Endocrine Pathology

, Volume 28, Issue 3, pp 253–268 | Cite as

Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel–Lindau (VHL), Succinate Dehydrogenase (SDHX) and Transmembrane Protein 127 (TMEM127)

  • Sounak Gupta
  • Jun Zhang
  • Dragana Milosevic
  • John R. Mills
  • Stefan K. Grebe
  • Steven C. Smith
  • Lori A. Erickson


Alterations of von Hippel-Lindau (VHL), succinate dehydrogenase (SDHX), and TMEM127 have been associated with the development of pheochromocytomas (PCs) and paragangliomas (PGLs) and are also associated with the development of renal neoplasms. This study involved 2 primary renal PGL and 12 cases of PC/PGL with associated renal neoplasia with a mean follow up of 74 months. Germline VHL and SDHX mutation status was obtained from the medical record. Immunohistochemistry for SDHB and mutation analysis for TMEM127 was performed, in addition to analysis of The Cancer Genome Atlas datasets for SDHX and TMEM127 mutated renal cell carcinomas (RCCs). The spectrum of renal neoplasia included clear cell and tubulocystic and papillary RCC, as well as a case of multiple papillary adenomas. Three patients had metastatic PC/PGL and three patients had VHL syndrome. Previously unreported TMEM127 alterations were identified in two patients, both without evidence of VHL syndrome or SDH-deficiency, and were classified as variants of uncertain significance. Primary renal PGL and neoplasia was associated with about 2% of 710 cases of PC/PGL. These were diagnosed concurrently or on average 27 months prior to the PC/PGL, and most were low-grade, low-stage clear cell RCCs. Up to half of patients with PC/PGL and renal neoplasia had VHL syndrome, SDH deficiency, or alterations in TMEM127. One (of three) case of metastatic PC/PGL had SDHB mutation and loss of SDHB by immunohistochemistry. The other two cases had retained SDHB expression.


Paraganglioma Pheochromocytoma Renal cell carcinoma Succinate dehydrogenase SDHA SDHB SDHC SDHD SDHAF1 SDHAF2 TMEM127 Von Hippel–Lindau VHL 

Supplementary material

12022_2017_9489_MOESM1_ESM.docx (25 kb)
ESM 1 (DOCX 24.8 kb)


  1. 1.
    Favier, J., L. Amar, and A.P. Gimenez-Roqueplo, Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nature reviews. Endocrinology, 2015. 11(2): p. 101–111.CrossRefPubMedGoogle Scholar
  2. 2.
    Lenders, J.W., et al., Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. The Journal of clinical endocrinology and metabolism, 2014. 99(6): p. 1915–1942.CrossRefPubMedGoogle Scholar
  3. 3.
    Chen, Y.B., 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. The American journal of surgical pathology, 2014. 38(5): p. 627–637.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lubensky, I.A., et al., Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. The American journal of pathology, 1999. 155(2): p. 517–526.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Schmidt, L.S. and W.M. Linehan, Molecular genetics and clinical features of Birt-Hogg-Dube syndrome. Nature reviews. Urology, 2015. 12(10): p. 558–569.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gill, A.J., et al., Renal tumors associated with germline SDHB mutation show distinctive morphology. The American journal of surgical pathology, 2011. 35(10): p. 1578–1585.CrossRefPubMedGoogle Scholar
  7. 7.
    Hernandez, K.G., et al., Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association. Virchows Archiv : an international journal of pathology, 2015. 466(6): p. 727–732.CrossRefGoogle Scholar
  8. 8.
    Lonser, R.R., et al., von Hippel-Lindau disease. Lancet, 2003. 361(9374): p. 2059–2067.CrossRefPubMedGoogle Scholar
  9. 9.
    Ong, K.R., et al., Genotype-phenotype correlations in von Hippel-Lindau disease. Human mutation, 2007. 28(2): p. 143–149.CrossRefPubMedGoogle Scholar
  10. 10.
    Qin, Y., et al., The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function. Human molecular genetics, 2014. 23(9): p. 2428–2439.CrossRefPubMedGoogle Scholar
  11. 11.
    Ricketts, C., et al., Germline SDHB mutations and familial renal cell carcinoma. Journal of the National Cancer Institute, 2008. 100(17): p. 1260–1262.CrossRefPubMedGoogle Scholar
  12. 12.
    Vanharanta, S., et al., Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. American journal of human genetics, 2004. 74(1): p. 153–159.CrossRefPubMedGoogle Scholar
  13. 13.
    Walther, M.M., 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. The Journal of urology, 1995. 154(6): p. 2010–2014; discussion 2014-5.CrossRefPubMedGoogle Scholar
  14. 14.
    Williamson, S.R., et al., Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2015. 28(1): p. 80–94.CrossRefGoogle Scholar
  15. 15.
    Melmon, K.L. and S.W. Rosen, Lindau's Disease. Review of the Literature and Study of a Large Kindred. The American journal of medicine, 1964. 36: p. 595–617.CrossRefPubMedGoogle Scholar
  16. 16.
    Molino, D., et al., The history of von Hippel-Lindau disease. Journal of nephrology, 2006. 19 Suppl 10: p. S119–S123.PubMedGoogle Scholar
  17. 17.
    Ricketts, C.J., et al., Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. The Journal of urology, 2012. 188(6): p. 2063–2071.CrossRefPubMedGoogle Scholar
  18. 18.
    Welander, J., P. Soderkvist, and O. Gimm, Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-related cancer, 2011. 18(6): p. R253–R276.CrossRefPubMedGoogle Scholar
  19. 19.
    Gill, A.J., et al., Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. The American journal of surgical pathology, 2014. 38(12): p. 1588–1602.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    van Nederveen, F.H., et al., An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. The Lancet. Oncology, 2009. 10(8): p. 764–771.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Guo, Z. and R.V. Lloyd, Pheochromocytomas and Paragangliomas: An Update on Recent Molecular Genetic Advances and Criteria for Malignancy. Advances in anatomic pathology, 2015. 22(5): p. 283–293.CrossRefPubMedGoogle Scholar
  22. 22.
    Qin, Y., et al., Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nature genetics, 2010. 42(3): p. 229–233.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yao, L., et al., Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA, 2010. 304(23): p. 2611–2619.CrossRefPubMedGoogle Scholar
  24. 24.
    Kimura, N., et al., Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocrine-related cancer, 2014. 21(3): p. 405–414.CrossRefPubMedGoogle Scholar
  25. 25.
    Gupta, S., et al., Urinary Bladder Paragangliomas: Analysis of Succinate Dehydrogenase and Outcome. Endocrine pathology, 2016. 27(3): p. 243–252.CrossRefPubMedGoogle Scholar
  26. 26.
    Gaal, J., et al., SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2011. 24(1): p. 147–151.CrossRefGoogle Scholar
  27. 27.
    Gupta, S., et al., High grade neuroendocrine carcinoma of the urinary bladder treated by radical cystectomy: a series of small cell, mixed neuroendocrine and large cell neuroendocrine carcinoma. Pathology, 2015. 47(6): p. 533–542.CrossRefPubMedGoogle Scholar
  28. 28.
    Li, M.M., et al., Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. The Journal of molecular diagnostics : JMD, 2017. 19(1): p. 4–23.CrossRefPubMedGoogle Scholar
  29. 29.
    Richards, S., et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine : official journal of the American College of Medical Genetics, 2015. 17(5): p. 405–424.CrossRefGoogle Scholar
  30. 30.
    Gill, A.J., et al., Germline SDHC mutation presenting as recurrent SDH deficient GIST and renal carcinoma. Pathology, 2013. 45(7): p. 689–691.CrossRefPubMedGoogle Scholar
  31. 31.
    Henderson, A., et al., SDHB-associated renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis. Familial cancer, 2009. 8(3): p. 257–260.CrossRefPubMedGoogle Scholar
  32. 32.
    Housley, S.L., et al., Renal carcinoma with giant mitochondria associated with germ-line mutation and somatic loss of the succinate dehydrogenase B gene. Histopathology, 2010. 56(3): p. 405–408.CrossRefPubMedGoogle Scholar
  33. 33.
    Malinoc, A., et al., Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3. Endocrine-related cancer, 2012. 19(3): p. 283–290.CrossRefPubMedGoogle Scholar
  34. 34.
    Ricketts, C.J., et al., Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Human mutation, 2010. 31(1): p. 41–51.CrossRefPubMedGoogle Scholar
  35. 35.
    Srirangalingam, U., et al., Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. Clinical endocrinology, 2008. 69(4): p. 587–596.CrossRefPubMedGoogle Scholar
  36. 36.
    Neumann, H.P., et al., Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA, 2004. 292(8): p. 943–951.CrossRefPubMedGoogle Scholar
  37. 37.
    Ni, Y., et al., Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. American journal of human genetics, 2008. 83(2): p. 261–268.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Calio, A., et al., Renal cell carcinoma with TFE3 translocation and succinate dehydrogenase B mutation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2016.Google Scholar
  39. 39.
    Miettinen, M., et al., Mapping of succinate dehydrogenase losses in 2258 epithelial neoplasms. Applied immunohistochemistry & molecular morphology : AIMM, 2014. 22(1): p. 31–36.CrossRefGoogle Scholar
  40. 40.
    Ozluk, Y., et al., Renal carcinoma associated with a novel succinate dehydrogenase A mutation: a case report and review of literature of a rare subtype of renal carcinoma. Human pathology, 2015. 46(12): p. 1951–1955.CrossRefPubMedGoogle Scholar
  41. 41.
    Papathomas, T.G., et al., Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis. European journal of endocrinology, 2014. 170(1): 1–12.CrossRefPubMedGoogle Scholar
  42. 42.
    Yakirevich, E., et al., A Novel SDHA-deficient Renal Cell Carcinoma Revealed by Comprehensive Genomic Profiling. The American journal of surgical pathology, 2015. 39(6): p. 858–863.CrossRefPubMedGoogle Scholar
  43. 43.
    Hao X, et al., Succinate Dehydrogenase (SDH)-Deficient Renal Cell Carcinoma, a Report of 7 Cases with an Emphasis on High Grade Morphologic Features. Modern Pathology, 2016. 29(S2): p. 236A.Google Scholar
  44. 44.
    Lopez T, et al., Frequency of Succinate Dehydrogenase and Fumarate Hydratase Deficient Renal Cell Carcinoma Based On Immunohistochemical Screening with SDHA/SDHB and FH/2SC. Modern Pathology, 2017. 30(S2): p. 239A.Google Scholar
  45. 45.
    Cascon, A., et al., Molecular characterisation of a common SDHB deletion in paraganglioma patients. Journal of medical genetics, 2008. 45(4): p. 233–238.CrossRefPubMedGoogle Scholar
  46. 46.
    Fleming, S., et al., Signalling pathways in succinate dehydrogenase B-associated renal carcinoma. Histopathology, 2014. 64(4): p. 477–483.CrossRefPubMedGoogle Scholar
  47. 47.
    Gill, A.J., et al., Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. The New England journal of medicine, 2011. 364(9): p. 885–886.CrossRefPubMedGoogle Scholar
  48. 48.
    Jasperson, K.W., et al., Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. Familial cancer, 2014. 13(2): p. 257–265.CrossRefPubMedGoogle Scholar
  49. 49.
    Paik, J.Y., et al., Renal carcinoma associated with succinate dehydrogenase B mutation: a new and unique subtype of renal carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014. 32(6): p. e10–e13.CrossRefGoogle Scholar
  50. 50.
    Solis, D.C., et al., Penetrance and clinical consequences of a gross SDHB deletion in a large family. Clinical genetics, 2009. 75(4): p. 354–363.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Fairchild, R.S., et al., Neuroblastoma, pheochromocytoma, and renal cell carcinoma. Occurrence in a single patient. JAMA, 1979. 242(20): p. 2210–2211.CrossRefPubMedGoogle Scholar
  52. 52.
    Schimke, R.N., D.L. Collins, and C.A. Stolle, Paraganglioma, neuroblastoma, and a SDHB mutation: Resolution of a 30-year-old mystery. American journal of medical genetics. Part A, 2010. 152A(6): p. 1531–1535.Google Scholar
  53. 53.
    Cornejo, K.M., et al., Succinate dehydrogenase B: a new prognostic biomarker in clear cell renal cell carcinoma. Human pathology, 2015. 46(6): p. 820–6.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Smith, S.C., et al., Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci: A Frequent Morphologic Pattern of Fumarate Hydratase-deficient Renal Cell Carcinoma. The American journal of surgical pathology, 2016. 40(11): p. 1457–1472.CrossRefPubMedGoogle Scholar
  55. 55.
    Lefebvre, S., et al., Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2012. 44(5): p. 334–338.CrossRefPubMedGoogle Scholar
  56. 56.
    Bahrami, A., et al., Synchronous renal and adrenal masses: an analysis of 80 cases. Annals of diagnostic pathology, 2009. 13(1): p. 9–15.CrossRefPubMedGoogle Scholar
  57. 57.
    Preger, L., et al., Intrarenal pheochromocytoma: preoperative angiographic diagnosis. Urology, 1976. 8(2): p. 194–196.CrossRefPubMedGoogle Scholar
  58. 58.
    Simon, H., et al., Intrarenal pheochromocytoma: report of a case. The Journal of urology, 1979. 121(6): p. 805–807.CrossRefPubMedGoogle Scholar
  59. 59.
    Takahashi, M., et al., cDNA microarray analysis assists in diagnosis of malignant intrarenal pheochromocytoma originally masquerading as a renal cell carcinoma. Journal of medical genetics, 2005. 42(8): p. e48.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Lagace, R. and M. Tremblay, Non-chromaffin paraganglioma of the kidney with distant metastases. Canadian Medical Association journal, 1968. 99(22): p. 1095–1098.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Daskalopoulos, G., et al., Coexisting non-functioning pheochromocytoma and renal oncocytoma: a case report and review of the literature. European journal of radiology, 1996. 23(2): p. 138–142.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Sounak Gupta
    • 1
  • Jun Zhang
    • 2
  • Dragana Milosevic
    • 1
  • John R. Mills
    • 1
  • Stefan K. Grebe
    • 1
  • Steven C. Smith
    • 3
  • Lori A. Erickson
    • 1
  1. 1.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  2. 2.Department of Laboratory Medicine and PathologyMayo ClinicPhoenixUSA
  3. 3.Departments of Pathology and UrologyVCU HealthRichmondUSA

Personalised recommendations