Top

Pituitary

Published in:

01-04-2015

Silent corticotroph adenomas

Author: Odelia Cooper

Published in: Pituitary | Issue 2/2015

Abstract

Purpose

Silent corticotroph adenomas (SCAs) comprise 20 % of all corticotroph adenomas and 3–19 % of nonfunctioning adenomas (NFAs). As they do not manifest clinical or biochemical hypercortisolism, they are diagnosed after pathologic examination of resected tumor tissue demonstrates positive ACTH expression. While preoperative features are similar to those of NFAs, SCAs may have more cavernous sinus invasion. Further, patients with SCAs tend to have more frequent and earlier recurrences than those with NFAs, often necessitating multiple surgeries and other modalities of treatment. This article reviews the incidence, pathogenesis, and clinical behavior of SCAs.

Methods

A systematic literature review was performed using PubMed for information regarding SCAs.

Results

Up to date findings regarding epidemiology, pathogenesis, pathology, clinical presentation, postoperative course, and management of patients with SCAs are presented.

Conclusion

This review highlights the necessity of rigorous monitoring for recurrences and hypopituitarism in patients with SCAs.

Abe T, Ludecke DK, Saeger W (1998) Clinically nonsecreting pituitary adenomas in childhood and adolescence. Neurosurgery 42:744–750 discussion 750–741CrossRefPubMed

Alahmadi H, Lee D, Wilson JR, Hayhurst C, Mete O, Gentili F, Asa SL, Zadeh G (2012) Clinical features of silent corticotroph adenomas. Acta Neurochir (Wien) 154:1493–1498. doi:10.1007/s00701-012-1378-1 CrossRef

Ambrosi B, Colombo P, Bochicchio D, Bassetti M, Masini B, Faglia G (1992) The silent corticotropinoma: Is clinical diagnosis possible? J Endocrinol Invest 15:443–452CrossRefPubMed

Baldeweg SE, Pollock JR, Powell M, Ahlquist J (2005) A spectrum of behaviour in silent corticotroph pituitary adenomas. Br J Neurosurg 19:38–42. doi:10.1080/02688690500081230 CrossRefPubMed

Bradley KJ, Wass JA, Turner HE (2003) Non-functioning pituitary adenomas with positive immunoreactivity for ACTH behave more aggressively than ACTH immunonegative tumours but do not recur more frequently. Clin Endocrinol (Oxf) 58:59–64CrossRef

Brown RL, Wollman R, Weiss RE (2007) Transformation of a pituitary macroadenoma into to a corticotropin-secreting carcinoma over 16 years. Endocr Pract 13:463–471. doi:10.4158/EP.13.5.463 CrossRefPubMed

Cazabat L, Dupuy M, Boulin A, Bernier M, Baussart B, Foubert L, Raffin-Sanson ML, Caron P, Bertherat J, Gaillard S (2014) Silent, but not unseen: multimicrocystic aspect on T2-weighted MRI in silent corticotroph adenomas. Clin Endocrinol (Oxf) 81:566–572. doi:10.1111/cen.12443 CrossRef

Cho HY, Cho SW, Kim SW, Shin CS, Park KS, Kim SY (2009) Silent corticotroph adenomas have unique recurrence characteristics as compared with other non-functioning pituitary adenomas. Clin Endocrinol (Oxf). doi:10.1111/j.1365-2265.2009.03673.x

Cho HY, Cho SW, Kim SW, Shin CS, Park KS, Kim SY (2010) Silent corticotroph adenomas have unique recurrence characteristics compared with other nonfunctioning pituitary adenomas. Clin Endocrinol (Oxf) 72:648–653. doi:10.1111/j.1365-2265.2009.03673.x CrossRef

10.

Cooper O, Ben-Shlomo A, Bonert V, Bannykh S, Mirocha J, Melmed S (2010) Silent corticogonadotroph adenomas: clinical and cellular characteristics and long-term outcomes. Horm Cancer 1:80–92. doi:10.1007/s12672-010-0014-x CrossRefPubMedCentralPubMed

11.

Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A (2006) High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 91:4769–4775. doi:10.1210/jc.2006-1668 CrossRefPubMed

12.

DeLellis RA, Lloyd RV, Heitz PU, Eng C (2004) Pathology and genetics of tumors of endocrine organs. In: PU K, LH S (eds) World Health Organization classification of tumours. IARC Press, Lyon

13.

Fernandez A, Karavitaki N, Wass JA (2010) Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 72:377–382. doi:10.1111/j.1365-2265.2009.03667.x CrossRef

14.

Gogel EL, Salber PR, Tyrrell JB, Rosenblum ML, Findling JW (1983) Cushing’s disease in a patient with a ‘nonfunctioning’ pituitary tumor. Spontaneous development and remission. Arch Intern Med 143:1040–1042CrossRefPubMed

15.

Holck S, Wewer UM, Albrechtsen R (1988) Heterogeneity of secretory granules of silent pituitary adenomas. Mod Pathol 1:212–215PubMed

16.

Horvath E, Kovacs K, Killinger DW, Smyth HS, Platts ME, Singer W (1980) Silent corticotropic adenomas of the human pituitary gland: a histologic, immunocytologic, and ultrastructural study. Am J Pathol 98:617–638PubMedCentralPubMed

17.

Horvath E, Kovacs K, Lloyd RV (1999) Pars intermedia of the human pituitary revisited: morphologic aspects and frequency of hyperplasia of POMC-peptide immunoreactive cells. Endocr Pathol 10:55–64CrossRef

18.

Ikuyama S, Mu Y-M, Ohe K, Nakagaki H, Fukushima T, Takayanagi R, Nawata H (1998) Expression of an orphan nuclear receptor DAX-1 in human pituitary adenomas. Clin Endocrinol (Oxf) 48:647–654CrossRef

19.

Ioachimescu AG, Eiland L, Chhabra VS, Mastrogianakis GM, Schniederjan MJ, Brat D, Pileggi AV, Oyesiku NM (2012) Silent corticotroph adenomas: emory University cohort and comparison with ACTH-negative nonfunctioning pituitary adenomas. Neurosurgery 71:296–303. doi:10.1227/NEU.0b013e318257c1f0 discussion 304CrossRefPubMed

20.

Jahangiri A, Wagner JR, Pekmezci M, Hiniker A, Chang EF, Kunwar S, Blevins L, Aghi MK (2013) A comprehensive long-term retrospective analysis of silent corticotrophic adenomas vs hormone-negative adenomas. Neurosurgery 73:8–17. doi:10.1227/01.neu.0000429858.96652.1e discussion 17–18CrossRefPubMed

21.

Jin L, Riss D, Ruebel K, Kajita S, Scheithauer BW, Horvath E, Kovacs K, Lloyd RV (2005) Galectin-3 expression in functioning and silent ACTH-producing adenomas. Endocr Pathol 16:107–114CrossRefPubMed

22.

Jouanneau E, Wierinckx A, Ducray F, Favrel V, Borson-Chazot F, Honnorat J, Trouillas J, Raverot G (2012) New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15:37–43. doi:10.1007/s11102-011-0341-0 CrossRefPubMed

23.

Kawabe K, Shikayama T, Tsuboi H, Oka S, Oba K, Yanase T, Nawata H, Morohashi K (1999) Dax-1 as one of the target genes of Ad4BP/SF-1. Mol Endocrinol 13:1267–1284CrossRefPubMed

24.

Kojima Y, Suzuki S, Yamamura K, Ohhashi G, Yamamoto I (2002) Comparison of ACTH secretion in Cushing’s adenoma and clinically silent corticotroph adenoma by cell immunoblot assay. Endocr J 49:285–292CrossRefPubMed

25.

Lamolet B, Pulichino A-M, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, Drouin J (2001) A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104:849–859CrossRefPubMed

26.

Lavoie P-L, Budry L, Balsalobre A, Drouin J (2008) Developmental dependence on NurRE and EboxNeuro for expression of pituitary proopiomelanocortin. Mol Endocrinol 22:1647–1657. doi:10.1210/me.2007-0567 CrossRefPubMed

27.

Liu J, Lin C, Gleiberman A, Ohgi KA, Herman T, Huang H-P, Tsai M-J, Rosenfeld MG (2001) Tbx19, a tissue-selective regulator of POMC gene expression. Proc Natl Acad Sci USA 98:8674–8679CrossRefPubMedCentralPubMed

28.

Lloyd RV, Fields K, Jin L, Horvath E, Kovacs K (1990) Analysis of endocrine active and clinically silent corticotropic adenomas by in situ hybridization. Am J Pathol 137:479–488PubMedCentralPubMed

29.

Lopez JA, Kleinschmidt-Demasters BK, Sze CI, Woodmansee WW, Lillehei KO (2004) Silent corticotroph adenomas: further clinical and pathological observations. Hum Pathol 35:1137–1147CrossRefPubMed

30.

Meier CA, Biller BM (1997) Clinical and biochemical evaluation of Cushing’s syndrome. Endocrinol Metab Clin North Am 26:741–762CrossRefPubMed

31.

Melcescu E, Gannon AW, Parent AD, Fratkin JF, Nicholas WC, Koch CA, Galhom A (2013) Silent or subclinical corticotroph pituitary macroadenoma transforming into Cushing disease: 11-year follow-up. Neurosurgery 72:E144–E146. doi:10.1227/NEU.0b013e3182750850 CrossRefPubMed

32.

Melmed S (2003) Mechanisms for pituitary tumorigenesis: the plastic pituitary. J Clin Invest 112:1603–1618CrossRefPubMedCentralPubMed

33.

Mete O, Hayhurst C, Alahmadi H, Monsalves E, Gucer H, Gentili F, Ezzat S, Asa SL, Zadeh G (2013) The role of mediators of cell invasiveness, motility, and migration in the pathogenesis of silent corticotroph adenomas. Endocr Pathol 24:191–198. doi:10.1007/s12022-013-9270-y CrossRefPubMed

34.

Moshkin O, Syro LV, Scheithauer BW, Ortiz LD, Fadul CE, Uribe H, Gonzalez R, Cusimano M, Horvath E, Rotondo F et al (2011) Aggressive silent corticotroph adenoma progressing to pituitary carcinoma: the role of temozolomide therapy. Hormones (Athens) 10:162–167CrossRef

35.

Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540. doi:10.1210/jc.2008-0125 CrossRefPubMedCentralPubMed

36.

Ohta S, Nishizawa S, Oki Y, Yokoyama T, Namba H (2002) Significance of absent prohormone convertase 1/3 in inducing clinically silent corticotroph pituitary adenoma of subtype I: immunohistochemical study. Pituitary 5:221–223CrossRefPubMed

37.

Ortiz LD, Syro LV, Scheithauer BW, Ersen A, Uribe H, Fadul CE, Rotondo F, Horvath E, Kovacs K (2012) Anti-VEGF therapy in pituitary carcinoma. Pituitary 15:445–449. doi:10.1007/s11102-011-0346-8 CrossRefPubMed

38.

Oyama K, Sanno N, Teramoto A, Osamura RY (2001) Expression of neuro D1 in human normal pituitaries and pituitary adenomas. Mod Pathol 14:892–899CrossRefPubMed

39.

Pawlikowski M, Kunert-Radek J, Radek M (2008) “Silent”corticotropinoma. Neuro Endocrinol Lett 29:347–350PubMed

40.

Poulin G, Turgeon B, Drouin J (1997) NeuroD1/beta2 contributes to cell-specific transcription of the proopiomelanocortin gene. Mol Cell Biol 17:6673–6682PubMedCentralPubMed

41.

Psaras T, Honegger J, Buslei R, Saeger W, Klein D, Capper D, Meyermann R, Mittelbronn M (2007) Atypical type II silent corticotrophic adenoma developing into Cushing’s disease upon second recurrence. Exp Clin Endocrinol Diabetes 115:610–615. doi:10.1055/s-2007-984437 CrossRefPubMed

42.

Raverot G, Wierinckx A, Jouanneau E, Auger C, Borson-Chazot F, Lachuer J, Pugeat M, Trouillas J (2010) Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing’s disease. Eur J Endocrinol 163:35–43. doi:10.1530/eje-10-0076 CrossRefPubMed

43.

Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S (2007) Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol 156:203–216. doi:10.1530/eje.1.02326 CrossRefPubMed

44.

Sahli R, Christ ER, Seiler R, Kappeler A, Vajtai I (2006) Clinicopathologic correlations of silent corticotroph adenomas of the pituitary: report of four cases and literature review. Pathol Res Pract 202:457–464. doi:10.1016/j.prp.2006.01.007 CrossRefPubMed

45.

Sakaguchi H, Koshiyama H, Sano T, Inoue D, Hashimoto N, Aoki N, Nakao K (1997) A case of nonfunctioning pituitary adenoma resembling so-called silent corticotroph adenoma. Endocr J 44:329–333CrossRefPubMed

46.

Salehi F, Scheithauer BW, Kovacs K, Horvath E, Syro LV, Sharma S, Manoranjan B, Cusimano M (2012) O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemical expression in pituitary corticotroph adenomas. Neurosurgery 70:491–496. doi:10.1227/NEU.0b013e318230ac63 discussion 496CrossRefPubMed

47.

Sano T, Kovacs K, Asa SL, Yamada S, Sanno N, Yokoyama S, Takami H (2002) Pituitary adenoma with “honeycomb Golgi” appearance showing a phenotypic change at recurrence from clinically nonfunctioning to typical Cushing disease. Endocr Pathol 13:125–130CrossRefPubMed

48.

Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF Jr, Meyer FB, Kuroki T et al (2006) Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59:341–353. doi:10.1227/01.NEU.0000223437.51435.6E discussion 341–353CrossRefPubMed

49.

Scheithauer BW, Jaap AJ, Horvath E, Kovacs K, Lloyd RV, Meyer FB, Laws ER Jr, Young WF Jr (2000) Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery 47:723–729 discussion 729–730PubMed

50.

Tateno T, Izumiyama H, Doi M, Akashi T, Ohno K, Hirata Y (2007) Defective expression of prohormone convertase 1/3 in silent corticotroph adenoma. Endocr J 54:777–782CrossRefPubMed

51.

Tateno T, Izumiyama H, Doi M, Yoshimoto T, Shichiri M, Inoshita N, Oyama K, Yamada S, Hirata Y (2007) Differential gene expression in ACTH -secreting and non-functioning pituitary tumors. Eur J Endocrinol 157:717–724. doi:10.1530/EJE-07-0428 CrossRefPubMed

52.

Tateno T, Kato M, Tani Y, Oyama K, Yamada S, Hirata Y (2009) Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas. Endocr J 56:579–584CrossRefPubMed

53.

Thearle MS, Freda PU, Bruce JN, Isaacson SR, Lee Y, Fine RL (2011) Temozolomide (Temodar(R)) and capecitabine (Xeloda(R)) treatment of an aggressive corticotroph pituitary tumor. Pituitary 14:418–424. doi:10.1007/s11102-009-0211-1 CrossRefPubMedCentralPubMed

54.

Thodou E, Argyrakos T, Kontogeorgos G (2007) Galectin-3 as a marker distinguishing functioning from silent corticotroph adenomas. Hormones (Athens) 6:227–232

55.

Tourniaire J (1991) The so-called silent corticotropic pituitary adenoma. Presse Med 20:197–198PubMed

56.

Ueyama T, Tamaki N, Kondoh T, Kurata H (1998) Large and invasive silent corticotroph-cell adenoma with elevated serum ACTH: a case report. Surg Neurol 50:30–31 discussion 32CrossRefPubMed

57.

Vallette-Kasic S, Figarella-Branger D, Grino M, Pulichino A-M, Dufour H, Grisoli F, Enjalbert A, Drouin J, Brue T (2003) Differential regulation of proopiomelanocortin and pituitary-restricted transcription factor (TPIT), a new marker of normal and adenomatous human corticotrophs. J Clin Endocrinol Metab 88:3050–3056CrossRefPubMed

58.

Vaughan NJ, Laroche CM, Goodman I, Davies MJ, Jenkins JS (1985) Pituitary Cushing’s disease arising from a previously non-functional corticotrophic chromophobe adenoma. Clin Endocrinol (Oxf) 22:147–153CrossRef

59.

Webb KM, Laurent JJ, Okonkwo DO, Lopes MB, Vance ML, Laws ER Jr (2003) Clinical characteristics of silent corticotrophic adenomas and creation of an internet-accessible database to facilitate their multi-institutional study. Neurosurgery 53:1076–1084 discussion 1084–1075CrossRefPubMed

60.

Xu Z, Ellis S, Lee CC, Starke RM, Schlesinger D, Lee Vance M, Lopes MB, Sheehan J (2014) Silent corticotroph adenomas after stereotactic radiosurgery: a case–control study. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2014.07.013 PubMedCentral

61.

Yamada S, Ohyama K, Taguchi M, Takeshita A, Morita K, Takano K, Sano T (2007) A study of the correlation between morphological findings and biological activities in clinically nonfunctioning pituitary adenomas. Neurosurgery 61:580–584. doi:10.1227/01.NEU.0000290906.53685.79 discussion 584-585CrossRefPubMed

62.

Yokoyama S, Kawahara Y, Sano T, Nakayama M, Kitajima S, Kuratsu J (2001) A case of non-functioning pituitary adenoma with Cushing’s syndrome upon recurrence. Neuropathology 21:288–293CrossRefPubMed

63.

Zacharia BE, Gulati AP, Bruce JN, Carminucci AS, Wardlaw SL, Siegelin M, Remotti H, Lignelli A, Fine RL (2014) High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM): a case series. Neurosurgery 74:E447–E455. doi:10.1227/NEU.0000000000000251 discussion E455CrossRefPubMed

64.

Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER Jr (2011) Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg 114:336–344. doi:10.3171/2010.8.JNS10290 CrossRefPubMed

Title: Silent corticotroph adenomas
Author: Odelia Cooper
Publication date: 01-04-2015
Publisher: Springer US
Published in: Pituitary / Issue 2/2015
Print ISSN: 1386-341X
Electronic ISSN: 1573-7403
DOI: https://doi.org/10.1007/s11102-014-0624-3

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2015

Comorbidities in Cushing’s disease

Quality of life in Cushing’s syndrome

Clinical and biochemical manifestations of Cushing’s

Update on radiation therapy in patients with Cushing’s disease

Surgical management of Cushing’s disease

Cushing disease: Where do we stand, where are we heading?

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage