Inherited endocrine tumors have been more and more known in clinical setting, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. For example, paraganglionic tumors might arise in an apparently sporadic manner in SDH mutation carriers. Morphologic traits of endocrine and/or endocrine-related cancer can raise the suspicion of hereditary disease, for example, multiple cellular adenomatous thyroid nodules seen in Cowden syndrome, or a specific type of thyroid tumor, as the cribriform-morular variant of papillary thyroid carcinoma (CMv-PT) in Familial Adenomatous Polyposis (FAP), parafibromin-deficient parathyroid tumors in Hyperparathyroidism Jaw Tumor syndrome, succinate dehydrogenase (SDH)-deficient renal cell carcinomas and gastrointestinal stromal tumors in SDH-related Pheochromocytoma/Paraganglioma (PPGL) syndromes, fumarate hydratase (FH)-deficient renal cell carcinomas and uterine smooth muscle tumors in Hereditary Leiomyomatosis and Renal Cell Cancer syndrome, multiple pancreatic micro-differentiated as well as well-differentiated neuroendocrine tumors in glucagon cell adenomatosis.47–50 Immunohistochemistry should be subsequently performed and integrated in a comprehensive molecular genetic approach.
Hereditary thyroid neoplasms arising from calcitonin-producing C cells are known as familial medullary thyroid carcinomas, and include well-documented syndromes such as multiple endocrine neoplasia type 2A or 2B, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial nonmedullary thyroid carcinoma, or familial follicular cell–derived carcinoma. Familial nonmedullary thyroid carcinoma are subdivided into 2 groups. Among the first group are found syndromes characterized by a predominance of nonthyroidal tumors, including FAP, PTEN hamartoma tumor syndrome/Cowden syndrome, Carney complex, Werner syndrome, and Pendred syndrome. The markers are more specific for these tumors in the first group. The second group is composed by a variety of familial syndromes characterized by a predominance of nonmedullary thyroid tumors, such as pure familial PTC with or without oxyphilia, familial PTC with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goiter. No markers for this group are available.49,51,52
Apart from an established application to complement morphologic or clinical suspicion of FCS/HTPS, that is, early onset of disease, multifocal synchronous or metachronous disease, precursor lesions with or without concurrent tumors, genotype-specific entities or histopathologic features and specific combinations of histogenetically distinct tumors,48 functional markers might serve as a cost-effective screen for identification of aggressive endocrine neoplastic disease. Parafibromin immunohistochemistry can be utilized to identify aggressive CDC73-related parathyroid neoplasia including parathyroid carcinomas and parathyroid tumors lacking overt malignant features.1 Exemplifying the latter, parafibromin-deficient CDC73-mutated tumors, lacking WHO 2017 criteria for malignancy, can rarely metastasize,56 whereas parafibromin-deficient atypical tumors, as defined by WHO 2004 criteria, have a low risk for recurrence.80 Long-term or even life-long close follow-up of patients with parafibromin-deficient tumors has been accordingly recommended.
Emerging molecular biomarkers in the field of thyroid oncology, such as mutations in noncoding functional genomic regions (ie, TERT-p mutations), multiple oncogenic mutations (eg, BRAF, RAS, TP53, PIK3CA, AKT1, and TERT-p mutations) and/or total mutation burden, might have clinical applicability as prognosticators in follicular cell–derived thyroid neoplasms independent of histopathology.44,92–96 On the basis of data deriving from a meta-analysis investigating the impact of genomic aberrations on the prognosis of PTC-affected patients, TERT-p mutations have been highlighted as independent and reliable predictive biomarker for patient outcome and risk stratification, whereas BRAF mutation should be cautiously utilized as stand-alone prognostic marker given poor predictive value in long-term prognosis.92 The latter further supports previous inconsistencies with regard to prognostic significance of BRAF mutations potentially reflecting molecular genetic heterogeneity within BRAFV600E-like PTCs.44,92,93 In keeping with a stepwise progression model in thyroid tumorigenesis, TERT-p mutations have been identified in 8% to 27% of PTCs, 20% of follicular thyroid carcinomas, <25% of Hürthle cell carcinomas, 40% of poorly differentiated thyroid carcinomas, and nearly 75% of undifferentiated thyroid carcinomas.44 These noncoding mutations might also occur in rare subset of aggressive follicular thyroid tumors without overt malignant histologic features and hence be predictive of malignant potential.94,97
Integrated genomic studies revealed subsets of adrenal cortical carcinoma with different pattern of molecular aberrations, associated with different clinical outcome: (i) 2-tier classification into C1A subgroup with poor outcome, characterized by numerous mutations and DNA methylation alterations, and C1B subgroup with good prognosis, characterized by specific microRNA deregulation;98 and (ii) 3-tier classification into 3 subtypes, Cluster of Cluster (CoC) I/II/III: CoC I with good outcome, significantly unregulated genes in immune-mediated pathways and lower Ki67-defined proliferative activity; CoC II with a heterogenous outcome; and CoC III with a dismal outcome, significant dysregulation of genes in mitotic pathways and higher Ki67-defined proliferative activity.99 The latter further reinforces the prognostic value of proliferation marker Ki67 in both localized and advanced adrenocortical cancer, with combined assessment of Ki67 labelling index and VAV2 expression leading to improved patient stratification into low-risk and high-risk subgroups and hence refining prognostic prediction.100–102 Tumor DNA methylation, that is, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, and PAX6), has recently emerged as independent prognostic marker for survival in adrenocortical cancer.103 Towards improved personalized prognostication, it has been recently shown that integrating molecular genetic data (>1 somatic mutation, alterations in Wnt/β-catenin and p53 pathways, high methylation pattern) and clinico-pathologic parameters (tumor stage, age, symptoms, resection status, and Ki67 labeling index) into a combined score yielded the best prediction of progression-free survival.104
Robust biomarkers of response to current therapies in well-differentiated thyroid and adrenocortical cancer should be developed to accurately determine which patients will benefit from radioiodine therapy and mitotane, respectively. In this context, TERT-p mutations might serve as early predictor of radioiodine-refractory cases of distant metastatic differentiated thyroid cancer, while human cytochrome P450 2W1, ribonucleotide reductase large subunit 1, and sterol-O-acyl-transferase 1 might represent predictive markers for the response of adrenal cortical carcinoma–affected patients to mitotane, an adrenolytic but significantly toxic agent.107–110 Preliminary evidence also suggests that somatostatin receptor subtype 1 might be a predictor of better response to therapy in medullary thyroid carcinoma.111 Nevertheless, these should be validated on large series and in the prospective setting before being utilized in routine practice.
In this comprehensive review, we summarize tumor-specific biomarkers in endocrine organs as well as anatomic site-related and site-specific markers for diagnostic evaluation of challenging neoplasms. Functional markers as tools to uncover some of the FCSs and/or HTPSs are discussed along with limitations in their applicability and/or potential pitfalls in endocrine pathology. We also discuss new and emerging prognostic biomarkers in follicular cell–derived thyroid, parathyroid, paraganglionic, and adrenocortical tumors, as well as biomarkers of therapeutic response in endocrine oncology.
The authors are grateful to Professor M. Beatriz S. Lopes, MD, PhD, Professor of Pathology and Neurological Surgery, Director of Neuropathology and Autopsy, University of Virginia Medical Center for providing us with figures of pituitary tumors.
1. Lloyd RV, Osamura RY, Kloppel G, et al. WHO Classification of Tumors of Endocrine Organs, 4th ed. Lyon: IARC; 2017.
2. Asa SL, Casar-Borota O, Chanson P, et al. and the attendees of 14th Meeting of the International Pituitary Pathology Club, Annecy, France, November 2016. From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal. Endocr Relat Cancer. 2017;24:C5–8.
3. Lopes MBS. The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol. 2017;134:521–535.
4. Asa SL, Mete O. Immunohistochemical biomarkers in pituitary pathology. Endocr Pathol. 2018;29:130–136.
5. Liu H, Lin F. Application of immunohistochemistry in thyroid pathology. Arch Pathol Lab Med. 2015;139:67–82.
6. Baloch ZW, LiVolsi VA. Special types of thyroid carcinoma. Histopathology. 2018;72:40–52.
7. Dogan S, Wang L, Ptashkin RN, et al. Mammary analog secretory carcinoma of the thyroid gland: a primary thyroid adenocarcinoma harboring ETV6-NTRK3 fusion. Mod Pathol. 2016;29:985–995.
8. Lam AK, Saremi N. Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer. Endocr Relat Cancer. 2017;24:R109–121.
9. Mohindra S, Sakr H, Sturgis C, et al. LEF-1 is a sensitive marker of cribriform morular variant of papillary thyroid carcinoma. Head Neck Pathol. 2018;12:455–462.
10. Papathomas TG, de Krijger RR, Tischler AS. Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments. Semin Diagn Pathol. 2013;30:207–223.
11. Miettinen M, McCue PA, Sarlomo-Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol. 2014;38:13–22.
12. Mete O, Kefeli M, Çalişkan S, et al. GATA3 immunoreactivity expands the transcription factor profile of pituitary neuroendocrine tumors. Mod Pathol. 2018. Doi: 10.1038/s41379-018-0167-7.
13. Yokoyama H, Adachi T, Tsubouchi K, et al. Non-functioning adrenocortical carcinoma arising in an adrenal rest: immunohistochemical study of an adult patient. Tohoku J Exp Med. 2013;229:267–270.
14. Park WY, Seo HI, Choi KU, et al. Three cases of adrenocortical tumors mistaken for hepatocellular carcinomas/diagnostic pitfalls and differential diagnosis. Ann Diagn Pathol. 2017;31:9–13.
15. Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carcinoma located in the ovary. Eur J Endocrinol. 2016;175:K17–23.
16. Sugiyama T, Tajiri T, Hiraiwa S, et al. Hepatic adrenal rest tumor: diagnostic pitfall and proposed algorithms to prevent misdiagnosis as lipid-rich hepatocellular carcinoma. Pathol Int. 2015;65:95–999.
17. Jain SH, Sadow PM, Nosé V, et al. A patient with ectopic cortisol production derived from malignant testicular masses. Nat Clin Pract Endocrinol Metab. 2008;4:695–700.
18. Lloyd RV, Douglas BR, Young WF. Endocrine Diseases, AFIP Atlas of Non-Tumor Pathology, Series 1(1). Washington, DC: American Registry of Pathology; 2002.
19. Gourmaud J, Bongiovanni M, Triponez F, et al. Ectopic thyroid tissue in the adrenal gland. Endocr Pathol. 2014;25:353–355.
20. Romero-Rojas A, Bella-Cueto MR, Meza-Cabrera IA, et al. Ectopic thyroid tissue in the adrenal gland: a report of two cases with pathogenetic implications. Thyroid. 2013;23:1644–1650.
21. Bohinc BN, Parker JC, Hope WW, et al. Micropapillary thyroid carcinoma and concomitant ectopic thyroid tissue in the adrenal gland: metastasis or metaplasia? Thyroid. 2011;21:1033–1038.
22. Lin DM, Javidiparsijani S, Vardouniotis A, et al. Ectopic thyroid tissue: immunohistochemistry and molecular analysis. Appl Immunohistochem Mol Morphol. 2018;26:734–739.
23. Kandalaft PL, Gown AM. Practical applications in immunohistochemistry: carcinomas of unknown primary site. Arch Pathol Lab Med. 2016;140:508–523.
24. Kandukuri SR, Lin F, Gui L, et al. Application of immunohistochemistry in undifferentiated neoplasms: a practical approach. Arch Pathol Lab Med. 2017;141:1014–1032.
25. Lin F, Liu H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138:1583–1610.
26. Wang HL, Kim CJ, Koo J, et al. Practical immunohistochemistry in neoplastic pathology of the gastrointestinal tract, liver, biliary tract, and pancreas. Arch Pathol Lab Med. 2017;141:1155–1180.
27. Churg A, Sheffield BS, Galateau-Salle F. New markers for separating benign from malignant mesothelial proliferations: are we there yet? Arch Pathol Lab Med. 2016;140:318–321.
28. Lagana SM, Salomao M, Remotti HE, et al. Bile salt export pump: a sensitive and specific immunohistochemical marker of hepatocellular carcinoma. Histopathology. 2015;66:598–602.
29. Mendez-Pena JE, Sadow PM, Nose V, et al. RNA chromogenic in situ hybridization assay with clinical automated platform is a sensitive method in detecting high-risk human papillomavirus in squamous cell carcinoma. Hum Pathol. 2017;63:184–189.
30. Stelow EB, Yaziji H. Immunohistochemistry, carcinomas of unknown primary, and incidence rates. Semin Diagn Pathol. 2018;35:143–152.
31. Bochtler T, Löffler H, Krämer A. Diagnosis and management of metastatic neoplasms with unknown primary. Semin Diagn Pathol. 2018;35:199–206.
32. Oien KA, Dennis JL. Diagnostic work-up of carcinoma of unknown primary: from immunohistochemistry to molecular profiling. Ann Oncol. 2012;23(suppl 10):x271–217.
33. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet. 2012;379:1428–1435.
34. Papathomas T, Nose VWass JAH, Arlt W, Semple R. Metastatic disease in endocrine organs. Oxford Textbook of Endocrinology and Diabetes, 3rd ed. Oxford: Oxford University Press; 2019. [In Press].
35. Soh KP, Szczurek E, Sakoparnig T, et al. Predicting cancer type from tumor DNA signatures. Genome Med. 2017;9:104.
36. Marquard AM, Birkbak NJ, Thomas CE, et al. TumorTracer: a method to identify the tissue of origin from the somatic mutations of a tumor specimen. BMC Med Genomics. 2015;8:58.
37. Søndergaard D, Nielsen S, Pedersen CNS, et al. Prediction of primary tumors in cancers of unknown primary. J Integr Bioinform. 2017;14:1–7.
38. Moran S, Martinez-Cardús A, Boussios S, et al. Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary. Nat Rev Clin Oncol. 2017;14:682–694.
39. Moran S, Martínez-Cardús A, Sayols S, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 2016;17:1386–1395.
40. Varghese AM, Arora A, Capanu M, et al. Clinical and molecular characterization of patients with cancer of unknown primary in the modern era. Ann Oncol. 2017;28:3015–3021.
41. Ross JS, Wang K, Gay L, et al. Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies. JAMA Oncol. 2015;1:40–49.
42. Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–713.
43. Chou A, Fraser S, Toon CW, et al. A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma. Am J Surg Pathol. 2015;39:652–659.
44. Giordano TJ. Genomic hallmarks of thyroid neoplasia. Annu Rev Pathol. 2018;13:141–162.
45. Kakudo K, El-Naggar AK, Hodak SP, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in thyroid tumor classification
. Pathol Int. 2018;68:327–333.
46. Jones JL, Oien KA, Lee JL, et al. Morphomolecular pathology: setting the framework for a new generation of pathologists. Br J Cancer. 2017;117:1581–1582.
47. Andrici J, Gill AJ, Hornick JL. Next generation immunohistochemistry: emerging substitutes to genetic testing? Semin Diagn Pathol. 2018;35:161–169.
48. Agaimy A, Hartmann A. Uncovering hereditary tumor syndromes: emerging role of surgical pathology. Semin Diagn Pathol. 2018;35:154–160.
49. Guilmette J, Nosé V. Hereditary and familial thyroid tumors. Histopathology. 2018;72:70–81.
50. Laury AR, Bongiovanni M, Tille JC, et al. Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid. 2011;21:135–144.
51. Nosé V. Familial thyroid cancer: a review. Mod Pathol. 2011;24(suppl 2):S19–33.
52. Nosé V. Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv Anat Pathol. 2010;17:428–436.
53. Barletta JA, Bellizzi AM, Hornick JL. Immunohistochemical staining of thyroidectomy specimens for PTEN can aid in the identification of patients with Cowden syndrome. Am J Surg Pathol. 2011;35:1505–1511.
54. Jayakody S, Reagh J, Bullock M, et al. Medullary thyroid carcinoma: survival analysis and evaluation of mutation-specific immunohistochemistry in detection of sporadic disease. World J Surg. 2018;42:1432–1439.
55. Reagh J, Bullock M, Andrici J, et al. NRASQ61R mutation-specific immunohistochemistry also identifies the HRASQ61R mutation in medullary thyroid cancer and may have a role in triaging genetic testing for MEN2. Am J Surg Pathol. 2017;41:75–81.
56. Gill AJ, Lim G, Cheung VKY, et al. Parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol. 2019;43:35–46.
57. Papathomas TG, Oudijk L, Persu A, et al. SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). Mod Pathol. 2015;28:807–821.
58. Niemeijer ND, Papathomas TG, Korpershoek E, et al. Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum. J Clin Endocrinol Metab. 2015;100:E1386–1393.
59. Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–667.
60. Daly AF, Castermans E, Oudijk L, et al. Pheochromocytomas and pituitary adenomas in three patients with MAX
exon deletions. Endocr Relat Cancer. 2018;25:L37–L42.
61. Stenman A, Svahn F, Welander J, et al. Immunohistochemical NF1 analysis does not predict NF1 gene mutation status in pheochromocytoma. Endocr Pathol. 2015;26:9–14.
62. Burnichon N, Buffet A, Parfait B, et al. Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Hum Mol Genet. 2012;21:5397–405.
63. Wadt K, Choi J, Chung JY, et al. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res. 2012;25:815–818.
64. Bengtsson D, Joost P, Aravidis C, et al. Corticotroph pituitary carcinoma in a patient with Lynch syndrome (LS) and pituitary tumors in a nationwide LS cohort. J Clin Endocrinol Metab. 2017;102:3928–3932.
65. Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013;31:3012–3018.
66. Ohara N, Kaneko M, Ikeda M, et al. Lung adenocarcinoma and adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Respir Med Case Rep. 2016;20:77–81.
67. Grolmusz VK, Borka K, Kövesdi A, et al. MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism. Virchows Arch. 2017;471:401–411.
68. Corbo V, Dalai I, Scardoni M, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadicneoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. 2010;17:771–783.
69. Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol. 2008;32:534–543.
70. Mete O, Cintosun A, Pressman I, et al. Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Mod Pathol. 2018;31:900–909.
71. Haller F, Moskalev EA, Faucz FR, et al. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 2014;21:567–577.
72. Richter S, Klink B, Nacke B, et al. Epigenetic mutation of the succinate dehydrogenase C promoter in a patient with two paragangliomas. J Clin Endocrinol Metab. 2016;101:359–363.
73. Remacha L, Comino-Méndez I, Richter S, et al. Targeted exome sequencing of Krebs cycle genes reveals candidate cancer-predisposing mutations in pheochromocytomas and paragangliomas. Clin Cancer Res. 2017;23:6315–6324.
74. Evenepoel L, Papathomas TG, Krol N, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015;17:610–620.
75. Djordjevic B, Westin S, Broaddus RR. Application of immunohistochemistry and molecular diagnostics to clinically relevant problems in endometrial cancer. Surg Pathol Clin. 2012;5:859–878.
76. Witkowski L, Carrot-Zhang J, Albrecht S, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 2014;46:438–443.
77. Goodfellow PJ, Billingsley CC, Lankes HA, et al. Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: an NRG Oncology and Gynecologic Oncology Group Study. J Clin Oncol. 2015;33:4301–4308.
78. Shattuck TM, Välimäki S, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med. 2003;349:1722–1729.
79. Rossi S, Gasparotto D, Cacciatore M, et al. Neurofibromin C terminus-specific antibody (clone NFC) is a valuable tool for the identification ofNF1-inactivated GISTs. Mod Pathol. 2018;31:160–168.
80. Kruijff S, Sidhu SB, Sywak MS, et al. Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol. 2014;21:426–433.
81. Blank A, Schmitt AM, Korpershoek E, et al. SDHB loss predicts malignancy in pheochromocytomas/sympathethic paragangliomas, but not through hypoxia signalling. Endocr Relat Cancer. 2010;17:919–928.
82. Kimura N, Takayanagi R, Takizawa N, et al. Phaeochromocytoma Study Group in Japan. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014;21:405–414.
83. Fishbein L, Wilkerson MD. Chromaffin cell biology: inferences from The Cancer Genome Atlas. Cell Tissue Res. 2018;372:339–346.
84. Crona J, Taïeb D, Pacak K. New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocr Rev. 2017;38:489–515.
85. Fishbein L, Leshchiner I, Walter V, et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31:181–193.
86. Buffet A, Morin A, Castro-Vega LJ, et al. Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition to metastatic paragangliomas. Cancer Res. 2018;78:1914–1922.
87. Richter S, Gieldon L, Pang Y, et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019;21:705–717.
88. Papathomas TG, Oudijk L, Zwarthoff EC, et al. Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia. Endocr Relat Cancer. 2014;21:653–661.
89. Dwight T, Flynn A, Amarasinghe K, et al. TERT
structural rearrangements in metastatic pheochromocytomas. Endocr Relat Cancer. 2018;25:1–9.
90. Svahn F, Juhlin CC, Paulsson JO, et al. Telomerase reverse transcriptase promoter hypermethylation is associated with metastatic disease in abdominal paraganglioma. Clin Endocrinol (Oxf). 2018;88:343–345.
91. Job S, Draskovic I, Burnichon N, et al. Telomerase activation and ATRX mutations are independent risk factors for metastatic pheochromocytoma and paraganglioma. Clin Cancer Res. 2019;25:760–770.
92. Vuong HG, Duong UN, Altibi AM, et al. A meta-analysis of prognostic roles of molecular markers in papillary thyroid carcinoma. Endocr Connect. 2017;6:R8–17.
93. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–690.
94. Wang N, Liu T, Sofiadis A, et al. TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA. Cancer. 2014;120:2965–2979.
95. Nicolson NG, Murtha TD, Dong W, et al. Comprehensive genetic analysis of follicular thyroid carcinoma predicts prognosis independent of histology. J Clin Endocrinol Metab. 2018;103:2640–2650.
96. Nikiforov YE. Role of molecular markers in thyroid nodule management: then and now. Endocr Pract. 2017;23:979–988.
97. Hysek M, Paulsson JO, Wang N, et al. TERT promoter mutational screening as a tool to predict malignant behaviour in follicular thyroid tumors-three examples from the clinical routine. Virchows Arch. 2018;473:639–643.
98. Assié G, Letouzé E, Fassnacht M, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014;46:607–612.
99. Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell. 2016;30:363.
100. Beuschlein F, Weigel J, Saeger W, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015;100:841–849.
101. Libé R, Borget I, Ronchi CL, et al. ENSAT network. Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol. 2015;26:2119–2125.
102. Sbiera S, Sbiera I, Ruggiero C, et al. Assessment of VAV2 expression refines prognostic prediction in adrenocortical carcinoma. J Clin Endocrinol Metab. 2017;102:3491–3498.
103. Jouinot A, Assie G, Libe R, et al. DNA methylation is an independent prognostic marker of survival in adrenocortical cancer. J Clin Endocrinol Metab. 2017;102:923–932.
104. Lippert J, Appenzeller S, Liang R, et al. Targeted molecular analysis in adrenocortical carcinomas: a strategy toward improved personalized prognostication. J Clin Endocrinol Metab. 2018;103:4511–4523.
105. De Sousa SMC, McCormack AIDe Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A. Aggressive pituitary tumors and pituitary carcinomas. Endotext. South Dartmouth, MA: MDText.com Inc. 2018 Nov 26.
106. Bengtsson D, Schrøder HD, Berinder K, et al. Tumoral MGMT content predicts survival in patients with aggressive pituitary tumors and pituitary carcinomas given treatment with temozolomide. Endocrine. 2018;62:737–739.
107. Yang X, Li J, Li X, et al. TERT promoter mutation predicts radioiodine-refractory character in distant metastatic differentiated thyroid cancer. J Nucl Med. 2017;58:258–265.
108. Ronchi CL, Sbiera S, Volante M, et al. CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma. PLoS One. 2014;9:e105855.
109. Volante M, Terzolo M, Fassnacht M, et al. Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012;18:3452–3461.
110. Sbiera S, Leich E, Liebisch G, et al. Mitotane inhibits sterol-O-acyl transferase 1 triggering lipid-mediated endoplasmic reticulum stress and apoptosis in adrenocortical carcinoma cells. Endocrinology. 2015;156:3895–3908.
111. Kendler DB, Araújo ML Jr, Alencar R, et al. Somatostatin receptor subtype 1 might be a predictor of better response to therapy in medullary thyroid carcinoma. Endocrine. 2017;58:474–480.