particularly those presenting with metastatic involvement, contributes to the framework on which to make clinical decisions for prompt surgical intervention.

5. Conclusions

This study of 30 patients with 39 pathology confirmed papillary type II RCC lesions demonstrates the diversity of lesion characteristics present amongst HLRCC-associated renal lesions. However, our study did find that the majority of lesions are T2-hyperintense and demonstrate restricted diffusion on MR imaging, are heterogeneous with well-defined margins, and commonly demonstrate nodularity. It is our aim that these imaging features can improve detection of HLRCC-associated renal lesions early in their presentations and prior to metastasis to provide a framework for future studies and to improve the morbidity and mortality of the disease.

Acknowledgements

The authors would like to thank Jana P. Lovell for her contribution to this paper.

Funding

This work was supported by the Intramural Research Programs (no grant number) of the Center for Cancer Research-National Cancer Institute and the National Institutes of Health Clinical Center, Bethesda, Maryland, USA. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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