Summary
In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted ...of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.
Purpose
The SAGIT® instrument, designed to assist clinicians to stage acromegaly, assess treatment response and adapt patient management, was well received by endocrinologists in a pilot study. We ...report an interim analysis of baseline data from the validation phase.
Methods
The SAGIT® validation study (ClinicalTrials.gov NCT02539927) is an international, non-interventional study. Data collection included: demographic/disease characteristics; medical/surgical histories; concomitant acromegaly treatments; investigators’ subjective evaluation of disease-control status (clinical global evaluation of disease control CGE-DC; controlled/not controlled/yet to be clarified) and clinical disease activity (active/not active); growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels; investigators’ therapeutic decision.
Results
Of 228 patients enrolled, investigators considered disease to be controlled in 110 (48.2%), not controlled in 105 (46.1%), and yet to be clarified in 13 (5.7%) according to CGE-DC. Thirty-three patients were treatment-naïve (not controlled,
n
= 31; yet to be clarified,
n
= 2). Investigators considered 48.2% patients in the controlled and 95.2% in the not-controlled groups to have clinically active disease. In the controlled group, 29.7% of patients did not exhibit hormonal control (GH ≤ 2.5 µg/L; normalized IGF-1) and 47.3% did not have rigorous hormonal control (GH < 1.0 µg/L; normalized IGF-1) by contemporary consensus. Current acromegaly treatment was continued with no change for 91.8% of patients in the controlled and 40.0% in the not-controlled groups.
Conclusions
These data highlight discrepancies between investigator-evaluated disease-control status, disease activity, hormonal control, and treatment decisions in acromegaly. Once validated, the SAGIT® instrument may assist clinicians in making active management decisions for patients with acromegaly.
Objectives
Prolactin (PRL)-secreting macroadenomas usually measure between 10 and 40 mm. Giant (adenoma size ≥40 mm) PRL-tumors are not common, and larger prolactinomas (maximal diameter ≥60 mm) are ...rare, and their management outcomes have not been well characterized.
Methods
We have identified 18 subjects (16 men, 2 females) with giant PRL-adenomas (size ≥60 mm; PRL > 1000 ng/ml) and summarized their characteristics and response to treatment.
Results
Mean age was 36.3 ± 13.5 years (range 12–59 years). Mean adenoma size was 71.8 ± 10.2 mm (60–92 mm). Complaints at presentation included headaches in 11 patients, visual deterioration in 9, sexual dysfunction in 9 males, and behavioral changes in two. Fourteen (78 %) had visual field defects. Mean PRL at presentation was 28,465 ng/ml (range 1300–270,000). All patients were treated with cabergoline (3.9 ± 2.0 mg/week), except for one who received bromocriptine. Treatment achieved PRL normalization in 11/18 patients within a median interval of 20 months. Visual improvement occurred in 12/14 patients with pre-treatment visual abnormalities. Nine patients underwent surgery (transsphenoidal, 7; transcranial, 2). None of the seven patients with elevated PRL before surgery achieved remission post-operatively. After a follow-up of 7.8 ± 5.1 years, 15/18 patients had significant adenoma shrinkage. Eleven patients are normoprolactinemic, 3 are partially controlled (PRL < 3 × ULN), and 4 remain with significantly elevated PRL. Most patients reported disappearance or improvement of their complaints.
Conclusions
These enormous PRL-adenomas are invasive but respond fairly well to medical treatment. Long-term therapy with high dose cabergoline together with a pituitary surgery in some patients was the key for their successful management, achieving biochemical and clinical remission in most patients.
In women, prolactinomas (mainly microprolactinomas) are commonly diagnosed between 20–40-year old. In postmenopausal women, prolactinomas are rarely encountered and usually do not present with ...hyperprolactinemia-related symptoms as these are dependent on intact ovarian function. Therefore, the true incidence of prolactin (PRL)-secreting adenomas in postmenopausal woman is unknown. Our study objective was to characterize these rare and unique pituitary tumors. A retrospective study including a consecutive group of postmenopausal women followed and treated at 3 Endocrine academic clinics. Baseline clinical characteristics (PRL and gonadotropins levels, other pituitary hormones, adenoma size and invasiveness, visual fields) and response to treatment are reported. The cohort included 14 postmenopausal women with prolactinomas (mean age at diagnosis, 63.6 ± 7.1 years; range, 54–75 years). Mean adenoma size at presentation was 25.6 ± 12.4 mm (range, 8–50 mm). Six out of the 14 women had significant visual fields damage. Mean baseline PRL level was 1,783 ng/ml, and median PRL was 827 ng/ml (range, 85–6,732 ng/ml). Medical treatment with cabergoline was given to twelve of the patients. Cabergoline normalized/near-normalized PRL in eleven women; one woman was dopamine agonist-resistant. Five of the six subjects with visual disturbances normalized or improved their vision, and a pre-treatment diplopia in another patient disappeared. Two large pituitary tumors disappeared on MRI following long-term dopamine agonist therapy. All other treated prolactinomas, except the resistant adenoma, shrank following medical treatment. Prolactinomas are rarely diagnosed in postmenopausal women. These women usually harbor large and invasive macroadenomas, secreting high PRL levels, and usually respond to dopamine agonist treatment.
Abstract
Context
Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in ...the treatment of acromegaly.
Objective
To develop a prediction model of therapeutic response of acromegaly to fg-SRL.
Methods
Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP).
Results
A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%.
Conclusion
We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.
Abstract
Context
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.
Objective
We explored the role of these markers in somatotropinomas.
Methods
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.
Results
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.
Conclusion
This study suggests that low survivin expression is predictive of resistance to fg-SRL in somatotropinomas, but not of tumor invasiveness.
ObjectivesPatients with acromegaly usually harbor macroadenomas measuring between 10 and 30 mm in maximal diameter. Giant (adenoma size ≥40 mm) GH-secreting pituitary tumors are rarely encountered ...and the aim of this study is to analyze different methods for managing them.Design and methodsWe have identified 34 patients (15 men and 19 females) with giant adenomas among 762 subjects (4.5%) with acromegaly in our records, and characterized their clinical characteristics and response to treatment.ResultsMean age at diagnosis was 34.9±12.5 years (range, 16–67 years). Mean adenoma size was 49.4±9.4 mm (range, 40–80 mm); 30 adenomas showed cavernous sinus invasion and 32 had suprasellar extension. Twenty-nine (85%) patients had visual field defects. Mean baseline IGF1 was 3.4±1.8×ULN. All patients except one underwent pituitary surgery (one to three procedures), but none achieved hormonal remission following first surgery. Among the 28 subjects with visual disturbances, 14 recovered post-operatively and 13 improved. Treatment with somatostatin analogs was given to all patients after surgical failure. Six achieved remission, nine others were partially controlled (IGF1<1.5×ULN; 3/9 when combined with cabergoline), and 17 did not respond (two were lost). Nine patients were treated with pegvisomant, alone (n=4) or in combination with somatostatin analogs (n=5); five are in remission and two are partially controlled. Pasireotide-LAR achieved hormonal remission in one of the six patients. Currently, after a mean follow-up period of 8.9 years, 17 patients are in biochemical remission, eight are partially controlled, and seven are uncontrolled (two were lost to follow-up).ConclusionsGiant GH-secreting adenomas are invasive, uncontrolled by surgery, and respond poorly to medical treatment. Aggressive multimodal therapy is critical for their management, enhancing control rate and biochemical remission.
Prolactinomas are the most common cause of pathological hyperprolactinemia, leading to central hypogonadism and, therefore, a frequent etiology of infertility. Treatment, usually with dopamine ...agonist (DA), can reverse hyperprolactinemia and hypogonadism, allowing pregnancy in the majority of cases. Bromocriptine is still the DA of choice for such purpose. Important issues in DA-induced pregnancies include fetal exposition, both malformations and neuropsychological development and tumor size increase. Regarding microprolactinomas and intrasellar macroprolactinomas, DA should be withdrawn as soon as pregnancy is confirmed. In expansive/invasive macroprolactinomas, DA maintenance should be individualized. Patient follow-up includes periodically clinical evaluation, sellar imaging only indicated in the presence of tumor mass effects related symptoms. Neurosurgery, both before and during gestation, is indicated in cases in which DA treatment failed. Breastfeeding is usually allowed. As tumor volume decrease and remission of hyperprolactinemia may occur after pregnancy, serum prolactin levels and tumor status should be reevaluated.
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