Renal Tumors Associated with Familial Syndromes – Updates on Diagnosis and Clinical Implication

Abstract

Renal tumors associated with familial syndromes, characterized by germline mutations in specific genes such as VHL, MET, FLCN, TSC1, TSC2, FH, and SDHB, offer critical insights into renal cell carcinoma tumorigenesis and necessitate tailored genetic counseling, screening, and surveillance. Each syndrome exhibits unique clinical manifestations, impacting treatment strategies and long-term patient management. This review summarizes recent advances in the clinicopathologic, immunohistochemical, and molecular characteristics of both established and emerging familial renal cell carcinoma syndromes. Key syndromes include von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, hereditary leiomyomatosis renal cell carcinoma, Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, hereditary paraganglioma-pheochromocytoma syndrome, BAP1 tumor predisposition syndrome, and PTEN hamartoma tumor syndrome. The review emphasizes the importance of pathological assessment in diagnosing these syndromes, especially in cases where clinical presentations are insufficient to raise specific suspicions. Understanding these familial syndromes is crucial for accurate diagnosis, effective patient management, and the development of surveillance programs to improve outcomes for patients and their families.

Keywords

Hereditary renal cell carcinoma familial VHL HLRCC Birt-Hogg-Dubé tuberous sclerosis complex

INTRODUCTION

Renal cell carcinoma (RCC) encompasses a heterogeneous group of tumors with diverse clinicopathologic features and underlying biological mechanisms. This broad spectrum of tumor characteristics and clinical behaviors is also observed among renal tumors associated with various familial renal cancer syndromes, posing diagnostic challenges and emphasizing a need for tailored management approaches. Importantly, beyond the task of treating renal tumors in individual patients, a diagnosis of familial RCC syndrome carries significant long-term implications for patients and their families and necessitates appropriate genetic counseling, screening, and surveillance.

Studies of renal tumors with syndromic associations have yielded invaluable insights into the oncogenic pathways implicated in RCC tumorigenesis, pinpointing germline alterations in genes such as VHL, MET, FLCN, TSC1, TSC2, FH, and SDHB as the molecular basis of predisposition to various familial RCC syndromes. These implicated genes are predominantly tumor suppressor genes (except the MET proto-oncogene) and typically require a somatic “second-hit” impairing the remaining wildtype allele and precipitating tumorigenesis. Consequently, while established familial RCC syndromes mostly follow an autosomal dominant inheritance pattern, the penetrance can vary significantly among different syndromes.

Clinical suspicion of RCC familial syndromes often stems from indicators such as a young age of onset (<46 years), bilateral or multifocal renal tumors, a family history of kidney cancer, and personal or familial extrarenal presentations, such as pneumothorax, skin leiomyoma, or early onset multiple uterine leiomyomas. While these clinical considerations aid in identifying some RCC syndrome patients, it has become evident that pathologic assessment plays a pivotal role in diagnosing familial RCC syndromes, particularly for patients whose clinical presentations are insufficient to raise specific suspicions.

This review aims to provide an update on recent advances in the clinicopathologic, immunohistochemical, and molecular characteristics of established and emerging familial renal cancer syndromes, along with a concise discussion of diagnostic and clinical implications to facilitate a comprehensive understanding of these syndromes. The key genetic, pathologic, and extrarenal presentations of established renal tumor-associated familial syndromes are summarized in Table 1. Accurate recognition of these hereditary renal tumors through pathological assessment requires not just familiarity with the tumors’ histologic characteristics, but also awareness of potential findings in the surrounding renal parenchyma and manifestations outside the kidneys.

Table 1.

Hereditary renal cancer syndromes.

Syndrome	Gene (locus) – Protein	Associated renal tumors	Immunohistochemical (IHC) features	Findings in the background renal parenchyma	Extrarenal manifestations
von Hippel-Lindau (VHL) Disease	VHL (3p25) – pVHL	Clear cell RCC	Similar to sporadic counterpart	Clear cell proliferation or aggregates, clear cell-lined renal cysts	CNS and retinal hemangioblastomas, pheochromocytoma, pancreatic endocrine tumors, cystadenoma (epididymal, broadligament), endolymphatic sac tumor, etc.
Hereditary Papillary RCC	MET (7q31) – MET (Mesenchymal Epithelial Transition)	Papillary RCC, classic (type 1) morphology	Similar to sporadic counterpart	Numerous or innumerable microscopic papillary adenomas	None
Fumarate Hydratase (FH)-Tumor Predisposition Syndrome [or Hereditaryleiomyomatosisand RCC (HLRCC) syndrome]	FH (1q42.1) – Fumarate Hydratase	FH-deficient RCC	Essential: - FH loss (∼80% cases) - 2SC positivity (diffuse, nuclear and cytoplasmic) Others: variable, often are CK7 (–)	Unremarkable (often), renal cysts	Cutaneous leiomyomas, uterine leiomyomas, pheochromocytoma-paraganglioma, and others (e.g. Leydig cell tumor*)
Birt-Hogg-Dubé (BHD) syndrome	FLCN (17p11.2) – Folliculin	Hybrid oncocytic tumors (HOT), chromophobe, and other types of RCCs	HOT: contains intermixed clear cells and eosinophilic/oncocytic cells or mimics eosinophilic chromophobe RCC/oncocytoma. Others: similar to sporadic counterparts	Microscopic oncocytic nodules/proliferations, cysts lined by oncocytic cells, or oncocytic changes in non-neoplastic renal tubules	Pulmonary cysts, skin fibrofolliculomas and other lesions (e.g.colon polyp or colorectal cancer*)
Tuberous Sclerosis Complex (TSC)	TSC1 (9q34) – Hamartin, TSC2 (16p13.3) – Tuberin	Angiomyolipoma (AML), RCC with a range of morphology, some are similar to sporadic counterparts [eosinophilic solid and cystic (ESC) RCC, RCC with fibromyomatous stroma, eosinophilic vacuolated tumor (EVT), low-grade oncocytic tumor (LOT), etc.]	Similar to sporadic counterparts	Renal cysts, microscopic AML, bilateral multiple renal lesions	Cardiac rhabdomyomas, hamartomas, neurologic disorders/seizures
Succinate dehydrogenase (SDH)-associated Pheochromocytoma/Paraganglioma Syndrome Type 4	SDHB (1p36), SDHA (5p15), SDHC (1q23.3), SDHD (11q23), and SDHAF2 (11q12.2) – Succinate dehydrogenase complex	SDH-deficient RCC (most cases with underlying SDHB gene alterations)	Essential: SDHB loss (IHC typically also detects SDH-deficiency caused by alterations of SDHA, SDHC, etc.)	Unremarkable (often)	Bilateral and extra-adrenal pheochromocytoma/paraganglioma, and other malignancies
BAP1 tumor predisposition syndrome	BAP1 (3p21.1) -BRCA1 Associated Protein 1	Clear cell RCC, other histologic subtypes of RCC*	Similar to sporadic counterparts; BAP1 loss by IHC is helpful but can also be seen in sporadic cases	Unknown	Increased risk for BAP1-inactivated atypical melanocytic tumors, uveal or cutaneous melanomas, mesothelioma
PTEN hamartoma tumor syndromes (Cowden syndrome etc.)	PTEN (10q23.3) – Phosphatidylinositol 3,4,5-triphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Papillary, chromophobe, clear cell RCC, and RCC, NOS	Similar to sporadic counterparts, no specific morphologic features identified yet; PTEN loss by IHC in a large portion of reported cases but not recommended as a screening/diagnostic tool	Renal cysts, distal tubular hyperplasia, intrarenal lipomas/lipomatous hamartoma	Increased risk for breast, thyroid, endometrial, and other cancers; benign breast, thyroid, GI tract, uterine, and skin lesions; neurodevelopmental disorders
Hyperparathyroidism-jaw tumor syndrome	CDC73 (1q31.2) – Parafibromin	Mixed epithelial and stromal tumors (MEST), Wilms tumors, Papillary RCC	Similar to sporadic counterparts; Parafibromin loss by IHC may be useful*	Renal cyst	Primary hyperparathyroidism from adenoma or carcinoma, ossifying fibromas of maxilla and mandible, uterine tumors
MITF predisposition to melanoma and familial RCC	MITF (3p13) – Melanocyte Inducing Transcription Factor (pE318K germline variant)	Uncertain, papillary and clear cell RCC reported	Similar to sporadic counterparts; utility of MITF IHC stainis uncertain	Unknown	Increased risk of melanoma

2SC: S-(2-succinyl) cysteine; CK: cytokeratin; CNS: central nervous system; GI: gastrointestinal; IHC: immunohistochemistry; NOS; not otherwise specified; RCC: renal cell carcinoma. *Limited data on the association with the corresponding germline alterations.

VON HIPPEL-LINDAU (VHL) DISEASE/SYNDROME

VHL disease is a rare hereditary syndrome caused by mutations in the VHL gene, located on the short arm of chromosome 3 (3p25-26). It occurs in approximately 1 in every 36,000 live births and has over 90% penetrance by 65 years of age; the estimated prevalence in the United States is 0.92 per 100,000 persons [1, 2]. The syndrome is characterized by a predisposition to develop cysts and benign or malignant tumors in multiple organs including the kidneys. The most common manifestations are clear cell RCCs, hemangioblastomas of the central nervous system (CNS) and retina, pheochromocytomas or paragangliomas, pancreatic neuroendocrine tumors and cystadenomas, endolymphatic sac tumors of the inner ear, and papillary cystadenomas of the epididymis or broad ligament. The tumorigenesis of this variety of tumors in VHL patients centers on the inactivation of VHL protein, a crucial regulator of ubiquitin-mediated degradation of hypoxia-inducible factor (HIF), which results in constitutive activation of HIF-mediated transcriptional pathways that promote tumor vascularization and growth [3,4].

RCCs associated with VHL syndrome are often early onset, bilateral, and multifocal. They typically exhibit the classic histomorphology of clear cell RCC, such as small acinar architecture and a rich vascular network surrounding tumor acini (Fig. 1A). The multifocal renal tumors observed in VHL patients usually develop independently and do not represent intrarenal tumor spread [5]. In the adjacent renal parenchyma, microscopic clear cell proliferation and clear cell-lined renal cysts (Fig. 1B) are commonly found. Together with multifocality, these are important clues to pathologists to distinguish VHL syndrome from sporadic clear cell RCC. Intriguingly, RCC associated with VHL syndrome rarely can exhibit morphologic and immunohistochemical features resembling clear cell papillary renal cell tumor (ccpRCT), which is somewhat counterintuitive as sporadic cases of ccpRCT typically lack VHL mutation or chromosomal 3p loss [6–8]. Additionally, driven by a similar biologic process, VHL-associated extra-renal tumors commonly share clear cell features, thus morphologically mimicking RCC and often requiring ancillary immunohistochemistry (IHC) markers to be distinguished from metastatic clear cell RCC.

Figure 1.

(A–B) VHL syndrome. A, Acini or nests of clear cells separated by a delicate vascular network. B, Adjacent clear cell-lined cysts. (C–D) Hereditary papillary RCC. C, Papillae lined by low cuboidal cells with scant cytoplasm and small oval nuclei. D, biphasic squamoid alveolar morphology is in transition with classic papillary RCC morphology. (E–H) HLRCC syndrome-associated FH-deficient RCC. Tumors demonstrate a spectrum of architectural patterns including papillary (E), tubular (F), solid (G) elements. Insets in E, positive 2SC staining confirms FH deficiency. Inset in F, loss of FH staining in tumor cells. Endothelial, stromal, or inflammatory cells serve as the internal positive control. H, low-grade FH-deficient renal tumors.

Given the early onset, multifocal, and frequently recurrent nature of renal tumors occurring in VHL patients, they are usually managed by a conservative approach: active surveillance and coordinated imaging studies to ensure that tumors are detected and managed in a timely fashion; nephron-sparing surgery is performed when the largest renal tumor reaches 3 cm in diameter to reduce the risk of metastatic clear cell RCC while maintaining renal function. Percutaneous ablation therapy has also been utilized in select patients with VHL-associated RCC, with comparable functional and oncologic outcomes [9]. An important therapeutic advance for VHL patients is the FDA approval of Belzutifan in 2021, a highly specific and well-tolerated HIF-2α inhibitor that demonstrated efficacy in controlling RCC and other tumors associated with VHL disease, with favorable responses observed in both renal and pancreatic tumors, as well as CNS hemangioblastomas [10].

Implementation of the surveillance program for VHL patients has resulted in improved survival. As reported in a recent analysis of the Danish national cohort of VHL mutation carriers, the life expectancy has become closer to that of siblings without VHL and the general population; while the main causes of death remain to be CNS hemangioblastomas and RCC, RCC-related death accounts for a decreasing portion of the overall mortality [11]. Intriguingly, in this cohort, female patients were found to have a significantly higher risk of mortality compared to males, and this sex-related survival difference showed an interaction with genotype (VHL missense vs. truncating mutations), suggesting a need to develop a tailored surveillance program to further improve the treatment and survival of VHL patients.

HEREDITARY PAPILLARY RENAL CELL CARCINOMA (HPRCC)

HPRCC is an autosomal dominant disorder that predisposes individuals to bilateral and multifocal papillary RCC. It is caused by germline activating mutations in the MET proto-oncogene located at chromosome 7q31. It is an exceptionally rare condition, and unlike other hereditary RCC syndromes, HPRCC is not associated with any known extrarenal manifestations. Meanwhile, HPRCC is highly penetrant, and patients develop bilateral and multiple papillary renal tumors with the classic (previously called “type 1”) morphology of papillary RCC (Fig. 1C) as well as numerous papillary adenomas (size≤15 mm) in the adjacent renal parenchyma. The tumor papillae are usually lined by single-layered cells with basophilic/amphophilic cytoplasm and low-grade nuclei, although it is not uncommon to encounter a range of other architectures such as tubular, solid, and glomeruloid patterns. Interestingly, biphasic squamoid alveolar papillary RCC, a morphologic variant of papillary RCC that has been associated with a high incidence of somatic and germline MET pathogenic mutations [1214], represents an important subset of tumors in HPRCC patients (Fig. 1D) [15]. Overall, the histologic findings of papillary RCC are similar to sporadic cases, with diffuse IHC reactivity to CK7 and AMACR. Although multifocal papillary RCC can occur in sporadic cases, the presence of numerous papillary adenomas in the adjacent kidney is the most important diagnostic feature of HPRCC [16]. Genetic testing to identify germline pathogenic mutations in the MET gene will support a definitive diagnosis. Rarely, non-papillary RCC may co-occur in patients with HPRCC and should not exclude the diagnostic suspicion of HPRCC if other classic features are present [17].

The multifocal renal tumors of HPRCC patients are usually indolent, confined within the kidney, and with slow growth. They are managed by surveillance and nephron-sparing surgery following the “3 cm rule”, similar to VHL patients. Understanding the crucial role of MET pathway in HPRCC also leads to studies of novel agents with potential efficacy: a phase II trial of dual MET/VEGFR2 inhibitor foretinib in papillary RCC showed a high response (50%) in patients with germline MET mutations [18]. Metastasis in HPRCC is relatively rare, currently, while there is no systemic therapy specifically approved for HPRCC, multi-kinase inhibitors approved for metastatic RCC such as cabozantinib can be considered [19], and newer agents targeting the MET pathway are also being investigated [20].

HEREDITARY LEIOMYOMATOSIS RENAL CELL CARCINOMA (HLRCC) SYNDROME

HLRCC syndrome is an autosomal dominant disorder marked by uterine and cutaneous leiomyomas and a higher risk of aggressive RCC [21]. Also known as Reed syndrome or Multiple Cutaneous and Uterine Leiomyomatosis (MCUL), HLRCC is a genetic predisposition caused by germline pathologic alterations of fumarate hydratase (FH) gene (1q42.1). Mutations in this gene lead to a deficiency in the FH enzyme, a crucial component of the Krebs cycle, disrupting normal cellular metabolism, leading to the accumulation of fumarate and activation of complex oncogenic cascades via aberrant protein succination as well as epigenetic and transcriptional reprogramming [22].

The clinical features of HLRCC syndrome vary, with patients typically presenting with at least one of a triad of phenotypic features, including cutaneous leiomyomas, uterine leiomyomas (fibroids), and renal cancers. Pheochromocytoma and paraganglioma are also rarely in association with HLRCC [23]. The prevalence of phenotypic features in affected individuals is highly variable, with cutaneous and uterine leiomyomas occurring in 50-80% and 30-80% of carriers, respectively, whereas a lifetime risk of developing RCC is estimated to be at 15% or lower [24, 25]. Thus, the term ‘FH tumor predisposition syndrome’, which encompasses presentations with isolated phenotypic features (e.g. patients without RCC), may be preferred to represent the broad spectrum of this syndrome [26].

Meanwhile, given the identification of sporadic renal tumors with biallelic somatic FH mutations and the practical need to render a definitive pathologic diagnosis for cases lacking family history or genetic confirmation, the term “FH-deficient RCC” has been adopted and is now used in WHO tumor classification system as a molecularly-defined tumor type that includes HLRCC-associated RCC [27]. Both germline and somatic FH-deficient RCCs are typically aggressive, when not identified via family screening or surveillance, the renal tumors often are solitary at diagnosis and may present with metastatic disease even at a small size. Regional lymph node involvement is common. Metachronous tumors and cystic lesions are more often encountered in the setting of surveillance and early intervention.

FH-deficient RCCs show a wide morphological spectrum with mixed architectural patterns, including papillary, tubular, tubulocystic, solid, and cystic elements (Fig. 1E-G); they may resemble collecting duct carcinoma or tubulocystic carcinoma and can show sarcomatoid differentiation. A characteristic feature is “cherry-red,” viral inclusion-like nucleoli with a perinucleolar halo, though this can be focal and similar to other high-grade RCCs [28, 29]. A small subset of FH-deficient renal tumors are composed of oncocytic/eosinophilic cells lacking the prominent nucleoli and perinucleolar halo (Fig. 1 H) and need to be considered as a differential diagnosis within the spectrum of renal oncocytic neoplasms [30, 31]. In recently described large clinical cohorts, the clinicopathologic features of HLRCC vs. sporadic FH-deficient RCC seem to overlap [32–34].

Loss of FH by IHC is a highly specific but less sensitive ancillary tool, as defective FH protein can sometimes be retained. IHC of S-(2-succino)-cysteine (2SC) is a more sensitive marker for detecting FH deficiency as it highlights the functional aberration – high levels of protein succination due to accumulated fumarate, although its may show complex staining patterns and requires caution for interpretion [28,35–37]. Using both FH and 2SC markers together improves diagnostic accuracy. Additionally, AKR1B10 expression by IHC has recently been reported as a useful ancillary tool, offering high sensitivity and specificity similar to 2SC [38].

For HLRCC patients with renal tumors, the current management strategy emphasizes early detection with immediate intervention, radical nephrectomy or partial nephrectomy with a wide margin via an open approach is preferred and regional lymph node dissection should be considered. The “3 cm rule” for surgical resection does not apply. Systemic treatments for disseminated HLRCC have made some progress: retrospective clinical data indicate that patients treated with a combination of immune checkpoint inhibitors and tyrosine kinase inhibitors experienced better survival outcomes [32]; the combination of bevacizumab and erlotinib has also shown clinical efficacy [39].

Pathologists are essential in identifying and managing FH-deficient RCC. Unlike the VHL or HPRCC described above, HLRCC-associated renal tumors are often solitary and unilateral, thus difficult to recognize as a syndromic condition clinically. Consequently, this specific pathological diagnosis frequently serves as the initial step leading to genetic counseling/testing and suitable surveillance programs for HLRCC patients and their families [40].

BIRT-HOGG-DUBÉ (BHD) SYNDROME

BHD Syndrome is an autosomal dominant disorder caused by mutations in the FLCN gene on chromosome 17p11.2. It is characterized by cutaneous hamartomas, kidney tumors, lung cysts, and spontaneous pneumothorax. Among the clinical presentations, lung cysts are the most common feature (over 80% of patients) and spontaneous pneumothorax occurs in about 40% of patients [41]. Folliculin, the gene product, is a highly preserved protein and tumor suppressor involved in numerous biological processes, recent studies have highlighted its roles in modulating AMPK and mTOR signaling pathways for nutrient signaling and lysosome regulation [42, 43].

The cumulative risk of developing renal tumors in BHD patients by the age of 70 years is estimated to be 19% in male carriers and 21% for females [44]. Renal tumors are bilateral and multifocal in approximately 50% of patients, and the most common histology is hybrid oncocytic tumors, which demonstrate morphologic features overlapping both chromophobe RCC and renal oncocytoma (Fig. 2A-B). Other histologies include chromophobe, clear cell, papillary, and unclassified RCCs, as well as angiomyolipomas [45–47]. Characteristically, a portion of oncocytic tumors in BHD syndrome contain clusters of clear cells, and the adjacent renal parenchyma can also show small clusters of cells with clear or pale eosinophilic cytoplasm percolating between non-neoplastic renal tubules (Fig. 2 C). The findings in the surrounding renal parenchyma of BHD patients appear to overlap with the morphologic features of renal oncocytosis where numerous microscopic oncocytic nodules, cysts lined by oncocytic cells, and oncocytic changes can be seen [46, 48]. Applying cell lineage markers, Wang et al. recently identified two distinctive tumor cell populations co-existing in hybrid oncocytic tumors of BHD patients, but not in sporadic cases of chromophobe RCC, renal oncocytoma, and other rare types of renal oncocytic neoplasms [47]. This finding suggests that these novel markers may serve as useful ancillary tools for distinguishing at least some BHD-associated renal tumors from sporadic oncocytic neoplasms.

Figure 2.

(A–C) BHD Syndrome. A, Representative hybrid oncocytic tumor with scattered foci of clear cells. B, Renal oncocytic tumor, NOS of a BHD patient shows cytoplasmic eosinophilic globules. C, Clusters of clear/pale cells percolating between native renal parenchyma. (D–F) TSC-associated renal tumors. D, Tumor predominantly comprises clear cells with voluminous cytoplasm and shows papillary and alveolar architectural patterns. E, Tumor composed of nests of cells with pale to eosinophilic or oncocytic cytoplasm, mimicking chromophobe RCC or hybrid oncocytic tumors. F, Tumor morphologically identical to the sporadic eosinophilic solid and cystic carcinoma. (G–I) SDH-deficient RCC. G, Tumor cells have intracytoplasmic vacuolations and inclusions, flocculated eosinophilic cytoplasm and uniform low-grade nuclei. H, tumor shows transition between a classic component and a high grade component. I, Tumor cells demonstrate loss of SDHB staining. Staining in the adjacent renal tubules and blood vessels serves as a positive internal control.

Consistent with its tumor suppressor role, biallelic alterations of FLCN gene - germline alteration and concomitant loss of heterozygosity (LOH) or somatic mutations in the wildtype allele - are frequently observed in BHD-associated renal tumors [49, 50]. Thus the underlying molecular alterations are different from sporadic tumors with similar morphology [51].

Multiple oncocytic neoplasms and features of oncocytosis in the background kidney should raise the possibility of BHD or renal oncocytosis. The definitive diagnosis of BHD relies on the presence of extrarenal and renal manifestations and is confirmed by a genetic test that is positive for a germline FLCN mutation.

Renal tumors associated with BHD syndrome tend to be indolent, treatment approaches may include nephron-sparing surgery (when tumor size exceeds 3 cm), ablative therapies, or active surveillance, depending on tumor size, location, and patient factors. The primary goal of surgery is to conserve non-neoplastic kidney tissue and maintain optimal renal function. With surveillance and management, metastasis is rare but has been reported in cases with clear cell or papillary morphology [41].

TUBEROUS SCLEROSIS COMPLEX

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from germline mutations in either TSC1 (9q34) or TSC2 (16p13). These two proteins form a complex that negatively regulates mechanistic target of rapamycin complex 1 (mTORC1), a critical regulator of cellular growth and metabolism [52, 53]. TSC is a multi-organ disease and mainly characterized by hamartomatous tumors of the brain, heart, skin, lung, and kidney. However, the clinical features vary widely between individuals and the disease can affect every organ system [54]. The incidence of TSC is approximately 1 per 6,000-10,000 live births, and only one-third of the cases are familial whereas about two-thirds occur in the absence of a family history and are attributed to de novo mutations [55]. Somatic mosaicism has also been reported in TSC, explaining some rare cases in which blood or saliva samples may be negative for TSC1 or TSC2 mutations [56].

Renal involvement occurs in approximately 80% of individuals with TSC and is the leading cause of death in TSC patients. Renal manifestations commonly observed in TSC patients include angiomyolipoma (AML) and renal epithelial cysts, affecting up to 50% to 80% and 40% of the patients, respectively. Renal cell carcinomas (RCCs) or renal epithelial neoplasia also occur in TSC patients but at much lower incidence (2% to 4%) [52, 57]. Interestingly, these renal epithelial neoplasms often display heterogeneous yet distinctive histomorphologies [58–60]. A subset of TSC-associated tumors shows clear, voluminous cytoplasm in papillary, acinar, tubular, or alveolar patterns, and often have prominent fibromuscular stroma (Fig. 2D); another group of renal tumors in TSC patients features nests or sheets of eosinophilic or oncocytic cells, similar to chromophobe RCC, oncocytoma, or hybrid oncocytic tumors (Fig. 2E); other tumors are unclassifiable based on morphology, consisting of eosinophilic cells with diverse architectures and high-grade nuclear features (Fig. 2F). A relatively common feature is the cytoplasm of TSC-associated tumors often contains eosinophilic, finely granular, fibrillary or stippling material, and sometimes displays aggregated eosinophilic globules. Immunohistochemically, clear cell tumors often express CA-IX, CD10, and CK7 variably, but not AMACR. Chromophobe-like or oncocytoma-like tumors may be positive for CD117. The tumors are positive for PAX8, supporting their renal epithelial origin.

Appreciation of this heterogeneous morphologic spectrum of TSC-associated renal epithelial tumors, together with increasingly utilized molecular analyses in clinical practice, has led to the recent identification of several new or emerging entities that primarily occur in sporadic settings but are similarly driven by TSC-mTORC1 pathway alterations and can also be seen in TSC patients. These include “RCC with fibromyomatous stroma (RCC FMS)” that shows clear cell features and has fibromuscular stroma, eosinophilic solid and cystic RCC (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT) [61, 62]. Multifocality, the presence of concurrent or microscopic AMLs and renal cysts, as well as extra-renal manifestations can be helpful for distinguish TSC patients from sporadic cases.

AMLs, the most commonly encountered renal tumor type in TSC patients, classically consist of 3 elements: dysmorphic vasculatures, smooth muscle, and fat. In TSC, its manifestation can start in childhood, and the most serious complication is acute hemorrhage. AMLs typically show low attenuation areas on CT due to fat content, but lipid-poor AMLs, seen in one-third of TSC patients, may require biopsy to differentiate from other renal tumors. Surveillance is the preferred management for AMLs until the risk of spontaneous hemorrhage becomes high. At this point, selective angioembolization is considered. Everolimus, an mTOR inhibitor, is FDA-approved for treating AMLs in TSC patients, but tumors tend to regrow upon discontinuation [63].

HEREDITARY PARAGANGLIOMA-PHEOCHROMOCYTOMA SYNDROME

Succinate dehydrogenase (SDH) is a crucial component of the Krebs cycle and the mitochondrial electron transport chain. Germline mutations in genes encoding its protein subunits (SDHA, SDHB, SDHC, and SDHD) or the regulatory factor SDHAF2 are the cause of hereditary paraganglioma-pheochromocytoma syndrome and other tumors such as gastrointestinal stromal tumors (GIST), pituitary adenomas, and RCCs. In particular, the association between germline SDHB mutation and RCC is well-established, and the estimated lifetime risk is 5% [64].

Renal tumors developed in these patients, SDH-deficient RCC, typically shows a relatively characteristic morphology with intracytoplasmic vacuolations and inclusions, flocculated eosinophilic cytoplasm and uniform low-grade nuclei (Fig. 2 G) [65–67]. However, high grade features, such as high-grade nuclear atypia (Fig. 2 H), coagulative necrosis, and sarcomatoid differentiation may occur and are associated with metastasis and aggressive clinical course [66, 68]. SDH-deficient RCC can be identified by a loss of SDHB expression (Fig. 2I), an IHC marker for dysfunctional mitochondrial complex II [69].

While SDHB-deficient RCC is rare with an estimated incidence of 0.05 to 0.1% of all resected renal cell tumors [66], this diagnosis can have a significant impact on patient management because of its strong link to germline SDHB mutations and the syndromic association. Similar to FH-deficient RCC, it is not infrequently an initial step to facilitate genetic counseling and subsequent management plans in the patients and their families. SDHB-deficient RCC cases can occur at a young age and be aggressive [70], thus requiring careful surveillance.

Due to the low incidences, the association between other genes of SDH complex and RCC remains to be further clarified. For example, although SDHA germline mutation is one of the driving molecular alterations of GISTs [71], there was only one RCC case with biallelic germline and somatic SDHA mutations reported [72].

BAP1 TUMOR PREDISPOSITION SYNDROME

BAP1 tumor predisposition syndrome is an autosomal dominant disorder linked to an elevated risk of several cancers, including uveal melanoma, mesothelioma, cutaneous melanoma, and RCC. This syndrome is caused by mutations in the BAP1 gene located on chromosome 3p21.1. The tumor suppressor BAP1 protein has dual activity that is cell type- and context-dependent: in the nucleus, it is implicated in a variety of processes including DNA repair and transcription; in the cytoplasm, it regulates cell death and mitochondrial metabolism [73].

Germline mutations in BAP1 were first associated with cancer in 2011, highlighting increased risks for melanoma and mesothelioma [74]. Subsequent research in 2013 confirmed the association of these mutations with familial clear cell RCC [75]. A recent review of 181 families confirms 4 core presentations including RCC, and expands the tumor spectrum to include skin basal cell carcinoma, meningioma, and cholangiocarcinoma [76].

The estimated risk of RCC in BAP1 carriers is around 10%, though this may be overstated due to ascertainment bias [76]. BAP1-associated RCCs are predominantly clear cell RCCs, consistent with the high prevalence of BAP1 somatic mutations of sporadic clear cell RCCs [77]. However, rare instances of non-clear cell RCC have also been reported [78]. While somatic BAP1 mutations have been associated with higher tumor grade and poorer survival [79, 80], it is uncertain if this applies to germline BAP1-associated RCC and needs further research.

Management of BAP1-associated RCC mirrors that of sporadic RCC, though some centers advocate for early intervention and vigilant monitoring due to potentially aggressive outcomes [81]. There are no standardized guidelines for cancer screening in individuals with germline BAP1 mutations, but annual abdominal imaging is recommended to detect RCC early.

PTEN HAMARTOMA TUMOR SYNDROME

The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a group of related genetic disorders that have been linked to germline mutations in the PTEN gene. The majority of the clinical information on PHTS came from Cowden syndrome (CS), a rare multi-organ syndrome that confers increased risks for malignancies or hamartomatous lesions involving breast, thyroid, endometrium, skin, gastrointestinal tract, brain, etc. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20 s [82, 83].

RCC is a minor criterion for the clinical diagnosis of PHTS. Tan et al. estimated that the lifetime risk of RCC among CS/PHTS patients is approximately 34%, with the increased risk beginning at age 40 [84]. In a series of 219 prospectively-accrued individuals with germline PTEN mutations, 9 (4%) had RCC [85]. The RCC types reported in this setting include papillary, chromophobe, clear cell RCC, and RCC, not otherwise specified (NOS) [85–87]. Papillary and chromophobe RCC are the common histologic types seen in PHTS; they morphologically resemble their sporadic counterparts and are mostly indolent. Microscopic intrarenal lipomas /lipomatous hamartomas were identified in 2 of 9 patients in a recent series, which may serve as a clue for this rare diagnosis [88]. While PTEN protein loss has been shown for most reported RCC occurring in PHTS, at least two RCC cases have retained protein expression [85, 89]. As PTEN protein loss can occur in many tumor types, PTEN IHC is not recommended as a screening tool for diagnosing PHTS-associated renal neoplasia.

OTHER FAMILIAL SYNDROMES ASSOCIATED WITH RENAL NEOPLASIA

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant disorder caused by mutations in the CDC73 gene (also known as HRPT2), which encodes the parafibromin protein. This syndrome is characterized by the development of primary hyperparathyroidism (PHPT) due to parathyroid adenomas or carcinomas, and jaw tumors, particularly ossifying fibromas. Patients may also develop renal and uterine tumors. HPT-JT is extremely rare, with an estimated prevalence of less than 1 in 100,000 individuals. Renal involvement in HPT-JT syndrome can manifest as renal cysts, mixed epithelial and stromal tumor (MEST), Wilms tumor, and an increased risk of RCC [90–92].

The E318K variant of MITF (Microphthalmia-associated transcription factor) gene has been associated with a fivefold increased risk of developing melanoma and RCC [93]. The reported types of RCC associated with MITF E318K variant are papillary type 1 and clear cell RCC [94, 95]. Renal tumors in these patients may present at a younger age compared to sporadic cases, and surveillance for RCC is recommended in individuals known to have this MITF variant.

Constitutional chromosome 3 translocations have also been associated with a significantly increased risk of RCC and other cancers depending on the specific genes involved [96]. It co-segregates in families with multiple cases of RCC and testing for a translocation can be considered if inherited RCC is suspected.

Moreover, a small number of other germline gene variants have also been associated with an increased risk of RCC, these include TMEM127, PBRM1, ELOC, and CDKN2B [97–100].

GENETIC TESTING FOR FAMILIAL KIDNEY CANCER

The comprehensive tumor profiling efforts in recent years have led to new information on the prevalence and spectrum of germline predisposition genes. In addition to identifying mutations in established hereditary RCC syndrome-associated genes in 6% to 16% of analyzed RCCs, germline variants of other cancer-predisposition genes not traditionally associated with RCC are also identified [78,101–103]. This latter group of variants often involve DNA damage (DDR)-related genes (e.g., CHEK2, MUTYH, ATM, and BRCA1/2) and non-DDR-related genes (e.g., APC); the significance of these germline variants in RCC tumor development remains to be elucidated. On the other hand, the current methods of germline testing (multigene panel or single gene test) may be insufficient to detect the causal alterations, thus for patients with strong clinical suspicions but negative genetic testing results, additional investigation should be pursued.

Genetic counseling and testing are vital for identifying those at risk and for establishing effective monitoring and management plans for the patients and their families. The NCCN guidelines now recommend genetic risk assessment for individuals with kidney cancer who are under 46 years old, have bilateral or multiple renal masses, or have at least one first- or second-degree relative with RCC. Additionally, the guidelines identify five tumor histologic subtypes that should prompt genetic risk assessment: FH-deficient RCC/HLRCC, BHD syndrome, angiomyolipoma with another symptom of tuberous sclerosis complex, SDH-deficient tumors, and multifocal papillary RCC [104].

The timing of the genetic testing is important for patients, as this information guides surgical management and may identify therapeutic targets (e.g. Belzutifan for VHL). Timely genetic screening of patients with renal tumors suspicious for familial syndromes also enables early detection of at-risk family members through cascade testing. Given the wide spectrum of clinical presentations of these familial conditions, it is essential to develop tailored and personalized screening and surveillance approaches. Pathology evaluation is a crucial component of this process.

CONCLUSIONS

Renal neoplasia in the context of familial renal cancer syndromes represents a group of complex and multifaceted clinical entities, necessitating a nuanced understanding of the genetic, molecular, and pathological underpinnings. The syndromic associations with genes such as VHL, MET, FLCN, TSC1, TSC2, FH, and SDHB highlight the diverse oncogenic pathways driving RCC tumorigenesis and underscore the importance of tailored diagnostic and management strategies. Effective management of familial RCC syndromes hinges on a multidisciplinary approach that integrates clinical management, genetic counseling, and vigilant surveillance to mitigate the risks of tumor development and progression.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments.

FUNDING

Y-B. Chen is supported by a Cycle for Survival research grant and funded in part by an NIH/NCI Cancer Center Support Grant (P30 CA008748).

AUTHOR CONTRIBUTIONS

Not applicable.

CONFLICT of INTEREST

Y-B. Chen has no conflict of interest to report.

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