The type of manuscript: Review The word count of the text: 3992 words Imaging evaluation of hereditary renal tumors: A pictorial review Title Title Page

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Title Page

Title

Imaging evaluation of hereditary renal tumors: A pictorial review

The type of manuscript: Review The word count of the text: 3992 words

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ABSTRACT

More than 10 hereditary renal tumor syndromes (HRTSs) and related germline mutations have been reported with HRTS-associated renal and extrarenal manifestations with benign and malignant tumors.

Radiologists play an important role in detecting solitary or multiple renal masses with or without extrarenal findings on imaging and may raise the possibility of an inherited predisposition to renal cell carcinoma,providing direction for further screening, intervention and surveillance of the patients and their close family members before the development of potentially lethal renal and extrarenal tumors.

Renal cell carcinomas (RCCs) associated with von Hippel–Lindau are typically slow growing while RCCs associated with HRTSs such as hereditary leiomyomatosis and renal cell carcinoma syndrome are highly aggressive. Therefore, radiologists need to be familiar with clinical and imaging findings of renal and extrarenal manifestations of HRTS. This article reviews clinical and imaging findings for the evaluation of patients with well-established HRTSs from a radiologist’s perspective to facilitate the clinical decision-making process for patient management.

Keywords: Hereditary renal tumor syndrome, Von Hippel–Lindau disease, Birt-Hogg-Dubé syndrome,

Tuberous sclerosis complex, Hereditary leiomyomatosis and renal cell carcinoma syndrome

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INTRODUCTION

Systemic diseases can involve the renal parenchyma, perirenal, or renal sinus spaces, which can be seen as renal masses, wedge-shaped lesions, diffuse renal enlargement, or perirenal or renal sinus soft tissues on radiological imaging [1, 2]. Renal masses are common and important findings in hereditary renal tumor syndromes (HRTSs); however renal masses have other differential diagnoses apart from HRTSs, which include various systemic diseases, such as metastases, hematopoietic tumors (e.g., lymphoma, leukemia, immunoglobulin G4-related disease, and post-transplant lymphoproliferative disorders), infections, and granulomatous diseases. The most common kidney cancer is renal cell cancer (RCC), accounting for 90% of all kidney and renal pelvis cancers. Hereditary forms of renal cell carcinoma (RCC) account for 5%–8% of all malignant kidney neoplasms [3, 4]. More than 10 HRTSs have been reported including von Hippel–Lindau disease (VHL), Birt-Hogg-Dubé Syndrome (BHD), tuberous sclerosis complex (TSC), hereditary papillary renal cell carcinoma (HPRC), hereditary leiomyomatosis and RCC syndrome (HLRCC), hereditary paraganglioma-pheochromocytoma syndrome, breast cancer–

associated protein 1 - tumor predisposition syndrome (BAP1-TPDS), constitutional chromosome 3 translocations, phosphatase and tensin (PTEN) hamartoma tumor syndrome, and microphthalmia- associated transcription factor (MiTF)-associated cancer syndrome [5, 6]. In general, familial renal

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tumors are characterized by early tumor onset (≤ 46 years of age), and multifocal bilateral disease (synchronous and metachronous), and associated extrarenal tumors[3, 4]. Patients with HRTS present with renal and extrarenal manifestations with associated benign and malignant tumors, which can be detected on imaging [7, 8]. Familiarity to characteristic renal and extrarenal radiographic findings associated with HRTSs can help in making an appropriate diagnosis. Furthermore, nephron-sparing approaches (e.g., partial nephrectomy and cryoablation) tend to be prioritized because of the lifetime risk of repetitive therapeutic interventions for synchronous or metachronous multifocal renal masses in patients with a hereditary predisposition (e.g., VHL, BHD). HLRCC-associated RCC and succinate dehydrogenase (SDH)-deficient RCC in hereditary paraganglioma-pheochromocytoma syndrome were recognized as new entities in the 2016 World Health Organization (WHO) classification based on molecular and genetic features [9]. Histologic renal tumor types and associated HRTSs are shown in

Table 1 [3, 6, 9-12].

This article presents a review of clinical and imaging findings in well-established HRTSs with illustration of representative cases and their key imaging findings.

Von Hippel–Lindau Disease

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Genetics and clinical manifestations

VHL disease is an autosomal-dominant inherited disorder and the most common HRTS that results from germline mutations of the VHL tumor suppressor gene, located on chromosome 3p25–26, characterized by the development of various benign and malignant hypervascular tumors, including retinal and central nervous system (CNS) hemangioblastomas, endolymphatic sac tumor, clear cell RCC, pancreatic neuroendocrine tumor, pheochromocytoma, and epididymal cystadenoma [13, 14]. (Fig. 1) Clinical diagnostic criteria in patients with known family history of VHL include the presence of a single CNS hemangioblastoma (including retinal hemangioblastoma), pheochromocytoma, or RCC. In cases without known family history of VHL, clinical diagnostic criteria of VHL include two or more CNS

hemangioblastomas, or a single hemangioblastoma with a visceral tumor characteristic of VHL (e.g., clear cell RCC, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor) [13, 15]. The diagnosis of VHL can be also made by the confirmation of genetic mutations of VHL gene and single characteristic VHL tumor. About 80% of the VHL patients have a family history, while, about 20%

of VHL patients do not, but meet the VHL criteria [16]. More than 90% of individuals who have a pathogenic variant in the VHL gene are symptomatic by age 65 years [17].

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Renal manifestation and imaging findings

Renal lesions associated with VHL arise from simple cysts, cystic masses with hyperenhancing nodules, and solid hypervascular masses with or without cystic components [18]. Renal cysts are present in 59%–

63% of VHL patients, and RCC is reported to develop in 24%–45% of patients [19]. Clear cell RCC typically exhibits the peak hyperenhancement during the corticomedullary differentiation phase with rapid washout and with a heterogeneous appearance, consisting of areas of necrosis, hemorrhage, and cysts [20]. (Fig. 2) Although the Bosniak cystic renal mass classification system is helpful in

characterizing VHL-related cystic renal masses, the Bosniak management guidelines cannot be directly applied to VHL-related renal tumors [20]. Management of the cystic renal masses should be based on the size of the largest solid enhancing component.

Extrarenal manifestations

Extrarenal tumors associated with VHL include retinal (45–60%) and CNS (60–80%)

hemangioblastomas, pheochromocytomas (25–30%) and paragangliomas (15%), pancreatic cysts (7–

72%), serous cystadenomas (9–17%) and neuroendocrine tumors (5–17%), endolymphatic sac tumors (10–16%), and epididymal (25–60%) and broad ligament (<10%) papillary cystadenomas, which are

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hypervascular in nature [13, 14]. Several subtypes of VHL are now recognized based on genotype–

phenotype correlations. VHL without pheochromocytoma is classified as VHL type 1, families of which can develop VHL-associated tumors. On the other hand, VHL with pheochromocytoma is classified as VHL type 2, families of which have been further divided into type 2A, VHL with pheochromocytoma but without RCC, type 2B, VHL with pheochromocytoma and RCC, and type 2C, VHL with

pheochromocytoma as the only manifestation of VHL [13]. Type 1 and type 2B have high-risk for RCC.

The difference between type 1 and type 2 is related to the difference of molecular etiology between pheochromocytoma and other VHL-associated tumors [15].

Screening and management

The recommended age to begin screening examinations can be different depending on the frequencies of the age at onset of each VHL lesions. For the screening of retinal hemangioblastomas, ophthalmoscopy is recommended from infancy, and for CNS hemangioblastoma, craniospinal MRI with contrast-agents is recommended from 11 years of age [13, 21]. As for RCC, alternative screening with abdominal ultrasonography (US) and MRI every other year is recommended from 15 years of age, and dynamic

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contrast-enhanced computed tomography (CT) exams are recommended for the confirmation of RCC according to the VHL clinical guideline created by the VHL disease study group in Japan [21].

Generally, intervention is considered when the RCC reaches 3 cm in size due to the low risk of metastases in smaller tumors [22]. RCCs smaller than 3 cm were successfully treated with ablative procedures with up to a 100% 3-year cancer-specific survival rate [23]. Hence, small solid RCCs can be a candidate for nephron-sparing procedures. In the Japanese VHL clinical guideline, therapeutic

interventions are considered when the index RCC becomes larger than 2cm in size [21]. In such cases, a nephron-sparing procedure is recommended. For any renal cyst, observation is recommended. In type 2 families with pheochromocytomas, medical examination with urinary and blood hormone tests are recommended from 2 years of age and alternate screening for abdominal US and MRI every other year are recommended from 10 years of age. RCC is the leading cause of the death in persons affected by VHL disease [24]. It is essential to preserve as much renal functions as possible because of higher lifetime risks of surgical interventions in VHL patients [25]. Another common cause of death is neurologic complications from cerebellar hemangioblastomas [26].

Birt-Hogg-Dubé Syndrome

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BHD is an autosomal-dominant disorder caused by germline mutations in the folliculin gene, located on chromosome 17p11.2 and is clinically characterized by cutaneous lesions (e.g., fibrofolliculomas, and acrochordons) (84%), pulmonary cysts (70–85%), and renal tumors (19–35%) [20, 27]. Although the penetrance of BHD gene is unclear, lung cysts can be seen in more than 80% of cases where a family history is present [28]. The rate of de novo cases has not been fully evaluated due to the low rate of genetic testing of parents of symptomatic patients. Molecular/genetic testing for BHD is recommended in patients who meet the following criteria: typical cutaneous lesions (≥5 lesions); multiple or bilateral chromophobe RCC, oncocytoma, or hybrid oncocytic tumors; single chromophobe RCC, oncocytoma, or hybrid oncocytic/chromophobe tumors with family history of RCC; and a history of familial spontaneous pneumothorax without any smoking history [27].

Common histologic tumor subtypes of BHD-associated renal tumors include hybrid

oncocytic/chromophobe tumor (mixed pattern of chromophobe RCC and oncocytoma) (50%) (Fig.3), chromophobe RCC (34%), and clear cell RCC (12%) [29]. Chromophobe RCC can present as a

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homogeneously hyperenhancing solid mass with less enhancement than clear cell RCC [20]. In addition, a central stellate scar can be present. On the other hand, oncocytoma can present as a hyperenhancing mass with or without a central stellate scar [20]. However, chromophobe RCCs and oncocytomas can present similarly with homogeneously enhancing masses, and it is often difficult to differentiate between them. The differential diagnoses of multiple renal masses with homogeneous enhancements include BHD, oncocytosis, papillary RCCs, metastases, lymphoma, and leukemia [30].(Fig.4) In the Japanese clinical practice guideline for renal cancer, the recommended criteria for the biopsy of renal tumors are as follows: candidates for active surveillance or ablation therapies; homogeneously enhancing renal masses with high attenuations on plain CT, suspicious for benign lesions; renal tumors suspicious for malignant lymphoma, abscess, and metastases; and, clinical necessity of the histological confirmation of renal tumors for candidates for neoadjuvant therapy or non-eligible patients for nephrectomy [31].

Pulmonary cysts associated with BHD are frequently found in basal lungs [32]. Spontaneous

pneumothorax can be seen in up to 25% of BHD patients [33]. BHD is one of the differential diagnoses to be considered when dealing with such a disease status, along with other cystic lung diseases with

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spontaneous pneumothorax, such as alpha 1 antitrypsin deficiency, Marfan syndrome, Ehlers–Danlos syndrome, pulmonary lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, and cystic fibrosis [27, 32]. Limited CT scans through the lung bases need to be scrutinized with lung window settings to assess for thin-walled cysts and/or pneumothorax when multiple homogeneously enhancing renal masses are present on abdominal CT scans. (Fig.3c,d）

Management

BHD-associated renal tumors diagnosed at a mean age of 50 years commonly present as bilateral and multifocal [29]. Usually, the progression of BHD-associated RCCs is slow, and nephron-sparing surgery is indicated rather than radical nephrectomy [28]. Minimally-invasive nephron-sparing techniques such as cryoablation and radiofrequency ablation might be considered for tumors < 3 cm [28]. However, not all diseases should be considered indolent because metastatic RCCs in patients with BHD have been reported [34].

Tuberous Sclerosis Complex

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TSC is an autosomal dominant neurocutaneous disorder caused by germline mutations in either the TSC1 gene on chromosome 9q34, which encodes for hamartin, or the TSC2 gene on chromosome 16p13.3, which encodes for tuberin. It is characterized by the formation of hamartomas in multiple organ systems, including the kidney, lung, brain, heart, eye, skin, and bone [5, 35]. Although about 30% of TSC patients have a family history, and the penetrance of TSC gene is about 100%, spontaneous germline mutations occur in 70% of all TSC patients [5]. The clinical criteria of TSC revised in 2012 consists of 11 major features, which include hypomelanotic macules (≥3, at least 5-mm diameter), angiofibromas (≥3) or fibrous cephalic plaque, ungual fibromas (≥2), shagreen patch, multiple retinal hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytoma (SEGA), cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), and angiomyolipomas (≥2). In addition, there were 6 minor features, which include “Confetti” skin lesions, dental enamel pits (>3), intraoral fibromas (≥2), retinal achromic patch, multiple renal cysts, and nonrenal hamartomas [36]. A definite diagnosis of TSC is made when two major features or one major feature with ≥2 minor features are present. A possible diagnosis of TSC is made when either one major feature or ≥2 minor features are present.

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AML is the most common renal manifestation in 55%–80% of patients with TSC [35, 37]. The second most common renal lesion in patients with TSC is the renal cyst (20%–50% of cases) [37]. AML is typically seen as multiple bilateral fat-containing renal masses without calcification [20]. Fat poor AML (hyperattenuating type) is seen as a hyperattenuating homogeneous mass on unenhanced CT, a

hypointensity on T2-weighted images, and an early hyperenhancement with subsequent washout on dynamic contrast-enhanced imaging [20, 38, 39]. (Fig.5) RCCs occur at a younger age (average age 28 years) in 1%–4% of patients with TSC, which is a slightly higher estimated incidence than that in the general population [5, 40]. In addition, patients with epithelioid AML were more commonly associated with TSC, compared to those without epithelioid component. (26.7% vs. 6.7%) [41]. (Fig.6)

In addition to skin lesions (90% of TSC patients), brain lesions, such as cortical dysplasia (90% of TSC patients), and subependymal nodules (80% of TSC patients) (Fig.5), are common manifestations in TSC [36]. Other tumors including pulmonary lymphangioleiomyomatosis (26%–39% of TSC patients) characterized by numerous thin-walled cysts throughout the lungs (Fig.5), multifocal micronodular pneumocyte hyperplasia (MMPH) (40%–58% of infants with TSC) seen as focal ground-glass nodules on

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imaging (Fig.5), and cardiac rhabdomyoma (50%–70% of TSC patients) (Fig.7) are also common radiological manifestations in TSC [35, 36]. The diagnosis of LAM occurs in up to 42% of women with TSC by the age of 40 years and in 13% of males with TSC [42]. Symptomatic LAM in male patients is reported to be rare [42]. Sclerotic bone lesions in TSC patients are a common finding on radiologic studies. (Fig.5) A previous study showed that the presence of 4 or more sclerotic bone lesions on the CT of the body differentiates patients with sporadic LAM from those with TSC/LAM or TSC, with high sensitivity (89%–100%) and specificity (97%) [43]. Sclerotic bone lesions can be the radiological diagnostic clue of TSC in patients without any detectable renal tumors and LAM lesions on imaging.

Cardiac rhabdomyoma is the most common primary cardiac tumor in infants and is one of the major characteristic manifestations suggesting TSC [36, 44]. Although cardiac rhabdomyoma often regresses spontaneously, the tumor can cause outflow obstruction or arrhythmia depending on its location [36]. In terms of prognosis, CNS tumors, including subependymal nodules, cortical dysplasia, and SEGA (Fig.8), are the leading cause of morbidity and mortality in TSC, followed by renal lesions [45].

Management

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In a Japanese clinical practice guideline for renal AML associated with TSC, abdominal US is recommended for the initial screening of AML and subsequent CT or MRI examinations are recommended in patients with symptoms or any renal lesions suspicious for malignancy [46].

Prophylactic arterial embolization for classic triphasic AML can be considered depending on the size and growth rate of tumors or aneurysms. Generally, prophylactic arterial embolization for AML is

recommended in patients who have AMLs ≥ 4 cm or aneurysms ≥ 5 mm [47]. Emergency arterial embolization for hemostasis is also recommended [46, 48]. The dysregulation of the mammalian target of rapamycin (mTOR) pathway is implicated in the TSC disease pathology; hence, the pathway has been investigated as a potential treatment target for TSC [45, 49]. In the 2012 international TSC consensus conference, for asymptomatic AML growing larger than 3 cm in diameter, treatment with an mTOR inhibitor is the recommended first-line treatment [50]. In the Japanese clinical practice guideline for renal AML in TSC, everolimus is recommended in adult patients with a renal AML ≥ 3 cm or diffuse renal AMLs including asymptomatic patients [46]. AML volume and mean CT value at baseline were factors influencing the short-term volume response of everolimus or sirolimus for TSC-AML [51]. (Fig.9) In TSC patients with enlarging SEGA, LAM, skin lesions, symptomatic cardiac rhabdomyomas, and partial seizures, mTOR inhibitors can be a therapeutic option [45].

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Hereditary Papillary Renal Cell Carcinoma

HPRC is an autosomal-dominant syndrome, caused by germline mutations in the MET gene, on chromosome 7q31, characterized by multifocal bilateral type I papillary RCCs [5, 52].

It is estimated that an HPRC patient has approximately 90% likelihood of developing kidney cancer by 80 years of age [53]. RCCs in HPRC usually have a late onset (50–70 years of age) and are typically not associated with extrarenal manifestations [5]. Renal lesions may range from microscopic papillary adenomas to papillary carcinomas, and HPRC patients are at risk for the development of up to 3,400 microscopic papillary tumors in a single kidney [5]. The imaging features of hereditary papillary RCC are typical of papillary RCC, which are seen as multifocal hypovascular renal masses [4, 20]. (Fig.10)

No known extrarenal manifestations.

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Management

Papillary RCCs in HPRC are less likely to have metastases, recurrence and RCC-specific death than other RCC subtypes [54]. Similar to the management in VHL patients, active surveillance until the largest tumors reach the 3-cm threshold is recommended for HPRC patients [53].

Hereditary Leiomyomatosis and Renal Cell Cancer

HLRCC is an autosomal-dominant familial tumor syndrome characterized by skin and uterine leiomyomas and HLRCC-associated RCC [5, 55]. In 2002, the fumarate hydratase (FH) gene on chromosome 1q42.3–q43 was detected to be an oncogene, the function of which was lost in germline cells [55]. FH is one of the major metabolic enzymes of the tricarboxylic acid (TCA) cycle and loss of FH enzymatic activity leads to the intracellular accumulation of fumarate, which was recently defined as an oncometabolite due to its role in tumorigenesis [56].

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HLRCC-associated RCC is currently recognized as a separate entity in the latest WHO classification for 2016 [9]. RCCs occur in approximately 20% of HLRCC patients [5]. HLRCC-associated RCC is highly aggressive and has poor prognosis compared to other HRTSs [57]. Metastases can be observed in patients with HLRCC-associated RCCs sized < 3 cm unlike in RCCs sized < 3 cm in other HRTSs, including VHL and BHD [58]. A solitary unilateral renal tumor of HLRCC-associated RCC with a size of 0.9–20 cm in size is more common than multiple renal lesions [55, 59]. HLRCC-associated RCC is a spectrum disease from papillary type 2 RCC, tubullopapillary RCC, and collecting duct carcinoma, which can be seen as hypovascular lesions on imaging [4, 20, 55]. The current genetic analyses revealed that in papillary RCC, the group with genetic abnormalities in FH had the worst prognosis [60]. HLRCC- associated RCCs can be depicted as solid, cystic, or mixed lesions [55, 59]. Cystic RCCs which can be shown as cystic renal masses with thickened wall or septa have good prognoses relative to solid clear cell RCCs [61-63]. On the other hand, FH-deficient HLRCC-associated RCC possibly presenting with cystic components is often related to poor prognosis. Hence, a more proactive approach and close follow-up will be necessary for the appropriate patient management. (Fig.11) ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging is useful for the evaluation of tumor distributions because of the uptake of glucose by tumor cells, Warburg physiology [64, 65].

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Skin leiomyomas which locate in limbs, trunk and occasionally in the face, are usually from 0.2 to 2 cm, but can be up to 4 cm [66]. The risk of skin leiomyomas by the age of 35 years was higher in men (100%) than in women (55%) [67]. Uterine leiomyomas in female patients with HLRCC, tend to be large, numerous, early onset, and highly symptomatic [68]. The average age for hysterectomies for uterine leiomyomas in HLRCC patients was 30 years compared to 45 years age in the general population [69].

Management

Early surgical intervention with a wide surgical margin is recommended in HLRCC-associated RCC due to the aggressive nature compared to other HRTSs, including VHL, BHD, and HPRC [8].

Hereditary Paraganglioma-Pheochromocytoma Syndrome

Germline mutations in genes encoding subunits of mitochondrial succinate dehydrogenase (SDH), which is a part of the TCA cycle and the mitochondrial electron transport chain, have been shown to cause

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hereditary paraganglioma-pheochromocytoma syndrome [70, 71]. Patients with mutations in SDH subunit genes have increased risk of developing tumors in several organs, including pheochromocytoma, paraganglioma, gastrointestinal stromal tumor (GIST), and RCC [72].

SDH-deficient RCC is a recently recognized distinct subtype of RCC in the 2016 World Health Organization classification [9]. (Fig.12) SDHB-mutated RCC is the most frequent SDH-deficient RCC [10]. The lifetime risk of renal tumor in patients with the SDHB gene mutation has been estimated as 14% [10, 73]. Germline SDHB mutations are associated with increased risk of early-onset and metastatic disease, even in small RCCs [70, 71]. Patients can develop various RCCs including clear cell,

chromophobe, and oncocytomas, which is characterized by an oncocytic histologic appearance with eosinophilic cytoplasm consistent with mitochondrial accumulation [10]. Similar to HLRCC, SDH- deficient RCC has potential to behave aggressively and FDG-PET imaging is helpful for the evaluation of the tumor because of the similarity of their metabolic basis with the impairment of TCA cycle function and a metabolic shift to aerobic glycolysis [71].

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Hereditary paraganglioma-pheochromocytoma syndrome needs to be differentiated from other hereditary neoplasia syndromes, such as multiple-endocrine neoplasia type 2, VHL, and type 1 neurofibromatosis [70, 72]. Mutations in one of the SDH subunit genes (most commonly SDHB and SDHD mutations) may be present in up to 25% of all patients with pheochromocytoma/paragangliomas [74]. The cumulative risk of clinically apparent pheochromocytomas or paragangliomas by the age of 60 years in carriers with SDHB, SDHD, and SDHC are 22%, 43%, and 25%, respectively [75]. The incidence of GISTs has been estimated as 2% of carriers of SDHB mutation [74]. The majority of GISTs associated with

paragangliomas occur in individuals with a germline pathogenic variant in SDHA or SDHC [72].

Management

In patients with SDHB gene mutation, MRI-based imaging protocols 1–2 yearly for the detection of SDHB-related tumors, including paraganglioma, phaeochromocytoma, RCC, and GIST are recommended as a surveillance, thereby minimizing radiation exposure [76]. Active surveillance for SDH-deficient RCC is not an option, and surgical intervention is recommended due to their aggressive nature [8, 70].

Individuals with SDHB pathogenic variants and pheochromocytoma/paragangliomas may benefit from

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resection over watchful waiting because up to 50% of patients with metastatic extra-adrenal tumors have a germline SDHB mutation [77].

Other Hereditary Tumor Syndromes

BAP1-TPDS is an autosomal-dominant hereditary tumor syndrome first described in 2011 and is caused by germline mutations in BAP1, which is associated with BAP1-inactivated melanocytic tumors, uveal melanoma, malignant mesothelioma, and cutaneous melanoma [6, 78]. RCC is also reported to be associated with this syndrome, particularly early-onset aggressive clear cell RCC [79, 80]. In management recommendations for families with germline BAP1 mutation proposed by Rai K, et al., yearly abdominal US with MRI every 2 years were recommended in reference to the protocol for renal lesions in VHL patients [81].

Constitutional chromosome 3 translocations are associated with the increased risk of clear cell RCCs [5].

Multiple genes including VHL, protein polybromo-1, BAP1, and SET domain containing 2 located on chromosome 3p are relevant to the pathogenesis of clear cell RCC [82]. Similar to VHL, close imaging follow-up and nephron-sparing surgery are recommended [7]. However, the risk of RCC is not high in

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individuals without a family history of clear cell RCC, or the translocation breakpoint involving a tumor suppressor gene; hence, annual renal surveillance should not be routinely offered to such patients [5, 83].

In the PTEN hamartoma tumor syndrome which is characterized by hamartomatous tumors and germline mutations of the PTEN tumor suppressor gene, the Cowden syndrome with high estimated lifetime risks for breast (35%), thyroid (85%), and endometrial (28%) cancers has been reported to be related to RCC (34%) [84, 85]. Patients most frequently present with unilateral papillary RCCs [86]. Biannual renal surveillance with US or MRI has been suggested starting at the age of 40 [84].

MiTF-associated cancer syndrome which has a specific germline mutation of the melanoma oncogene, MiTF (p.E318K), has been identified to be associated with malignant melanoma and RCC [12, 87].

Although the histological subtype of RCC associated with MiTF (p.E318K) has not been characterized well, clear cell and papillary histology were most often reported [88, 89]. Currently, no specific imaging recommendations are available.

Conclusion

Hereditary renal tumor syndrome (HRTS) is a systemic disease with a wide spectrum of clinical and imaging manifestations. Integrating renal and extrarenal imaging findings with the clinical manifestation

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for each patient with systemic disease can help narrow the differential diagnosis and lead to the appropriate clinical diagnosis to improve patient care.

Compliance with ethical standards

Conflict of interest The authors declare no conflicts of interest associated with this

manuscript.

Ethical statement This article does not contain any studies with human participants or

animals performed by any of the authors.

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Table1. Histologic renal tumor type and associated hereditary renal tumor syndromes Common histologic renal

tumor type

Syndrome ^a Gene Extrarenal manifestations

Clear cell RCC VHL VHL Retinal and central nervous system hemangioblastomas,

endolymphatic sac tumor, pancreatic neuroendocrine tumor, pheochromocytoma, epididymal cystadenoma, others

BAP1-TPDS BAP1 BAP1-inactivated melanocytic tumors, uveal melanoma,

malignant mesothelioma, cutaneous melanoma, others

Constitutional chromosome 3 translocations Chromosome 3 -

Chromophobe RCC BHD ^b FLCN Cutaneous lesions (e.g., fibrofolliculomas, and acrochordons),

pulmonary cysts

Papillary RCC PTEN hamartoma tumor syndrome PTEN Breast cancer, thyroid cancer, endometrial cancer, others

Type1 papillary RCC HPRC MET -

Type2 Papillary RCC HLRCC FH Skin leiomyomas, uterine leiomyomas

Angiomyolipoma TSC TSC1, TSC2 Cutaneous lesions (e.g., angiomyofibromas), cortical dysplasia

subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis

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RCC = renal cell carcinoma, VHL = von Hippel–Lindau disease, BAP1-TPDS = Breast cancer–associated protein 1 - tumor predisposition syndrome, BHD = Birt-Hogg- Dubé syndrome, HPRC = hereditary papillary renal carcinoma, PTEN = Phosphatase and tensin homolog, HLRCC = hereditary leiomyomatosis and renal cell cancer, TSC = tuberous sclerosis complex, FLCN = folliculin, MET = mesenchymal-epithelial transition, FH = fumarate hydratase

a In succinate dehydrogenase-deficient RCC of hereditary paraganglioma-pheochromocytoma syndrome, various patterns overlapping with other known histological subtypes including clear cell RCC, chromophobe RCC, papillary RCC, sarcomatoid RCC, unclassified RCC and renal oncocytoma have been described. (Source—

Reference 10)

b The most frequent histologic RCC subtype is the hybrid oncocytic/chromophobe tumor which was classified as a subcategory of chromophobe RCC. (Source—Reference 11)

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Figure Legends

Figure 1a

Fig. 1 A 60-year-old male with von Hippel–Lindau (VHL) disease. (a) Contrast-enhanced computed

tomography (CT) scan in the corticomedullary phase reveals an exophytic heterogeneously

hyperenhancing renal mass in the left lower renal pole (arrow) and a hyperenhancing pancreatic mass (pathologically confirmed pancreatic neuroendocrine tumor) (arrowhead), which were pathologically proven to be clear cell renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor, respectively. (b) Enhanced CT scan obtained at the level of the upper liver also depicts a hyperenhancing nodule in the spinal canal (arrow), consistent with spinal cord hemangioblastoma. (c) Gadolinium-based contrast-

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enhanced T1-weighted image shows a hyperenhancing mass with a cystic component centered in the periphery of the cerebellum near the prior postoperative change of the posterior cranial fossa and a nodule in the left cerebellum (arrows), consistent with recurrent hemangioblastomas.

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Figure 1b

hyperenhancing renal mass in the left lower renal pole (arrow) and a hyperenhancing pancreatic mass (pathologically confirmed pancreatic neuroendocrine tumor) (arrowhead), which were pathologically proven to be clear cell renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor, respectively. (b) Enhanced CT scan obtained at the level of the upper liver also depicts a hyperenhancing nodule in the spinal canal (arrow), consistent with spinal cord hemangioblastoma. (c) Gadolinium-based contrast- enhanced T1-weighted image shows a hyperenhancing mass with a cystic component centered in the

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periphery of the cerebellum near the prior postoperative change of the posterior cranial fossa and a nodule in the left cerebellum (arrows), consistent with recurrent hemangioblastomas.

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Figure 1c

hyperenhancing renal mass in the left lower renal pole (arrow) and a hyperenhancing pancreatic mass (pathologically confirmed pancreatic neuroendocrine tumor) (arrowhead), which were pathologically proven to be clear cell renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor, respectively. (b) Enhanced CT scan obtained at the level of the upper liver also depicts a hyperenhancing nodule in the spinal canal (arrow), consistent with spinal cord hemangioblastoma. (c) Gadolinium-based contrast- enhanced T1-weighted image shows a hyperenhancing mass with a cystic component centered in the

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periphery of the cerebellum near the prior postoperative change of the posterior cranial fossa and a nodule in the left cerebellum (arrows), consistent with recurrent hemangioblastomas.

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Figure 2

Fig. 2 A 44-year-old male with history of VHL. Corticomedullary phase contrast-enhanced CT scan

reveals hyperenhancing solid nodules (white arrows) consistent with clear cell RCCs, a cystic tumor with enhancing components (black arrow), and multiple renal cysts (arrowheads).

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Figure 3

Fig. 3 A 42-year-old female without a family history of RCC. (a) Corticomedullary phase contrast-

enhanced CT scan shows a homogeneously enhancing right renal mass (pathologically confirmed hybrid oncocytic/chromophobe tumor) (arrow) with washout on excretory phase contrast-enhanced CT (not shown). (b) CT scan with the lung window setting reveals bilateral lung cysts with septations

predominantly in the lower and peripheral lungs (arrows). (c) CT scan with the lung window setting also shows left mild pneumothorax (arrow) and post-surgical state of the right upper lung for pneumothorax.

The patient was genetically diagnosed with Birt-Hogg-Dubé Syndrome.

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Figure 3b

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Figure 3c

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Figure 4a

Fig. 4 A 65-year-old male with multiple renal masses without a family history of RCC. (a, b) Contrast-

enhanced CT scan in the corticomedullary phase reveals bilateral renal masses with homogeneous hypoenhancement relative to that of the background renal cortex (arrows), which are not typical of conventional clear cell RCC. Additional renal masses with similar imaging features were also present on CT (not shown). Image-guided percutaneous renal biopsy revealed B-cell lymphoblastic

leukemia/lymphoma.

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Figure 4b

Fig. 4 A 65-year-old male with multiple renal masses without a family history of RCC. (a, b) Contrast-

enhanced CT scan in the corticomedullary phase reveals bilateral renal masses with homogeneous hypoenhancement relative to that of the background renal cortex (arrows), which are not typical of conventional clear cell RCC. Additional renal masses with similar imaging features were also present on CT (not shown). Image-guided percutaneous renal biopsy revealed B-cell lymphoblastic

leukemia/lymphoma.

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Figure 5a

Fig. 5 A 35-year-old female with tuberous sclerosis complex (TSC). (a) Unenhanced CT scan shows

multiple bilateral renal masses with slight hyperattenuation relative to the renal parenchyma (arrows), suggestive of renal angiomyolipoma (AML) with minimal fat. (b) CT scan with the lung window setting shows multiple pulmonary cysts in the upper lungs with well-defined thin walls distributed randomly throughout the lungs (not shown) and a focal ground-glass nodule (arrow), suggestive of pulmonary lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia, respectively. (c) CT scan with the bone window setting reveals multiple sclerotic lesions in the sacrum and left ilium (arrows), suggestive of osteomas. (d) Unenhanced CT scan reveals calcified subependymal tubers associated with TSC (arrows).

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Figure 5b

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Figure 5c

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Figure 5d

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Figure 6

Fig. 6 A 40-year-old female with multiple AML related to TSC. Corticomedullary phase contrast-

enhanced CT scan shows a right exophytic heterogeneously hyperenhancing renal mass (arrow). It increased in size for 2 years and was pathologically confirmed to be epithelioid angiomyolipoma by needle biopsy. Right partial nephrectomy was subsequently performed. Bilateral fat-containing AMLs are also present.

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Figure 7

Fig. 7 A 16-day-old boy with multiple cardiac masses and subependymal nodules on prenatal

ultrasonography (not shown), suggestive of TSC. (a) Steady-state free precession cine image shows a dominant homogeneous hypointense cardiac mass occupying the right ventricle (arrow), which was shown to be of slight hyperattenuation on unenhanced CT (not shown). Other smaller cardiac masses were not shown. Findings were indicative of cardiac rhabdomyoma associated with TSC. After the introduction of mTOR inhibitor therapy, the cardiac masses gradually decreased in size over months (not shown).

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Figure 8

Fig. 8 An 8-year-old female with bilateral small renal cysts related to known TSC (not shown). (a) Fluid-

attenuated inversion recovery image shows a hyperintense left intraventricular tumor, obstructing the foramen of Monro with hydrocephalus (arrow) with strong enhancement on Gd-enhanced T1-weighted images (not shown). Multiple cortical tubers are also present (arrowheads). Histopathologically, the left intraventricular tumor was proven to be subependymal giant cell astrocytoma.

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Figure 9a

Fig. 9 A 39-year-old female with multiple AMLs associated with TSC. (a) Unenhanced CT scan shows

bilateral renal AMLs with both fat and non-fat components (arrows). (b) A follow-up unenhanced CT scan 6 months after the introduction of mTOR inhibitor therapy reveals a substantial decrease in the amount of the non-fat components of bilateral AMLs (arrows) compared to the fat components in the AMLs.

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Figure 9b

Fig. 9 A 39-year-old female with multiple AMLs associated with TSC. (a) Unenhanced CT scan shows

bilateral renal AMLs with both fat and non-fat components (arrows). (b) A follow-up unenhanced CT scan 6 months after the introduction of mTOR inhibitor therapy reveals a substantial decrease in the amount of the non-fat components of bilateral AMLs (arrows) compared to the fat components in the AMLs.

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Figure 10a

Fig. 10 A 51-year-old male presented with recurrent multifocal papillary RCCs five years after bilateral

partial nephrectomies. (a, b) Nephrogenic phase enhanced CT scan shows a dominant 5.5 cm hypoenhancing right renal mass arising at the previous partial nephrectomy site with perinephric fat invasion (arrow) and smaller hypoenhancing masses in the bilateral kidneys (arrowheads). No metastatic lesions were present. Right and then left radical nephrectomies were subsequently performed.

Histopathologic examinations revealed the dominant right renal mass with perinephric fat invasion (pT3a) and left renal mass with renal sinus invasion (pT3a). Other multifocal renal masses were confined to the kidneys. All of renal masses were identified as type I papillary RCC. Molecular genetic testing identified a pathogenic mutation in mesenchymal-epithelial transition (MET), consistent with a diagnosis of hereditary papillary renal cell carcinoma.

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Figure 10b

Fig. 10 A 51-year-old male presented with recurrent multifocal papillary RCCs five years after bilateral

partial nephrectomies. (a, b) Nephrogenic phase enhanced CT scan shows a dominant 5.5 cm hypoenhancing right renal mass arising at the previous partial nephrectomy site with perinephric fat invasion (arrow) and smaller hypoenhancing masses in the bilateral kidneys (arrowheads). No metastatic lesions were present. Right and then left radical nephrectomies were subsequently performed.

Histopathologic examinations revealed the dominant right renal mass with perinephric fat invasion (pT3a) and left renal mass with renal sinus invasion (pT3a). Other multifocal renal masses were confined to the kidneys. All of renal masses were identified as type I papillary RCC. Molecular genetic testing identified a pathogenic mutation in mesenchymal-epithelial transition (MET), consistent with a diagnosis of hereditary papillary renal cell carcinoma.

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Figure 11a

Fig. 11 A 60-year-old male with history of cutaneous leiomyomatosis presented with an incidentally

detected left renal mass. (a) Nephrogenic phase contrast-enhanced CT scan shows a unilocular left cystic renal mass with multiple hypoenhancing mural nodules relative to the renal parenchyma (arrows). No metastatic lesions were observed. (b) A high-power microscopic view of the surgical specimen reveals cells in mural nodules with papillary growth to have prominent nuclei with a clear halo (H&E, 200×, arrows). On subsequent immunohistochemistry, the cells demonstrated fumarate hydratase (FH) negative staining (not shown) indicative of FH-deficient papillary RCC and the patient was clinically diagnosed with hereditary leiomyomatosis and renal cell cancer syndrome. (c) ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT fusion image at 1 year after the resection of the left renal mass demonstrates an FDG avid enlarged lymph node in the left para-aortic retroperitoneum (arrow).

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Additional FDG avid mediastinal lymphadenopathy and multiple bone metastases in the rib and ilium were present (not shown).

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Figure 11b

detected left renal mass. (a) Nephrogenic phase contrast-enhanced CT scan shows a unilocular left cystic renal mass with multiple hypoenhancing mural nodules relative to the renal parenchyma (arrows). No metastatic lesions were observed. (b) A high-power microscopic view of the surgical specimen reveals cells in mural nodules with papillary growth to have prominent nuclei with a clear halo (H&E, 200×, arrows). On subsequent immunohistochemistry, the cells demonstrated fumarate hydratase (FH) negative staining (not shown) indicative of FH-deficient papillary RCC and the patient was clinically diagnosed with hereditary leiomyomatosis and renal cell cancer syndrome. (c) ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT fusion image at 1 year after the resection of the left renal mass

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demonstrates an FDG avid enlarged lymph node in the left para-aortic retroperitoneum (arrow).

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Figure 11c

detected left renal mass. (a) Nephrogenic phase contrast-enhanced CT scan shows a unilocular left cystic renal mass with multiple hypoenhancing mural nodules relative to the renal parenchyma (arrows). No metastatic lesions were observed. (b) A high-power microscopic view of the surgical specimen reveals cells in mural nodules with papillary growth to have prominent nuclei with a clear halo (H&E, 200×, arrows). On subsequent immunohistochemistry, the cells demonstrated fumarate hydratase (FH) negative staining (not shown) indicative of FH-deficient papillary RCC and the patient was clinically diagnosed with hereditary leiomyomatosis and renal cell cancer syndrome. (c) ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT fusion image at 1 year after the resection of the left renal mass

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demonstrates an FDG avid enlarged lymph node in the left para-aortic retroperitoneum (arrow).

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Figure 12

Fig. 12 A 24-year-old male with a family history of RCC.Late arterial phase contrast-enhanced T1-

weighted image with fat suppression shows a right heterogeneously hyperenhancing renal mass (arrow).

The renal mass was pathologically diagnosed with SDH-deficient RCC with sarcomatoid features, neoplastic cells of which show loss of succinate dehydrogenase (SDH)-B immunostaining. Metastatic carcinoma in the right adrenal gland was also present (not shown).