Macroprolactinomas in children and adolescents: factors associated with the response to treatment in 77 patients.

ORIGINAL

ARTICLE

Macroprolactinomas in Children and Adolescents: Factors Associated With the Response to Treatment in 77 Patients Sylvie Salenave, Deborah Ancelle, Thibaut Bahougne, Gérald Raverot, Peter Kamenicky´, Jérôme Bouligand, Anne Guiochon-Mantel, Agnès Linglart, Pierre-François Souchon, Marc Nicolino, Jacques Young, Françoise Borson-Chazot, Brigitte Delemer, and Philippe Chanson* Background: Pituitary adenomas are rare in children and adolescents. The response of macroprolactinomas to dopamine agonists (DA) in this age group has been less extensively studied than in adults. Objective: We retrospectively analyzed data on a large cohort of young patients with macroprolactinomas. Patients and Methods: Patients aged younger than 20 years at macroprolactinoma diagnosis and seen in three tertiary referral centers between 1983 and 2013 were studied by analyzing their clinical and genetic (AIP and MEN1) characteristics. Hormonal and tumoral responses to DA were analyzed, and the patients’ status at their last visit, after a mean (⫾SD) follow-up of 8.2 ⫾ 5.8 years, was assessed. Results: The cohort comprised 77 patients (26 males, 51 females). Mean age at diagnosis was 16.1 ⫾ 2.5 years (range, 4.5–20 y). In both sexes, the most frequent revealing symptom was a pubertal disorder (49%), followed by visual problems (24%) and growth retardation (24%). Basal prolactin (PRL) levels and maximal tumor diameter were significantly higher in boys than in girls (7168 ng/mL, 202– 40 168 vs 1433 ng/mL, 115–20 000, P ⫽ .002; and 33 ⫾ 14 mm, 15– 64 vs 19 ⫾ 9 mm; 10 –50, P ⬍ .001, respectively). PRL levels normalized in 74% of the patients treated with DA. A mutation of AIP or MEN1 was found in 14% of the patients. Factors associated with resistance to DA were young age, higher PRL levels, larger volume, and the presence of a MEN1 (but not an AIP) mutation. Conclusion: Macroprolactinomas are rare below the age of 20 years, mainly occurring in girls and during adolescence. Like adults, young patients are very sensitive to DA, which should therefore be considered the first-line treatment. DA resistance is associated with a higher PRL level and larger tumor size, both parameters being closely linked together. About 14% of these young patients have an AIP or MEN1 mutation, this latter being an independent predictor of DA resistance. (J Clin Endocrinol Metab 100: 1177–1186, 2015)

T

he prevalence of pituitary adenomas is much lower in childhood and adolescence than in adulthood (1). As in adults, most pituitary adenomas are prolactinomas, representing 50% of all pituitary adenomas in this age group (2–5). There are few studies of prolactinomas in children and adolescents (6 –13), and data on the effects of dopamine agonists (DA) and long-term patient outcome are scarce (8, 11).

The AIP gene has been implicated in pituitary tumorigenesis in families with pituitary adenomas, particularly those with somatotropinomas (14, 15). AIP mutations have also been detected in patients with apparently sporadic adenomas: we found that 2.2% of 433 patients in whom an adenoma was diagnosed in adulthood had AIP mutations; such mutations were more frequent in children (23%), particularly those with a GH- or mixed

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received September 28, 2014. Accepted December 17, 2014. First Published Online December 22, 2014

* Author Affiliations are shown at the bottom of the next page. Abbreviations: DA, dopamine agonist; MEN1, multiple endocrine neoplasia type 1 syndrome; PRL, prolactin.

doi: 10.1210/jc.2014-3670

J Clin Endocrinol Metab, March 2015, 100(3):1177–1186

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Macroprolactinomas in Children and Adolescents

GH-prolactin (PRL)-secreting macroadenoma and also, but more rarely, those with prolactinomas (16, 17). Apparently sporadic pituitary adenomas in young patients may also be one of the first manifestations of multiple endocrine neoplasia type 1 syndrome (MEN1) (18). Here we report clinical, therapeutic and genotypic data on a cohort of 77 children and adolescents with macroprolactinomas, collected over the past 30 years.

Patients and Methods Clinical and biochemical data The cohort comprised 77 patients in whom a macroprolactinoma was diagnosed before age 20 years in one of three French teaching hospitals (Hôpital Bicêtre in Hôpitaux Universitaires Paris-Sud, Centre Hospitalier Universitaire de Reims, and Centre Hospitalier Universitaire de Lyon) between 1983 and 2013 and who were followed up for an average (⫾SD) of 8.2 ⫾ 5.8 years. A macroprolactinoma was diagnosed when a macroadenoma (⬎10 mm maximal diameter on magnetic resonance imaging) was associated with an increased PRL level (⬎150 ␮g/L); the PRL level was below 150 ␮g/L in five patients, but the diagnosis was finally retained because the macroadenoma, which was cystic (patients 24, 32, and 54) or necrotic (patient 11), shrank during DA therapy (patients 11, 24, and 32) or because its lactotroph nature was confirmed by immunohistochemical analysis after surgery (patients 21 and 54). The following clinical data were extracted from the patients’ records: sex, age and body mass index, menstrual history (primary or secondary amenorrhea), presence of galactorrhea or gynecomastia in boys, age at puberty and pubertal delay (Tanner stage), growth retardation (⬎⫺2SD), and the presence of a mass effect with headache and/or visual problems at diagnosis. PRL levels and other pituitary functions were determined at diagnosis and regularly during follow-up, using commercial assays and procedures proper to each center. Corticotropic deficiency was defined by a 8:00 AM plasma cortisol level of less than 4 ␮g per 100 mL and normal or low plasma ACTH level or an abnormal response (plasma cortisol ⬍20 ␮g per 100 mL) to ACTH-stimulation or to insulin-tolerance tests; GH deficiency was defined by a serum IGF-1 less than ⫺2 SD or abnormal response to GH stimulation tests. Magnetic resonance imaging signs of tumor invasion included evidence of bone destruction and/or tumor extension within the sphenoid and/or the cavernous sinuses and/or brain. Hormonal resistance to DA was defined by the absence of control at DA doses up to 15 mg/d bromocriptine, 600 ␮g/d


quinagolide, or 3.5 mg/wk cabergoline taken for at least 3 months (19 –22). Serial pituitary images of all the patients were reviewed by a neuroradiologist and an endocrinologist. Tumor resistance was defined as a failure to normalize PRL levels and to reduce tumor volume by at least 50% (21, 22) after 6 months of DA therapy.

Genetic analysis Information on genetic or familial diagnoses was systematically sought from the patients’ files (MEN1, Carney complex, families with pituitary adenomas, or McCune-Albright syndrome) and more than two-thirds of the patients had a genetic analysis: the entire AIP coding region (exons 1– 6) and intronexon junctions were amplified and sequenced as reported (17). All these patients were also screened for large deletions or duplication of the AIP and MEN1 genes by multiplex ligationdependent probe amplification (17, 23). All the patients gave their informed consent for the study.

Statistical analysis Statistical analyses were carried out using SPSS statistical software, version 13.0 (SPSS Inc). Medians were compared using the nonparametric Kruskal-Wallis test and frequencies using the ␹2 test. The correlation study was performed by the linear regression analysis calculating the Pearson’s coefficient. The multiple regression analysis was performed among the variables correlated at the linear correlation. P values are given for these analyses. The significance was set at 5%.

Results Clinical, biochemical, and imaging characteristics at diagnosis (Table 1) Age at diagnosis Seventy-seven patients were included in the study (26 males and 51 females). The mean age at diagnosis was 16.1 ⫾ 2.5 years (range 4.5–20 y), and median age was 17 years (Figure 1). Eighteen patients (23%) were younger than 15 years old at diagnosis; only two patients (both boys) were diagnosed during childhood (10 y and 4 y). The mean age at diagnosis did not differ between boys (15.5 ⫾ 3.2 y; range 4.5–20 y) and girls (16.5 ⫾ 2 y; range 11–20 y) (P ⫽ .12; Figure 1). Signs and symptoms at diagnosis In both sexes the most frequent revealing symptom was a pubertal disorder (49% of cases), followed by visual problems (24%) and growth retardation (24%).

Service d’Endocrinologie et des Maladies de la Reproduction and Centre de Référence des Maladies Endocriniennes Rares de la Croissance (S.S., T.B., P.K., J.Y., P.C.), and Service de Génétique Moléculaire, Pharmacogénétique, et Hormonologie (J.B., A.G.-M.), and Service d’Endocrinologie Pédiatrique and Centre de Référence des Maladies Rares du Métabolisme Phospho-Calcique, (A.L.), Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin-Bicêtre, F-94275, France; Service d’Endocrinologie (D.A., B.D.) and Service de Pédiatrie (P.-F.S.), Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré, Reims, F-51092, France; Faculté de Médecine (G.R., M.N., F.B.-C.), Université de Lyon, Lyon 1, Lyon-Est, Lyon F-69372 France; Fédération d’Endocrinologie (G.R., F.B.-C.) and Service d’Endocrinologie Pédiatrique (M.N.), Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, F-69003, France; Institut National de la Santé et de la Recherche Médicale Unité 1028 (G.R.), Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5292, Lyon Neuroscience Research Center, Service de Neurooncology-Neuroinflammation, and INSERM Unité 1052 (F.B.-C.), Unité Mixte de Recherche Centre National de la Recherche Scientifique Unité 5286, Centre de Recherche en Cancérologie de Lyon, Equipe Tumeurs Endocrines, Lyon, F-69000, France; Unité Mixte de Recherche Scientifique Unité 693 (P.K., J.B., A.M., A.L., J.Y., P.C.), Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre F-94276, France; INSERM Unité 986 (A.L.) and INSERM Unité 693 (P.K., J.B., A.M., J.Y., P.C.), Le Kremlin-Bicêtre F-94276, France


doi: 10.1210/jc.2014-3670

Weight gain was one reason for seeking medical advice in 18 cases (23%). At diagnosis, 24 of the 52 patients with available information (46%) were overweight or obese. In girls, primary amenorrhea was the leading symptom in 22 of the 51 cases (43%) and was associated with growth retardation in six cases (12%); only three girls had no signs of puberty. Eight of the 22 amenorrheic patients had galactorrhea. Twenty-seven (53%) patients presented with secondary amenorrhea, associated with galactorrhea in 24 cases. One patient had oligomenorrhea and galactorrhea and another patient had regular but short menstrual cycles and galactorrhea. A mass effect with visual problems was also present at diagnosis in seven female patients (14%). In boys, the diagnosis was suggested by pubertal delay in 16 of the 26 cases (61%); seven boys had no signs of puberty and 13 had growth retardation. Gynecomastia and visual problems were found in five and seven cases, respectively. Isolated visual problems were the presenting symptom in five patients. Twelve (46%) of the 26 boys had visual disorders at diagnosis, and the youngest two boys were blind in one eye (patients 1 and 2). In four other patients, the main presenting symptom was headaches in one case, gynecomastia in two cases (associated with galactorrhea in one case), and isolated diminished libido in one case; the tumor was discovered fortuitously in one case. Eight patients (10%) had panhypopituitarism, nine (11%) had thyrotropic deficiency, and four (5%) had corticotropic deficiency. Prolactin levels The mean basal PRL level at diagnosis was 3278 ng/mL (115– 40 168). Basal PRL levels were significantly higher in boys (7168 ng/mL, 202– 40 168) than in girls (1433 ng/mL, 115–20 000) (P ⫽ .002, Figure 2). Age and PRL levels were significantly associated (r ⫽ 0.380, P ⫽ .001). Tumor characteristics The average maximal diameter of the adenoma was 24 ⫾ 13 mm (10 – 64 mm) (Figure 3). The macroadenoma was invasive, particularly into the cavernous sinus, in 29 of the 59 patients for whom this information was available (49%). The adenomas were significantly larger in boys (33 ⫾ 14 mm; range 15– 64 mm) than in girls (19 ⫾ 9 mm; range 10 –50 mm) (P ⬍ .001, Figure 3). The size of the tumor was not related to age at diagnosis. The adenomas were more frequently invasive in boys (14 of 20 documented cases, 70%) than in girls (15 of 39, 38%).


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Genetic analysis (Table 1) Respectively, 55 and 59 patients were analyzed for AIP and MEN1 mutations. Five patients (three girls and two boys) had an AIP mutation (9%), and three patients (two girls and one boy) (5%) had a MEN1 mutation. Each patient had a distinct mutation. None of the mutated patients were consanguineous. Effect of DA treatment on PRL levels One patient (patient 21) never received DAs because he was operated on immediately because of pituitary apoplexy associated with visual disorders. He was cured by surgery and had no recurrence of the hyperprolactinemia or the tumor. All the remaining 76 patients received DAs, either as first-line treatment or after surgery. Sixty-eight patients received DAs as first-line treatment. Cabergoline was prescribed in 58 cases, either immediately (n ⫽ 49) or after a trial of another DA (n ⫽ 9), whereas 10 patients received a DA other than cabergoline. The results of medical treatment could not be assessed in two patients (patients 44 and 63), who discontinued treatment very early because of intolerance or nonadherence. Nine patients received first-line surgery for visual disorders (n ⫽ 4, patients 16, 45, 47, and 62), personal preference (n ⫽ 1, patient 65), doubtful diagnosis (n ⫽ 1, patient 54), or other reasons (n ⫽ 3, patients 13, 49, and 69). These nine patients received DAs after surgery (cabergoline immediately in five cases and after another DA in four cases) because hyperprolactinemia either recurred (n ⫽ 2, patients 54 and 65) or persisted (n ⫽ 7). Overall, PRL levels normalized in 56 of the 76 patients treated with DA (74%) (Table 1). Twenty of the 76 patients (26%) were resistant to DAs as soon as the treatment was initiated: 16 of these patients received DA as first-line therapy and four after surgery. Eight of the 16 patients resistant to first-line DAs subsequently underwent surgery (patients 1, 7, 17, 27, 40, 43, 51, and 56). Surgical debulking normalized PRL levels without the need to resume DA therapy in one case (patient 27) and after DA resumption in two other cases, at a low dose in one patient (patient 43) and a high dose (3.5 mg/wk) in the second patient (patient 17). In two patients who were persistently DA resistant, PRL finally normalized after radiotherapy (patients 1 and 56), allowing cabergoline discontinuation. Irradiation failed to control the PRL level in another patient (patient 40). Among the resistant patients, two received replacement therapy for gonadotropic insufficiency (patients 40 and 51), one patient still has moderate hyperprolactinemia but has regular menstrual cycles (patient 7), and PRL levels


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Table 1. Clinical, Biochemical, Neuroradiological, Pharmacological, and Genetic Characteristics of a Cohort of 77 Patients Aged Less Than 20 y With Macroprolactinomas Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70

67 62 21 27 35 44 64 3 5 11 16 19 37 50 52 55 65 66 18 20 28 33 38 40 49 53 57 58 69 73 2 10 15 23 41 47 51 60 1 4 8 12 22 24 25 26 30 31 36 45 48 56 70 72 76 7 9 14 29 42 54 63 74 75 6 13 34 39 46 61

Gender

Age at Diagnosis, y

Signs and Symptoms at Diagnosis

Other Pituitary Hormone Deficiencies

Serum PRL Levels, ng/mL

Tumor Maximal Diameter, mm

M M F M F M F F F F F F F M M M M F F F M F F F F F M M F M F F F F F F M F F F F F F M M M M M F M F M F F M F F F M F M F F F F F F F F M

4.5 10 11 13 13 13 13 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 15 15 15 15 15 15 15 16 16 16 16 16 16 16 16 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 18 18 18 18 18 18 18 18 18 19 19 19 19 19 19

VFD, H, PGD VFD, H, PGD, GAL AI, H, PGD VFD, PGD, Gy AI, GAL, WG VFD, H AII AI, GAL AI, GAL, H AI, WG AI, GAL, WG AII, GAL AI, GAL, PGD, H VFD, H, PD Fortuitous H, VFD PGD, H VFD, AI, H, WG AI, PGD AI, H, PGD VFD, H AI AII, GAL AII, GAL, H, WG AII, GAL, H VFD, AI, GAL PD PGD, H GAL PGD, H, Gy, GAL AII, GAL, WG AII AII, GAL, WG AII, WG AI AII, GAL VFD, PGD, H, VFD, AII, GAL, H AI, GAL AII, GAL AII, GAL, H AI VFD, AII, GAL, WG H, WG VFD, PGD PGD, Gy VFD Gy, WG AII, GAL, H H, PD VFD, AI, H, PGD VFD, Gy, GAL AII, GAL, WG VFD, H, AI, PGD Gy, GAL VFD, AII, GAL AII, GAL AII, GAL PGD AI, GAL, H PGD, WG, Gy AII, GAL, WG AI, GAL, H, WG AII, GAL AII, GAL AII, GAL AII, GAL, WG AII, GAL, H AI VFD, H, Gy, PGD

TSH, ACTH, GH ACTH, TSH, GH None ACTH, TSH, GH None TSH, ACTH None None None TSH, ACTH None None None None None TSH, ACTH, GH GH None None None ACTH, TSH, GH None None None None None None None None TSH None None None None None None TSH, GH TSH GH TSH None ACTH None ACTH, TSH, GH ACTH, TSH, GH TSH, GH None None None TSH TSH None None none None ACTH, GH None None None None TSH, ACTH, GH None None None None None None None None TSH, GH

36 000 2500 528 9898 485 6200 151 447 885 761 130 270 2400 930 6659 40 168 2264 1340 280 20 000 6, 2a 343 769 115 448 5400 202 641 180 2946 358 140 480 300 510 238 1320 1160 1993 3030 598 430 ND 5300 33 000 1865 320 979 ND 4200 11 139 276 260 100 490 514 915 380 2020 880 4800 192 397 341 164 1160 397 3317 611 6860

39 40 22 45 14 40 19 (C) 13 13 25 15 27 ND 20 40 64 25 19 15 ND NA 19 12 16 (C) 10 32 12 16 15 19 17 12 (C) 22 15 14 15 42 25 28 32 16 22 ND 46 60 35 30 27 33 35 44 12 12 20 (C) 15 50 17 15 30 11 35 12 10 ND 13 14 ND 27 20 53 (Continued)


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Table 1.


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Cavernous Sinus Invasion

DA

Maximal Dose (CAB, mg/w, QUI, ␮g/d, and BRC, mg/d)

Hormonal Sensitivity to DA

Shrinkage, %

AIP Mutation

MEN1 Mutation

Follow-Up, y

⫹ ⫹ ND ⫹ 0 0 0 0 0 0 0 ⫹ ⫹ ND ND ⫹ ⫹ 0 0 ND NA ⫹ ND 0 ND 0 0 ND ND 0 0 0 ⫹ 0 ND ND ND ⫹ ⫹ ⫹ 0 0 0 ⫹ ⫹ ⫹ ⫹ ⫹ 0 ⫹ ⫹ 0 0 ND ND ⫹ 0 ⫹ ⫹ ND 0 0 ⫹ ND 0 ⫹ ⫹ 0 ND ⫹

BRC BRC CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB No treatment CAB CAB CAB CAB CAB CAB CAB BRC CAB CAB CAB BRC CAB CAB CAB QUI CAB CAB CAB CAB QUI CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB CAB QUI CAB CAB CAB CAB CAB CAB

25 15 0.5 4.5 0.75 2.0 3.5 1.0 1.5 0.5 3.0 1.0 1.0 1.0 3.0 7.0 10.5 3.5 0.5 7.0 NA 2.0 3.0 1.0 0.5 7.0 9.0 3.5 15.0 1.5 0.5 0.5 2.5 0.5 1.0 0.5 300 0.5 3.5 3.5 0.5 75 4.5 3.0 1.5 2.5 8.0 2.5 3.5 3.5 7.0 0.5 0.5 0.5 1.0 4.0 3.5 2.0 2.0 1.0 3.5 1.0 3.0 75 1.0 0.5 7.0 1.0 1.0 1.0

R R S R S S R S S S S S S S S R R R S R NA S S S S R R S S S S S S S S S S S R R S S R Noncompliant S S R S R S R S S S S R R S S S R S Noncompliant S S S R S S S

⬍50% ⬍50% No remnant ⬎50% ⬎50% No remnant ⬍50% (C) No remnant ⬎50% 90% 75% 75% ⬎50% ⬎50% ⬎50% ⬍50% ⬍50% ⬎50% No remnant ⬎50 No remnant ⬎50% ⬍50% ⬍50% ⬎50% ⬍50% ⬍50% ⬎50% ⬎50% ⬎50% No remnant 75% 75% ⬎50% ⬎50% No remnant No remnant ⬎50% 75% 0% No remnant No remnant ⬍50% ⬎50% 75% 75% ⬎50% ⬍50% ⬍50% ⬍50% ⬎50% No remnant ⬎50% No remnant ⬎50% 0% ⬍50% ⬎50% ⬎50% No remnant ⬍50% ⬎50% ⬍50% ND No remnant 75% No remnant ⬎50% ⬎50% ⬎50%

Negative Positive Negative Negative Négative Negative ND Negative Negative Positive Negative Negative Negative Negative Negative Negative Negative ND Negative Negative Positive Negative ND Negative Negative Negative ND Negative ND Negative Negative ND ND Negative ND ND ND ND Negative Negative ND Negative Negative Negative Negative Negative Negative Positive Negative Negative Negative Negative Negative ND ND Negative Positive ND Negative ND Negative Negative ND ND Negative Negative Negative Negative ND Negative

Negative Negative Negative Negative Negative Negative ND Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative ND Negative Negative Negative Negative ND Negative Negative Positive Negative Negative ND Negative Negative ND Negative Negative ND ND ND Negative Negative Negative Negative Negative Negative Negative Negative Negative Positive Negative Negative Negative Negative Negative Negative ND ND Positive Negative Negative Negative ND Negative Negative ND ND Negative Negative Negative Negative ND Negative

16 14 3 8 1 7 7, LTF 9 10 3 9 12 27 7 11 2 16 8 13 3 6 3 6, LTF 4 6 12 17, LTF 8, LTF 8, LTF 5 3 6 4, LTF 1 15, LTF 4, LTF 11, LTF 4, LTF 3 5 6, LTF 9 3 12 5 9 15 1.5 27 13 5,5 18, LTF 6 5 1, LTF 4 1, LTF 13 8 13, LTF 9 10 6 13, LTF 9 14 11 3 16, LTF 4 (Continued)


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Table 1.


Continued

Patient Number 71 72 73 74 75 76 77


71 77 17 32 43 59 68

Gender

Age at Diagnosis, y

Signs and Symptoms at Diagnosis

Other Pituitary Hormone Deficiencies

Serum PRL Levels, ng/mL

Tumor Maximal Diameter, mm

F F F M M F F

19 19 20 20 20 20 20

AII, GAL AII, GAL O, GAL Decreased libido H, PGD AI, H AI, H, WG

None None None None GH None None

300 400 274 1200 3265 3400 2150

11 10 15 24 24 27 19

Abbreviations: AI, primary amenorrhea; AII, secondary amenorrhea; BRC, bromocriptine; C, cystic adenoma; CAB, cabergoline; F, female; GAL, galactorrhea; GY, gynecomastia; H, headache; LTF, lost to follow up after the duration indicated; M, male; NA, not applicable; ND, not determined; O, oligomenorrhea; PD, pubertal delay; PGD, pubertal and growth delay; QUI, quinagolide; VFD, visual field defect; WG, weight gain. a

Patient with apoplexy.

normalized in two patients after increasing the dose of cabergoline to 7 mg/wk (patients 26 and 67). Among the four patients who were resistant to DA after initial surgery, one received replacement therapy for gonadotropic insufficiency (patient 16), one patient had PRL normalization after increasing the dose of cabergoline to 8 mg/wk (patient 47), one patient underwent further surgery and resumed cabergoline postoperatively, leading to PRL normalization (patient 49), and one patient had PRL normalization after radiotherapy (patient 2), allowing cabergoline withdrawal. At last follow-up, nine patients had panhypopituitarism (but two of them had been irradiated), five patients had both gonadotropic and thyrotropic deficits, five patients had isolated persistent gonadotropic failure, and five patients had isolated thyrotropic failure. All four of the patients with isolated secondary adrenal failure recovered after DA treatment, allowing the discontinuation of hydrocortisone treatment. Impact of DA on tumor volume Fourteen of the 20 patients with hormonal resistance to DA (70%) also had tumoral DA resistance, whereas only four (patients 23, 24, 38, and 50; 8%) of the 54 patients

Figure 1. Age at diagnosis in a series of 77 young patients with macroprolactinomas.

whose PRL normalized on DA had no tumor shrinkage (patient 24 had a cystic adenoma). Overall, DA treatment achieved tumor shrinkage in 56 of 74 assessable patients (76%). Factors associated with hormonal resistance to DA (Table 2) Patients with DA-resistant adenomas were younger, had higher baseline PRL levels, and had larger tumors. Patients with MEN1 mutations were also more often resistant to DA. The presence of an AIP mutation did not influence the response to DA (Table 2). In a univariate analysis, MEN1 mutation (r ⫽ 0.348; P ⫽ .007), PRL levels (r ⫽ ⫺0.342; P ⫽ .003), and tumoral diameter (r ⫽ ⫺0.403; P ⫽ .001) were significantly correlated to DA resistance. In a multivariate analysis, the correlation between resistance to DA and the presence of a MEN1 mutation remains highly significant after adjusting for PRL levels and/or tumoral diameter (P ⬍ .005). After adjustment for the MEN1 mutation, the correlations between resistance to DA and PRL levels or tumoral diameter remain significant (P ⬍ .009). Regression analysis showed

Figure 2. Individual serum PRL levels at diagnosis in a series of 77 young patients with macroprolactinomas.


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Cavernous Sinus Invasion

DA

Maximal Dose (CAB, mg/w, QUI, ␮g/d, and BRC, mg/d)

Hormonal Sensitivity to DA

Shrinkage, %

AIP Mutation

MEN1 Mutation

Follow-Up, y

⫹ 0 0 0 ⫹ ND ⫹

QUI CAB CAB CAB CAB BRC CAB

75 1.0 0.5 2.0 2.0 15 1.5

S S S S S S S

⬎50% ⬎50% No remnant 75% ⬎50% ⬍50% ⬎50%

ND ND Negative Negative ND Negative Negative

ND ND ND Negative ND Negative Negative

4, LTF 2 8 3 2 25 6

that PRL levels and tumoral diameter were closely associated because significance disappeared when each variable was withdrawn from the model. By contrast, the presence of a MEN1 mutation was a significant and independent predictor of DA resistance (t ⫽ 3.052; P ⫽ .004). In eight patients resistant to DA who were operated on and in whom histological and immunocytochemical data were available, prolactinoma was invasive in six cases. In those patients, mitosis were rarely described except in two cases (patients 16 and 49) (up to four mitosis per field) and proliferation index, Ki67, positivity was present in greater than 3% of adenomatous cells (10%, 13%, 5%, 4%, and 3% in patients 40, 16, 56, 51, and 43, respectively); in the two other patients, there were no mitosis (patients 7 and 17), and Ki67 was 1%–2%. In the patients responsive to DA who were operated on, only three had available histological and immunocytochemical data: none of the tumors display mitosis and Ki67 was positive in 3% and less than 5% of cells in patients 65 and 54, respectively.

Figure 3. Maximal macroprolactinoma diameter at diagnosis in a series of 77 young patients.

Discussion In this retrospective study of a large cohort of patients aged younger than 20 years at macroprolactinoma diagnosis, we found that most patients were adolescent girls in whom amenorrhea led to diagnosis. The pituitary adenomas had an average maximal diameter of approximately 20 mm and were invasive in half the cases. Mass effects were relatively rare. DA therapy normalized PRL levels in threequarters of these young patients. An AIP or MEN1 mutation was found in 14% of cases. Resistance to DA was associated with baseline PRL level, tumor size (both parameters being closely linked together), and the presence of a MEN1 mutation. Pituitary adenomas are rare in children and adolescents; they are generally lactotrophic and are more frequent in girls than in boys. A compilation of various series involving 386 patients shows that, in this age group, prolactinomas are mainly observed in girls (79%) and that macroprolactinomas are more prevalent than microprolactinomas (58% vs 42%) (6 –13). In our experience at Bicêtre Hospital, of 52 patients (43F/9M), 23 (45%) had a microprolactinoma (20 females, three males), and 29 (55%) had a macroprolactinoma (23 females, six males) (S. Salenave, P. Chanson, unpublished results). This high proportion of macroprolactinomas is clearly very different from what is observed in adults (1, 24, 25) in whom microprolactinomas predominate. As previously reported (6 –13), most macroprolactinomas in this age group were diagnosed during adolescence (median 17 y) and only two patients were younger than 10 years old at diagnosis. Prolactinomas appear to develop around puberty, a phase associated with increased sex steroid secretion. It is conceivable that they develop earlier but are diagnosed only because of their effect on puberty (eg, amenorrhea). The impact on gonadotroph function is more likely due to hyperprolactinemia than to a mass effect on normal pituitary cells because growth perturbations were not as frequent as pubertal disorders (24% vs 49% in our series)


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Table 2. Comparison Between DA-Resistant and DA-Sensitive Children and Adolescents With Macroprolactinomas.

n

Males, %

Mean age, y

Mean PRL, ␮g/L

Maximal Diameter of Invasive Patients AIP Patients MEN1 the Adenoma Tumors, %a Mutated, %a Mutated, %a

DA-resistant 20 8/25 (32%) 15 ⫾ 1 7835 ⫾ 2835 33 ⫾ 2 adenomas DA-sensitive 56 12/51 (23%) 16.5 ⫾ 0.8 1858 ⫾ 598 21.5 ⫾ 1.5 adenomas P value NS .03 .002 .0006 a

11/19 (57%)

2/17 (11%)

3/18 (16%)

18/40 (45%)

2/37 (5%)

0/40 (0%)

NS

NS

.026

The number in each category may be lower due to lack of available data in some patients.

and panhypopituitarism was relatively rare (only eight patients). Our data on the pubertal and growth consequences of macroprolactinomas largely confirm previous reports (6 – 13). Growth impairment was more frequent in older publications (12, 26 –28), but this may be related to the definition (slowing of the growth rate, or true growth retardation to ⬍⫺2 SD or less than the third percentile). GH treatment is rarely necessary (only five of our patients received GH; data not shown) because DA therapy is generally sufficient to normalize GH deficiency and to restore growth (11, 28 –30). Weight gain represented one reason for seeking medical advice in 18 of our patients (23%, both sexes), and about half of our patients were overweight or obese at diagnosis, as is also reported in a study of similarly aged patients (11) and also in adults (31, 32). This is clearly a higher prevalence than that observed in the French general population within this age range (14.3% and 3.5% for overweight and obesity, respectively) according to a survey covering a similar period (33). The precise mechanisms of this weight gain remains speculative. It seems to be related to the high levels of PRL because it is also observed in patients with microprolactinomas, which have no hypopituitarism or hypothalamic involvement; moreover, at similar rate of hypopituitarism or hypothalamic involvement, patients with macroprolactinomas gained more weight than patients with nonfunctioning pituitary macroadenomas (32); this may also be a direct feedback regulatory effect of hyperprolactinemia on dopaminergic tone (34) or to the inhibitory effect of prolactin on adiponectin secretion by adipose tissue, which promotes insulin resistance (35). We found some differences between boys and girls with macroprolactinomas: in particular, the tumors seemed to affect puberty or growth more often in boys than in girls (61% vs 43% and 46% vs 14%, respectively). This cannot be explained by age at diagnosis, which was similar in the two genders, but is probably rather related to the size of the adenoma, which was larger in boys, as it is in male adults (11, 36); this would also explain the higher prevalence of

visual consequences in boys. It must be also pointed out that many of the youngest patients do not complain of visual disorders, which can delay the diagnosis (6 –13); this was the case of the two youngest boys in our series, who had unilateral blindness. A DA is the first-line treatment of choice for adults with macroprolactinomas (37). This was also the treatment chosen for 89% of our patients, only three of whom initially underwent surgery, for visual problems. The response to DA (cabergoline in 87% of cases) was good, with PRL normalization in more than three-quarters of cases during first-line treatment and half of the cases when started after surgery. Overall, PRL levels normalized in 73% of these young patients and tumor shrinkage was observed in 76% of cases. These results confirm that DA therapy is as effective at this young age as in adulthood (6 –13). We also show for the first time that, in this age range, DA-resistant patients tend to be younger males with larger adenomas, as in adults (19, 21, 38 – 40). Finally, it seems that DA-resistant prolactinomas are more often invasive, as in adults (19, 41), and display higher proliferation index. Because this was a retrospective study, we have no data on cardiac valve status in most of these 76 DA-treated patients. In this series of young patients with apparently sporadic macroprolactinomas, the prevalence of AIP mutations was relatively low (five patients, 9%) and close to that of MEN1 mutations (three patients, 5%). A genetic analysis was not possible for the entire cohort, owing to the retrospective design of the study: only 70% and 74% of patients were tested, respectively. The prevalence of AIP mutations was similar to that already published in this age range (42– 44), and our findings confirm that screening for MEN1 mutations is also important in children and adolescents (18, 42). AIP mutations are less frequent than in patients of the same age with pure GH- or mixed PRLGH-secreting adenomas (16 –18, 42– 44). AIP mutations did not seem to be associated with DA resistance in our patients, contrary to their reported effect on somatostatin analog efficacy in acromegaly (45, 46). MEN1 mutations, in contrast, may be associated with more aggressive and


doi: 10.1210/jc.2014-3670

more resistant macroprolactinomas (18, 21, 42, 47– 49). To confirm this relationship, it would be useful to study a higher number of MEN1-positive patients. The low prevalence of AIP and MEN1 mutations and the fact that each patient had a distinct mutation impair to perform any genotype/phenotype analysis, as already emphasized in the literature (18). Nevertheless, DA resistance was more frequent whereas PRL levels or tumor size appears to be similar in mutated (AIP or MEN1 as a whole) patients, compared with nonmutated patients (data not shown). In conclusion, macroprolactinomas are rare before the age of 20 years. They generally affect girls, occur during adolescence, and are very rare in young children. They are as sensitive to DA therapy as macroprolactinomas in adults, making this the first-choice treatment for this young population. As in adult patients, DA resistance is associated with higher PRL levels and larger tumors, the latter two parameters being linked, as expected with regard to adult patients with macroprolactinoma. AIP mutations are less frequent than in young patients with acromegaly or gigantism. MEN1 mutations are not rare in these patients and seem to be an independent predictor of DA resistance. More studies are needed before recommending routine MEN1 screening in young patients with isolated, nonfamilial macroprolactinomas.

Acknowledgments Address all correspondence and requests for reprints to: Philippe Chanson, MD, Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France, E-mail: [email protected]. Disclosure Summary: The authors have nothing to declare.

References 1. Raappana A, Koivukangas J, Ebeling T, Pirila T. Incidence of pituitary adenomas in Northern Finland in 1992–2007. J Clin Endocrinol Metab. 2010;95:4268 – 4275. 2. Kane LA, Leinung MC, Scheithauer BW, et al. Pituitary adenomas in childhood and adolescence. J Clin Endocrinol Metab. 1994;79: 1135–1140. 3. Kunwar S, Wilson CB. Pediatric pituitary adenomas. J Clin Endocrinol Metab. 1999;84:4385– 4389. 4. Mindermann T, Wilson CB. Pediatric pituitary adenomas. Neurosurgery. 1995;36:259 –268; discussion 269. 5. Partington MD, Davis DH, Laws ER Jr, Scheithauer BW. Pituitary adenomas in childhood and adolescence. Results of transsphenoidal surgery. J Neurosurg. 1994;80:209 –216. 6. Acharya SV, Gopal RA, Bandgar TR, Joshi SR, Menon PS, Shah NS. Clinical profile and long term follow up of children and adolescents with prolactinomas. Pituitary. 2009;12:186 –189. 7. Cannavo S, Venturino M, Curto L, et al. Clinical presentation and outcome of pituitary adenomas in teenagers. Clin Endocrinol (Oxf). 2003;58:519 –527.


1185

8. Colao A, Loche S, Cappa M, et al. Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up. J Clin Endocrinol Metab. 1998;83:2777–2780. 9. Eren E, Yapici S, Cakir ED, Ceylan LA, Saglam H, Tarim O. Clinical course of hyperprolactinemia in children and adolescents: a review of 21 cases. J Clin Res Pediatr Endocrinol. 2011;3:65– 69. 10. Fideleff HL, Boquete HR, Sequera A, Suarez M, Sobrado P, Giaccio A. Peripubertal prolactinomas: clinical presentation and long-term outcome with different therapeutic approaches. J Pediatr Endocrinol Metab. 2000;13:261–267. 11. Gillam MP, Molitch ME, Lombardi G, Colao A. Advances in the treatment of prolactinomas. Endocr Rev. 2006;27(5):485–534. 12. Howlett TA, Wass JA, Grossman A, et al. Prolactinomas presenting as primary amenorrhoea and delayed or arrested puberty: response to medical therapy. Clin Endocrinol (Oxf). 1989;30:131–140. 13. Steele CA, MacFarlane IA, Blair J, et al. Pituitary adenomas in childhood, adolescence and young adulthood: presentation, management, endocrine and metabolic outcomes. Eur J Endocrinol. 2010; 163:515–522. 14. Vierimaa O, Georgitsi M, Lehtonen R, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science. 2006;312:1228 –1230. 15. Daly AF, Vanbellinghen JF, Khoo SK, et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab. 2007;92:1891–1896. 16. Cazabat L, Bouligand J, Chanson P. AIP mutation in pituitary adenomas. N Engl J Med. 2011;364:1973–1974; author reply 1974 – 1975. 17. Cazabat L, Bouligand J, Salenave S, et al. Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. J Clin Endocrinol Metab. 2012;97:E663–E670. 18. Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P. Genetic mutations in sporadic pituitary adenomas-what to screen for? Nat Rev Endocrinol. 2015;11(1):43–54. 19. Delgrange E, Daems T, Verhelst J, Abs R, Maiter D. Characterization of resistance to the prolactin-lowering effects of cabergoline in macroprolactinomas: a study in 122 patients. Eur J Endocrinol. 2009;160:747–752. 20. Di Sarno A, Landi ML, Cappabianca P, et al. Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: prevalence, clinical definition, and therapeutic strategy. J Clin Endocrinol Metab. 2001;86:5256 –5261. 21. Vroonen L, Jaffrain-Rea ML, Petrossians P, et al. Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients. Eur J Endocrinol. 2012;167:651– 662. 22. Molitch ME. Pharmacologic resistance in prolactinoma patients. Pituitary. 2005;8:43–52. 23. Thevenon J, Bourredjem A, Faivre L, et al. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d’Etude des Tumeurs Endocrines (GTE) cohort study. Hum Mol Genet. 2013;22:1940 –1948. 24. Berinder K, Stackenas I, Akre O, Hirschberg AL, Hulting AL. Hyperprolactinaemia in 271 women: up to three decades of clinical follow-up. Clin Endocrinol (Oxf). 2005;63:450 – 455. 25. Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf). 2010;72:377–382. 26. Duntas LH. Prolactinomas in children and adolescents— consequences in adult life. J Pediatr Endocrinol Metab. 2001;14(suppl 5):1227–1232; discussion 1261–1222. 27. Oberfield SE, Nino M, Riddick L, et al. Combined bromocriptine and growth hormone (GH) treatment in GH-deficient children with macroprolactinoma in situ. J Clin Endocrinol Metab. 1992; 75:87–90. 28. Tyson D, Reggiardo D, Sklar C, David R. Prolactin-secreting mac-


1186

29.

30.

31.

32.

33.

34. 35.

36.

37.

38.

39.

Salenave et al


roadenomas in adolescents. Response to bromocriptine therapy. Am J Dis Child. 1993;147:1057–1061. Dalzell GW, Atkinson AB, Carson DJ, Sheridan B. Normal growth and pubertal development during bromocriptine treatment for a prolactinsecreting pituitary macroadenoma. Clin Endocrinol (Oxf). 1987;26: 169 –172. George LD, Nicolau N, Scanlon MF, Davies JS. Recovery of growth hormone secretion following cabergoline treatment of macroprolactinomas. Clin Endocrinol (Oxf). 2000;53:595–599. Creemers LB, Zelissen PM, van’t Verlaat JW, Koppeschaar HP. Prolactinoma and body weight: a retrospective study. Acta Endocrinol (Copenh). 1991;125:392–396. Greenman Y, Tordjman K, Stern N. Increased body weight associated with prolactin secreting pituitary adenomas: weight loss with normalization of prolactin levels. Clin Endocrinol (Oxf). 1998;48: 547–553. Peneau S, Salanave B, Maillard-Teyssier L, et al. Prevalence of overweight in 6- to 15-year-old children in central/western France from 1996 to 2006: trends toward stabilization. Int J Obes (Lond). 2009; 33:401– 407. Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22:724 –763. Nilsson L, Binart N, Bohlooly YM, et al. Prolactin and growth hormone regulate adiponectin secretion and receptor expression in adipose tissue. Biochem Biophys Res Commun. 2005;331:1120 – 1126. Delgrange E, Trouillas J, Maiter D, Donckier J, Tourniaire J. Sexrelated difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab. 1997;82: 2102–2107. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:273–288. Calle-Rodrigue RD, Giannini C, Scheithauer BW, et al. Prolactinomas in male and female patients: a comparative clinicopathologic study. Mayo Clin Proc. 1998;73:1046 –1052. Colao A, Vitale G, Cappabianca P, et al. Outcome of cabergoline treatment in men with prolactinoma: effects of a 24-month treat-

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.


ment on prolactin levels, tumor mass, recovery of pituitary function, and semen analysis. J Clin Endocrinol Metab. 2004;89:1704 –1711. Verhelst J, Abs R, Maiter D, et al. Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab. 1999;84:2518 –2522. Delgrange E, Duprez T, Maiter D. Influence of parasellar extension of macroprolactinomas defined by magnetic resonance imaging on their responsiveness to dopamine agonist therapy. Clin Endocrinol (Oxf). 2006;64:456 – 462. Cuny T, Pertuit M, Sahnoun-Fathallah M, et al. Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don’t forget MEN1 genetic analysis. Eur J Endocrinol. 2013;168: 533–541. Georgitsi M, De Menis E, Cannavo S, et al. Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas. Clin Endocrinol (Oxf). 2008;69:621– 627. Tichomirowa MA, Barlier A, Daly AF, et al. High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol. 2011;165: 509 –515. Daly AF, Tichomirowa MA, Petrossians P, et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab. 2010;95:E373–E383. Gadelha MR, Kasuki L, Korbonits M. Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol Metab. 2013;24:238 –246. Verges B, Boureille F, Goudet P, et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab. 2002;87:457– 465. Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol. 2008;32:534 –543. Naves LA, Jaffrain-Rea ML, Vencio SA, et al. Aggressive prolactinoma in a child related to germline mutation in the ARYL hydrocarbon receptor interacting protein (AIP) gene. Arq Bras Endocrinol Metab. 2010;54:761–767.


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