A vesedaganatok egy része örökletes tumorszindrómákhoz társultan alakul ki. Ezek klinikai megjelenése változatos, és előfordulhat, hogy a vesedaganat a betegség első manifesztációja, ezért fontos, hogy a patológusok tisztában legyenek azokkal a makroszkópos jelekkel és szöveti elváltozásokkal, amelyek alapján a tumorszindróma lehetősége felvethető. Ebben a közleményben összefoglaljuk és szemléltetjük a kialakuló vesedaganatok jellemzőit, a genetikai hátteret és az extrarenalis eltéréseket a következő kórképekben: Von Hippel–Lindau-szindróma, örökletes papillaris vesesejtes carcinoma szindróma, örökletes leiomyomatosis és vesesejtes carcinoma szindróma, Birt–Hogg–Dubé-szindróma, sclerosis tuberosa, örökletes paraganglioma/phaeochromocytoma szindróma, illetve BAP1-tumorszindróma. A dolgozat végén tárgyaljuk azokat a tumorszindrómákat, amelyekben fokozott a Wilms-tumor kialakulásának kockázata. Az ilyen betegek ellátása holisztikus szemléletet és multidiszciplináris megközelítést igényel, ezért munkánk célja, hogy felhívjuk a vesetumorok ellátásában részt vevő kollégák figyelmét ezekre a ritka, ugyanakkor élethosszig tartó ellátást igénylő betegségekre. Orv Hetil. 2023; 164(10): 363–375.
Haas NB, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014; 21: 81–90.
Menko FH, Maher ER. Diagnosis and management of hereditary renal cell cancer. Recent Results Cancer Res. 2016; 205: 85–104.
Richards FM, Crossey PA, Phipps ME, et al. Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene. Hum Mol Genet. 1994; 3: 595–598.
Coppin L, Plouvier P, Crépin M, et al. Optimization of next-generation sequencing technologies for von Hippel Lindau (VHL) mosaic mutation detection and development of confirmation methods. J Mol Diagn. 2019; 21: 462–470.
Maher ER, Iselius L, Yates JR, et al. Von Hippel–Lindau disease: a genetic study. J Med Genet. 1991; 28: 443–447.
Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399: 271–275.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3: 721–732.
Kim W, Kaelin WG Jr. The von Hippel–Lindau tumor suppressor protein: new insights into oxygen sensing and cancer. Curr Opin Genet Dev. 2003 13: 55–60.
Ong KR, Woodward ER, Killick P, et al. Genotype–phenotype correlations in von Hippel–Lindau disease. Hum Mutat. 2007; 28: 143–149.
Chauveau D, Duvic C, Chrétien Y, et al. Renal involvement in von Hippel–Lindau disease. Kidney Int. 1996; 50: 944–951.
Kanno H, Yoshizumi T, Shinonaga M, et al. Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel–Lindau disease. J Neurooncol. 2020; 148: 29–38.
Vortmeyer AO, Falke EA, Gläsker S, et al. Nervous system involvement in von Hippel–Lindau disease: pathology and mechanisms. Acta Neuropathol. 2013; 125: 333–350.
World Health Organization, International Agency for Research on Cancer. Central nervous system tumours. WHO classification of tumours, 5th edn., vol. 6. Lyon, 2021.
Sangoi AR, Karamchandani J, Kim J, et al. The use of immunohistochemistry in the diagnosis of metastatic clear cell renal cell carcinoma: a review of PAX-8, PAX-2, hKIM-1, RCCma, and CD10. Adv Anat Pathol. 2010; 17: 377–393.
Mete O, Asa SL, Gill AJ, et al. Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas. Endocr Pathol. 2022; 33: 90–114.
Reid MD, Choi HJ, Memis B, et al. Serous neoplasms of the pancreas: a clinicopathologic analysis of 193 cases and literature review with new insights on macrocystic and solid variants and critical reappraisal of so-called “serous cystadenocarcinoma”. Am J Surg Pathol. 2015; 39: 1597–1610.
Kimura W, Moriya T, Hirai I, et al. Multicenter study of serous cystic neoplasm of the Japan Pancreas Society. Pancreas 2012; 41: 380–387. Erratum: Pancreas 2013; 42: 186.
Penitenti F, Landoni L, Scardoni M, et al. Clinical presentation, genotype–phenotype correlations, and outcome of pancreatic neuroendocrine tumors in Von Hippel–Lindau syndrome. Endocrine 2021; 74: 180–187.
Louise M, Binderup M, Smerdel M, et al. Von Hippel–Lindau disease: updated guideline for diagnosis and surveillance. Eur J Med Genet. 2022; 65: 104538.
Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. N Engl J Med. 2021; 385: 2036–2046.
Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997; 16: 68–73.
Schmidt L, Junker K, Nakaigawa N, et al. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 1999; 18: 2343–2350.
Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol. 1999; 155: 517–526.
Sudarshan S, Sourbier C, Kong HS, et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol. 2009; 29: 4080–4090.
Menko FH, Maher ER, Schmidt LS, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer 2014; 13: 637–644.
Merino MJ, Torres-Cabala C, Pinto P, et al. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007; 31: 1578–1585.
Jenei A, Hes O, Kuthi L. Provisional renal cell carcinoma subsets following the 2016 WHO classification. [Provizórikus veserákaltípusok a 2016. évi WHO-klasszifikációt követően.] Orv Hetil. 2020; 161: 83–94. [Hungarian]
Trpkov K, Hes O, Agaimy A, et al. Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol. 2016; 40: 865–875.
Chen YB, Brannon AR, Toubaji A, et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 2014; 38: 627–367.
Grubb RL 3rd, Franks ME, Toro J, et al. Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol. 2007; 177: 2074–2079. Discussion 2079–2080.
Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dube syndrome. Nat Rev Urol. 2015; 12: 558–569.
Hartman TR, Nicolas E, Klein-Szanto A, et al. The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis. Oncogene 2009; 28: 1594–1604.
Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt–Hogg–Dubé syndrome. Am J Surg Pathol. 2002; 26: 1542–1552.
Tickoo SK, Reuter VE, Amin MB, et al. Renal oncocytosis: a morphologic study of fourteen cases. Am J Surg Pathol. 1999; 23: 1094–1101.
Menko FH, van Steensel MA, Giraud S, et al. Birt–Hogg–Dubé syndrome: diagnosis and management. Lancet Oncol. 2009; 10: 1199–1206.
Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006; 355: 1345–1356.
European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75: 1305–1315.
Van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805–808.
Curatolo P, Moavero R. mTOR inhibitors in tuberous sclerosis complex. Curr Neuropharmacol. 2012; 10: 404–415.
Cascarino M, Leclerc-Mercier S. Histological patterns of skin lesions in tuberous sclerosis complex: a panorama. Dermatopathology (Basel) 2021; 8: 236–252.
Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015; 14: 733–745.
McCarthy C, Gupta N, Johnson SR, et al. Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis, and management. Lancet Respir Med. 2021; 9: 1313–1327.
Yang P, Cornejo KM, Sadow PM, et al. Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol. 2014; 38: 895–909.
Fejes Z, Sánta F, Jenei A, et al. Angiomyolipoma of the kidney. Clinicopathological analysis of 52 cases. Pathol Oncol Res. 2023; 28: 1610831.
Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381: 817–824.
Gill AJ, Hes O, Papathomas T, et al. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol. 2014; 38: 1588–1602.
Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007; 92: 3822–3828.
Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001; 69: 49–54. Erratum: Am J Hum Genet. 2002; 70: 565.
Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011; 35: 1578–1585.
Ricketts CJ, Shuch B, Vocke CD, et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012; 188: 2063–2071.
Williamson SR, Eble JN, Amin MB, et al. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod Pathol. 2015; 28: 80–94.
Gill AJ, Hes O, Papathomas T, et al. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol. 2014; 38: 1588–1602.
Jensen DE, Proctor M, Marquis ST, et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 1998; 16: 1097–112.
Gallan AJ, Parilla M, Segal J et al. BAP1-mutated clear cell renal cell carcinoma. Am J Clin Pathol. 2021; 155: 718–728.
Farley MN, Schmidt LS, Mester JL, et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol Cancer Res. 2013; 11: 1061–1071.
Popova T, Hebert L, Jacquemin V, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet. 2013; 92: 974–980.
Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012; 44: 751–759. Erratum: Nat Genet. 2012; 44: 1072.
Shuch B, Ricketts CJ, Vocke CD, et al. Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer. J Urol. 2013; 190: 1990–1998.
Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012; 18: 400–407.
van der Tuin K, Tops CM, Adank MA, et al. CDC73-related disorders: clinical manifestations and case detection in primary hyperparathyroidism. J Clin Endocrinol Metab. 2017; 102: 4534–4540.
Trpkov K, Hes O, Williamson SR, et al. New developments in existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol. 2021; 34: 1392–1424.
Breslow N, Olshan A, Beckwith JB, et al. Epidemiology of Wilms tumor. Med Pediatr Oncol. 1993; 21: 172–181.
Scott RH, Stiller CA, Walker L, et al. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet. 2006; 43: 705–715.
Buglyó G, Magyar Z, Romicsné Görbe É, et al. miRNA profiling of Hungarian regressive Wilms’ tumor formalin-fixed paraffin-embedded (FFPE) samples by quantitative real-time polymerase chain reaction (RT-PCR). Med Sci Monit. 2021; 27: e932731.
Watson JA, Bryan K, Williams R, et al. miRNA profiles as a predictor of chemoresponsiveness in Wilms’ tumor blastema. PLoS ONE 2013; 8: e53417.
Breslow NE, Norris R, Norkool PA, et al. Characteristics and outcomes of children with the Wilms tumor – aniridia syndrome: a report from the National Wilms Tumor Study Group. J Clin Oncol. 2003; 21: 4579–4585.
Mussa A, Russo S, De Crescenzo A, et al. Prevalence of Beckwith–Wiedemann syndrome in North West of Italy. Am J Med Genet A. 2013; 161A: 2481–2486.
Wesseler K, Kraft F, Eggermann T. Molecular and clinical opposite findings in 11p15.5 associated imprinting disorders: characterization of basic mechanisms to improve clinical management. Int J Mol Sci. 2019; 20: 4219.
Brioude F, Toutain A, Giabicani E, et al. Overgrowth syndromes – Clinical and molecular aspects and tumour risk. Nat Rev Endocrinol. 2019; 15: 299–311.
Vujanić GM, Gessler M, Ooms AH, et al. The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol. Nat Rev Urol. 2018; 15: 693–701. Erratum: Nat Rev Urol. 2019; 16: 563.
Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019; 30: 706–720.