Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors

Abstract

Context: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).

Objective: To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.

Design: 12-year prospective, observational study.

Participants & setting: We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.

Interventions & outcome: AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).

Results: Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).

Conclusions: Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Keywords: aryl hydrocarbon receptor-interacting protein; familial isolated pituitary adenoma; gigantism; pituitary adenoma; pituitary neuroendocrine tumor; somatotropinoma.

Figure 1.

Distribution of AIPmut vs AIPneg PitNETs according to age at onset (A) and to clinical diagnosis (B). Numbers above columns represent percentage of patients. We note that the two AIPmut cases with first symptoms in the 5th and 6th decade, both had macroprolactinomas, 1 presenting with apoplexy. ACTHoma, ACTH-secreting adenoma or Cushing’s disease; AIPmut, AIP mutation-positive; AIPneg, AIP mutation-negative; PitNET NS, pituitary neuroendocrine tumor not specified; NF-PitNET, non-functioning PitNET; PRLoma, prolactinoma; TSHoma, thyrotropinoma; yr, years.

Figure 2.

Patient characteristics (A) and treatment modalities (B,C). Clinical variables (A) and treatment characteristics (B,C) in patients with a clinically presenting PitNET, with or without AIP mutation (AIPmut and AIPneg), and in AIPmut carriers with an abnormality identified at clinical screening (prospectively diagnosed cases). (C) Data are shown as mean ± standard deviation.