ABSTRACT
INTRODUCTION: Transsphenoidal surgery is the treatment of choice in Cushing's disease (CD), although even late recurrences occur in some patients. Low expression of O-6-methylguanine-DNA methyltransferase (MGMT) has been linked to a high risk of relapse in pituitary tumours, but the evidence for corticotroph adenomas is limited. Therefore, we investigated whether MGMT expression was associated with CD remission or clinicopathological markers of tumour aggressiveness among patients with corticotroph adenomas. MATERIAL AND METHODS: We included 72 consecutive patients (83% female, mean age ±SD: 44.15 ±15.15 years) with CD, who underwent transsphenoidal adenomectomy between 2012 and 2018. The invasiveness of corticotroph tumours was assessed based on the Knosp scale. Immunohistochemistry was used to analyse MGMT expression as well as the proliferation markers (Ki-67, p53, mitotic index). Electron microscopy was used to categorise tumours into densely or sparsely granulated. Early biochemical remission was evaluated in all patients 6 months after pituitary surgery. RESULTS: Early remission was observed in 47 (65%) patients 6 months after surgery. MGMT expression was > 75% in half of all tumours, < 25% in 14 tumours, and 25-50% or 50-75% in 11 tumours. Lower MGMT expression was associated with a larger tumour diameter (p = 0.001), higher adrenocorticotropic hormone (ACTH) concentration (p = 0.002), higher p53 expression (p = 0.026), and higher frequency of sparsely granulated corticotroph adenomas (p = 0.009). Low MGMT expression was significantly related to lower frequency of early clinical remission (p = 0.005). CONCLUSIONS: MGMT predicted the outcomes of transsphenoidal surgery for CD. Pituitary corticotroph adenomas with low MGMT expression may be associated with increased invasiveness and poorer prognosis.
Subject(s)
ACTH-Secreting Pituitary Adenoma/pathology , Adenoma/pathology , DNA Modification Methylases/biosynthesis , DNA Repair Enzymes/biosynthesis , Pituitary ACTH Hypersecretion/metabolism , Tumor Suppressor Proteins/biosynthesis , ACTH-Secreting Pituitary Adenoma/metabolism , ACTH-Secreting Pituitary Adenoma/ultrastructure , Adenoma/metabolism , Adenoma/ultrastructure , Adult , Aged , Female , Humans , Male , Middle Aged , Pituitary ACTH Hypersecretion/etiologyABSTRACT
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the IL-6 family that activates the hypothalamic-pituitary-adrenal axis and promotes corticotrope cell differentiation during development. The aim of this study was to investigate the expression of LIF and its receptor (LIFR) in the canine pituitary gland and in corticotrope adenomas, and to perform a mutation analysis of LIFR. Using immunohistochemistry, immunofluorescence, and quantitative expression analysis, LIF and LIFR expression were studied in pituitary glands of control dogs and in specimens of corticotrope adenoma tissue collected through hypophysectomy in dogs with pituitary-dependent hypercortisolism (PDH, Cushing's disease). Using sequence analysis, cDNA was screened for mutations in the LIFR. In the control pituitary tissues and corticotrope adenomas, there was a low magnitude of LIF expression. The LIFR, however, was highly expressed and co-localized with ACTH(1-24) expression. Cytoplasmatic immunoreactivity of LIFR was preserved in corticotrope adenomas and adjacent nontumorous cells of pars intermedia. No mutation was found on mutation analysis of the complete LIFR cDNA. Surprisingly, nuclear to perinuclear immunoreactivity for LIFR was present in nontumorous pituitary cells of the pars distalis in 10 of 12 tissue specimens from PDH dogs. These data show that LIFR is highly co-expressed with adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH) in the canine pituitary gland and in corticotrope adenomas. Nuclear immunoreactivity for LIFR in nontumorous cells of the pars distalis may indicate the presence of a corticotrope adenoma.
Subject(s)
ACTH-Secreting Pituitary Adenoma/veterinary , Dog Diseases/metabolism , Leukemia Inhibitory Factor/analysis , Pituitary Gland/chemistry , Pituitary Neoplasms/veterinary , Receptors, OSM-LIF/analysis , ACTH-Secreting Pituitary Adenoma/chemistry , ACTH-Secreting Pituitary Adenoma/ultrastructure , Animals , Cell Nucleus/chemistry , Cosyntropin/analysis , Cytoplasm/chemistry , DNA, Complementary/analysis , Dogs , Female , Fluorescent Antibody Technique , Immunohistochemistry , Male , Mutation , Pituitary Gland/ultrastructure , Pituitary Neoplasms/chemistry , Pituitary Neoplasms/ultrastructure , Polymerase Chain Reaction , Receptors, OSM-LIF/genetics , Sequence Analysis, DNA , alpha-MSH/analysisABSTRACT
A 44-year-old male suffered from an inactive pituitary adenoma measuring 20mm in computed tomography (CT) scan and nuclear magnetic resonance tomography (NMR). The tumor was surgically resected via the transnasal-transsphenoidal route. Surgical specimens revealed a typical, sparsely granulated adrenocorticotropic hormone (ACTH) cell adenoma, but also a granulomatous inflammation mostly in the periphery of the tumor, corresponding to a granulomatous hypophysitis. This coincidence appears to be unique and has yet not been described in the literature. Therefore, the clinical data and the pathohistologic and ultrastructural findings are presented here.
