Journal of Neuro-Oncology

, Volume 141, Issue 3, pp 585–593 | Cite as

Use of optical fluorescence agents during surgery for pituitary adenomas: current state of the field

  • Stephanie W. Chang
  • Daniel A. Donoho
  • Gabriel ZadaEmail author
Topic Review



Differentiation of normal pituitary from abnormal tumor tissue remains a surgical challenge despite improvements in optical visualization technology for pituitary adenoma (PA) surgery. During neurosurgical procedures for other tumor types, 5-aminolevulinic acid (5-ALA) has become a focus of investigation based on its high specificity in differentiating tumor tissue. However, the role of 5-ALA and other optical fluorescent agents in PA surgery remains less clear.


To perform a systematic review on the use of various optical fluorescent agents in PA surgery.


Using PRISMA guidelines, a systematic literature review to identify reports describing 5-ALA and other optical agents for fluorescence-guided surgery for PA was performed. Eleven research studies met inclusion criteria and were reviewed.


In two studies, 5-ALA was not shown to be effective in aiding PA resection using standard neurosurgical endoscopic/microscopic approaches. 5-ALA photodynamic therapy was evaluated in two in-vitro models with inconsistent results. Intraoperative use of indocyanine green (ICG) concluded with varying results, but showed a tendency towards improved differentiation of functional PA. OTL38 showed potential for intraoperative identification of nonfunctioning PA, particularly in tumors with high folate receptor expression. One study reported clinically useful fluorescence following sodium fluorescein administration.


We conclude that selected optical fluorescent agents, including ICG and folate receptors, are most likely to hold promise for clinical use in differentiating PA from normal tissue.


Pituitary adenoma 5-Aminolevulinic acid Fluorescence guided surgery Optical fluorescence agents 


Compliance with ethical standards

Conflict of interest

Author Stephanie Wan-Ting Chang declares that she has no conflict of interest. Author Daniel A. Donoho declares that he has no conflict of interest. Author Gabriel Zada declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Melmed S (2011) Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7:257–266. CrossRefGoogle Scholar
  2. 2.
    Kovacs K, Horvath E, Vidal S (2001) Classification of pituitary adenomas. J Neurooncol 54:121–127. CrossRefGoogle Scholar
  3. 3.
    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. Google Scholar
  4. 4.
    Dusek T, Kastelan D, Melada A, Baretic M, Skoric Polovina T, Perkovic Z, Giljevic Z, Jelcic J, Paladino J, Korsic M, Aganovic I (2011) Clinical features and therapeutic outcomes of patients with acromegaly: single-center experience. Endocrinol Invest 32:e382–e385. Google Scholar
  5. 5.
    Juszczak A, Ertorer ME, Grossman A (2013) The therapy of Cushing’s disease in adults and children: an update. Horm Metab Res 45:109–117. Google Scholar
  6. 6.
    Krzentowska-Korek A, Gołkowski F, Bałdys-Waligórska A, Hubalewska-Dydejczyk A (2011) Efficacy and complications of neurosurgical treatment of acromegaly. Pituitary 14:157–162. CrossRefGoogle Scholar
  7. 7.
    Berkmann S, Schlaffer S, Nimsky C, Fahlbusch R, Buchfelder M (2014) Follow-up and long-term outcome of nonfunctioning pituitary adenoma operated by transsphenoidal surgery with intraoperative high-field magnetic resonance imaging. Acta Neurochir 156:2233–2243. CrossRefGoogle Scholar
  8. 8.
    Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C, Franz K, Pietsch T (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564–576. CrossRefGoogle Scholar
  9. 9.
    Biller BMK, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JAH, Boscaro M (2008) Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 93:2454–2462CrossRefGoogle Scholar
  10. 10.
    Jane JA Jr., Laws ER Jr. (2000) Surgical treatment of pituitary adenomas BTI-Endotext. In: De Groot LJCG, Dungan K et al (ed), Inc., South DartmouthGoogle Scholar
  11. 11.
    Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA (2011) Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:273–288. CrossRefGoogle Scholar
  12. 12.
    Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, van der Lely AJ, Strasburger CJ, Lamberts SW, Ho KK, Casanueva FF, Melmed S (2014) Expert consensus document: a consensus on the medical treatment of acromegaly. Nat Rev Endocrinol 10:243. CrossRefGoogle Scholar
  13. 13.
    Carr SB, Kleinschmidt-DeMasters BK, Kerr JM, Kiseljak-Vassiliades K, Wierman ME, Lillehei KO (2017) Negative surgical exploration in patients with Cushing’s disease: benefit of two-thirds gland resection on remission rate and a review of the literature. J Neurosurg 8:1–8. Google Scholar
  14. 14.
    Ausiello JC, Bruce JN, Freda PU (2008) Postoperative assessment of the patient after transsphenoidal pituitary surgery. Pituitary 11:391–401. CrossRefGoogle Scholar
  15. 15.
    Bellut D, Hlavica M, Muroi C, Woernle CM, Schmid C, Bernays RL (2012) Impact of intraoperative MRI-guided transsphenoidal surgery on endocrine function and hormone substitution therapy in patients with pituitary adenoma. Swiss Med Wkly 142:w13699. Google Scholar
  16. 16.
    Fomekong E, Duprez T, Docquier MA, Ntsambi G, Maiter D, Raftopoulos C (2014) Intraoperative 3T MRI for pituitary macroadenoma resection: initial experience in 73 consecutive patients. Clin Neurol Neurosurg 126:143–149. CrossRefGoogle Scholar
  17. 17.
    Paterno V, Fahlbusch R (2014) High-field iMRI in transsphenoidal pituitary adenoma surgery with special respect to typical localization of residual tumor. Acta Neurochir (Wien) 156:463–474. (discussion 474)CrossRefGoogle Scholar
  18. 18.
    Semple PL, Vance ML, Findling J, Laws ER Jr. (2000) Transsphenoidal surgery for Cushing’s disease: outcome in patients with a normal magnetic resonance imaging scan. Neurosurgery 46:553–558CrossRefGoogle Scholar
  19. 19.
    Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K (1998) Headache associated with pituitary adenomas. Headache 38:782–786CrossRefGoogle Scholar
  20. 20.
    Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B (1988) Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand 223:327–335CrossRefGoogle Scholar
  21. 21.
    Etxabe J, Vazquez JA (1994) Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol (Oxf) 40:479–484CrossRefGoogle Scholar
  22. 22.
    Holdaway IM, Bolland MJ, Gamble GD (2008) A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol 158:89–95. CrossRefGoogle Scholar
  23. 23.
    Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. Lancet 367:1605–1617. CrossRefGoogle Scholar
  24. 24.
    Nomikos P, Buchfelder M, Fahlbusch R (2005) The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure’. Eur J Endocrinol 152:379–387CrossRefGoogle Scholar
  25. 25.
    Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM (2018) European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol 178:G1–G24. CrossRefGoogle Scholar
  26. 26.
    Sughrue ME, Blevins LS, Chang EF, Gabriel RA, Aghi MK, Blevins LS (2011) Excess mortality for patients with residual disease following resection of pituitary adenomas. Pituitary 14:276–283. CrossRefGoogle Scholar
  27. 27.
    Hansen TM, Batra S, Lim M, Gallia GL, Burger PC, Salvatori R, Wand G, Quinones-Hinojosa A, Kleinberg L, Redmond KJ (2014) Invasive adenoma and pituitary carcinoma: a SEER database analysis. Neurosurg Rev 37:279–286. CrossRefGoogle Scholar
  28. 28.
    Alander JT, Kaartinen I, Laakso A, Patila T, Spillmann T, Tuchin VV, Venermo M, Valisuo P (2012) A review of indocyanine green fluorescent imaging in surgery. Int J Biomed Imaging 2012:7. CrossRefGoogle Scholar
  29. 29.
    Hide T, Yano S, Shinojima N, Kuratsu J (2015) Usefulness of the indocyanine green fluorescence endoscope in endonasal transsphenoidal surgery. J Neurosurg 122:1185–1192. CrossRefGoogle Scholar
  30. 30.
    Verstegen MJT, Tummers QRJG, Schutte PJ, Pereira AM, van Furth WR, van de Velde CJH, Malessy MJA, Vahrmeijer AL (2016) Intraoperative identification of a normal pituitary gland and an adenoma using near-infrared fluorescence imaging and low-dose indocyanine green. Oper Neurosurg 12:260–268. CrossRefGoogle Scholar
  31. 31.
    Cho SS, Zeh R, Pierce JT, Jeon J, Nasrallah M, Adappa ND, Palmer JN, Newman JG, White C, Kharlip J, Snyder P, Low P, Singhal S, Grady MS, Lee JYK (2018) Folate receptor near-infrared optical imaging provides sensitive and specific intraoperative visualization of nonfunctional pituitary adenomas. Oper Neurosurg. Google Scholar
  32. 32.
    Lee JYK, Cho SS, Zeh R, Pierce JT, Martinez-Lage M, Adappa ND, Palmer JN, Newman JG, Learned KO, White C, Kharlip J, Snyder P, Low PS, Singhal S, Grady MS (2018) Folate receptor overexpression can be visualized in real time during pituitary adenoma endoscopic transsphenoidal surgery with near-infrared imaging. J Neurosurg 129:390–403. CrossRefGoogle Scholar
  33. 33.
    Shinoda J, Yano H, Yoshimura S, Okumura A, Kaku Y, Iwama T, Sakai N (2003) Fluorescence-guided resection of glioblastoma multiforme by using high-dose fluorescein sodium. Technical note. J Neurosurg 99:597–603CrossRefGoogle Scholar
  34. 34.
    Zhang DY, Singhal S, Lee JYK (2018) Optical principles of fluorescence-guided brain tumor surgery: a practical primer for the neurosurgeon. Neurosurgery. Google Scholar
  35. 35.
    Coburger J, Hagel V, Wirtz CR, König R (2015) Surgery for glioblastoma: impact of the combined use of 5-aminolevulinic acid and intraoperative MRI on extent of resection and survival. PLoS ONE 10:e0131872. CrossRefGoogle Scholar
  36. 36.
    Marbacher S, Klinger E, Schwyzer L, Fischer I, Nevzati E, Diepers M, Roelcke U, Fathi AR, Coluccia D, Fandino J (2014) Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases. Neurosurg Focus 36:E10. CrossRefGoogle Scholar
  37. 37.
    Hadjipanayis CG, Widhalm G, Stummer W (2015) What is the surgical benefit of utilizing 5-ALA for fluorescence-guided surgery of malignant gliomas? Neurosurgery 77:663–673. CrossRefGoogle Scholar
  38. 38.
    Haj-Hosseini N, Richter JCO, Hallbeck M, Wårdell K (2015) Low dose 5-aminolevulinic acid: implications in spectroscopic measurements during brain tumor surgery. Photodiagn Photodyn Ther 12:209–214. CrossRefGoogle Scholar
  39. 39.
    Kennedy JC, Pottier RH (1992) Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol 14:275–292CrossRefGoogle Scholar
  40. 40.
    Moher D, Liberati A, Tetzlaff J, Altman DG, The PG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS Med 6:e1000097CrossRefGoogle Scholar
  41. 41.
    Eljamel MS, Leese G, Moseley H (2009) Intraoperative optical identification of pituitary adenomas. J Neurooncol 92:417–421. CrossRefGoogle Scholar
  42. 42.
    Nemes A, Fortmann T, Poeschke S, Greve B, Prevedello D, Santacroce A, Stummer W, Senner V, Ewelt C (2016) 5-ALA fluorescence in native pituitary adenoma cell lines: resection control and basis for photodynamic therapy (PDT)? PLoS ONE 11:e0161364. CrossRefGoogle Scholar
  43. 43.
    Neumann LM, Beseoglu K, Slotty PJ, Senger B, Kamp MA, Hänggi D, Steiger HJ, Cornelius JF (2016) Efficacy of 5-aminolevulinic acid based photodynamic therapy in pituitary adenomas-experimental study on rat and human cell cultures. Photodiagn Photodyn Ther 14:77–83. CrossRefGoogle Scholar
  44. 44.
    Litvack ZN, Zada G, Laws ER (2012) Indocyanine green fluorescence endoscopy for visual differentiation of pituitary tumor from surrounding structures. J Neurosurg 116:935–941. CrossRefGoogle Scholar
  45. 45.
    Sandow N, Klene W, Elbelt U, Strasburger CJ, Vajkoczy P (2015) Intraoperative indocyanine green videoangiography for identification of pituitary adenomas using a microscopic transsphenoidal approach. Pituitary 18:613–620. CrossRefGoogle Scholar
  46. 46.
    da Silva CE, da Silva JL, da Silva VD (2010) Use of sodium fluorescein in skull base tumors. Surg Neurol Int 1:70. CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Keck School of Medicine, University of Southern CaliforniaLos AngelesUSA
  2. 2.Department of Neurological SurgeryKeck School of Medicine, University of Southern CaliforniaLos AngelesUSA

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