Endocrinol Metab.  2025 Feb;40(1):39-46. 10.3803/EnM.2024.2074.

Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia

• Chin SO
• Chik C
• Tateno T

• KMID: 2565249
• DOI: http://doi.org/10.3803/EnM.2024.2074

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterized by tumors of the pituitary, parathyroid, and endocrine-gastrointestinal tract. Pituitary neuroendocrine tumors (PitNETs) occur in about 40% of MEN1 cases, with 10% being the first manifestation. Recent studies show a slight female predominance, with microPitNETs (<1 cm) being more common than macroPitNETs (>1 cm). Functional PitNETs (FPitNETs) are more frequent than non-functional ones (36% to 48%), with prolactinomas being the most common FPitNETs. MEN1-associated PitNETs are often plurihormonal, larger, and more invasive compared to sporadic types, though patient age and FPitNET proportions are similar. MEN1 mutation-negative patients tend to have larger, symptomatic PitNETs at diagnosis. Six patients with MEN1 have been reported to have pituitary carcinomas, including a mutation- negative patient. Treatment approach between PitNETs in MEN1 and sporadic types appears to be similar. PitNETs also occur in MEN4, but their epidemiology is less understood. In patients with a MEN1-like phenotype and negative genetic testing, MEN4 should be considered.

Keyword

Multiple endocrine neoplasia; Pituitary diseases; Neuroendocrine tumors

Figure

• 

  Fig. 1. Clinical features and management of pituitary neuroendocrine tumors (PitNETs) in multiple endocrine neoplasia type 1 (MEN1) and multiple endocrine neoplasia type 4 (MEN4).

Reference

1. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012; 97:2990–3011.

2. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008; 29:22–32.

3. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014; 386:2–15.

4. Occhi G, Regazzo D, Trivellin G, Boaretto F, Ciato D, Bobisse S, et al. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genet. 2013; 9:e1003350.

5. Frederiksen A, Rossing M, Hermann P, Ejersted C, Thakker RV, Frost M. Clinical features of multiple endocrine neoplasia type 4: novel pathogenic variant and review of published cases. J Clin Endocrinol Metab. 2019; 104:3637–46.

6. Lavezzi E, Brunetti A, Smiroldo V, Nappo G, Pedicini V, Vitali E, et al. Case report: new CDKN1B mutation in multiple endocrine neoplasia type 4 and brief literature review on clinical management. Front Endocrinol (Lausanne). 2022; 13:773143.

7. Asa SL, Mete O, Perry A, Osamura RY. Overview of the 2022 WHO classification of pituitary tumors. Endocr Pathol. 2022; 33:6–26.

8. de Laat JM, Dekkers OM, Pieterman CR, Kluijfhout WP, Hermus AR, Pereira AM, et al. Long-term natural course of pituitary tumors in patients with MEN1: results from the DutchMEN1 Study Group (DMSG). J Clin Endocrinol Metab. 2015; 100:3288–96.

9. Saito T, Miura D, Taguchi M, Takeshita A, Miyakawa M, Takeuchi Y. Coincidence of multiple endocrine neoplasia type 2A with acromegaly. Am J Med Sci. 2010; 340:329–31.

10. Heinlen JE, Buethe DD, Culkin DJ, Slobodov G. Multiple endocrine neoplasia 2a presenting with pheochromocytoma and pituitary macroadenoma. ISRN Oncol. 2011; 2011:732452.

11. Naziat A, Karavitaki N, Thakker R, Ansorge O, Sadler G, Gleeson F, et al. Confusing genes: a patient with MEN2A and Cushing’s disease. Clin Endocrinol (Oxf). 2013; 78:966–8.

12. Li Y, Tan YQ, Tang ZX, Liao QH, Guo ZQ, Lai KB, et al. Multiple endocrine neoplasia 2A with RET mutation p.Cys611Tyr: a case report. Medicine (Baltimore). 2021; 100:e26230.

13. Scheithauer BW, Laws ER Jr, Kovacs K, Horvath E, Randall RV, Carney JA. Pituitary adenomas of the multiple endocrine neoplasia type I syndrome. Semin Diagn Pathol. 1987; 4:205–11.

14. Burgess JR, Shepherd JJ, Parameswaran V, Hoffman L, Greenaway TM. Spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN 1): clinical, biochemical, and radiological features of pituitary disease in a large MEN 1 kindred. J Clin Endocrinol Metab. 1996; 81:2642–6.

15. O’Brien T, O’Riordan DS, Gharib H, Scheithauer BW, Ebersold MJ, van Heerden JA. Results of treatment of pituitary disease in multiple endocrine neoplasia, type I. Neurosurgery. 1996; 39:273–9.

16. Verges B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab. 2002; 87:457–65.

17. Pieterman CR, Valk GD. Update on the clinical management of multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf). 2022; 97:409–23.

18. Le Bras M, Leclerc H, Rousseau O, Goudet P, Cuny T, Castinetti F, et al. Pituitary adenoma in patients with multiple endocrine neoplasia type 1: a cohort study. Eur J Endocrinol. 2021; 185:863–73.

19. Wu Y, Gao L, Guo X, Wang Z, Lian W, Deng K, et al. Pituitary adenomas in patients with multiple endocrine neoplasia type 1: a single-center experience in China. Pituitary. 2019; 22:113–23.

20. Cohen-Cohen S, Brown DA, Himes BT, Wheeler LP, Ruff MW, Major BT, et al. Pituitary adenomas in the setting of multiple endocrine neoplasia type 1: a single-institution experience. J Neurosurg. 2020; 134:1132–8.

21. Simonds WF, Varghese S, Marx SJ, Nieman LK. Cushing’s syndrome in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf). 2012; 76:379–86.

22. Benito M, Asa SL, Livolsi VA, West VA, Snyder PJ. Gonadotroph tumor associated with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2005; 90:570–4.

23. Gordon MV, Varma D, McLean CA, Bittar RG, Burgess JR, Topliss DJ. Metastatic prolactinoma presenting as a cervical spinal cord tumour in multiple endocrine neoplasia type one (MEN-1). Clin Endocrinol (Oxf). 2007; 66:150–2.

24. Scheithauer BW, Kovacs K, Nose V, Lombardero M, Osamura YR, Lloyd RV, et al. Multiple endocrine neoplasia type 1-associated thyrotropin-producing pituitary carcinoma: report of a probable de novo example. Hum Pathol. 2009; 40:270–8.

25. Philippon M, Morange I, Barrie M, Barlier A, Taieb D, Dufour H, et al. Long-term control of a MEN1 prolactin secreting pituitary carcinoma after temozolomide treatment. Ann Endocrinol (Paris). 2012; 73:225–9.

26. Incandela F, Feraco P, Putorti V, Geraci L, Salvaggio G, Sarno C, et al. Malignancy course of pituitary adenoma in MEN1 syndrome: clinical-neuroradiological signs. Eur J Radiol Open. 2020; 7:100242.

27. Trouillas J, Labat-Moleur F, Sturm N, Kujas M, Heymann MF, Figarella-Branger D, 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; 32:534–43.

28. Coppin L, Giraud S, Pasmant E, Lagarde A, North MO, LeCollen L, et al. Multiple endocrine neoplasia type 1 caused by mosaic mutation: clinical follow-up and genetic counseling? Eur J Endocrinol. 2022; 187:K1–6.

29. Stratakis CA, Tichomirowa MA, Boikos S, Azevedo MF, Lodish M, Martari M, et al. The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clin Genet. 2010; 78:457–63.

30. Cuny T, Pertuit M, Sahnoun-Fathallah M, Daly A, Occhi G, Odou MF, et al. Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don’t forget MEN1 genetic analysis. Eur J Endocrinol. 2013; 168:533–41.

31. Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P. Genetic mutations in sporadic pituitary adenomas: what to screen for? Nat Rev Endocrinol. 2015; 11:43–54.

32. Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BM, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international consensus statement. Nat Rev Endocrinol. 2023; 19:722–40.

33. Al-Salameh A, Cadiot G, Calender A, Goudet P, Chanson P. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021; 17:207–24.

34. Molatore S, Marinoni I, Lee M, Pulz E, Ambrosio MR, degli Uberti EC, et al. A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum Mutat. 2010; 31:E1825–35.

35. Chevalier B, Odou MF, Demonchy J, Cardot-Bauters C, Vantyghem MC. Multiple endocrine neoplasia type 4: novel CDNK1B variant and immune anomalies. Ann Endocrinol (Paris). 2020; 81:124–5.

36. Mazarico-Altisent I, Capel I, Baena N, Bella-Cueto MR, Barcons S, Guirao X, et al. Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism. J Endocrinol Invest. 2023; 46:829–40.

37. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A. 2006; 103:15558–63.

38. Sambugaro S, Di Ruvo M, Ambrosio MR, Pellegata NS, Bellio M, Guerra A, et al. Early onset acromegaly associated with a novel deletion in CDKN1B 5’UTR region. Endocrine. 2015; 49:58–64.

39. Tichomirowa MA, Lee M, Barlier A, Daly AF, Marinoni I, Jaffrain-Rea ML, et al. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocr Relat Cancer. 2012; 19:233–41.

40. Georgitsi M, Raitila A, Karhu A, van der Luijt RB, Aalfs CM, Sane T, et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab. 2007; 92:3321–5.

41. Chasseloup F, Pankratz N, Lane J, Faucz FR, Keil MF, Chittiboina P, et al. Germline CDKN1B loss-of-function variants cause pediatric Cushing’s disease with or without an MEN4 phenotype. J Clin Endocrinol Metab. 2020; 105:1983–2005.

42. Seabrook A, Wijewardene A, De Sousa S, Wong T, Sheriff N, Gill AJ, et al. MEN4, the MEN1 mimicker: a case series of three phenotypically heterogenous patients with unique CDKN1B mutations. J Clin Endocrinol Metab. 2022; 107:2339–49.

43. Singeisen H, Renzulli MM, Pavlicek V, Probst P, Hauswirth F, Muller MK, et al. Multiple endocrine neoplasia type 4: a new member of the MEN family. Endocr Connect. 2023; 12:e220411.

44. Morokuma H, Ando T, Hayashida T, Horie I, Inoshita N, Murata F, et al. A case of nonfunctioning pituitary carcinoma that responded to temozolomide treatment. Case Rep Endocrinol. 2012; 2012:645914.

45. Alrezk R, Hannah-Shmouni F, Stratakis CA. MEN4 and CDKN1B mutations: the latest of the MEN syndromes. Endocr Relat Cancer. 2017; 24:T195–208.

46. Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, et al. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 1, general recommendations. Nat Rev Endocrinol. 2024; 20:278–89.