Leon D. Ortiz

MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy

Temozolomide, an alkylating imidazol tetrazine derivative, inhibits DNA replication and is used successfully in the management of patients with gliomas and other malignancies [5, 12]. Recent studies showed the drug to be eVective in patients with pituitary carcinoma and aggressive pituitary adenoma [1, 2, 7, 10, 14]. We reported the case of a 46-year-old man with an aggressive, prolactin (PRL) secreting pituitary tumor [4, 13]. Temozolomide treatment caused marked clinical improvement, reduction in blood PRL levels, and tumor shrinkage [13]. Morphologically, the treated tumor showed necrosis, hemorrhage, Wbrosis and neuronal transformation. Mitotic activity and Ki-67 labeling were signiWcantly decreased [4]. Based on these dramatic clinical, laboratory, imaging and morphologic changes, temozolomide was given to a 41-year-old man with an aggressive silent subtype 2 corticotroph pituitary adenoma. Neither clinical improvement nor tumor shrinkage was observed. No morphologic diVerences were seen between the preand posttreatment tumors. The cytotoxic eVect of the temozolomide depends upon methylation of guanine at the O-6 position in DNA. O-6 methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme, which removes the alkyl group adducts from the O-6 position and induces resistance to temozolomide [6, 9, 11]. Previous immunohistochemical studies showed that gliomas with low MGMT levels respond, whereas those with high levels resist temozolomide eVect [6, 9, 11]. This suggests that MGMT immunostaining may serve as an indicator of treatment responsiveness. Based on the results of previous studies, we investigated MGMT immunopositivity in the above noted cases and in an additional three pituitary adenomas. The immunohistochemical method was described in previous publication [3, 8]. Similar to the results obtained in gliomas, our study showed lack of MGMT staining in the responsive tumor (Fig. 1) and high expression in the resistant tumor (Fig. 2) as well as in the three other adenomas studied. We suggest that MGMT expression should be immunohistochemically assessed before embarking upon temozolomide treatment of aggressive pituitary tumors. If MGMT expression is K. Kovacs Department of Pathology, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

Antitumour effects of temozolomide in a man with a large, invasive prolactin‐producing pituitary neoplasm

1 Libe, R., Morpurgo, P.S., Cappiello, V., Maffini, A., Bondioni, S., Locatelli, M., Zavarone, M., Beck-Peccoz, P. & Spada, A. (2005) Ghrelin and adiponectin in patients with Cushing’s disease before and after transsphenoidal surgery. Clinical Endocrinology , 62 , 30–36. 2 Degawa-Yamauchi, M., Moss, K.A., Bovenkerk, J.E., Shankar, S.S., Morrison, C.L., Lelliott, C.J., Vidal-Puig, A., Jones, R. & Considine, R.V. (2005) Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor alpha. Obesity Research , 13 , 662–669. 3 Shojima, N., Sakoda, H., Ogihara, T., Fujishiro, M., Katagiri, H., Anai, M., Onishi, Y., Ono, H., Inukai, K., Abe, M., Fukushima, Y., Kikuchi, M., Oka, Y. & Asano, T. (2002) Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes , 51 , 1737–1744. 4 Arnaldi, G., Angeli, A., Atkinson, A.B., Bertagna, X., Cavagnini, F., Chrousos, G.P., Fava, G.A., Findling, J.W., Gaillard, R.C., Grossman, A.B., Kola, B., Lacroix, A., Mancini, T., Mantero, F., Newell-Price, J., Nieman, L.K., Sonino, N., Vance, M.L., Giustina, A. & Boscaro, M. (2003) Diagnosis and complications of Cushing’s syndrome: a consensus statement. Journal of Clinical Endocrinology and Metabolism , 88 , 5593–5602 5 Fallo, F., Scarda. A., Sonino, N., Paoletta, A., Boscaro, M., Pagano, C., Federspil, G. & Vettor, R. (2004) Effect of glucocorticoids on adiponectin: a study in healthy subjects and in Cushing syndrome. European Journal of Endocrinology , 150 , 339–344.

Treatment of pituitary neoplasms with temozolomide: a review.

Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O6‐methylguanine‐DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had high‐level MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low‐level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011.

Temozolomide in aggressive pituitary adenomas and carcinomas.

Temozolomide is an alkylating agent used in the treatment of gliomas and, more recently, aggressive pituitary adenomas and carcinomas. Temozolomide methylates DNA and, thereby, has antitumor effects. O6-methylguanine-DNA methyltransferase, a DNA repair enzyme, removes the alkylating adducts that are induced by temozolomide, thereby counteracting its effects. A Medline search for all of the available publications regarding the use of temozolomide for the treatment of pituitary tumors was performed. To date, 46 cases of adenohypophysial tumors that were treated with temozolomide, including 30 adenomas and 16 carcinomas, have been reported. Eighteen of the 30 (60%) adenomas and 11 of the 16 (69%) carcinomas responded favorably to treatment. One patient with multiple endocrine neoplasia type 1 and an aggressive prolactin-producing adenoma was also treated and demonstrated a good response. No significant complications have been attributed to temozolomide therapy. Thus, temozolomide is an effective treatment for the majority of aggressive adenomas and carcinomas. Evidence indicates that there is an inverse correlation between levels of O6-methylguanine-DNA methyltransferase immunoexpression and therapeutic response. Alternatively, high-level O6-methylguanine-DNA methyltransferase immunoexpression correlates with an unfavorable response. Here, we review the use of temozolomide for treating pituitary neoplasms.

Autophagy in the endocrine glands

Autophagy is an important cellular process involving the degradation of intracellular components. Its regulation is complex and while there are many methods available, there is currently no single effective way of detecting and monitoring autophagy. It has several cellular functions that are conserved throughout the body, as well as a variety of different physiological roles depending on the context of its occurrence in the body. Autophagy is also involved in the pathology of a wide range of diseases. Within the endocrine system, autophagy has both its traditional conserved functions and specific functions. In the endocrine glands, autophagy plays a critical role in controlling intracellular hormone levels. In peptide-secreting cells of glands such as the pituitary gland, crinophagy, a specific form of autophagy, targets the secretory granules to control the levels of stored hormone. In steroid-secreting cells of glands such as the testes and adrenal gland, autophagy targets the steroid-producing organelles. The dysregulation of autophagy in the endocrine glands leads to several different endocrine diseases such as diabetes and infertility. This review aims to clarify the known roles of autophagy in the physiology of the endocrine system, as well as in various endocrine diseases.

Pituitary tumors in patients with MEN1 syndrome

We briefly review the characteristics of pituitary tumors associated with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 is an autosomal-dominant disorder most commonly characterized by tumors of the pituitary, parathyroid, endocrine-gastrointestinal tract, and pancreas. A MEDLINE search for all available publications regarding multiple endocrine neoplasia type 1 and pituitary adenomas was undertaken. The prevalence of pituitary tumors in multiple endocrine neoplasia type 1 may vary from 10% to 60% depending on the studied series, and such tumors may occur as the first clinical manifestation of multiple endocrine neoplasia type 1 in 25% of sporadic and 10% of familial cases. Patients were younger and the time between initial and subsequent multiple endocrine neoplasia type 1 endocrine lesions was significantly longer when pituitary disease was the initial manifestation of multiple endocrine neoplasia type 1. Tumors were larger and more invasive and clinical manifestations related to the size of the pituitary adenoma were significantly more frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Normalization of pituitary hypersecretion was much less frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Pituitary tumors in patients with multiple endocrine neoplasia type 1 syndrome tend to be larger, invasive and more symptomatic, and they tend to occur in younger patients when they are the initial presentation of multiple endocrine neoplasia type 1.

Non-uniform response to temozolomide therapy in a pituitary gonadotroph adenoma.

Endocrinologically active pituitary adenomas are treated either with surgery, radiotherapy or various drugs, including dopamine agonists, long-acting somatostatin analogs, growth hormone receptor antagonists, or corticosteroid secretion inhibitors. Fully 35% to 55% of pituitary adenomas invade adjacent structures. This figure is lower in gonadotroph adenomas, less than 5% compared to other adenoma types. Clinical management of invasive adenomas is challenging, and most of them tend to recur after surgery. Hormonally active pituitary adenomas may even be resistant to combined medical, surgical, and radiotherapy treatments. In comparison, pituitary carcinomas represent 0.2% of all adenohypophysial neoplasms1, and not only invade adjacent structures but give rise to cerebrospinal and/or systemic metastases with high mortality. The lack of response to aggressive pituitary adenomas, particularly carcinomas to conventional therapies, drives search for new approaches1. Temozolomide (TMZ) is a chemotherapeutic agent which can cross the blood-brain barrier and has proven utility in the treatment of glioblastoma. More recently, it has been used to treat aggressive pituitary adenomas and carcinomas2. To date, cases of such aggressive pituitary tumors have been reported in terms of clinical outcomes. The morphologic effects of therapy have been described in only three patients2. Of these, two tumors responded, both radiologically and morphologically. The first case, a prolactin cell adenoma, did not express MGMT (06methylguanine-DNA methyltransferase), a DNA repair protein that counteracts TMZ anti-neoplastic action. The second case, an aggressive silent subtype 2 corticotroph adenoma, showed no morphological change after therapy. This tumor showed highlevel immunoexpression of MGMT by immunohistochemistry. The third case, a corticotroph adenoma in a patient with Cushing’s disease, showed no MGMT immunoexpression, and 80% reduction in tumor volume was noted on magnetic resonance imaging (MRI) scan. The Ki-67 labeling index decreased after the therapy. Herein, we report a recurrent pituitary gonadotroph adenoma in which the partial response to TMZ appeared to result from non-uniform MGMT immunoexpression, portions of the tumor lacking immunoreactivity and the remainder showing high-level immunostaining.

Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary

IntroductionHistologic, immunohistochemical and electron microscopic studies have provided conclusive evidence that a marked diversity exists between tumors which secrete growth hormone (GH) in excess. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH—releasing hormone secreting tumors or in familial pituitary tumor syndromes.Materials and methodsA literature search was performed for information regarding pathology, GH-producing tumors and acromegaly.ResultsThis review summarizes the current knowledge on the morphology of GH-producing and silent GH adenomas, as well as GH hyperplasia of the pituitary.ConclusionThe importance of morphologic classification and identification of different subgroups of patients with GH-producing adenomas and their impact on clinical management is discussed.

Treatment of pituitary tumors with temozolomide: an update

Temozolomide is an alkylating chemotherapeutic agent used in malignant neuroendocrine neoplasia, melanoma, brain metastases and an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and anaplastic astrocytoma. Since 2006, it has been used for the treatment of pituitary carcinomas and aggressive pituitary adenomas. Here, we discuss the current indications and results of temozolomide therapy in pituitary tumors, as well as frequently asked questions regarding temozolomide treatment, duration of therapy, dosage, tumor recurrence and resistance.

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions

Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.