Daly Adrian F, Cano David A, Venegas-Moreno Eva, Petrossians Patrick, Dios Elena, Castermans Emilie, Flores-Martínez Alvaro, Bours Vincent, Beckers Albert, Soto-Moreno Alfonso
Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Liège Université, Liège, Belgium.
Unidad de Gestión de Endocrinología y Nutrición, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Endocr Connect. 2019 Apr;8(4):338-348. doi: 10.1530/EC-19-0027.
Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy.
We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center.
Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response.
Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen.
Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients.
垂体腺瘤因肿瘤生长/侵袭及激素分泌紊乱而具有较高的疾病负担。MEN1和AIP等基因的种系突变与侵袭性垂体腺瘤的早发相关，这些腺瘤可能对药物治疗耐药。
我们使用已发表的风险标准进行了一项回顾性筛查研究，以评估三级转诊中心垂体腺瘤患者中AIP和MEN1突变的频率。
对儿科/青少年期发病、30岁及以下出现的大腺瘤、家族性孤立性垂体腺瘤（FIPA）家系以及药物治疗无法控制的肢端肥大症或泌乳素瘤病例的垂体腺瘤患者进行基因研究。我们还评估了生长激素瘤中AIP的免疫组化染色（AIP-IHC）是否与生长抑素类似物（SSA）反应相关。
55例患者符合研究标准并接受了AIP/MEN1突变的基因筛查。未发现突变，使用多重连接探针扩增（MLPA）排除了大片段缺失/重复。在一组散发性生长激素瘤中，低AIP-IHC肿瘤比高AIP-IHC肿瘤明显更大（P = 0.002），且更频繁地为稀疏颗粒型（P = 0.046）。未观察到AIP-IHC与SSA反应之间存在显著关系。
垂体腺瘤患者中AIP/MEN1的种系突变罕见，使用一般风险标准在大型三级转诊机构中未识别出病例。在肢端肥大症中，低AIP-IHC与肿瘤较大及更频繁的稀疏颗粒型亚型相关，但未观察到与SSA反应性的关系。垂体腺瘤的遗传学在很大程度上仍未得到解释，AIP筛查标准可显著优化，以聚焦于年轻患者中的大型侵袭性肿瘤。
