Adenomas no funcionantes: análisis retrospectivo de 202 pacientes / Non-functional adenomas: retrospective analysis of 202 patients

RESUMEN Los pacientes con adenomas hipofisarios constituyen una población heterogénea y requieren un enfoque individualizado. El objetivo de nuestro trabajo fue analizar nuestra población con adenomas hipofisarios no funcionantes (ACNF) y evaluar factores pronóstico de crecimiento (como el Ki-67) que ayuden en la toma de decisiones. Se realizó un análisis retrospectivo de 202 pacientes, incluyendo evaluación basal, enfoque terapéutico y evolución tumoral en 2 grupos: pacientes con conducta expectante (n = 69) y pacientes con cirugía (n = 133). La serie tuvo 55% de pacientes mujeres y la edad media al diagnóstico fue de 49 años. Los motivos de consulta más frecuentes fueron incidentaloma hipofisario y alteraciones visuales. Radiológicamente, 83% fueron macroadenomas, 77% invasivos y 55% mostraron compromiso visual. Entre los adenomas invasores, el 53% tenían disfunción hipofisaria, siendo el hipogonadismo el hallazgo más frecuente. El tratamiento inicial fue la cirugía en el 65,8% realizándose por vía transnasal en el 79% de los casos. Las complicaciones más frecuentes fueron diabetes insípida transitoria e hiponatremia, con mayor incidencia de diabetes insípida permanente en la cirugía transcraneal. La inmunohistoquímica mostró gonatropinomas en el 43,4% de los casos y fue negativa en el 37,7%. Doce adenomas tuvieron índice de proliferación Ki-67 ≥3%. Luego de la cirugía 56,8% de los pacientes mejoraron el campo visual, 22,6% recuperó alguna función endocrina y 18,8% agregó un nuevo déficit. En pacientes no operados, se observó crecimiento tumoral en 5,6% de los adenomas Hardy 1-2 y en el 21% de los Hardy 3-4. Entre los adenomas operados, aquellos sin resto tumoral postoperatorio no presentaron recurrencia. De los tumores con remanente postoperatorio (78,6%) no irradiados, el 41,5% mostró recrecimiento lesional al seguimiento. Este porcentaje se eleva a 66,6% en aquellos con Ki-67 ≥3% y disminuye a 12% en los que recibieron radioterapia.

ABSTRACT Patients with pituitary adenomas are a heterogeneous population and require an individualized approach. The aim of our study was to analyze our population of patients with nonfunctioning pituitary adenomas (NFA) and to evaluate prognostic growth factors (such as Ki-67) that help in decision making. A retrospective analysis of 202 patients, including baseline assessment, therapeutic approach and tumor evolution was performed in 2 groups: expectant management (n = 69) and surgery (n = 133). The mean age at diagnosis was 49 years, 55% women. The most frequent reasons for consultation were pituitary incidentaloma and visual impairment. Eighty three percent were macroadenomas, 77% invasive, and 55% with visual impairment. Among the invasive adenomas, 53% had pituitary dysfunction, with hypogonadism being the most frequent finding. The initial treatment was surgery in 65.8%, 79% of them through transnasal approach. The most frequent complications were transient diabetes insipidus and hyponatremia, with a higher incidence of permanent diabetes insipidus in transcranial surgery. The immunohistochemistry showed: 43.4% gonadotropinomas, 37.7% negative. Twelve adenomas had proliferation index Ki-67 ≥3%. After surgery, 56.8% improved the visual fields, 22.6% recovered some endocrine function and 18.8% added a new deficit. In non-operated patients, tumor growth was observed in 5.6% of the Hardy 1-2 adenomas and 21% of the Hardy 3-4 adenomas. Among the operated adenomas, those without postoperative tumor residue did not present recurrence. In tumors with non-irradiated postoperative remnant (78.6%), 41.5% increased. This percentage rises to 66.6% in those with Ki-67 ≥3%, and decreases to 12% in those who received radiotherapy.

Radioterapia como indicación post operatoria en macroadenomas hipofisiarios no funcionantes: a propósito de un caso / Surgical treatment of a non functioning pituitary macroadenoma without postoperative radiotherapy: report of one case

We report a 45 years old female that consulted for amenorrhea and galactorrhea after discontinuing oral contraceptives, that she used for several years. The patient had hyperprolactinemia, a hypogonadotrophic hypogonadism and a primary hypothyroidism. Sella turcica magnetic resonance showed a pituitary macroadenoma with a diameter of 23 mm and supraselar extension. The patient was subjected to a transsphenoidal excision of the tumor with good clinical and surgical results. Therefore radiotherapy was not used for the treatment of the tumor.

Avaliação do perfil e resposta ao tratamento de pacientes portadores de adenoma hipofisário submetidos a radioterapia / Clinical profile and response to treatment of patients with pituitary

OBJETIVO: Avaliar o perfil de pacientes portadores de adenoma hipofisário e a resposta à radioterapia externa. MATERIAL E MÉTODO: Foi realizado estudo retrospectivo com 22 pacientes portadores de adenoma hipofisário, os quais foram submetidos à radioterapia entre março de 2004 e dezembrode 2008. Foram analisadas características dos pacientes, como sexo, idade e quadro clínico, tipo de cirurgia, perfil imuno-histoquímico, dose de radioterapia, resposta à terapia com dosagens hormonais e exames de imagem. RESULTADOS: Observou-se idade mediana de 51 anos, com distribuição semelhante em ambos os sexos. De acordo com a classificação de Hardy para tumores hipofisários, 27,5% apresentavam grau II, 27,5% eram grau III e 45%, grau IV. O principal sintoma apresentado pelos pacientes na ocasião do diagnóstico foi deficiência visual em 77% dos casos, seguido de cefaleia em 68%, acromegalia em 27%, amenorreia em 18% e galactorreia em 4,5%. A abordagem cirúrgica por via transesfenoidal ocorreu em 21 pacientes e em somente um por viatranscraniana, sendo realizadas ressecções parciais em 91% dos casos. Quanto à imuno-histoquímica, a expressão de ACTH foi a mais frequente, estando presente em 41% dos casos. Os pacientes foram tratados em aparelhos de megavoltagem, em sua grande maioria com acelerador linear de 6 MV, com dose total de 45 Gy em 68% e dose de 50,4 Gy em 13% dos casos. O planejamento tridimensional foi utilizado em 20 pacientes. O seguimento mediano foi de 41 meses, sendo observado, no seguimento laboratorial e de imagem, melhora em 73% dos pacientes, estabilidade do quadro em 22,5% e piora em 4,5%. CONCLUSÃO: Os resultados encontrados mostram bons índices de resposta e controle dos tumores de hipófise após radioterapia adjuvante à cirurgia, e por ser uma doença de resposta lenta ao tratamento é grande a probabilidade de melhora ainda maior dos resultados a médio prazo.

OBJECTIVE: To evaluate the clinical profile of patients with pituitaryadenoma and their response to radiotherapy. MATERIAL AND METHOD: Retrospective study with 22 patients with diagnosis of pituitary adenoma which were submitted to radiotherapy between March 2004 and December 2008. Patients' characteristics such as gender, age, clinical presentation, surgical approach, immunohistochemistry profile, dose of radiation and the response to therapy were analyzed using hormonal dosages and imaging exams. RESULTS: The median age was 51 years and equally distributed in both genders. The tumors were divided according to the Hardy's classification: 27.5% had grade II, 27.5% had grade III and 45% had grade IV. The main symptoms presented by patients at diagnosis were visual impairment in 77% of cases, headache in68%, amenorrhea and acromegaly in 27% and galactorrhea in 4.5%. Transphenoidal surgery was performed in 21 patients and only 1 patient was submitted to transcranial approach; 91% of cases had partial resection. Concerning to immunohistochemistry, the expression of ACTH was the most frequent, being present in 41% of cases.The patients were treated in megavoltage equipment mostly with6 MV linear accelerator. The total radiation dose was 45 Gy in 68%of patients and a dose of 50.4 Gy in 13% of cases. Three-dimensionalplanning was used in 20 patients. The median follow-up was 41 months. Laboratory and imaging improvement were observed in 73% of patients, stability in 22.5%, and worsening in 4.5%. CONCLUSION: The results show good rates of response and control of pituitary adenomas by radiation in the first four years after treatment. Considering it has a slow response to treatment, there is a high chance of improvement in results later during the follow-up. Keywords: Radiotherapy; Pituitary; Adenoma.

Radiotherapy and radiosurgery for Cushing's disease

Patients with residual or recurrent Cushing's disease receive external beam radiotherapy (RT) with the aim of achieving long-term tumour control and normalization of elevated hormone levels. Treatment is given either as conventional radiotherapy using conformal techniques or as stereotactic radiotherapy, which is either used as fractionated treatment (SCRT) or as single fraction radiosurgery (SRS). We describe the technical aspects of treatment and report a systematic review of the published literature on the efficacy and toxicity of conventional RT, SCRT and SRS. There are no studies directly comparing the different radiation techniques and the reported results are inevitably of selected patients by investigators with interest in the treatment tested. Nevertheless the review of the published literature suggests better hormone and tumour control rates after fractionated irradiation compared to single fraction radiosurgery. Hypopituitarism represents the most commonly reported late complication of radiotherapy seen after all treatments. Although the incidence of other late effects is low, the risk of radiation injury to normal neural structures is higher with single fraction compared to fractionated treatment. Stereotactic techniques offer more localized irradiation compared with conventional radiotherapy, however longer follow-up is necessary to confirm the potential reduction of long-term radiation toxicity of fractionated SCRT compared to conventional RT. On the basis of the available literature, fractionated conventional and stereotactic radiotherapy offer effective treatment for Cushing's disease not controlled with surgery alone. The lower efficacy and higher toxicity of single fraction treatment suggest that SRS is not the appropriate therapy for the majority of patients with Cushing's disease.

Pacientes com doença de Cushing residual ou recorrente recebem radioterapia externa em feixe (RT) com o objetivo de alcançar um controle tumoral prolongado e a normalização dos níveis hormonais elevados. O tratamento é realizado tanto com RT convencional, usando técnicas conformacionais, ou com RT estereotáxica, que é usada tanto como tratamento fracionado (RTF) ou como radiocirurgia em procedimento único (RCU). Descreveremos os aspectos técnicos do tratamento e mostraremos uma revisão sistemática da literatura sobre a eficácia e toxicidade da RT convencional, da RTF e da RCU. Não existem estudos comparando diretamente as diferentes técnicas de radiação, e os resultados reportados são inevitavelmente os de pacientes selecionados pelos investigadores com interesse no tratamento testado. De qualquer maneira, a revisão dos dados publicados sugere que há melhores taxas de controle hormonal e tumoral após RTF em comparação com RCU. O hipopituitarismo representa a complicação tardia mais comumente relatada da RT, vista após todos os tipos de tratamento. Embora a incidência de outros efeitos tardios seja baixa, o risco de a radiação comprometer estruturas neurais normais é mais elevado com RCU do que com RTF. Técnicas estereotáxicas oferecem irradiação mais localizada se comparadas com a RT convencional, embora um acompanhamento prolongado seja necessário para confirmar a possível redução da toxicidade continuada da radiação na RTF em comparação com a RT convencional. Com base na literatura disponível, a RT fracionada convencional e a estereotáxica oferecem tratamento efetivo para a doença de Cushing não controlada isoladamente pela cirurgia. A baixa eficácia e alta toxicidade do tratamento em dose única sugere que a RCU não seja a terapia mais apropriada para a maioria dos pacientes com doença de Cushing.

Pregnancy in a patient with hypopituitarism following surgery and radiation for a pituitary adenoma.

This is a case of partial hypopituitarism resulting from surgery and radiation for a non- functioning pituitary macroadenoma. The patient had amenorrhea which was secondary to hypogonadotrophic hypogonadism and had been on L-thyroxine for central hypothyroidism. For pregnancy, ovulation was induced by gonadotrophins and this was followed by an intrauterine insemination. The antenatal period was uneventful and a Caesarean section was done at 33 weeks when the patient presented with preterm labour. Both infant and mother are well, eight months after delivery.