CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

First report of medulloblastoma in a patient with MUTYH-associated polyposis.

AIMS: The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH-associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH. METHODS: Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma. RESULTS: The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis. CONCLUSIONS: Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.

Mismatch Repair Deficiency and Lynch Syndrome Among Adult Patients With Glioma.

PURPOSE: The Lynch syndrome (LS)-glioma association is poorly documented. As for mismatch repair deficiency (MMRd) in glioma, a hallmark of LS-associated tumors, there are only limited data available. We determined MMRd and LS prevalence in a large series of unselected gliomas, and explored the associated characteristics. Both have major implications in terms of treatment, screening, and prevention. METHODS: Somatic next-generation sequencing was performed on 1,225 treatment-naive adult gliomas referred between 2017 and June 2022. For gliomas with ≥1 MMR pathogenic variant (PV), MMR immunohistochemistry (IHC) was done. Gliomas with ≥1 PV and protein expression loss were considered MMRd. Eligible patients had germline testing. To further explore MMRd specifically in glioblastomas, isocitrate dehydrogenase (IDH)-wild type (wt), we performed IHC, and complementary sequencing when indicated, in a series of tumors diagnosed over the 2007-2021 period. RESULTS: Nine gliomas were MMRd (9/1,225; 0.73%). Age at glioma diagnosis was <50 years for all but one case. Eight were glioblastomas, IDH-wt, and one was an astrocytoma, IDH-mutant. ATRX (n = 5) and TP53 (n = 8) PV were common. There was no TERT promoter PV or EGFR amplification. LS prevalence was 5/1,225 (0.41%). One 77-year-old patient was a known LS case. Four cases had a novel LS diagnosis, with germline PV in MSH2 (n = 3) and MLH1 (n = 1). One additional patient had PMS2-associated constitutional mismatch repair deficiency. Germline testing was negative in three MSH6-deficient tumors. In the second series of glioblastomas, IDH-wt, MMRd prevalence was 12.5% in the <40-year age group, 2.6% in the 40-49 year age group, and 1.6% the ≥50 year age group. CONCLUSION: Screening for MMRd and LS should be systematic in glioblastomas, IDH-wt, diagnosed under age 50 years.

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study.

OBJECTIVE: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. DESIGN: Follow-up of a cohort of consecutive patients treated by surgery. METHODS: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission. RESULTS: Median follow-up was 18.2 months (range: 2.8-155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33-41.8) after surgery. From Kaplan-Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6-96.4%) and 81% (95% CI: 71.2-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. CONCLUSIONS: In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

Pangenomic Classification of Pituitary Neuroendocrine Tumors.

Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.

Chordoid Glioma Infiltrating Optic Structures.

Chordoid glioma of the third ventricle (CGTV) is a rare, slow-growing, World Health Organization Grade II glial tumor, with stereotyped localization in the anterior third ventricle. Despite being considered a noninvasive tumor, CGTV is usually associated with a poor clinical outcome due to its close proximity to important cerebral structures, such as the hypothalamus and visual pathways. Our patient with CGTV experienced visual involvement, but after subtotal surgical resection showed no evidence of progression at 5-year follow-up.

The 2016 World Health Organization classification of tumours of the central nervous system.

The 2016 WHO classification of tumours of the central nervous system represents the new paradigm among the specialists in the brain tumours and proposes a new approach combining histopathological and molecular features into diagnosis named 'integrated diagnosis'. The aim of this challenge is to overstep the interobserver variability of diagnosis based on previous classifications in order to ensure homogenous biological entities with a more accurate clinical significance. Over the last two decades, several molecular aberrations into gliomagenesis were highlighted and then confirmed as emerging biomarkers through prognostic stratification. In particular, IDH1/IDH2 genes mutations, 1p/19q codeletion and mutations in genes encoding histone H3 variants drastically changed the knowledge about diffuse gliomas inducing the WHO working group to consider the phenotype-genotype approach. In the present review, the historical development of the diagnosis of brain tumours from the 3D spatial configuration to the integration of multidisciplinary data up to recent molecular alterations is discussed. At the national level, the RENOCLIP network (supported by the National Cancer Institute) contributes to improve the standardization of histological diagnosis and the facilitation of access to molecular biology platforms for the detection of genetic aberrations necessary for integrated diagnosis. Importantly, the French POLA cohort allowed to test the clinical impact of the new criteria introduced by 2016 WHO classification of CNS tumours confirming the high accuracy in predicting clinical behaviour for diffuse gliomas.

Diffuse gliomas with FGFR3-TACC3 fusion have characteristic histopathological and molecular features.

Adult glioblastomas, IDH-wildtype represent a heterogeneous group of diseases. They are resistant to conventional treatment by concomitant radiochemotherapy and carry a dismal prognosis. The discovery of oncogenic gene fusions in these tumors has led to prospective targeted treatments, but identification of these rare alterations in practice is challenging. Here, we report a series of 30 adult diffuse gliomas with an in frame FGFR3-TACC3 oncogenic fusion (n = 27 WHO grade IV and n = 3 WHO grade II) as well as their histological and molecular features. We observed recurrent morphological features (monomorphous ovoid nuclei, nuclear palisading and thin parallel cytoplasmic processes, endocrinoid network of thin capillaries) associated with frequent microcalcifications and desmoplasia. We report a constant immunoreactivity for FGFR3, which is a valuable method for screening for the FGFR3-TACC3 fusion with 100% sensitivity and 92% specificity. We confirmed the associated molecular features (typical genetic alterations of glioblastoma, except the absence of EGFR amplification, and an increased frequency of CDK4 and MDM2 amplifications). FGFR3 immunopositivity is a valuable tool to identify gliomas that are likely to harbor the FGFR3-TACC3 fusion for inclusion in targeted therapeutic trials.

Efficacy of endoscopic endonasal transsphenoidal surgery for Cushing's disease in 230 patients with positive and negative MRI.

OBJECT: The primary objective was to assess the remission rate, and the secondary objectives were to evaluate the early complications and recurrence rate and to define the predictive factors for the remission and recurrence rates. PATIENTS AND METHODS: This prospective single-center study included 230 consecutive patients, operated on by a single surgeon for Cushing's disease via a transsphenoidal endoscopic endonasal approach, over a 6-year period (2008-2013). The patients included in this series were all adults (>18 years of age), who presented with clinical and biological characteristics of Cushing's disease confirmed based on dedicated MRI pituitary imaging. Biochemical remission was defined as a postoperative serum cortisol level <5 µg/dl on the 2nd day following surgery that required glucocorticoid replacement therapy. RESULTS: The remission rate for the global population (n = 230) with a follow-up of 21 ± 19.2 months concerned 182 patients (79.1%) divided into 132 patients (82.5%) with positive MRI and 50 patients (71.4%) with negative MRI with no statistically significant difference (p = 0.077). Complications occurred in 77 patients with no deaths. A total of 22% of patients had transient diabetes insipidus and 6.4% long-term diabetes insipidus, and no postoperatively CSF leakage was observed. The recurrence rate was 9.8% with a mean time of 32.7 ± 15.2 months. The predictive factors for the remission rate were the presence of pituitary microadenoma and a positive histology. No risk factors were involved regarding the recurrence rate. CONCLUSION: Whatever the MRI results, the transsphenoidal endonasal endoscopic approach remains the gold standard treatment for Cushing's disease. It was maximally effective with a remission rate of 79.1% and lower morbidity.

Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with an increased risk of cancer. Most BWS patients show a molecular defect in the 11p15 region that contains imprinted genes. BWS has been associated with malignant neoplasms during infancy. Descriptions of benign tumors, especially in adult patients, are rarer. METHODS/RESULTS: We report the case of a BWS patient with pituitary adenoma caused by loss of methylation (LOM) at ICR2 (locus CDKN1C/KCNQ1OT1). The patient was referred to an endocrinology unit for suspicion of Cushing's disease due to a history of macroglossia and hemihyperplasia. Biological tests led to the diagnosis of ACTH-dependent hypercortisolism. MRI showed a microadenoma of the pituitary gland, confirming the diagnosis of Cushing's disease. DNA methylation analysis revealed LOM at ICR2 that was in a mosaic state in the patient's leukocytes, but was present in nearly all cells of the pituitary adenoma. The epigenetic defect was associated with a somatic USP8 mutation in the adenoma. CONCLUSION: Pituitary adenoma rarely occurs in patients with BWS. However, BWS should be considered in cases of pituitary adenoma with minor and/or major signs of BWS. The association between ICR2 LOM and USP8 mutation in the adenoma is questionable. © 2016 S. Karger AG, Basel.

The Great Imitator in Endocrinology: A Painful Hypophysitis Mimicking a Pituitary Tumor.

CONTEXT: The incidence of syphilis has been increasing in recent decades in Western countries. Pituitary involvement is very unusual in syphilis. This infectious disease is not often considered in the workup of a patient with hypophysitis. CASE: We report the case of a 28-year-old man who was admitted for headaches worsening over 1 month that became resistant to paracetamol. A magnetic resonance imaging scan revealed a heterogeneous pituitary mass suggesting a pituitary tumor. Hormonal investigations showed partial corticotropic and thyrotropic deficiencies. Headaches required high doses of morphine. Transsphenoidal surgery was performed, and histological examination revealed an aspect of hypophysitis. One month later, clinical reexamination showed skin and tongue lesions very suggestive of a syphilis infection, which was serologically confirmed. Immunohistochemistry on paraffin sections of the resected pituitary revealed an abundant presence of Treponema pallidum, confirming the diagnosis of a syphilitic hypophysitis. Intravenous therapy by benzylpenicillin for 14 days was rapidly efficient. Headaches stopped within a few days, and the skin and tongue lesions disappeared during the following month. Thyrotropic deficiency resolved in 2 weeks, but partial corticotropic deficiency persisted at 3 months. CONCLUSION: This is the first case of a pituitary involvement in acquired syphilis, pathologically proven, in a non-HIV-infected patient. In a context of the resurgence of syphilis, this diagnosis should be considered in the case of a pituitary lesion with unusually intense headaches.

Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis.

Chordoid glioma of the third ventricle (CG3V) is a rare tumor developing in a stereotyped localization. It has been related to the circumventricular organ of the lamina terminalis, in the anterior part of the third ventricle, but its oncogenesis is poorly understood. TTF-1 transcription factor is involved in the development and adult physiology of the ventral forebrain. We studied the histopathologic and immunohistochemical features of a multicentric series of 17 cases of CG3V. We described additional histologic patterns (solid, fibrosing, and fusiform) to the typical chordoid pattern. TTF-1 was constantly expressed in CG3V, as in developing and adult lamina terminalis. The anti-TTF-1 SPT24 clone was more sensitive than the 8G7G3/1 clone. No mutation of IDH1 R132, IDH2 R172, or BRAF V600 codons was found. We showed TTF-1 as a useful marker for the diagnosis of CG3V and the understanding of its oncogenesis.

The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue.

Intestinal invasion by the protozoan parasite Entamoeba histolytica is characterized by remodelling of the extracellular matrix (ECM). The parasite cysteine proteinase A5 (CP-A5) is thought to cooperate with human matrix metalloproteinases (MMPs) involved in ECM degradation. Here, we investigate the role CP-A5 plays in the regulation of MMPs upon mucosal invasion. We use human colon explants to determine whether CP-A5 activates human MMPs. Inhibition of the MMPs' proteolytic activities abolishes remodelling of the fibrillar collagen structure and prevents trophozoite invasion of the mucosa. In the presence of trophozoites, MMPs-1 and -3 are overexpressed and are associated with fibrillar collagen remodelling. In vitro, CP-A5 performs the catalytic cleavage needed to activate pro-MMP-3, which in turn activates pro-MMP-1. Ex vivo, incubation with recombinant CP-A5 was enough to rescue CP-A5-defective trophozoites. Our results suggest that MMP-3 and/or CP-A5 inhibitors may be of value in further studies aiming to treat intestinal amoebiasis.

Silent, but not unseen: multimicrocystic aspect on T2-weighted MRI in silent corticotroph adenomas.

OBJECTIVE: Silent corticotroph adenomas (SCAs) present as nonfunctional pituitary tumours in routine pre-operative evaluation. The objective of this study was to evaluate the diagnostic accuracy of MRI T2-weighted sequences for detecting the corticotroph subtype pre-operatively. DESIGN: The pre-operative T2-weighted MRI sequences were retrospectively evaluated in patients with SCA and two control groups: clinically manifest corticotroph macroadenomas (CSMs) and nonfunctional gonadotroph macroadenomas (NFGMs). All were selected from a registry of 1096 patients in whom transsphenoidal surgery was performed in the same tertiary reference centre. T2-weighted MRI sequences were independently classified by one senior endocrinologist and one senior radiologist who were blinded to the clinical and histological features. PATIENTS: Seventeen patients with SCA, 14 with CSM and 60 with NFGM were included in this study. MEASUREMENTS: Pituitary MRI with T2-weighted sequences. Two aspects were retained: multiple microcysts (MMs) and the absence of microcysts. Hormonal data included plasma prolactin, IGF-1, testosterone or oestradiol, LH, FT4, TSH, morning plasma cortisol and an ACTH-stimulation test, when available. RESULTS: Multiple microcysts were present in 76% (13/17) of SCAs, 21% (3/14) of CSMs and 5% (3/60) of NFGMs. The presence of MMs in clinically nonfunctioning macroadenomas had a sensitivity of 76% and a specificity of 95% for predicting SCA. CONCLUSION: The presence of MMs in T2-weighted MRI is a good diagnostic tool to suggest the corticotroph subtype in an apparently nonfunctional pituitary tumour.

Two patients with a solitary fibrous tumor of the thoracic spinal cord.

We report two patients with thoracic spinal solitary fibrous tumor (SFT). This report includes a patient with the first secondary SFT arising in the central nervous system from a pleural origin to our knowledge. The diagnosis was confirmed by histological and immunohistochemical analysis. Both patients underwent gross total resection of their tumors and did not show signs of local recurrence. The patient with the secondary lesion later presented with visceral dissemination. We review the reports of spinal SFT and discuss the diagnosis and therapeutic management of this intriguing entity.

Histopathologic and ultrastructural features and claudin expression in papillary tumors of the pineal region: a multicenter analysis.

Neuroepithelial papillary tumor of the pineal region (PTPR) has been defined as a distinct entity that is increasingly being recognized, with 96 cases now reported. This tumor shares morphologic features with both ependymomas and choroid plexus tumors. PTPR is characterized by an epithelial-like growth pattern in which the vessels are covered by layers of tumor cells forming perivascular pseudorosettes. These tumors exhibit various combinations of papillary and solid architecture, making the differential diagnosis of PTPR difficult to establish. We report the detailed description of the histopathologic features of a large series of PTPRs from 20 different centers and distinguish 2 subgroups of tumors with either a striking papillary growth pattern or a papillary and solid growth pattern. We highlight the findings that PTPRs have unusual vessels with multiple lumina and frequently show detachment of the border of the tumoral cells from the vascular wall. The 2 PTPR subgroups present similar clinical characteristics and immunophenotypes. We confirmed and extended the results of previous ultrastructural studies on the presence of intercellular junctions at the apical part of tumoral cells. The expression of the tight junction proteins claudin-1, claudin-2, and claudin-3 was investigated by immunohistochemistry. Claudin-1 and claudin-3, but not claudin-2, were expressed in PTPRs and in the fetal subcommissural organ, potentially the origin of this tumor. In contrast, all 3 claudins were expressed in choroid plexus papillomas. Claudin expression may help in the diagnosis of PTPRs and can be used in combination with other markers, such as CK18, NCAM, E-cadherin, MAP-2, and Kir 7.1.

Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients.

CONTEXT: Germline mutations of the AIP (aryl-hydrocarbon receptor interacting protein) gene are associated with a predisposition to pituitary adenomas. Such mutations are found in about half of patients with familial acromegaly, but penetrance is incomplete. OBJECTIVE: We studied the prevalence of germline AIP mutations in a large cohort of patients with apparently sporadic pituitary adenomas. PATIENTS AND SETTING: A total of 443 patients with pituitary adenomas of all histotypes, who had no familial history of pituitary adenomas or multiple endocrine neoplasia and who were examined at Bicêtre University Hospital, a tertiary referral center, between 2007 and 2010, were enrolled in this prospective study. METHODS: The entire coding sequence of the AIP gene was screened for germline mutations. A subgroup of patients were screened for large deletions or duplications of the AIP and MEN1 genes by multiplex ligation-dependent probe amplification. RESULTS: AIP mutations were detected in 16 (3.6%) of the 443 patients, comprising six of 148 patients with acromegaly (4.1%), six of 132 patients with prolactinomas (4.5%), one of 113 patients with nonfunctioning adenomas (0.9%), three of 44 patients with corticotropic adenomas (6.8%), and none of the six patients with thyrotropic adenomas. This is the first report of an AIP mutation leading to a truncated protein in a patient with Cushing's disease. Patients with AIP mutation were younger at diagnosis (24.1 vs. 42.8 yr) and had predominantly macroadenoma (12 of 16). No mutations were found in patients diagnosed after age 40 yr, whereas the prevalence before this age was 7.2% (16 of 222). Studies of seven of the AIP-mutated patients' families showed that one asymptomatic parent carried the same mutation in each case. CONCLUSION: This large prospective cohort study confirms the very low prevalence of germline AIP mutations in patients with apparently sporadic pituitary adenomas. We propose to limit AIP testing to patients diagnosed before age 40 yr with apparently sporadic large pituitary adenomas, especially GH- or PRL-secreting adenomas.

Newly visualized fibrillar collagen scaffolds dictate Entamoeba histolytica invasion route in the human colon.

The extracellular matrix (ECM) and its role in the outcome of infectious diseases have been poorly investigated. In this study, we determined the impact of the collagen fibres architecture on the invasive process of the enteric parasite Entamoeba histolytica. The behaviour of E. histolytica wild-type and silenced for the cysteine protease A5 (CP-A5) were compared on a three-dimensional collagen matrix and within human colon fragments for fibrillar collagen cleavage and migration. The interstitial collagen fibres within the connective tissue of the human colon, visualized by multiphoton and second harmonic generation signals imaging, presented a dense scaffold at the subepithelial level and a loose meshwork within the chorion. To penetrate the tissue, E. histolytica migrated on the dense scaffold that remained intact, reached the crypt of Lieberkhün, migrated along and then disorganized the loose scaffold to escape into the mucosa. Interestingly, in vitro, CP-A5 was not required for collagenase activity and migration through the matrix but was necessary within the tissue environment for collagen meshwork remodelling and subsequent invasion. The data point out that further step of invasion relay with ECM destruction that requires human components induced or activated in the presence of CP-A5.

Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience.

CONTEXT: To date only 18 patients with aggressive pituitary tumors or carcinomas treated with temozolomide have been reported. Increased expression of O6-methylguanine-DNA-methyltranferase (MGMT) has been suggested to predict resistance to temozolomide. OBJECTIVES: The objective of the study was to describe the antitumoral efficacy and toxicity of temozolomide in patients with aggressive pituitary tumors or carcinomas and evaluate the possible prognostic value of MGMT promoter methylation and protein expression. PATIENTS: Eight patients, five with pituitary carcinomas (three prolactin (PRL) and two ACTH) and three with aggressive pituitary tumors (one PRL and two ACTH), all treated with temozolomide administered orally for four to 24 cycles, were included in our French multicenter study. DESIGN: MGMT expression was assessed by immunohistochemistry and MGMT promoter methylation by pyrosequencing. RESULTS: Three of the eight patients (two ACTH adenomas and one PRL carcinoma) responded to temozolomide as demonstrated by significant tumor shrinkage and reduced hormone secretion. Three cycles of temozolomide were sufficient to identify treatment-responsive patients. Additional cycles did not improve treatment efficacy in those not responding, even when associated with carboplatin and vepeside. MGMT expression did not predict tumoral response to temozolomide because it was positive in one responder and negative in two nonresponders. Similarly, MGMT promoter methylation (three of seven tumors) did not predict clinical response. Toxicity remained mild in all patients. CONCLUSION: Temozolomide treatment may be an effective option for some aggressive pituitary tumors or carcinomas. Response to a trial of three cycles of treatment seems sufficient to identify responders and more reliable than patient MGMT status.