MGMT immunohistochemistry in pituitary tumors: controversies with clinical implications
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Temozolomide (TMZ) is currently considered as a rational therapeutic option for patients with progressively aggressive pituitary adenomas and carcinomas not responding to conventional therapies. Administration of TMZ results in clinical response and improvement in survival of many of these patients depending upon the expression of the DNA repair enzyme O-6 methylguanine DNA transferase (MGMT). Low or negative MGMT immunoreactivity predicts responsiveness to TMZ therapy. Therefore, MGMT serves as a criterion to select candidate patients anticipating response to treatment.
Materials and Methods
The MGMT expression was investigated in 25 pituitary adenomas with Ki-67 labeling index more that 3% and p53 expression, using various antigen retrieval protocols. After direct application of the antibody, only one adenoma yielded positive for MGMT. However, after pretreatment of tissue sections with antigen retrieval protocols, another 3 adenomas, initially negative turned to positive.
These findings could explain lack of response to TMZ treatment in patients with false negative MGMT immunohistochemistry. Evaluation of tumor samples for MGMT expression should carefully be carried-out using the optimum immunohistochemical protocol to obtain consistent and reliable results that help to identify patients that could respond to TMZ therapy.
KeywordsAntigen retrieval protocols Immunohistochemistry Ki-67 MGMT p53 Temozolomide
No funding from official organization was received. We thank Mrs. Magda Pateraki and Soula Roumelioti for excellent technical support.
Compliance with ethical standards
Conflict of interest
The authors certify that they have NO involvement in any organization or entity with any financial interest in the context or materials discussed in this manuscript.
- 2.Raverot G, Castinetti F, Jouanneau E, Morange I, Figarella-Branger D, Dufour H, Trouillas J, Brue T (2012) Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment. Clin. Endocrinol. (Oxf.) 76:769–775. https://doi.org/10.1111/j.1365-2265.2012.04381.x CrossRefGoogle Scholar
- 3.O’Reilly SM, Newlands ES, Glaser MG, Brampton M, Rice-Edwards JM, Illingworth RD, Richards PG, Kennard C, Colquhoun IR, Lewis P, Stevens MFG (1993) Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer 29A:940–942. Erratum in: Eur J Cancer 29A:1500 (1993)CrossRefGoogle Scholar
- 4.Gilbert MR, Friedman HS, Kuttesch JF, Prados MD, Olson JJ, Reaman GH, Zaknoen SL (2002) A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy. Neuro. Oncol. 4:261–267. https://doi.org/10.1093/neuonc/4.4.261 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P (2002) Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J. Clin. Oncol. 20:1375–1382. https://doi.org/10.1200/JCO.2002.20.5.1375 CrossRefPubMedGoogle Scholar
- 15.Moshkin O, Syro LV, Scheithauer BW, Ortiz LD, Fadul CE, Uribe H, Gonzalez R, Cusimano M, Horvath E, Rotondo F, Kovacs K (2011) Aggressive silent corticotroph adenoma progressing to pituitary carcinoma: the role of temozolomide therapy. Hormones (Athens) 10:162–167. https://doi.org/10.14310/horm.2002.1307 CrossRefGoogle Scholar
- 16.McCormack AI, McDonald KL, Gill AJ, Clark SJ, Burt MG, Campbell KA (2009) Low 06-methylguanine-DNA methyltransferase [p1] (mgmt) expression and response to temozolomide in aggressive pituitary tumors. Clin. Endocrinol. (Oxf.) 71:226–233. https://doi.org/10.1111/j.1365-2265.2008.03487.x CrossRefGoogle Scholar
- 18.Lloyd RV, Kovacs K, Young WF Jr, Farell WE, Asa SL, Touillas J, Kontogeorgos G, Sano T, Scheithauer BW, Horvath E (2004) Pituitary Tumours: Introduction. In: DeLellis RA, Heitz P, Lloyd RV, Eng C (eds) WHO Classification of Tumours, Pathology and Genetics, Tumours of Endocrine Organs. IARC Press, Lyon, pp 10–13Google Scholar
- 20.Jaffrain-Rea ML (2014) From resistant to aggressive and malignant prolactinomas: a translational approach. J Endocr Disord 1:1–10Google Scholar
- 21.Osamura RY, Lopes MBS, Grossman A, Kontogeorgos G, Trouillas J (2017) Tumours of the pituitary gland. Introduction. In: Lloyd RV, Osamura RV, Klöppel G (eds) WHO classification of tumours of endocrine organs. IARC Press, LyonGoogle Scholar
- 28.Bengtsson D, Schrøder HD, Andersen M, Maiter D, Berinder K, Feldt Rasmussen U, Krogh Rasmussen Å, van der Lely A, Petersson M, Johannsson G, Andersen M, Burman P (2015) Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. J. Clin. Endocrinol. Metab. 100:1689–1698. https://doi.org/10.1210/jc.2014-4350 CrossRefPubMedGoogle Scholar
- 30.Murakami M, Mizutani A, Asano S, Katakami H, Ozawa Y, Yamazaki K, Ishida Y, Takano K, Okinaga H, Matsuno A (2011) A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma: case report. Neurosurg. 68:E1761–E1767. https://doi.org/10.1227/NEU.0b013e318217161a CrossRefGoogle Scholar