https://orcid.org/0000-0003-1958-4459
ABSTRACT
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications, the vast majority of FH-deficient RCCs exhibit an aggressive behaviour with invasive growth and the potential for early metastatic spread. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as adrenal gland and Leydig cell tumours. The aggressive behaviour of FH-deficient RCC challenges nephron-sparing resection strategies, as a wide margin is recommended. Even after early nephrectomy for surgical removal of FH-deficient renal cell carcinomas, there is a relevant risk for distant metastasis as well as the remaining
predisposition for de novo primary renal tumours in the other kidney. Active screening is central to HLRCC care since no preventative HLRCC-specific treatment exists. Vascular endothelial growth factor/epidermal growth factor receptor–directed treatment regimes, such as erlotinib/bevacizumab, demonstrate efficacy against HLRCC-associated RCC. This emphasizes the importance of establishing the correct diagnosis in HLRCC early on to guide therapeutic decisions. Morphologic criteria as well as specific immunohistochemical staining and molecular genetics allow the identification of FH-deficient RCC. Changes made in the recent 2022 World Health Organization classification impact the diagnosis of HLRCC in multiple ways. This commentary aims to discuss this impact and raise awareness among pathologists as well as clinicians involved in the care of patients with HLRCC.
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HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA (HLRCC): AN INTERDISCIPLINARY CHALLENGE WITH DISEASE-SPECIFIC IMPLICATIONS FOR THE MANAGEMENT OF KIDNEY INVOLVEMENT
HLRCC syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene [1, 2]. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma [3]. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications [4]. The vast majority of FH-deficient RCCs exhibit an aggressive behaviour with invasive growth and potential for early metastatic spread [5]. HLRCC is an autosomal dominant disorder characterized by the formation of cutaneous leiomyomas, uterine fibroids and a predisposition to the formation of mostly aggressive FH-deficient RCC. Approximately 10–30% of carriers develop RCC in their lifetime [3, 6, 7]. The prevalence of RCC varies between affected families. However, a genotype–phenotype correlation for the development of RCC or other organ manifestations has not been established. Also, patients with HLRCC are more likely to develop multiple kidney cysts than the general population, potentially leading to a phenotype resembling other renal tumour syndromes associated with polycystic kidneys [e.g. Von Hippel–Lindau (VHL) syndrome or Birt–Hogg–Dubé (BHD) syndrome]. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as pheochromocytomas and adrenal gland [7] and Leydig cell tumours [8, 9].
Mechanistically, carcinogenesis occurs typically upon somatic biallelic FH inactivation, which leads to metabolic reprogramming with activation of adenosine monophosphate-activated protein kinase and hypoxia-inducible factor signalling [10] and accumulation of oncometabolites [11]. Importantly, FH-deficient RCC shows highly aggressive characteristics including early formation of metastases. In patients with HLRCC, kidney cancer develops earlier than sporadic RCC, with a mean age at diagnosis of 44 years [12] and cases occurring even in young children [13]. This aspect, as well as the continued risk for tumour formation after treatment and the potential predisposition of other family members, emphasizes the importance of a timely and precise diagnosis of HLRCC among patients with RCC. The common management strategy of employing active surveillance for small tumours in other hereditary RCC syndromes (e.g. in VHL [14] or BHD [15, 16] syndrome) is not appropriate in HLRCC cases, which require prompt tumour removal upon detection [5]. In addition, early treatment might allow nephron-sparing surgery, mitigating the impact of kidney function loss.
Clinical clues pointing towards a hereditary cause of RCC include a positive family history, early onset (≤46 years) and bilateral/multifocal tumours [17]. Specific histologic and immunohistochemical features, along with extrarenal manifestations such as skin leiomyomas or uterine fibroids in young women, are critical in guiding the histopathological workup and referral to geneticists or clinical specialists.
The recent update of the World Health Organization (WHO) classification introduced important changes with great relevance for HLRCC diagnostics, and awareness of these adaptations among all disciplines involved is pivotal to provide optimal patient care.
MODERN WHO CLASSIFICATION OF KIDNEY TUMOURS AND THE PLACE OF HLRCC
The 5th edition of the WHO Classification of Urinary and Male Genital Tumors [18] summarizes several tumour entities as ‘molecularly defined renal cell carcinomas’. This category is very heterogeneous, both morphologically and regarding epidemiological and clinical features. However, this approach underscores the recent success of genitourinary pathology in identifying and systematizing multiple RCC subtypes driven by a specific molecular–genetic alteration. Besides the newly included FH-deficient RCC, other new molecularly defined RCCs include transcription factor E3/transcription factor EB rearranged/altered RCCs and succinate dehydrogenase–deficient RCC, among others.
Subclassification of type 1 and 2 papillary RCCs is no longer recommended. Clear cell papillary carcinomas have been redesignated as tumours instead of carcinomas, given their indolent clinical behaviour. Moreover, several provisional new papillary tumour entities are proposed, subject to more extensive research, such as papillary renal neoplasm with reversed polarity with frequent renin–angiotensin system mutations [19], biphasic hyalinizing psammomatous RCC with frequent NF2 mutations [20], biphasic squamoid/alveolar RCC [21] or thyroid-like follicular RCC [22]. These subtypes might have been diagnosed as classical papillary RCC earlier but might confer specific molecular driver alterations and crystallize as recognized tumour entities in further editions. FH-deficient carcinomas occur in the context of HLRCC syndrome but can be also sporadic. While the updated approach to HLRCC diagnosis in histopathology is timely, it is now important that all disciplines involved are aware of these changes. Previously, despite its shortcomings, the term type 2 papillary RCC was one of the key triggers for clinicians to consider HLRCC, making awareness of this change an important asset.
HISTOPATHOLOGICAL DIAGNOSIS OF FH-DEFICIENT CARCINOMAS
From a histomorphologic point of view, FH-deficient carcinomas were first described as papillary tumours. Although they frequently show papillary morphology (Fig. 1A, B, H, I), it is now recognized that these tumours can show numerous histomorphological patterns, which makes their diagnosis challenging. FH-deficient carcinomas typically demonstrate multiple admixed morphological patterns, such as solid (Fig. 1G) and tubulocystic (Fig. 1C, D, F), and even including low-grade oncocytic morphology. This often leads to their classification as unclassified RCC. In general, FH-deficient carcinomas are rare and therefore might be underdiagnosed if awareness levels of pathologists are low or because of a lack of experience in kidney tumour pathology. The presence of eosinophilic macronucleoli is common but is a very non-specific feature of FH-deficient RCC.
Morphological patterns and immunohistochemistry of FH-deficient RCC. (A) Papillary pattern with a single epithelial layer. (B) Papillary pattern with pseudostratification. (C) High-grade tubular pattern. (D) Low-grade clear cell tubular pattern. (E) Low-grade papillary clear cell pattern. (F) Cystic pattern. (G) Solid/sieve-like pattern. (H) FH-deficient RCC showing benign tissue (left side) and tumour tissue with papillary architecture (right side). (I) Higher magnification of region H, displaying benign tissue (left side) and tumour tissue with papillary architecture (right side). (J) Fumarate hydratase (FH) staining: retained expression in benign kidney tissue, immune cells and stromal cells (left side), with complete loss of FH expression in tumour cells (right side). Note positive staining in stromal cells within the papillary cores. (K) 2SC staining shows the opposite pattern of FH: significant positivity in tumour cells (right side), absent in benign kidney tissue and stromal and inflammatory cells (left side).
Two immunohistochemical markers can be utilized in combination to establish the diagnosis of FH-deficient RCC: fumarate hydratase (FH) and 2SC. Negative immunohistochemical staining for FH is highly specific for diagnosis (Fig. 1J). However, this marker might not be sensitive enough to exclude FH-deficient RCC [23], considering that there are many different FH variants and some pathogenic variants maintain normal expression despite a loss of heterozygosity [24]. 2SC positivity (Fig. 1K) is highly sensitive in detecting FH deficiency but has lower specificity [25]. 2SC generation is believed to be a direct result of the post-translational modification of cysteine residues due to aberrant levels of fumarate [26]. The application of both FH and 2SC markers is crucial for differentiating FH-deficient tumours from other papillary tumours. Arguably, in cases with either loss of FH staining or marked induction of 2SC, this finding will often be sufficient to initiate genetic testing. However, the combination of FH and 2SC staining increases diagnostic confidence, particularly in ambiguous cases with mild 2SC positivity or uncertain results towards FH positivity, and will allow the community to learn how closely the findings in these two markers correlate.
2SC staining can be considered a reflex immunohistochemical (IHC) test, especially in high-grade non-clear cell tumours, papillary tumours with mixed morphological patterns, tubulocystic tumours and eosinophilic tumours and in cases with inactivating FH mutations or deletions identified through next-generation sequencing.
IMPORTANCE OF REFERRAL TO EXPERT CENTERS FOR EVALUATION AND GENETIC TESTING IN CASE OF FH DEFICIENCY
Advances in understanding the mechanisms underlying hereditary tumour predisposition further emphasize timely and accurate diagnosis of these conditions. Meanwhile, diagnostic pathology of kidney tumours besides the classic histological subtypes can be very challenging. This underlines the critical role of the interface between specialties, starting with detailed collection of medical and family histories, as well as assessment of possible HLRCC-associated extrarenal manifestations at RCC diagnosis. It is of importance that unclear or complex cases from the morphological point of view, as well as cases where proper classification will require additional stainings not established in all pathology institutes, are being consulted with departments with sufficient expertise. Diagnosis of FH-deficient RCC should trigger the offer of genetic counselling and genetic testing to identify cases with causative pathogenic germline variants in FH (as an alternative to biallelic somatic inactivation). The majority of FH variants characterized as pathogenic or likely pathogenic are missense variants, which are more likely to retain positive FH IHC staining compared with the less frequent truncating variants or large deletions. Also, as more clinical information becomes available, it is anticipated that many variants of uncertain significance will be reclassified with greater accuracy [27]. A confirmation of the diagnosis through genetic testing has substantial consequences for the RCC patient and other affected family members. Extrarenal findings underscore the importance of close interdisciplinary collaboration, including urologists, nephrologists, radiologists, dermatologists, gynaecologists, geneticists and pathologists, with important implications for early referral for genetic workup, both upon renal and extrarenal findings pointing towards HLRCC, such as cutaneous leiomyomas. This close interaction is also crucial to coordinate optimal genetic counselling, renal surveillance, surgical and systemic RCC treatment and specific treatment for uterine and skin manifestations and to provide psychosocial resources and support for patients with HLRCC.
CONCLUSION
The 5th edition of the WHO Classification of Urinary and Male Genital Tumors [18] provides a timely and very reasonable update to the approach towards diagnosis of hereditary forms of kidney cancer by considering molecular pathogenesis. For HLRCC, this includes both abolition of the previous distinction of type 1 and 2 papillary RCC and the introduction of new IHC markers into clinical routine. Considering the need for close interdisciplinary interaction to allow for early diagnosis and optimal care in HLRCC, it is important that all disciplines involved are aware of this update.
ACKNOWLEDGEMENTS
The Genes & Kidney Working Group is an official body of the European Renal Association (ERA). R.U.M., J.D., J.D.C., D.E., C.F., B.S., E.R.M., A.H. and G.L. are founding members of the HLRCC Alliance. J.D. is the medical coordinator of the HLRCC Alliance. J.D.C. and D.E. are members of the board of directors of the HLRCC Foundation. G.L. is vice chair of the HLRCC Foundation Board of Trustees and chair of VHL UK/Ireland. M.J. is chair of the board of directors of the IKCC. R.U.M. is chair of the Genes & Kidney Working Group. E.C.L.G. is vice chair of the Genes & Kidney Working Group. J.H. is a board member of the Genes & Kidney Working Group and co-chair of the AD Structural Disorders Working Group at ERKNet. POL and IBG are members of the ERN GENTURIS. IBG is chairman of the Board of National Coordinators and Spanish National Coordinator of the ERN GENTURIS. E.R.M. is a supporting partner of the ERN GENTURIS. P.M. and G.M. are members and coordinators of the ERN eUROGEN. G.M. is president of the Italian Society of Pediatric Urology. A.H. is a board member of the Uropathology Working Group of the European Society for Pathology (ESP). D.E.B. is chair of the Uropathology Working Group of the ESP. M.C. is chair of the Uropathology section of the European Society of Urology and past chair of the Uropathology Working Group of the ESP.
FUNDING
None declared.
AUTHORS’ CONTRIBUTIONS
RUM, BS, AH, YT and JD: Conception: JD and YT: Drafting of the manuscript. all authors: Revising of the manuscript.
DATA AVAILABILITY STATEMENT
No new data were generated or analysed in support of this research.
CONFLICT OF INTEREST STATEMENT
None declared.
REFERENCES
Author notes
These authors contributed equally.
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