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Clinical and morphologic review of 60 hereditary renal tumors from 30 hereditary renal cell carcinoma syndrome patients: lessons from a contemporary single institution series

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Abstract

Hereditary renal cell carcinoma syndromes (HRCCS) are characterized by the presence of pathogenic germline variants that predispose patients to renal cell carcinomas as well as additional extra-renal manifestations. The importance of identifying HRCCS patients cannot be overemphasized, as patients and their families can begin surveillance for syndrome-associated manifestations once identified. The present study is a retrospective clinical and morphologic review of 60 hereditary renal tumors from 30 HRCCS patients treated at our institution with either Von Hippel-Lindau disease (VHL), Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex (TSC), hereditary leiomyomatosis and renal cell cancer syndrome, or succinate dehydrogenase (SDH) deficiency syndrome. Hereditary renal cell carcinoma syndromes kidney tumors often demonstrate specific morphologic features, characteristic background changes in renal parenchyma, and extra-renal manifestations, which, when recognized by the pathologist, can trigger genetic testing referral for specific familial cancer syndromes. Our study demonstrates the majority of tumors were consistent with the anticipated clinicopathologic profile of renal tumors found within HRCCS patients, although we found some unique characteristics within this cohort including a case of clear cell papillary renal cell carcinoma within a VHL patient, and a unique renal tumor with tubulopapillary features present in a patient with a germline SDHD mutation. Additionally, although the literature reports the presence of epithelioid angiomyolipoma (AML) as a common occurrence in TSC patients, our cohort of 3 patients with AMLs demonstrated only classic features. The findings we describe facilitate pathologist-based recognition of HRCCS and can prompt genetic evaluation for relevant patients.

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References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. 2018;68:394–424.

    PubMed  Google Scholar 

  2. Adeniran AJ, Shuch B, Humphrey PA. Hereditary renal cell carcinoma syndromes: clinical, pathologic, and genetic features. Am J Surg Pathol. 2015;39:e1–18.

    Article  Google Scholar 

  3. Barrisford GW, Singer EA, Rosner IL, et al. Familial renal cancer: molecular genetics and surgical management. Int J Surg Oncol. 2011;2011:658767.

    PubMed  PubMed Central  Google Scholar 

  4. Gaur S, Turkbey B, Choyke P. Hereditary renal tumor syndromes: update on diagnosis and management. Semin Ultrasound CT MR. 2017;38:59–71.

    Article  Google Scholar 

  5. Menko FH, Maher ER. Diagnosis and management of hereditary renal cell cancer. Recent Results Cancer Res. 2016;205:85–104.

    Article  Google Scholar 

  6. Coleman JA, Russo P. Hereditary and familial kidney cancer. Curr Opin Urol. 2009;19:478–85.

    Article  Google Scholar 

  7. Maher ER. Genetics of familial renal cancers. Nephron Exp Nephrol. 2011;118:e21–6.

    Article  Google Scholar 

  8. Sampson JR, Yates JR, Pirrit LA, et al. Evidence for genetic heterogeneity in tuberous sclerosis. J Med Genet. 1989;26:511–6.

    Article  CAS  Google Scholar 

  9. Przybycin CG, Magi-Galluzzi C, McKenney JK. Hereditary syndromes with associated renal neoplasia: a practical guide to histologic recognition in renal tumor resection specimens. Adv Anat Pathol. 2013;20:245–63.

    Article  Google Scholar 

  10. Moch HP, Humphrey PA, Ulbright TM, Reuter VE. WHO classification of tumors of the urinary system and male genital organs. 4th ed. Lyon: IARC; 2016.

    Google Scholar 

  11. Crespigio J, Berbel LCL, Dias MA, et al. Von Hippel-Lindau disease: a single gene, several hereditary tumors. J Endocrinol Invest. 2018;41:21–31.

    Article  CAS  Google Scholar 

  12. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dube syndrome: diagnosis and management. Lancet Oncol. 2009;10:1199–206.

    Article  CAS  Google Scholar 

  13. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 iinternational tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:243–54.

    Article  Google Scholar 

  14. Menko FH, Maher ER, Schmidt LS, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13:637–44.

    Article  CAS  Google Scholar 

  15. Hovelson DH, McDaniel AS, Cani AK, et al. Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. Neoplasia. 2015;17:385–99.

    Article  CAS  Google Scholar 

  16. Wang L, Zhang Y, Chen YB, et al. VSTM2A overexpression is a sensitive and specific biomarker for mucinous tubular and spindle cell carcinoma (MTSCC) of the Kidney. Am J Surg Pathol. 2018;42:1571–84.

    Article  Google Scholar 

  17. Varshney N, Kebede AA, Owusu-Dapaah H, et al. A Review of Von Hippel-Lindau Syndrome. J Kidney Cancer VHL. 2017;4:20–9.

    Article  Google Scholar 

  18. Ashouri K, Mohseni S, Tourtelot J, et al. Implications of Von Hippel-Lindau syndrome and renal cell carcinoma. J Kidney Cancer VHL. 2015;2:163–73.

    Article  Google Scholar 

  19. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361:2059–67.

    Article  CAS  Google Scholar 

  20. Nielsen SM, Rhodes L, Blanco I, et al. Von Hippel-Lindau disease: genetics and role of genetic counseling in a multiple neoplasia syndrome. J Clin Oncol. 2016;34:2172–81.

    Article  CAS  Google Scholar 

  21. Kawashima A, Young SW, Takahashi N, et al. Inherited renal carcinomas. Abdom Radiol. 2016;41:1066–78.

    Article  Google Scholar 

  22. Walther MM, Lubensky IA, Venzon D, et al. Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications. J Urol. 1995;154:2010–4. discussion 2014–15.

    Article  CAS  Google Scholar 

  23. Chen YB, Tickoo SK. Spectrum of preneoplastic and neoplastic cystic lesions of the kidney. Arch Pathol Lab Med. 2012;136:400–9.

    Article  Google Scholar 

  24. Montani M, Heinimann K, von Teichman A, et al. VHL-gene deletion in single renal tubular epithelial cells and renal tubular cysts: further evidence for a cyst-dependent progression pathway of clear cell renal carcinoma in von Hippel-Lindau disease. Am J Surg Pathol. 2010;34:806–15.

    Article  Google Scholar 

  25. Phillips JL, Ghadimi BM, Wangsa D, et al. Molecular cytogenetic characterization of early and late renal cell carcinomas in von Hippel-Lindau disease. Genes Chromosom Cancer. 2001;31:1–9.

    Article  CAS  Google Scholar 

  26. Matoso A, Chen YB, Rao V, et al. Atypical renal cysts: a morphologic, immunohistochemical, and molecular study. Am J Surg Pathol. 2016;40:202–11.

    PubMed  Google Scholar 

  27. Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006;30:141–53.

    Article  Google Scholar 

  28. Rohan SM, Xiao Y, Liang Y, et al. Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod Pathol. 2011;24:1207–20.

    Article  CAS  Google Scholar 

  29. Williamson SR, Eble JN, Cheng L, et al. Clear cell papillary renal cell carcinoma: differential diagnosis and extended immunohistochemical profile. Mod Pathol. 2013;26:697–708.

    Article  CAS  Google Scholar 

  30. Diolombi ML, Cheng L, Argani P, et al. Do clear cell papillary renal cell carcinomas have malignant potential? Am J Surg Pathol. 2015;39:1621–34.

    Article  Google Scholar 

  31. Rao P, Monzon F, Jonasch E, et al. Clear cell papillary renal cell carcinoma in patients with von Hippel-Lindau syndrome–clinicopathological features and comparative genomic analysis of 3 cases. Hum Pathol. 2014;45:1966–72.

    Article  CAS  Google Scholar 

  32. Williamson SR, Zhang S, Eble JN, et al. Clear cell papillary renal cell carcinoma-like tumors in patients with von Hippel-Lindau disease are unrelated to sporadic clear cell papillary renal cell carcinoma. Am J Surg Pathol. 2013;37:1131–9.

    Article  Google Scholar 

  33. Toro JR, Wei MH, Glenn GM, et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008;45:321–31.

    Article  CAS  Google Scholar 

  34. Benusiglio PR, Giraud S, Deveaux S, et al. Renal cell tumour characteristics in patients with the Birt-Hogg-Dube cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis. 2014;9:163.

    Article  Google Scholar 

  35. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomark Prev. 2002;11:393–400.

    Google Scholar 

  36. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol. 2002;26:1542–52.

    Article  Google Scholar 

  37. Tickoo SK, Reuter VE, Amin MB, et al. Renal oncocytosis: a morphologic study of fourteen cases. Am J Surg Pathol. 1999;23:1094–101.

    Article  CAS  Google Scholar 

  38. Gobbo S, Eble JN, Delahunt B, et al. Renal cell neoplasms of oncocytosis have distinct morphologic, immunohistochemical, and cytogenetic profiles. Am J Surg Pathol. 2010;34:620–6.

    PubMed  Google Scholar 

  39. Chung JY, Ramos-Caro FA, Beers B, et al. Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome. Int J Dermatol. 1996;35:365–7.

    Article  CAS  Google Scholar 

  40. Rakowski SK, Winterkorn EB, Paul E, et al. Renal manifestations of tuberous sclerosis complex: incidence, prognosis, and predictive factors. Kidney Int. 2006;70:1777–82.

    Article  CAS  Google Scholar 

  41. Yang P, Cornejo KM, Sadow PM, et al. Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol. 2014;38:895–909.

    Article  Google Scholar 

  42. Tello R, Blickman JG, Buonomo C, et al. Meta analysis of the relationship between tuberous sclerosis complex and renal cell carcinoma. Eur J Radiol. 1998;27:131–8.

    Article  CAS  Google Scholar 

  43. Guo J, Tretiakova MS, Troxell ML, et al. Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am J Surg Pathol. 2014;38:1457–67.

    Article  Google Scholar 

  44. Aydin H, Magi-Galluzzi C, Lane BR, et al. Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. Am J Surg Pathol. 2009;33:289–97.

    Article  Google Scholar 

  45. Jimenez RE, Eble JN, Reuter VE, et al. Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases. Mod Path. 2001;14:157–63.

    Article  CAS  Google Scholar 

  46. He W, Cheville JC, Sadow PM, et al. Epithelioid angiomyolipoma of the kidney: pathological features and clinical outcome in a series of consecutively resected tumors. Mod Pathol. 2013;26:1355–64.

    Article  Google Scholar 

  47. Nese N, Martignoni G, Fletcher CD, et al. Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: a clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification. Am J Surg Pathol. 2011;35:161–76.

    Article  Google Scholar 

  48. Brimo F, Robinson B, Guo C, et al. Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. Am J Surg Pathol. 2010;34:715–22.

    PubMed  Google Scholar 

  49. Schreiner A, Daneshmand S, Bayne A, et al. Distinctive morphology of renal cell carcinomas in tuberous sclerosis. Int J Surg Pathol. 2010;18:409–18.

    Article  Google Scholar 

  50. Kopp RP, Stratton KL, Glogowski E, et al. Utility of prospective pathologic evaluation to inform clinical genetic testing for hereditary leiomyomatosis and renal cell carcinoma. Cancer. 2017;123:2452–8.

    Article  CAS  Google Scholar 

  51. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA. 2001;98:3387–92.

    Article  CAS  Google Scholar 

  52. 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;31:1578–85.

    Article  Google Scholar 

  53. 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;40:865–75.

    Article  Google Scholar 

  54. 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;38:1588–602.

    Article  Google Scholar 

  55. Andrews KA, Ascher DB, Pires DEV, et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018;55:384–94.

    CAS  PubMed  Google Scholar 

  56. 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.

    Article  CAS  Google Scholar 

  57. Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011;35:1578–85.

    Article  Google Scholar 

  58. Ricketts CJ, Shuch B, Vocke CD, et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012;188:2063–71.

    Article  CAS  Google Scholar 

  59. Linehan WM, Pinto PA, Bratslavsky G, et al. Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer. 2009;115:2252–61.

    Article  CAS  Google Scholar 

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This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    John M. Kennedy, Komal R. Plouffe, Arul M. Chinnaiyan, Aaron M. Udager & Rohit Mehra

  2. Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA

    Khaled Hafez, Ganesh S. Palapattu, Alon Z. Weizer, Todd M. Morgan, Matthew S. Davenport & Arul M. Chinnaiyan

  3. Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    Tobias Else

  4. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA

    Daniel E. Spratt

  5. Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA

    Arul M. Chinnaiyan, Aaron M. Udager & Rohit Mehra

  6. Michigan Center for Translational Pathology, Ann Arbor, MI, USA

    Xiaoming Wang, Saravana M. Dhanasekaran, Arul M. Chinnaiyan, Aaron M. Udager & Rohit Mehra

  7. Howard Hughes Medical Institute, Ann Arbor, MI, USA

    Arul M. Chinnaiyan

  8. Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Matthew S. Davenport

  9. Department of Pathology, Michigan Medicine, University of Michigan, 2800 Plymouth Road, Building 35, Ann Arbor, MI, 48109, USA

    Rohit Mehra

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  1. John M. Kennedy
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Kennedy, J.M., Wang, X., Plouffe, K.R. et al. Clinical and morphologic review of 60 hereditary renal tumors from 30 hereditary renal cell carcinoma syndrome patients: lessons from a contemporary single institution series. Med Oncol 36, 74 (2019). https://doi.org/10.1007/s12032-019-1297-6

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