Tratamiento multimodal de los adenomas de hipófisis recidivantes clínicamente no funcionales. Reporte de caso y revisión de la literatura / Multimodal treatment of non-functional recidivant hypophyseal adenomas. A case report and literature review

Resumen Antecedentes: Los adenomas hipofisarios no funcionales generalmente tienen un comportamiento benigno y naturaleza no invasiva, sin embargo, pueden mostrar características de agresividad con invasión a tejidos circundantes, alto índice mitótico, un índice de Ki67 > 3%y positividad extensa para la tinción de p53, diferenciándose de los carcinomas hipofisarios por la ausencia de diseminación cerebroespinal o metástasis a distancia. Los adenomas agresivos muestran resistencia al tratamiento guirúrgico, médico y radioterapia, y los agentes guimioterapéuticos como temozolamida son una opción terapéutica prometedora de acuerdo con los reportes de la literatura médica internacional. Caso clínico: Paciente del sexo femenino en la sexta década de la vida con padecimiento caracterizado por síndrome guiasmático progresivo e hipopituitarismo ante la presencia de un macroadenoma hipofisario no funcional, con resistencia a tratamiento neuroguirúrgico inicial, tratamiento médico con un agonista dopaminérgico y análogo de receptor de la somatostatina así como radioterapia convencional fraccionada, y cumple con los criterios de agresividad. Se establece tratamiento guimioterapéutico a base de temozolamida, y durante su vigilancia muestra tanto estabilidad clínica como ausencia de progresión tumoral. Conclusiones: La determinación de agresividad es de crucial importancia para mejorar el tratamiento del paciente y, con ello, ofrecer un mejor pronóstico y efectividad terapéutica. El tratamiento de los adenomas hipofisarios no funcionales con características de agresividad es un reto clínico gue involucra un abordaje multidisciplinario. La resistencia al tratamiento quirúrgico, médico y radioterapéutico han dado lugar a la investigación de opciones terapéuticas con agentes quimioterapéuticos como la temozolamida, con tasas de respuesta prometedoras.

Abstract Background: Non-functional pituitary adenomas generally have a benign and non-invasive nature, however, it may show aggressiveness with invasion of surrounding tissues, high mitotic index, an index of Ki67> 3% and extensive positive staining for the cellular tumor antigen p53, differing from the pituitary carcinomas by the absence of craniospinal dissemination or systemic metastases. Aggressive adenomas show resistance to surgical, medical and radiation therapy, including chemotherapeutic agents such as temozolomide, a promising therapeutic option according to reports in the international literature. Case presentation: This is a woman in her 6th decade of life with a clinical presentation characterized by a progressive chiasm syndrome and hypopituitarism in the presence of non-functional pituitary macroadenoma, with initial resistance of neurosurgical treatment, medical treatment with a dopaminergic agonist plus a somatostatin receptor agonist and conventional fractionated radiotherapy, meeting the criteria of aggressive pituitary adenoma. After the treatment with temozolomide as a chemotherapy regimen, the patient showed clinical stability and absence of tumor progression during her follow-up. Conclusion: Defining aggressiveness is of crucial importance for improving the management of patients by enhancing prognostic predictions and effectiveness of treatment. The treatment of nonfunctioning pituitary adenomas with aggressiveness is a clinical challenge that involves a multidisciplinary approach. Resistance to surgical, medical and radiotherapeutic treatment have resulted in the investigation of therapeutic options with chemotherapeutic agents such as temozolomide, with promising response rates.

A review on the diagnosis and treatment of patients with clinically nonfunctioning pituitary adenoma by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism

ABSTRACT Clinically nonfunctioning pituitary adenomas (NFPA) are the most common pituitary tumors after prolactinomas. The absence of clinical symptoms of hormonal hypersecretion can contribute to the late diagnosis of the disease. Thus, the majority of patients seek medical attention for signs and symptoms resulting from mass effect, such as neuro-ophthalmologic symptoms and hypopituitarism. Other presentations include pituitary apoplexy or an incidental finding on imaging studies. Mass effect and hypopituitarism impose high morbidity and mortality. However, early diagnosis and effective treatment minimizes morbidity and mortality. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism is to provide a review of the diagnosis and treatment of patients with NFPA, emphasizing that the treatment should be performed in reference centers. This review is based on data published in the literature and the authors’ experience. Arch Endocrinol Metab. 2016;60(4):374-90.

Clomiphene fails to revert hypogonadism in most male patients with conventionally treated nonfunctioning pituitary adenomas / Clomifeno não reverte o hipogonadismo na maioria dos homens com adenomas pituitários não funcionais tratados de forma convencional

OBJETIVE: To evaluate the effect of clomiphene in men with hypogonadism and conventionally treated nonfunctioning pituitary adenomas (NFPA). PATIENTS AND METHODS: Open label, single-arm, prospective trial. Nine hypogonadal men (testosterone < 300 ng/dL and low/normal LH) with previously treated NFPA. Clomiphene (50 mg/day orally) for 12 weeks. Testosterone, estradiol, LH, FSH, prolactin and erectile function were evaluated before and after 10 days, 4, 8 and 12 weeks of clomiphene treatment. RESULTS: After clomiphene treatment, testosterone and erectile function improved in only one patient. In the remaining eight patients, testosterone levels decreased whereas LH, FSH, and estradiol remained unchanged. Insulin sensitivity increased in unresponsive patients. CONCLUSIONS: Compared with hypogonadal men with prolactinomas under dopaminergic therapy, clomiphene treatment failed to restore normal testosterone levels in most patients with conventionally treated NFPA.

OBJETIVO: Avaliar o efeito do clomifeno em homens com hipogonadismo e adenoma hipofisário não funcionante (NFPA) previamente tratados. PACIENTES E MÉTODOS: Aberto, braço único, prospectivo. Nove homens hipogonádicos (testosterona < 300 ng/dL e LH normal/baixo) com NFPA previamente tratados. Clomifeno (50 mg/dia oral) por 12 semanas. Testosterona, estradiol, LH, FSH, prolactina e função erétil foram avaliados antes e após 10 dias, 4, 8 e 12 semanas de clomifeno. RESULTADOS: Após clomifeno, a testosterona e a função erétil melhoraram em um paciente. Em outros oito pacientes, os níveis de testosterona reduziram enquanto os níveis de LH, FSH, e estradiol permaneceram inalterados. A sensibilidade à insulina aumentou nos não respondedores. CONCLUSÕES: Em contraste com homens hipogonádicos com prolactinomas tratados com agonistas dopaminérgicos, a maioria dos hipogonádicos com NFPA falha em restaurar os níveis de testosterona durante o uso de clomifeno.

Study on the Turnover and Treament of Postoperative Residues of Giant Nonfunctioning Pituitary Adenoma with Suprasellar Extension(SSE) / 中国肿瘤临床

Objective: To explore the turnover and treament of postoperative remainder of giant nonfunctioning pituitary adenoma with suprasellar extension(SSE). Methods: The clinical data of 68 cases suffering from giant nonfunctioning pituitary adenoma with suprasellar extension(SSE)admitted into our department were retrospectively analyzed.These patients underwent primary transsphenoidal surgery. Results: Twenty cases had SSE adenomas totally removed(20.6%).In other 48 cases(79.34%)，SSE residues were shown in MRI recheck at one day after surgery.After 3 months，the 3rd MRI scanning was performed only to find that tumor residues descended to sellar floor in 21 cases,into intrasella in 8 cases，and down to the level of stalk hypophysial and the entrance to the sella in 3 cases.All of Patients with residual tumors received retranssphenoidal resection(the total removal rate of desending SSE residues was 96.9%).There were 2 cases with adenoma residues with slight descending.Obvious SSE adenomas were treated with transtranial approach.The twelve cases with small SSE residues were consecutively observed and two of them received gamma knife treatment because of unobvious postoperative visual improvement.The surgical mortality was 0%.There was no death during follow up in all of these patients.There were no cases with rhinorrhea.meningitis or visual deterioration.Two patients had supradiaphragmatic bleeding detected by routine postoperative CT. Conclusion: Staged surgery with two or multiple transsphenoidal resections is an appropriate treatment for giant nonfunctioning pituitary adenoma with supresellar extension(SSE)，with few complications.Futher study is warranted to investigate the growth pattern of pituitary adenoma.

Endocrinological and Morphological Characteristics of Clinically Nonfunctioning Pituitary Adenoma / 대한내분비학회지

Forth-nine patients with clinically nonfunctioning pituitary adenomas were evaluated clinically, endocrinologically and morphologically in this study.The results obtained were as follows.1) The mean age was 47.1 years(range 23 to 76 years), and 22 were male(44.9%) and 27(55.1%) female.2) The major clinical manifestations of male patients were visual disturbance(72.7%), headache(54.5%), loss of libido(45.5%), but those of female visual disturbance(59.6%), headache(48.1%), amenorrhea(48.1%), loss of body hair(25.9%), and galactorrhea(22.2%).3) All were macroadenomas evaluated by CT scan, and in the male patients 16(72.7%) were grade III and 6(27.3%) grade IV by Hardy classification, and in the female patients 6(22.2%) were grade II, 12(44.4%) grade III, and 9(33.3%) grade IV.4) The elevation of serum prolactin were observed 7(31.8%) out of male, and 24(88.9%) of female.5) Combined stimulation test revealed that GH insufficiency was 89.6%, ACTH 58.9%, LH 58.7%, FSH 51.1 %, and TSH 50.0% and hormone insufficiency more than 4 pituitary hormone was 54.2%.6) Prolactin response to TRH decreased in 12(70.6%) of 17 patients with normal basal prolactin, and 19(76.0%) of 25 with elevated prolactin.7) Immunohistochemistry revealed that null cell adenoma was 57.1%, gonadotrope adenoma 26.5%, plurihormonal adenoma 8.0%, silent corticotrope adenoma 4.0%, thyrotrope adenoma(2.0%), and lactotrope adenoma(2.0%).8) The ultrastructural characteristics examined by electron-microscopy were similar despite of immunohistochemical differences.In summary, the prevalance of clinically nonfunctioning pituitary adenoma was middle aged men and women, and their main symptoms were visual disturbance and headache. Hyperprolactinemia and pituitary hormone insufficiency more than 4 hormone were observed commonly. Most of them were null cell adenoma and gonadotrope adenoma examined by immunohistochemistry. Further study using modern techniques: cell culture, subunit-immunostaining. And Northern blot analysis of mRNA for pituitary hormone or subunit, will be needed to clarify null cell adenomas.