Pituitary tumor transforming gene and insulin-like growth factor 1 receptor expression and immunohistochemical measurement of Ki-67 as potential prognostic markers of pituitary tumors aggressiveness.

INTRODUCTION AND OBJECTIVE: The ability to predict recurrence of pituitary adenoma (PA) after surgery may be helpful to determine follow-up frequency and the need for adjuvant treatment. The purpose of this study was to assess the prognostic capacity of pituitary tumor transforming gene (PTTG), insulin-like growth factor 1 receptor (IGF1R), and Ki-67. MATERIALS AND METHODS: In this retrospective study, the normalized copy number (NCN) of PTIG and IGF1R mRNA was measured using RT-PCR, and the Ki-67 index was measured by immunohistochemistry in 46 PA samples. Clinical data, histological subtype, and radiographic characteristics were collected to assess associations between variables and tumor behavior. Progression of tumor remnants and its association to markers was also studied in 14 patients with no adjuvant treatment after surgery followed up for 46±36 months. RESULTS: Extrasellar tumors had a lower PTTG expression as compared to sellar tumors (0.065 [1st-3rd quartile: 0.000-0.089] NCN vs. 0.135 [0.105-0.159] NCN, p=0.04). IGF1R expression changed depending on histological subtype (p=0.014), and was greater in tumor with remnant growth greater than 20% during follow-up (10.69±3.84 NCN vs. 5.44±3.55 NCN, p=0.014). CONCLUSIONS: Our results suggest that the IGF1R is a more helpful molecular marker than PTTG in PA management. Ki-67 showed no association to tumor behavior. However, the potential of these markers should be established in future studies with standardized methods and on larger samples.

High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas.

BACKGROUND: Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. METHODS: We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age. RESULTS: Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. CONCLUSION: Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.