Unification of pathomorphological examination of patients with neuroendocrine tumors of the pituitary gland. Controversial issues of the new classification

The progressive improvement of the classification using modern analytical methods is an essential tool for the development of precise and personalized approaches to the treatment of pituitary adenomas. In recent years, endocrinologists have witnessed evolutionary changes that have occurred in the histopathological identification of pituitary neoplasms, revealing new possibilities for studying tumorigenesis and predicting biological behavior.

The paper considers the historical aspects of the gradual improvement of the classification of pituitary adenomas, as well as the new international 2022 WHO classification, according to which pituitary adenomas are included in the list of neuroendocrine tumors (PitNETs) to reflect the biological aggressiveness of some non-metastatic pituitary adenomas. The characteristics of pituitary adenoma are presented, as well as a list of histological subtypes of aggressive neuroendocrine tumors of the pituitary gland, marked by the main potentials for invasive growth, an increased risk of recurrence and a negative clinical prognosis.

The expediency of changing the definition of «pituitary adenoma» to «neuroendocrine tumor» is discussed. It is emphasized that the introduction of a unified clinical, laboratory and morphological protocol into national clinical practice will help provide comparable comparative studies on the prognosis of the disease and the effectiveness of secondary therapy and also contribute to adequate management of potentially aggressive PitNETs.

1. Mete O, Cintosun A, Pressman I, Asa SL. Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Modern Pathology. 2018;31(6):900-909. doi: https://doi.org/10.1038/s41379-018-0016-8

2. Melmed S, Kaiser UB, Lopes MD, et al. Clinical Biology of the Pituitary Adenoma. Endocr Rev. 2022;43(6):1003-1037. doi: https://doi.org/10.1210/endrev/bnac010

3. Mehta GU, Lonser RR. Management of hormone-secreting pituitary adenomas. Neuro Oncol. 2017;19(6):762-773. doi: https://doi.org/10.1093/neuonc/now130

4. Chiloiro S, Doglietto F, Trapasso B, et al. Typical and atypical pituitary adenomas: A single-center analysis of outcome and prognosis. Neuroendocrinology. 2015;101(2):143-150. doi: https://doi.org/10.1159/000375448

5. Gounden V, Rampursat YD, Jialal I. Secretory tumors of the pituitary gland: a clinical biochemistry perspective. Clin Chem Lab Med. 2018;57(2):150-164. doi: https://doi.org/10.1515/cclm-2018-0552

6. Jaursch-Hancke C, Deutschbein T, Knappe UJ, et al. The Interdisciplinary Management of Newly Diagnosed Pituitary Tumors. Dtsch Arztebl Int. 2021;118(14):237-243. doi: https://doi.org/10.3238/arztebl.m2021.0015

7. Dai C, Kang J, Liu X, et al. How to Classify and Define Pituitary Tumors: Recent Advances and Current Controversies. Front Endocrinol (Lausanne). 2021;12:604644. doi: https://doi.org/10.3389/fendo.2021.604644

8. Vamvoukaki R, Chrosoulaki M, Betsi G, Xekouki P. Pituitary Tumorigenesis – Implications for Management. Medicina (Kaunas). 2023;59(4):812. doi: https://doi.org/10.3390/medicina59040812

9. Tritos NA, Miller KK. Diagnosis and Management of Pituitary Adenomas: A Review. JAMA. 2023;329(16):1386-1398. doi: https://doi.org/10.1001/jama.2023.5444

10. Fleseriu M, Bodach ME, Tumialan LM, et al. Congress of neurological surgeons systematic review and evidence-based guideline for pretreatment endocrine evaluation of patients with nonfunctioning pituitary adenomas. Neurosurgery. 2016;79(4):E527–E529. doi: https://doi.org/10.1227/NEU.0000000000001387

11. Zheng AC, Wang EJ, Aghi MK. Recent advancements in the molecular biology of pituitary adenomas. Expert Rev Endocrinol Metab. 2022;17(4):293-304. doi: https://doi.org/10.1080/17446651.2022.2082942

12. Chatzellis E, Alexandraki KI, Androulakis II, Kaltsas G. Aggressive Pituitary Tumors. Neuroendocrinology. 2015;101(2):87-104. doi: https://doi.org/10.1159/000371806

13. Mete O, Asa SL. Structure, Function, and Morphology in the Classification of Pituitary Neuroendocrine Tumors: the Importance of Routine Analysis of Pituitary Transcription Factors. Endocr Pathol. 2020;31(4):330-336. doi: https://doi.org/10.1007/s12022-020-09646-x

14. Daly AF, Beckers A. The Epidemiology of Pituitary Adenomas. Endocrinol Metab Clin North Am. 2020;49(3):347-355. doi: https://doi.org/10.1016/j.ecl.2020.04.002

15. Spada A, Mantovani G, Lania AG, et al. Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior. Neuroendocrinology. 2022;112(1):15-33. doi: https://doi.org/10.1159/000514862

16. Yamamoto M, Takahashi Y. Genetic and Epigenetic Pathogenesis of Acromegaly. Cancers (Basel). 2022;14(16):3861. doi: https://doi.org/10.3390/cancers14163861

17. Chang M, Yang C, Bao X, Wang R. Genetic and Epigenetic Causes of Pituitary Adenomas. Front Endocrinol (Lausanne). 2021;11:596554. doi: https://doi.org/10.3389/fendo.2020.596554

18. Guaraldi F, Morandi L, Zoli M, Mazzatenta D, et al. Epigenomic and somatic mutations of pituitary tumors with clinical and pathological correlations in 111 patients. Clin Endocrinol (Oxf). 2022;97(6):763-772. doi: https://doi.org/10.1111/cen.14827

19. Stefanidis P, Kyriakopoulus G, Seretis AM, et al. Prognostic Factors for Invasiveness and Recurrence of Pituitary Adenomas: A Series of 94 Patients. Diagnostics (Basel). 2022;12(10):2413. doi: https://doi.org/10.3390/diagnostics12102413

20. Bianchi A, Chiloiro S, Giampietro A, Gaudino S, et al. Multidisciplinary management of difficult/aggressive growth-hormone pituitary neuro-endocrine tumors. Front Endocrinol (Lausanne). 2023;14:1123267. doi: https://doi.org/10.3389/fendo.2023.1123267

21. Trouillas J, Jaffrain-Rea ML, Vasilijevic A, et al. How to Classify the Pituitary Neuroendocrine Tumors (PitNET)s in 2020. Cancers (Basel). 2020;12(2):514. doi: https://doi.org/10.3390/cancers12020514

22. Robertson IJ, Gregory TA, Waguespack SG, et al. Recent Therapeutic Advances in Pituitary Carcinoma. J Immunother Precis Oncol. 2022;6(2):74-83. doi: https://doi.org/10.36401/JIPO-22-25

23. Sathyakumar R, Chacko G. Newer Concepts in the Classification of Pituitary Adenomas. Neurol India. 2020;68(Suppl):S7-S12. doi: https://doi.org/10.4103/0028-3886.287667

24. Cushing H. The Pituitary Body and its Disorders. Lippincott; 1912

25. Bejlin I.A. Akromegalija. Minsk: Izdatel’stvo akademii nauk BSSR; 1938 (In Russ.)

26. Melmed S, Braunstein GD, Horvath E, et al. Pathophysiology of acromegaly. Endocr Rev. 1983;4(3):271-290. doi: https://doi.org/10.1210/edrv-4-3-271

27. Kovacs K, Horvath E. Pathology of pituitary tumors. Endocrinol Metab Clin North Am. 1987;16(3):529-551. doi: https://doi.org/10.1016/s1042-3680(02)00035-9

28. Kovacs K. The 2004 WHO classification of pituitary tumors: comments. Acta Neuropathol. 2006;111(1):62-63. doi: https://doi.org/10.1007/s00401-005-1095-4

29. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas: a systematic review. Cancer. 2004;101(3):613-619. doi: https://doi.org/10.1002/cncr.20412

30. Obari A, Sano T, Ohyama K, et al. Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr. Pathol. 2008;19(2):82-91. doi: https://doi.org/10.1007/s12022-008-9029-z

31. Osamura RY, Kajiya H, Takei M, et al. Pathology of the human pituitary adenomas. Histochem Cell Biol. 2008;130(3):495-507. doi: https://doi.org/10.1007/s00418-008-0472-1

32. Nishioka H, Inoshita N, Mete O, et al. The Complementary Role of Transcription Factors in the Accurate Diagnosis of Clinically Nonfunctioning Pituitary Adenomas. Endocr. Pathol. 2015;26(4):349-355. doi: https://doi.org/10.1007/s12022-015-9398-z

33. Cuevas-Ramos D, Carmichael JD, Cooper O, et al. A Structural and Functional Acromegaly Classification. J Clin Endocrinol Metab. 2015;100(1):122-131. doi: https://doi.org/10.1210/jc.2014-2468

34. Drummond J, Roncaroli F, Grossman AB, Korbonits M. Clinical and Pathological Aspects of Silent Pituitary Adenomas. J Clin Endocrinol Metab. 2019;104(7):2473-2489. doi: https://doi.org/10.1210/jc.2018-00688

35. Lopes MBS. The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol. 2017;134(4):521-535. doi: https://doi.org/10.1007/s00401-017-1769-8

36. Mete O, Lopes MB. Overview of the 2017 WHO Classification of Pituitary Tumors. Endocr Pathol. 2017;28(3):228-243. doi: https://doi.org/10.1007/s12022-017-9498-z

37. Asa SL, Mete O. Immunohistochemical biomarkers in pituitary pathology. Endocr Pathol. 2018;29(2):130-136. doi: https://doi.org/10.1007/s12022-018-9521-z

38. Gomez-Нernandez K, Ezzat S, Asa SL, Mete O. Clinical Implications of Accurate Subtyping of Pituitary Adenomas: Perspectives from the Treating Physician. Turk Patoloji Derg. 2015;31(Suppl 1):4-17. doi: https://doi.org/10.5146/tjpath.2015.01311

39. Kontogeorgos G, Thodou E, Osamura RY, Lloyd RV. High-Risk Pituitary Adenomas and Strategies for Predicting Response to Treatment. Hormones (Athens). 2022;21(1):1-14. doi: https://doi.org/10.1007/s42000-021-00333-y

40. Villa C, Baussart B, Assie G, et al. The World Health Organization classifications of pituitary neuroendocrine tumours: a clinico-pathological appraisal. Endocr Relat Cancer. 2023; 30(8): e230021. doi: https://doi.org/10.1530/ERC-23-0021.

41. Asa SL, Mete O, Cusimano MD, et al. Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification. Mod Pathol. 2021;34(9):1634-1650. doi: https://doi.org/10.1038/s41379-021-00820-y

42. Mete O, Wenig BM. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Overview of the 2022 WHO Classification of Head and Neck Neuroendocrine Neoplasms. Head Neck Pathol. 2022;16(1):123-142. doi: https://doi.org/10.1007/s12105-022-01435-8

43. Asa SL. Challenges in the diagnosis of pituitary neuroendocrine tumors. Endocr Pathol. 2021;32(2):222-227. doi: https://doi.org/10.1007/s12022-021-09678-x

44. Pearse AG. The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem. 1969;17(5):303-313. doi: https://doi.org/10.1177/17.5.303

45. Gheorghișan-Gălățeanu AA, Ilieșiu A, Lambrescu IM, Țăpoi DA. The Complex Histopathological and Immunohistochemical Spectrum of Neuroendocrine Tumors – An Overview of the Latest Classifications. Int J Mol Sci. 2023;24(2):1418. doi: https://doi.org/10.3390/ijms24021418

46. Duan K, Mete O. Algorithmic approach to neuroendocrine tumors in targeted biopsies: Practical applications of immunohistochemical markers. Cancer. Cytopathol. 2016;124(12):871-884. doi: https://doi.org/10.1002/cncy.21765

47. Yang M, Zeng L, Ke NW, et al. World Health Organization grading classification for pancreatic neuroendocrine neoplasms: a comprehensive analysis from a large Chinese institution. BMC Cancer. 2020;20(1):906. doi: https://doi.org/10.1186/s12885-020-07356-5

48. Rindi G, Mete O, Uccella S, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol. 2022;33(1):115-154. doi: https://doi.org/10.1007/s12022-022-09708-2

49. Lenders NF, Wilkinson AC, Wong SJ, et al. Transcription factor immunohistochemistry in the diagnosis of pituitary tumours. Eur J Endocrinol. 2021;184(6):891-901. doi: https://doi.org/10.1530/EJE-20-1273

50. Asa SL, Uccella S, Tischler A. The Unique Importance of Differentiation and Function in Endocrine Neoplasia. Endocr Pathol. 2023. doi: https://doi.org/10.1007/s12022-023-09762-4

51. Fushimi Y, Taoka T, Naganawa S. From pituitary adenoma to PitNET: it is time to discuss PitNET/pituitary adenoma. Jpn J Radiol. 2023;41(8):787-788. doi: https://doi.org/10.1007/s11604-023-01412-3

52. Lee CH. Pituitary Neuroendocrine Tumor: Is it Bening or Malignant? Brain Tumor Res Treat. 2023:11(3):173-176. doi: https://doi.org/10.14791/btrt.2023.0015

53. Liu X, Wang R, Li M, Chen G. Pituitary adenoma or pituitary neuroendocrine tumor: a narrative review of controversy and perspective. Transl Cancer Res. 2021;10(4):1916-1920. doi: https://doi.org/10.21037/tcr-20-3446

54. Ho K, Freseriu M, Kaiser U, et al. Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time? J Endocr Soc. 2021;5(3):bvaa205. doi: https://doi.org/10.1210/jendso/bvaa205

55. Ho KKY, Gadelha M, Kaiser UB, et al. The NETting of pituitary adenoma: a gland illusion. Pituitary. 2022;25(3):349-351. doi: https://doi.org/10.1007/s11102-022-01235-x

56. Ho KKY, Kaiser UB, Chanson P, et al. Pituitary adenoma or neuroendocrine tumour: the need for an integrated prognostic classification. Nat Rev Endocrinol. 2023. doi: https://doi.org/10.1038/s41574-023-00883-8

57. Asa SL, Mete O, Perry A, Osamura RY. Overview of the 2022 WHO classification of pituitary tumors. Endocr Pathol. 2022;33(1):6-26. doi: https://doi.org/10.1007/s12022-022-09703-7

58. Trouillas J, Jaffrain-Rea ML, Vasiljevic A, et al. How to Classify Pituitary neuroendocrine Tumor (PitNET) in 2020. Cancers (Basel). 2020;12(2):514. doi: https://doi.org/10.3390/cancers12020514

59. Trouillas J, Jaffrain-Rea ML, Vasiljevic A, et al. Are Aggressive Pituitary Tumors and Carcinomas Two Sides of the Same Coin? Pathologists Reply to Clinician’s Questions. Rev Endocr Metab Disord. 2020;21(2):243-251. doi: https://doi.org/10.1007/s11154-020-09562-9

60. Wan XY, Chen J, Wang JW, et al. Overview of the 2022 WHO Classification of Pituitary Adenomas/Pituitary Neuroendocrine Tumors: Clinical Practices, Controversies, and Perspectives. Curr Med Sci. 2022;42(6):1111-1118. doi: https://doi.org/10.1007/s11596-022-2673-6

61. Tsukamoto T, Miki Y. Imaging of pituitary tumors: an update with the 5th WHO Classifications-part 1. Pituitary neuroendocrine tumor (PitNET)/pituitary adenoma. Jpn J Radiol. 2023;41(8):789-806. doi: https://doi.org/10.1007/s11604-023-01400-7

62. Raverot G, Dantony E, Beauvy J, et al. Risk of Recurrence in Pituitary Neuroendocrine Tumors: A Prospective Study Using a Five-Tiered Classification. J Clin Endocrinol Metab. 2017;102(9):3368-3374. doi: https://doi.org/10.1210/jc.2017-00773

63. Raverot G, Burman P, McCormack A, et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2018;178(1):G1-G24. doi: https://doi.org/10.1530/EJE-17-0796

64. Ferres A, Reyes L, Di Somma A, et al. The Prognostic-Based Approach in Growth Hormone-Secreting Pituitary Neuroendocrine Tumors (PitNET): Tertiary Reference Center, Single Senior Surgeon, and Long-Term Follow-Up. Cancers (Basel). 2022;15(1):267. doi: https://doi.org/10.3390/cancers15010267