Aggressive prolactinoma (Review)

Abstract

Aggressive prolactinoma (APRL) is a subgroup of aggressive pituitary tumors (accounting for 10% of all hypophyseal neoplasia) which are defined by: invasion based on radiological and/or histological features, a higher proliferation profile when compared to typical adenomas and rapidly developing resistance to standard medication/protocols in addition to an increased risk of early recurrence. This is a narrative review focusing on APRL in terms of both presentation and management. Upon admission, the suggestive features may include increased serum prolactin with a large tumor diameter (mainly >4 cm), male sex, early age at diagnosis (<20 years), and genetic predisposition [multiple endocrine neoplasia type 1 (MEN1), aryl hydrocarbon receptor interacting protein (AIP), succinate dehydrogenase (SDHx) gene mutations]. Potential prognostic factors are indicated by assessment of E-cadherin, matrix metalloproteinase (MMP)-9, and vascular endothelial growth factor (VEGF) status. Furthermore, during management, APRL may be associated with dopamine agonist (DA) resistance (described in 10-20% of all prolactinomas), post-hypophysectomy relapse, mitotic count >2, Ki-67 proliferation index ≥3%, the need for radiotherapy, lack of response in terms of controlling prolactin levels and tumor growth despite multimodal therapy. However, none of these as an isolated element serves as a surrogate of APRL diagnosis. A fourth-line therapy is necessary with temozolomide, an oral alkylating chemotherapeutic agent, that may induce tumor reduction and serum prolactin reduction in 75% of cases but only 8% have a normalization of prolactin levels. Controversies surrounding the duration of therapy still exist; also regarding the fifth-line therapy, post-temozolomide intervention. Recent data suggest alternatives such as somatostatin analogues (pasireotide), checkpoint inhibitors (ipilimumab, nivolumab), tyrosine kinase inhibitors (TKIs) (lapatinib), and mTOR inhibitors (everolimus). APRL represents a complex condition that is still challenging, and multimodal therapy is essential.

Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy

“…Discerning signaling survival dependencies is essential for tailoring the adequate treatment of different tumors. For example, 10–20% of sporadic prolactinomas are resistant to the conventional therapy with dopamine agonists but, to date, only non-mechanistic clinical-histologic data are assessed in an attempt to predict aggressive behavior [ 52 ]. The LFS-associated recurrent prolactinoma was predictably resistant to the usual management by dopamine agonists not only due to its large size, elevated Ki-67 proliferation index and clinical relapse, but also to lack of expression of dopaminergic receptors, including D2, encoded by the DRD2 gene (Fig.…”

Prolactinoma e hiperprolactinemia. Posicionamiento de la SMNE

“…La NEM1 es la principal condición asociada a adenomas hipofisarios y representa el 2.7% de todos los adenomas de hipófisis [151][152][153][154] . Otros cuadros asociados a prolactinomas son el complejo de Carney (CC) 151 , el síndrome 3PA 155 , los cuadros de adenomas hipofisarios aislados familiares (FIPA) [156][157][158][159][160][161][162][163] y el acrogigantismo ligado a X (X-LAG) 164 . Otras asociaciones genéticas con adenomas de hipófisis solamente se asocian a hipersecreción de GH o ACTH, pero no de PRL (Tabla 3).…”

Modern concepts of genetic and immunohistochemical features of prolactin-secreting pituitary adenomas

“…В настоящее время парадигма резистентности к лечению АД включает в себя ряд положений. Резистентные пролактиномы зачастую демонстрируют признаки клинико-морфологической «агрессивности» — обладают большим размером (10 мм и более), плотно гранулированным типом строения, склонностью к инвазивному росту, более высоким уровнем ki-67 [ 9 ]. Отмечены характерные изменения рецепторного аппарата пролактин-секретирующих аденом, резистентных к терапии: уменьшение количества дофаминовых D2-рецепторов, снижение синтеза протеина G, обеспечивающего связывание агонистов дофамина с D2-рецептором, изменение количества эстрогеновых рецепторов (ERα), нарушение трансмембранной передачи сигнала D2-рецепторов [ 10 ].…”