Neuroendocrine Unit, Division of Endocrinology and Metabolism, Clinics Hospital, University of São Paulo Medical School, São Paulo, CEP 05403-010, Brazil.
Laboratory of Cellular and Molecular Endocrinology/LIM25 Division of Endocrinology and Metabology, Clinics Hospital, University of São Paulo Medical School, São Paulo, CEP 05403-010, Brazil.
J Clin Endocrinol Metab. 2023 Mar 10;108(4):876-887. doi: 10.1210/clinem/dgac610.
Invasive and somatostatin receptor ligand (SRL)-resistant pituitary tumors represent a challenge in the clinical practice of endocrinologists. Efforts have been made to elucidate reliable makers for both. Survivin and eukaryotic translation initiation factor-binding protein 1 (4EBP1) are upregulated in several cancers and involved in apoptosis and cell proliferation.
We explored the role of these markers in somatotropinomas.
Immunostains for survivin and 4EBP1, and also for somatostatin receptor type 2 (SSTR2), Ki-67, and cytokeratin 18, were analyzed in tissue microarrays containing 52 somatotropinoma samples. Tumor invasiveness was evaluated in all samples while drug resistance was evaluated in 34 patients who received SRL treatment. All these parameters were correlated with first-generation SRL (fg-SRL) responsiveness and tumor invasiveness.
Low survivin expression (P = 0.04), hyperintense signal on T2 weighted image (T2WI) (P = 0.01), younger age (P = 0.01), sparsely granular adenomas (SGA) (P = 0.04), high postoperative growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels (P = 0.049 and P < 0.001, respectively), and large postoperative tumor size (P = 0.02) were associated with resistance to fg-SRL. Low survivin and SSTR2 expression and high 4EBP1 expression were associated with SGA (P = 0.04, P = 0.01, and P = 0.001, respectively). Younger age (P = 0.03), large tumor pre- and postoperative (P = 0.04 and P = 0.006, respectively), low SSTR2 expression (P = 0.03), and high baseline GH and IGF-1 (P = 0.01 and P = 0.02, respectively) were associated with tumor invasiveness. However, survivin, 4EBP1, Ki-67, and granulation patterns were not associated with tumor invasion.
This study suggests that low survivin expression is predictive of resistance to fg-SRL in somatotropinomas, but not of tumor invasiveness.
侵袭性和生长抑素受体配体（SRL）耐药性垂体肿瘤是内分泌学家临床实践中的一个挑战。人们一直在努力寻找这两种肿瘤的可靠标志物。生存素和真核翻译起始因子结合蛋白 1（4EBP1）在多种癌症中上调，参与细胞凋亡和细胞增殖。
我们探讨了这些标志物在生长激素瘤中的作用。
在包含 52 例生长激素瘤样本的组织微阵列中分析了生存素和 4EBP1 以及生长抑素受体 2（SSTR2）、Ki-67 和细胞角蛋白 18 的免疫染色。对所有样本进行肿瘤侵袭性评估，对 34 例接受 SRL 治疗的患者进行药物耐药性评估。所有这些参数均与第一代 SRL（fg-SRL）反应性和肿瘤侵袭性相关。
低生存素表达（P=0.04）、T2 加权像（T2WI）高信号（P=0.01）、年龄较小（P=0.01）、稀疏颗粒性腺瘤（SGA）（P=0.04）、术后高生长激素（GH）和胰岛素样生长因子-1（IGF-1）水平（P=0.049 和 P<0.001）和术后大肿瘤体积（P=0.02）与 fg-SRL 耐药性相关。低生存素和 SSTR2 表达以及高 4EBP1 表达与 SGA 相关（P=0.04、P=0.01 和 P=0.001）。年龄较小（P=0.03）、术前和术后肿瘤较大（P=0.04 和 P=0.006）、低 SSTR2 表达（P=0.03）和基线 GH 和 IGF-1 较高（P=0.01 和 P=0.02）与肿瘤侵袭性相关。然而，生存素、4EBP1、Ki-67 和颗粒状模式与肿瘤侵袭性无关。
本研究表明，低生存素表达可预测生长激素瘤对 fg-SRL 的耐药性，但不能预测肿瘤侵袭性。
