Radiotherapy with concurrent temozolomide for the management of extraneural metastases in pituitary carcinoma

Background

Pituitary carcinomas (PC) are uncommon neuroendocrine tumors, accounting for 0.1 % of all pituitary tumors. The diagnosis of PC is based on the presence of metastases from a pituitary adenoma, and not by local invasion or pathological features alone. PC is typically resistant to therapy, with a median overall survival of only 31 months. There is no standard treatment for PC, but maximal safe resection and radiation are performed when possible. Encouraging preliminary data on the use of temozolomide (TMZ)-based therapy has been previously reported.

Methods

We report the response to therapy and safety of radiation with concurrent temozolomide (RT/TMZ) in 2 adult patients with heavily pretreated PC and extraneural metastases.

Results

Both patients had prior history of pituitary macroadenoma. At the time of diagnosis of PC, Ki-67 % was 24.2 and 10 %, with positive p53 staining in one case. Metastatic sites included lymph nodes, liver and bone. Case-1 received RT/TMZ to the tumor bed in the skull base and to the metastases in the cervical lymph nodes. Case-2 received RT/TMZ to recurrent tumor involving portacaval lymph nodes. Both patients achieved excellent long-term control of the sites of treated extraneural metastases, with no significant acute or delayed toxicity.

Conclusions

RT/TMZ was safely delivered and might provide sustained control of extraneural metastases in PC. Although this retrospective report has limitations, RT/TMZ can be considered as a therapeutic option for the management of extraneural metastases in PC.

     

Double pituitary adenomas are most commonly associated with GH- and ACTH-secreting tumors: systematic review of the literature

Introduction

Double adenomas in the pituitary gland are a rare occurrence. The ability to cure a hormone-producing adenoma with surgery is dependent on the ability to identify and completely remove the correct adenoma. The relative frequency of each subtype of hormone-secreting adenomas confirmed with magnetic resonance image (MRI), surgery and immunohistochemistry is not defined.

Methods

Following PRISMA guidelines, we performed a systematic review of PubMed Central, Google Scholar, Scopus Database, Cochrane database and Science Research, using the key-words: “double pituitary adenomas”, “multiple pituitary adenomas” and only papers where multiple or truly separate double pituitary adenomas were identified pre-surgically by MRI and/or confirmed by pathology/immunohistochemistry staining were included.

Results

We reviewed papers from 1975 to 2016 and found 17 cases with two pituitary adenomas and 1 with three pituitary adenomas. The ages ranged from 22 to 67 years old, and there were twelve females and five males. Immunohistochemical staining showed that the most common double pituitary adenomas were growth hormone (GH)- followed by adrenocorticotropic (ACTH)-secreting.

Conclusion

Double pituitary adenomas are rare but most commonly found with GH- or ACTH-producing tumors. It is critical to remove all identified possible adenomas to achieve biochemical cure and clinicians should have heightened sensitivity in patients with acromegaly or Cushing’s Disease.

     

Predictive role of dynamic contrast enhanced T1-weighted MR sequences in pre-surgical evaluation of macroadenomas consistency

Purpose

Our hypothesis was that pituitary macroadenomas show different areas of consistency detectable by enhanced magnetic resonance imaging (MRI) with Dynamic study during gadolinium administration.

Materials and methods

We analysed 21 patients with pituitary macroadenomas between June 2013 and June 2015. All patients underwent trans-sphenoidal surgery and neurosurgeon described macroadenomas consistency. Similarly, two neuroradiologists manually drew regions of interest (ROIs) inside the solid-appearing portions of macroadenoma and in the normal white matter both on dynamic and post-contrast acquisitions. The ratio between these ROIs, defined as Signal Intensity Ratio (SIR), allowed obtaining signal intensity curves over time on dynamic acquisition and a single value on post-contrast MRI. SIR values best differentiating solid from soft macroadenoma components were calculated and correlated with pathologic patterns. A two-sample T test and empiric receiver operating characteristic (ROC) curve of SIR was performed.

Results

According to ROC analysis, the SIR value of 1.92, obtained by dynamic acquisition, best distinguished soft and hard components. All the specimens from soft components were characterized by high cellularity, high representation of vascularization and micro-haemorrhage and low percentage of collagen content. The reverse was evident in hard components.

Conclusions

We demonstrated that dynamic MRI acquisition could distinguish with good accuracy macroadenomas consistency.

     

Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary

Introduction

Histologic, immunohistochemical and electron microscopic studies have provided conclusive evidence that a marked diversity exists between tumors which secrete growth hormone (GH) in excess. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH—releasing hormone secreting tumors or in familial pituitary tumor syndromes.

Materials and methods

A literature search was performed for information regarding pathology, GH-producing tumors and acromegaly.

Results

This review summarizes the current knowledge on the morphology of GH-producing and silent GH adenomas, as well as GH hyperplasia of the pituitary.

Conclusion

The importance of morphologic classification and identification of different subgroups of patients with GH-producing adenomas and their impact on clinical management is discussed.

     

Temozolomide for aggressive ACTH pituitary tumors: failure of a second course of treatment

Introduction

Temozolomide (TMZ) is an oral alkylating agent that has been used over the past 8 years to treat aggressive pituitary tumors resistant to conventional therapy. To date, only 25 patients treated with TMZ for ACTH producing pituitary tumors (14 adenomas and 11 carcinomas) have been reported.

Materials and Methods

We present a retrospective review of the medical records of three patients with aggressive ACTH producing adenomas treated with TMZ. In the three cases there was evidence of progression to conventional therapy before starting TMZ. We used the conventional scheme for the treatment of gliomas until completing 7, 12 and 6 cycles respectively. Reduction in tumor size was evident after the 3rd, 5th and 4th cycle of TMZ and progression free survival was 25, 19 and more than 12 months in the three patients respectively. Improvement of the ocular and visual symptoms was evident after the 4th cycle of treatment in all cases. Normalization of urinary free cortisol levels was achieved after the 3rd and 9th cycle in the two cases with hypercortisolism. Two of the three patients received a second course of treatment when the disease progressed but it did not stop tumor progression. The principal side effects were G3 neutropenia, G1 and G2 thrombocytopenia, G1 lymphopenia, asthenia and nausea.

Conclusion

The treatment with TMZ is effective and safe in patients with aggressive corticotrophin tumors resistant to conventional therapy. Nevertheless once the disease progresses, a second course of treatment does not seem to be effective.

     

Epidemiology,clinical presentation and diagnosis of non-functioning pituitary adenomas

Purpose

Non-functioning pituitary adenomas (NFPAs) are benign pituitary neoplasms that do not cause a hormonal hypersecretory syndrome. An improved understanding of their epidemiology, clinical presentation and diagnosis is needed.

Method

A literature review was performed using Pubmed to identify research reports and clinical case series on NFPAs.

Results

They account for 14–54% of pituitary adenomas and have a prevalence of 7–41.3/100,000 population. Their standardized incidence rate is 0.65–2.34/100,000 and the peak occurence is from the fourth to the eighth decade. The clinical spectrum of NFPAs varies from being completely asymptomatic to causing significant hypothalamic/pituitary dysfunction and visual field compromise due to their large size. Most patients present with symptoms of mass effect, such as headaches, visual field defects, ophthalmoplegias, and hypopituitarism but also hyperprolactinaemia due to pituitary stalk deviation and less frequently pituitary apoplexy. Non-functioning pituitary incidentalomas are found on brain imaging performed for an unrelated reason. Diagnostic approach includes magnetic resonance imaging of the sellar region, laboratory evaluations, screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm.

Conclusion

This article reviews the epidemiology, clinical behaviour and diagnostic approach of non-functioning pituitary adenomas.

     

Pituitary tumour apoplexy within prolactinomas in children: a more aggressive condition?

Objectives

To evaluate clinical presentations, diagnosis and management of paediatric patients presenting with pituitary apoplexy.

Methods

A retrospective case series describing a cohort of paediatric patients presenting with this condition from 2010–2016 to a tertiary referral children’s hospital in the United Kingdom.

Results

Pituitary apoplexy is a rare condition that seems to have a higher relative incidence in children than adults. Our series suggests that pituitary apoplexy in paediatric patients with adenomas appears more common than previously described. All our patients required surgery, either as an acute or delayed procedure, for visual compromise. Two patients had commenced growth hormone (GH) for GH deficiency two weeks prior to the onset of pituitary apoplexy.

Conclusions

With only a limited number of published case reports surrounding this topic our case series contributes to help further understand and manage this condition.

     

The dangers of the “Head Down” position in patients with untreated pituitary macroadenomas: case series and review of literature

Purpose

Cavernous sinus syndrome is a rare phenomenon, characterized by simultaneous neuropathies of cranial nerves III–VI. Various pathological processes have been reported as precipitating etiologies, including infection, inflammation, vascular lesions, and neoplasms.

Purpose

We report a unique case series of cavernous sinus syndrome attributable to prolonged Trendelenburg or prone positioning during non-cranial procedures and review the pertinent literature to enlighten on this rare but catastrophic phenomenon.

Methods

Retrospective case series.

Results

In the past year we encountered two patients who presented with acute cavernous sinus syndrome upon awakening from non-cranial operations. One patient underwent an extensive urologic resection of a bladder malignancy positioned in Trendelenburg for approximately 4 h. The second patient underwent a lumbar laminectomy and discectomy in prone position. Both patients were discovered to have infarcted large pituitary macroadenomas as the etiology of their acute ophthalmoplegias, and transnasal, transsphenoidal resection was performed acutely to decompress the cavernous sinus contents. Pathologic analysis of the resected specimens in each case confirmed necrotic, infarcted pituitary adenoma. Both patients made a complete recovery with no evidence of residual or recurrent tumor in short term follow-up.

Conclusion

We report a brief case series of acute cavernous sinus syndrome resulting from dependent positioning during non-cranial operations in patients with pituitary macroadenoma. Although rare, this highlights a potential danger of “head down” positioning in patients with intracranial pathology—particularly in or around the sella and cavernous sinus. Despite multiple cranial neuropathies upon presentation, both patients made complete recovery following surgical decompression of the cavernous sinuses.

     

Ovarian hyperstimulation syndrome due to follicle-stimulating hormone-secreting pituitary adenomas

Purpose

Gonadotroph adenomas are pituitary adenomas with inefficient and variable secretory characteristics, that is why they are usually considered as a subgroup of nonfunctioning pituitary adenomas (NFPA) and are recognized only at immunohistochemistry. When gonadotroph adenomas secrete active hormones, they may cause spontaneous ovarian hyperstimulation syndrome (OHSS) in premenopausal women. Aim of our study is to describe three women with OHSS diagnosed before the removal of the adenoma and to calculate the prevalence of OHSS in premenopausal women with a clinical diagnosis of NFPA.

Methods

We reviewed clinical records of premenopausal women that underwent neurosurgery for NFPA at our centre between 1993 and 2014. OHSS was diagnosed in patients with high levels of FSH, suppressed LH, hyperestrogenism, abdominal symptoms, polymenorrhea, enlarged ovaries with cysts or previous surgery for ovarian cysts.

Results

171 women were included into the study; 62 (36.6%) had a gonadotroph adenoma diagnosed at immunohistochemistry. Two patients were retrospectively diagnosed as having OHSS due to gonadotroph adenoma and three had OHSS diagnosed before neurosurgery. The prevalence of OHSS was 2.9% in the overall group of patients with NFPA and 8.1% among patients with a gonadotroph adenoma detected at immunohistochemistry.

Conclusions

Frequency of OHSS due to a gonadotroph adenoma is not negligible. Increased awareness of the characteristic clinical and hormonal picture should permit an early detection of this condition in premenopausal women with a pituitary adenoma.

     

Apparent diffusion coefficient and pituitary macroadenomas: pre-operative assessment of tumor atypia

Rationale and objectives

Pituitary macroadenomas are predominantly benign intracranial neoplasms that can be locally aggressive with invasion of adjacent structures. Biomarkers of aggressive behavior have been identified in the pathology literature, including the proliferative marker MIB-1. In the radiology literature, diffusion weighted imaging and low ADC values provide similar markers of aggressive behavior in brain tumors. The purpose of this study was to determine if there is a correlation between ADC and MIB-1 in pituitary macroadenomas.

Materials and methods

A retrospective review of diffusion imaging and immunohistochemical characteristics of pituitary macroadenomas was performed. The ADC ratio and specimen Ki-67 (MIB-1) indices were measured. Linear regression analysis of normalized ADC values and MIB-1 indices was used to compare these parameters.

Results

There were 17 patients with available ADC maps and MIB-1 indices. Local invasion was confirmed by imaging and intraoperative visualization in 11 patients. The mean ADC ratio for the invasive group was 0.68, with a mean MIB-1 index of 2.21 %. In the noninvasive group, the mean ADC ratio was 1.05, with a mean MIB-1 index of 0.9 %. Linear regression analysis of normalized ADC values versus MIB-1 demonstrates a negative correlation, with a linear slope significantly different from zero (p = 0.003, correlation coefficient of 0.77, and r squared = 0.59).

Conclusion

We determine a strong correlation of low ADC values and MIB-1, demonstrating the potential of diffusion imaging as a possible biomarker for atypical, proliferative adenomas, which may ultimately affect the surgical approach and postoperative management.

     

A high-throughput analysis of the IDH1(R132H) protein expression in pituitary adenomas

Purpose

Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas.

Methods

We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses.

Results

In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses.

Conclusion

IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1.

     

The experience with transsphenoidal surgery and its importance to outcomes

Purpose

Surgical experience is considered paramount for excellent outcome of transsphenoidal surgery (TSS). However, objective data demonstrating the surgical success in relation to the experience of pituitary surgery units or individual experience of pituitary surgeons is sparse.

Methods

Based on literature data, we have investigated the influence of experience with TSS for pituitary adenomas on endocrinological remission rates and on operative complications. The surgical experience was assessed by calculating the number of transsphenoidal operations per year.

Results

For TSS of microprolactinomas, mean remission rates were 77% in centers with <?2 operations per year for microprolactinomas, 82% with 2–4 operations, 84% with 4–6 operations, and 91% with >?6 operations. A yearly experience with more than 10 initial operations for Cushing’s disease (CD) warrants a remission rate exceeding 70%. Remission rates in CD exceeding 86% have only been reported for single surgeon series. Extraordinarily high complication rates were found in some series with <?25 yearly total operations for pituitary adenomas. Major vascular complications were less than 2% and revision rates for rhinorrhea usually?<?2.5% in centers performing?>?25 transsphenoidal operations per year.

Conclusions

We conclude that a center with experience of >?25 transsphenoidal operations for pituitary adenomas per year provides a high likelihood of safe TSS. Surgery for CD requires a particularly high level of practice to guarantee excellent remission rates. The endocrinologist has the unique opportunity to audit the surgical success by hormone measurement and to refer patients to neurosurgeons with proven excellence.

     

Aggressive tumors and difficult choices in acromegaly

Purpose

The current article looks at some of the factors associated with pituitary adenomas displaying unusually aggressive biological and clinical behaviour in patients with acromegaly.

Methods

This was a retrospective, narrative review of previously published evidence chosen at the authors’ discretion and presented from the perspective of a Latin American case study.

Findings and Conclusions

Although most pituitary tumors in acromegalic patients are benign and non-aggressive many can behave more aggressively, compromising local surrounding structures. These lesions tend to respond poorly to somatostatin analogs, have a higher risk of recurrence after surgery and, thus, a worse prognosis. Patients with more aggressive tumors constitute a particular challenge, as they often require several therapeutic approaches and may be difficult to manage, especially when options are restricted due to limited resources.

     

Pituitary tumors in MEN1: do not be misled by borderline elevated prolactin levels

Purpose

The objective of this case report is to demonstrate that the simple expedient of measuring periodic prolactin levels in patients with MEN1 who have modest hyperprolactinemia and normal pituitary MRI scans is insufficient to monitor for the development of pituitary adenomas.

Methods

Review of relevant literature and chart review.

Results

A 25 year old man with known MEN1 manifested by hyperparathyroidism and a gastrin-producing neuroendocrine tumor was found to have a prolactin [PRL] level of 20.0 ng/mL [1.6–16 ng/mL] but a normal pituitary MRI scan. The impression then was that he had prolactinoma too small to be visualized on the MRI. Over the next 3.5 years his PRL levels remained in this mildly elevated range but he then presented with severe headaches and visual field defects. An MRI showed a 3.1 × 1.7 × 1.9 cm pituitary adenoma with compression of the optic chiasm and invasion of the left cavernous sinus. Surgery revealed a gonadotroph adenoma and he subsequently required gamma knife radiotherapy for residual tumor. Postoperative PRL levels were normal.

Conclusions

Small, intrasellar microadenomas may be associated with elevated PRL levels due to possible direct hormone production [prolactinoma] or possibly to interference with portal vessel blood flow. In monitoring hyperprolactinemic MEN1 patients for the development of pituitary adenomas, measurement of PRL levels is insufficient and periodic MRI scans are necessary at a more frequent interval than every 3–5 years. This may also pertain to patients with “idiopathic” hyperprolactinemia.

     

Increased expression of the microRNA 106b~25 cluster and its host gene MCM7 in corticotroph pituitary adenomas is associated with tumor invasion and Crooke’s cell morphology

Purpose

MCM7 (minichromosome maintenance complex component 7), a DNA replication licensing factor, is a host gene for the oncogenic miR-106b~25 cluster. It has been recently revealed as a relevant prognostic biomarker in a variety of cancers, including pituitary adenomas. The purpose of this study was to assess whether miR-106b~25 and MCM7 levels correlate with tumor invasiveness in a cohort of ACTH-immunopositive adenomas.

Methods

Tissue samples were obtained intraoperatively from 25 patients with pituitary adenoma. Tumor invasiveness was assessed according to the Knosp grading scale. MCM7, Ki-67 and TP53 levels were assessed by immunohistochemical staining, while the expression of miR-106b-5p, miR-93-5p, miR-93-3p and miR-25-3p were measured using quantitative real-time PCR performed on RNA isolated from FFPE tissues.

Results

We have found a significant increase in MCM7 and Ki-67 labeling indices in invasive ACTHomas. Moreover, MCM7 was ubiquitously overexpressed in Crooke’s cell adenomas. The expression of miR-93-5p was significantly elevated in invasive compared to noninvasive tumors. In addition, all four microRNAs from the miR-106b~25 cluster displayed marked upregulation in Crooke’s cell adenomas. Remarkably, MCM7 and miR-106b-5p both strongly correlated with Knosp grade. A combination of MCM7 LI and miR-106b~25 cluster expression was able to accurately differentiate invasive from noninvasive tumors and had a significant discriminatory ability to predict postoperative tumor recurrence/progression.

Conclusions

miR-106b~25 and its host gene MCM7 are potential novel biomarkers for invasive ACTH-immunopositive pituitary adenomas. Additionally, they are both significantly upregulated in rare Crooke’s cell adenomas and might therefore contribute to their aggressive phenotype.

     

Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening

Introduction

Pituitary gigantism is a rare condition caused by growth hormone secreting hypersecretion, usually by a pituitary tumor. Acromegaly and gigantism cases that have a genetic cause are challenging to treat, due to large tumor size and poor responses to some medical therapies (e.g. AIP mutation affected cases and those with X-linked acrogigantism syndrome).

Materials and methods

We performed a retrospective study to identify gigantism cases among 160 somatotropinoma patients treated between 1985 and 2015 at the University Hospital of Caracas, Venezuela. We studied clinical details at diagnosis, hormonal responses to therapy and undertook targeted genetic testing. Among the 160 cases, eight patients (six males; 75 %) were diagnosed with pituitary gigantism and underwent genetic analysis that included array comparative genome hybridization for Xq26.3 duplications.

Results

All patients had GH secreting pituitary macroadenomas that were difficult to control with conventional treatment options, such as surgery or primary somatostatin receptor ligand (SRL) therapy. Combined therapy (long-acting SRL and pegvisomant) as primary treatment or after pituitary surgery and radiotherapy permitted the normalization of IGF-1 levels and clinical improvement. Novel AIP mutations were the found in three patients. None of the patients had Xq26.3 microduplications.

Conclusions

Treatment of pituitary gigantism is frequently challenging; delayed control increases the harmful effects of GH excess, such as, excessive stature and symptom burden, so early diagnosis and effective treatment are particularly important in these cases.

     

Silent corticotroph adenomas

Purpose

Silent corticotroph adenomas (SCAs) present clinically as non-functioning adenomas (NFAs) but are immunopositive for adrenocorticotrophic hormone (ACTH) without biochemical and clinical manifestation of hypercortisolism. Pathologic examination of resected NFAs that demonstrate positive ACTH and/or TPIT expression confirms its corticotroph lineage. SCAs comprise up to 20% of NFAs and exhibit a higher rate of recurrence. Studies of molecular mechanisms have generated multiple hypotheses on SCA tumorigenesis, pathophysiology, and growth that as yet remain to be proven. An improved understanding of their pathologic and clinical characteristics is needed.

Methods

A literature review was performed using PubMed to identify research reports and clinical case series on SCAs.

Results

Up to date findings regarding epidemiology, mechanisms of pathogenesis, differentiation, progression, and growth, as well as clinical presentation, postoperative course, and treatment options for patients with SCAs are presented. Pooled results demonstrate that 25–40% of cases show cavernous sinus invasion, preoperative hypopituitarism, new-onset hypopituitarism, and recurrence.

Conclusion

This article reviews the incidence, molecular pathology, and clinical behavior of these unique non-functioning pituitary corticotroph adenomas, and highlights the need for rigorous monitoring for recurrences and hypopituitarism in patients with SCAs.

     

Fecal microbiota transplantation in a kidney transplant recipient with recurrent urinary tract infection

Purpose

We report on a kidney transplant recipient treated with fecal microbiota transplantation (FMT) for recurrent urinary tract infections.

Methods

FMT was administered via frozen capsulized microbiota. Before and after FMT, urinary, fecal and vaginal microbiota compositions were analyzed.

Results

The patient remained without symptoms after FMT.

Conclusions

Underlying mechanisms of action need to be addressed in depth by future research.

     

Acromegaly: surgical results in 548 patients

Purpose

The goal of this study was to quantified the results of microsurgery, in all the patients with acromegaly treated by the same endocrinologist and the same surgeon between 1975 and 2015.

Methods

A series of 548 patients with acromegaly were operated and followed-up from 6 months to 40 years. Patients were selected according to five criteria: (1) Operated by the same surgeon. (2) No previous treatment. (3) Complete endocrinological preoperative studies including GH, OGTT, IGF-I, PRL test and TC/MRI. (4) Complete postoperative endocrinological evaluation for at least one determination of GH, OGTT, PRL test and IGF-I six months after surgery. (5) All the patients were supervised by the same endocrinologist.

Results

Microadenomas were present in 119 patients and 109 (91,5%) achieved remission. Non invasive macroadenomas were present in 200 patients and 164 achieved remission (82%). Results were worse for invasive macroadenomas but even with great invasions some patients achieved clinical remission. Follow-up range from 6 months to 40 years (mean 3.3?±?2.3) A long term follow-up of 15 years was achieved in 61 patients. Four of them had a recurrence 4, 7, 8, 12 years after surgery (6.5%). There was not mortality and the rate of complications was low.

Conclusions

Surgery remains the first line of therapy for a majority of acromegalic patients. This series proves to be very valuable in circumscribed adenomas but also in invasive tumours. Levels of GH and IGF-I were decreased in almost all the patients without remission.