Presentación atípica de un prolactinoma gigante en un adolescente de 15 años / Atypical presentation of a giant prolactinoma in a 15-year-old boy

El prolactinoma gigante es un adenoma pituitario poco frecuente caracterizado por su gran invasión local. Se reporta el caso de un varón de 15 años de edad con dolor retroocular izquierdo y exoftalmos ipsilateral de 4 meses de evolución secundario a un tumor en la base del cráneo que invadía la órbita. Los estudios hormonales revelaron prolactina sérica de 6913,7 ng/ml (valor normal < 20), que confirmó el diagnóstico de prolactinoma gigante. El paciente inició un tratamiento con el agonista dopaminérgico cabergolina en dosis crecientes. Luego de 7 meses de seguimiento, la prolactina había descendido a 349,8 ng/ml y el volumen del tumor se redujo un 70%, sin efectos adversos al tratamiento. El paciente se encontraba asintomático y había reiniciado la pubertad. La rápida remisión de los síntomas sin necesidad de tratamientos invasores subraya la importancia de considerar el diagnóstico de prolactinoma entre los posibles diagnósticos diferenciales de tumor de la base del cráneo.

Giant prolactinomas are rare pituitary adenomas characterized by their great local invasion. In this paper, we report a 15-year-old male with left retro-ocular pain and ipsilateral exophthalmos of 4 months of evolution, secondary to a tumour in the base of the skull that invaded the orbit. Hormonal studies revealed serum prolactin of 6913,7 ng/ml (normal value < 20), confirming the diagnosis of giant prolactinoma. The patient started treatment with the dopaminergic agonist cabergoline in increasing doses. After 7 months of follow-up the prolactin had decreased to 349.8 ng/ml and the tumor volume was reduced by 70%, without presenting adverse effects to the treatment. The patient was asymptomatic and had restarted puberty. The rapid remission of symptoms without the need for invasive treatments underlines the importance of considering the diagnosis of prolactinoma among the possible differential diagnoses of tumor of the skull base.

Polimorfismos del receptor D2 / D2 receptor polymorphisms

Los prolactinomas son tumores bien diferenciados que se originan en las células lactotropas pituitarias, una línea celular que secreta fisiológicamente prolactina (PRL). A nivel hipofisario, la dopamina está implicada en la regulación de la secreción de PRL por las células lactotropas y este efecto inhibitorio está mediado por la activación del receptor de prolactina tipo 2 (DRD2). Hay varios polimorfismos del DRD2, el primero y más estudiado es TaqI A1; está demostrado que este alelo se encuentra asociado a una reducción de la actividad cerebral dopaminérgica, además de observarse una reducción en su capacidad de unión de aproximadamente un 30%. Este alelo se ha vinculado con una menor densidad de DRD2 en el cuerpo estriado, especialmente en el putamen y caudado ventral, y la cantidad de DRD2 en portadores del alelo A1 fue un 30-40% más bajo que en los no portadores (es decir, TaqI A2 homocigotos). En la literatura, hay evidencia que apoya la posible participación de los polimorfismos DRD2 en la regulación de la secreción hormonal.

Prolactinomas are well differentiated tumours that originate in the pituitary lactotrope cells, a cell line that physiologically secretes prolactin (PRL). At pituitary level, dopamine is involved in the regulation of PRL secretion by lactotropes, and this inhibitory effect is mediated by activation of prolactin type 2 receptor (DRD2). Of the several DRD2 polymorphisms, the first and most studied is TaqI A1. It has been demonstrated that this allele is associated with a reduced dopaminergic brain activity, and a reduction in its binding capacity of approximately 30% also being observed. This allele was associated with a lower density of DRD2 in the striatum, especially in the putamen and ventral caudate. The amount of DRD2 in A1 allele carriers was 30 - 40% lower than in non-carriers (this is, TaqI A2 Homozygotes). There is evidence in the literature, that supports the possible involvement of DRD2 polymorphisms in the regulation of hormonal secretion.

Prolactinomas may have unusual presentations resulting from massive extrasellar tumor extension / Prolactinomas podem ter apresentações incomuns resultantes de maciça extensão tumoral extrasselar

ABSTRACT The purpose of this case series is to report eight patients with giant prolactinomas emphasizing presentations and a treatment complication. The study group included six men and two women. The median age was 29 years (18–54 years); median serum prolactin level was 4,562 ng/ml (1,543–18,690 ng/ml); three patients (37.5%) had panhypopituitarism; median tumor diameter was 50 mm (41–60 mm). Five patients (62.5%) had visual field defects and three had improvement during treatment; six patients (75%) reached prolactin normalization, with a median time of 10.5 months (7–84 months) and median dose of 2.0 mg/week (1.0 to 3.0 mg/week). One patient presented as a true incidentaloma. One patient presented a cerebrospinal fluid leakage during medical treatment and refused surgery, however this resolved with conservative measures. This case series illustrate a rare subtype of macroprolactinomas, the importance of considering unusual presentations at the diagnosis, the effectiveness of pharmacological treatment and its possible complications.

RESUMO O objetivo desta série de casos é relatar oito pacientes com prolactinomas gigantes enfatizando as formas de apresentação e uma complicação do tratamento. O estudo incluiu seis homens e duas mulheres. A mediana de idade foi 29 anos (18–54); e dos níveis de prolactina foi 4.562 ng/ml (1.543–18.690); três pacientes (37,5%) apresentaram pan-hipopituitarismo; a mediana do máximo diâmetro tumoral foi 50 mm (41–60 mm). Cinco pacientes (62,5%) apresentaram alterações no campo visual e três tiveram melhora durante o tratamento; seis pacientes (75%) alcançaram normalização da prolactina em 10,5 meses (7–84) com dose mediana de cabergolina de 2,0 mg / semana (1,0 a 3,0). Um paciente se apresentou como um verdadeiro incidentaloma. Um paciente apresentou uma fistula liquórica durante o tratamento medicamentoso e recusou correção cirúrgica. No entanto a fistula foi resolvida com medidas conservadoras. Esta série de casos ilustra um subtipo raro de macroprolactinomas, a importância de considerar apresentações incomuns no diagnóstico, a eficácia do tratamento farmacológico e suas possíveis complicações.

Prolactinomas: evolution after menopause

ABSTRACT Objetive The aim was to assess the evolution of tumor size and prolactin (PRL) levels in patients with micro and macroprolactinomas diagnosed and treated with dopamine agonists during fertile age, and the effects of suspension of drugs after menopause. Retrospective study, 29 patients with prolactinomas, 22 microadenomas and 7 macroadenomas, diagnosed during their fertile age were studied in their menopause; treatment was stopped in this period. Age at menopause was 49 ± 3.6 years. The average time of treatment was 135 ± 79 months. The time of follow-up after treatment suspension was 4 to 192 months. Results Pre-treatment PRL levels in micro and macroadenomas were 119 ± 57 ng/mL and 258 ± 225 ng/mL, respectively. During menopause after treatment suspension, and at the latest follow-up: in microadenomas PRL levels were 23 ± 13 ng/mL and 16 ± 5.7 ng/mL, respectively; in macroadenomas, PRL levels were 20 ± 6.6 ng/mL 5t5and 25 ± 18 ng/mL, respectively. In menopause after treatment suspension, the microadenomas had disappeared in 9/22 and had decreased in 13/22. In the group of patients whose tumor had decreased, in the latest follow-up, tumors disappeared in 7/13 and remained unchanged in 6/13. In macroadenomas, after treatment suspension 3/7 had disappeared, 3/7 decreased and 1/7 remained unchanged. In the latest control in the 3 patients whose tumor decreased, disappeared in 1/3, decreased in 1/3 and there was no change in the remaining. Conclusions Normal PRL levels and sustained reduction or disappearance of adenomas were achieved in most of patients, probably due to the decrease of estrogen levels. Dopamine agonists might be stopped after menopause in patients with prolactinomas.

Recovery pattern of hypothalamo-pituitary-testicular axis in patients with macroprolactinomas after treatment with cabergoline.

Background & objectives: Hyperprolactinaemia affects testicular functions by influencing hypothalamo-pituitary-testicular (HPT) axis at various levels. Available literature on the level of defect, time course of improvement of gonadal functions and its relation with decline in prolactin levels is scanty. We carried out this study to evaluate the HPT axis in patients with macroprolactinomas, before and six months after cabergoline therapy. Methods: Fifteen men with macroprolactinomas underwent gonadotropin and testosterone response to their respective stimuli before and after six months of cabergoline therapy. Results: Serum prolactin levels decreased after six months of therapy. Pretreatment, mean lutenizing and follicle stimulating hormones (LH and FSH) levels were 2.0 ± 0.4 and 1.4 ± 0.2 IU/l, respectively. However, LH and FSH responses to GnRH were preserved in majority of the patients and LH peaked to 12.1 ± 2.3 IU/l (P<0.01), while FSH to 2.9 ± 0.4 IU/l suggesting the influence of hyperprolactinaemia at the level of hypothalamus with preserved gonadotrope reserve. After cabergoline therapy, there was an increase in basal as well as stimulated LH and FSH levels, though these were not statistically significant when compared to respective pretherapy levels. Basal testosterone (T) levels significantly improved after therapy, but peak T response to hCG was similar at both pre- and post treatment. A significant correlation was observed between peak LH and peak T at baseline (r=0.53, P<0.01) and it further strengthened after therapy (r=0.70, P<0.01). After cabergoline therapy, there was significant improvement in seminal volume, sperm count and motility and sperm count correlated with peak FSH response (r=0.53, P<0.05). Interpretation & conclusions: Hyperprolactinaemia affects testicular functions probably by influencing at the level of hypothalamus resulting in subnormal basal secretion of gonadotropins required for optimal testicular functions.

Aggressive prolactinoma in a child related to germline mutation in the ARYL hydrocarbon receptor interacting protein (AIP) gene / Prolactinoma agressivo na infância relacionado à mutação no gene da proteína Aryl hidrocarbono (AIP)

The objective of this study was to describe a familial screening for AIP mutations in the context of aggressive prolactinoma in childhood. A 12-year-old boy, presented headaches and bilateral hemianopsia. He had adequate height and weight for his age (50th percentile), Tanner stage G1 P1. His bone age was 10 years. Prolactin was 10.560 ng/mL (3-25), FSH and LH were undetectable, IGF-1, TSH, Free T4, ACTH, and cortisol were within normal ranges. MRI showed a pituitary macroadenoma, 5.3 X 4.0 X 3.5 cm with compression of the optic chiasm, bilateral cavernous sinus invasion, encasement of carotids, and extension to clivus. Surgical debulking was performed. Resistance to cabergoline was characterized and he was submitted to two surgeries and radiotherapy. Immunohistochemical evaluation included prolactin, ACTH, GH, FSH, LH,AIP, c-erb B2, Ki-67, and p53. Genomic DNA was isolated from the index case and 48 relatives, PCR and sequencing were performed.A germline A195V mutation in AIP was identified in the index case and in five asymptomatic relatives. Germline mutations in the AIP gene may be involved in the predisposition to pituitary adenoma formation, as cause or co-factor in pathogenesis of aggressive tumors in young patients.

O objetivo deste estudo foi descrever o rastreamento familiar para mutações AIP em paciente portador de prolactinoma agressivo e resistente na infância. Um menino de 12 anos foi avaliado com queixa de cefaleia e hemianopsia bitemporal. Apresentava peso e altura adequados para a idade (percentil 50), estádio puberal Tanner G1 P1 e idade óssea de 10 anos. Prolactina 10.560 ng/mL (3-25), FSH e LH indetectáveis, IGF-1, TSH, T4 livre, ACTH, e cortisol normais. A ressonância magnética de sela evidenciou macroadenoma hipofisário, 53 X 40 X 35 mm com compressão de quiasma ótico, invasão de seios cavernosos, envolvimento de carótidas internas e extensão para o clivus. Foi realizada descompressão cirúrgica por via transesfenoidal e caracterizada resistência a doses máximas de cabergolina, sendo o paciente operado por mais duas vezes e submetido à radioterapia. Realizou-se imuno-histoquímica para prolactina, ACTH, GH, FSH, LH, AIP, c-erb B2, Ki-67 e p53. O DNA genômico foi extraído do caso índice e de 48 familiares, e PCR e sequenciamento. Uma mutação A195V na AIP foi detectada no paciente e em cinco parentes assintomáticos. As mutações no gene da AIP podem estar envolvidas na predisposição à formação de adenomas, como causa ou cofator na patogênese de tumores agressivos em jovens.

Prolactinoma gigante de inicio en la adolescencia: a propósito de 2 casos clínicos / Report of two adolecents with giant prolactinomas

The prevalence of pituitary among adolescents is 0.1 per million and the most common type is prolactinoma. We report two adolescents with pituitary adenomas. A 15 years old female presenting with a progressive reduction of visual acuity, headache and galactorrhea. Magnetic resonanceshowed a sellar tumor with suprasellar expansion. She was subjected to transcraneal surgery and the pathological study of the piece disclosed a prolactinoma. A 23 years old male presenting with weight gain, headache and decreased visual acuity of the left eye. Magnetic resonance demonstrateda tumor with sellar and suprasellar involvement. He was subjected to transsphenoidal surgery and the pathological study of the surgical piece disclosed a prolactinoma.

Expression of p53, Ki-67 and c-erb B2 in growth hormone-and/or prolactin-secreting pituitary adenomas

Os eventos subcelulares implicados na formação e comportamento dos adenomas hipofisários não são completamente compreendidos. Neste estudo nós investigamos a presença de p53, Ki-67 e c-erb B2 em 38 adenomas hipofisários com positividade imuno-histoquímica para GH e prolactina (n=26, 68,4%), para prolactina (n=9, 23,7%) e para GH (n=3, 7,8%). A análise revelou os seguintes resultados: 24 tumores (63,2%) expressaram positividade variável para c-erb B2, 11 (28,9%) expressaram positividade para p53 e 11 tumores (28,9%) foram variavelmente positivos para Ki-67. Nossos resultados demonstraram elevada percentagem de tumores secretores de GH/prolactina, prolactina e GH com positividade imuno-histoquímica para c-erb B2. Desde que este receptor de membrana está relacionado aos fatores de crescimento EGF e TGFa e ambos têm efeito definido no crescimento tumoral, nossos dados sugerem possível função para o c-erb B2 na evolução destes tumores.

Metastasising pituitary neuroendocrinal tumour with peptide secretion.

A 26-year-old male presented with prolactin-secreting invasive pituitary macroadenoma, which was partially excised with right pterional craniotomy. Post-operative computerized tomography revealed persistence of the tumour and hence he was started on oral bromocriptine therapy. His therapeutic compliance was poor. Seven years later he presented with further increase in size of the pituitary macroadenoma with hepatic and gastric metastasis. Upper gastrointestinal endoscopic biopsy of the metastatic lesions and immunohistochemical staining diagnosed it as a neuroendocrinal tumour with peptide secretion. He was initially treated with oral bromocriptine alone and later along with octreotide.

Aspectos clínicos e terapêuticos de prolactinomas em homens / Clinical and therapeutic aspects of prolactinoma in men

Em homens, macroprolactinomas predominam em relação aos microprolactinomas e têm maior invasividade que nas mulheres. O tratamento clínico é a primeira opção tanto em macro como em microadenomas, independente do sexo. Comparamos apresentação clínica, níveis de prolactina, invasividade neurorradiológica e resposta da prolactinemia em 42 homens com prolactinomas, 23 com terapia clínica (grupo 1) e 19 que também utilizaram tratamento cirúrgico e/ou radioterápico (grupo 2). Os dados obtidos foram submetidos a análise estatística utilizando-se os testes de qui-quadrado ou exato de Fisher para comparações de proporções. Para comparar médias foi aplicado o teste t de Student ou, na ausência de distribuição normal ou com número pequeno de eventos, o não paramétrico de Mann-Whitney. O nível de significância adotado foi de 5 por cento (p<0,05). Os grupos foram similares para idade (p=0,23), período entre primeiro sintoma e diagnóstico (p=0,82), níveis de prolactina pré tratamento (p=0,41) e proporção de macroadenomas invasivos (p=0,096). Ocorreu percentual significativamente maior de cefaléia (p=0,009), deficit visual (p=0,025), tempo de terapia (p=0,007) e período de acompanhamento (p=0,0005) no grupo 2. Variações dos níveis de prolactina antes e após terapia não apresentaram diferença significativa nos grupos (p=0,49), nem o percentual de normalização da prolactina após tratamento (p=0,20). Concluímos, enfatizando a importância do diagnóstico precoce do prolactinoma em homens, tendo em vista a morbidade demonstrada, e reforçamos a necessidade do uso do agonista dopaminérgico como opção terapêutica inicial independente do tamanho do adenoma