Indication to dynamic and invasive testing in Cushing's disease according to different neuroradiological findings.

PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

First-line surgery in prolactinomas: lessons from a long-term follow-up study in a tertiary referral center.

CONTEXT: Although consensus guidelines recommend dopamine agonists (DAs) as the first-line approach in prolactinomas, some patients may opt instead for upfront surgery, with the goal of minimizing the need for continuation of DAs over the long term. While this approach can be recommended in selected patients with a microprolactinoma, the indication for upfront surgery in macroprolactinomas remains controversial, with limited long-term data in large cohorts. We aimed at elucidating whether first-line surgery is equally safe and effective for patients with micro- or macroprolactinomas not extending beyond the median carotid line (i.e., Knosp grade ≤ 1). METHODOLOGY: Retrospective study of patients with prolactinomas Knosp grade ≤ 1 treated with upfront surgery. The primary endpoint was patients' dependence on DAs at last follow-up. The secondary endpoint was postoperative complications. Independent risk factors for long-term dependence on DAs were analyzed. RESULTS: A microadenoma was noted in 45 patients (52%) and a macroadenoma in 41 (48%), with 17 (20%) harboring a Knosp grade 1 prolactinoma. Median follow-up was 80 months. First-line surgery resulted in long-term remission in 31 patients (72%) with a microprolactinoma and in 18 patients (45%) with a macroprolactinoma (p = 0.02). DA therapy was ultimately required in 11 patients (24%) with microadenomas vs. 20 (49%) with macroadenomas (p = 0.03). As for the latter, DA was required in 13 patients (76%) with Knosp grade 1 macroadenomas vs. 7 patients (29%) with Knosp grade 0 macroadenomas (p = 0.004). There was no mortality, and morbidity was minimal. Knosp grade 1 prolactinomas (OR 7.3, 95% CI 1.4-37.7, p = 0.02) but not adenoma size (i.e., macroprolactinomas) were an independent predictor of long-term dependence on DAs. CONCLUSIONS: First-line surgery in patients with microprolactinomas or macroprolactinomas Knosp grade 0 resulted in a good chance of non-dependency on DA therapy. However, in patients with prolactinomas Knosp grade 1, first-line surgery cannot be recommended, as adjuvant DA therapy after surgery is required in the majority of them over the long term.

Natural History of Acromegaly: Incidences, Re-operations, Cancers, and Mortality Rates in a National Cohort.

BACKGROUND: Acromegaly is so rare that its natural history, including incidence, risk of cancers, and mortality rates, remains elusive. This natural study utilized a nationwide database to provide a better understanding of acromegaly's disease course. METHODS: A cohort of 1,195 acromegaly patients were identified and followed-up from 1997 to 2013. Incidence, operation, and re-operation rates were calculated. Excessive mortality and cancer risk related to acromegaly were estimated by standardized mortality ratio (SMR) and standardized incidence ratio (SIR). RESULTS: The incidence was 2.78 per million-person-years, with little gender predominance (female vs. male, 49.5 vs. 50.5%, respectively). There was female predominance only among 50 and 60 year-olds (incidence rate ratio: 1.37 and 1.43, p < 0.001 and p = 0.002). Among them, 673 (56.3%) had hypophysectomy surgery, and the young-onset (<40 years) patients had more re-operations (15.5%, p = 0.01). The overall mortality rate was 22.3 per 1,000 person-years, with a median survival of 4.67 years (with no gender differences, p = 0.38). The overall SMR of acromegaly patients was 1.41, and the onset-age-specific SMRs of the early- and middle-onset patients were higher than for those with late-onset. There were 87 newly diagnosed cancers in the cohort, with an incidence rate of 10.6 per 1,000 person-years (median 5.4 years). The overall SIR of cancers was 1.91, and there were no differences among gender, onset-age, and disease duration (all SIR >1, approximately 2). CONCLUSION: Acromegaly is associated with an excessive risk of mortality and two-fold higher risk of cancers. Patients with acromegaly should be managed appropriately after the diagnosis.

The Liege Acromegaly Survey (LAS): a new software tool for the study of acromegaly.

Acromegaly is a chronic rare disease associated with negative pathological effects on multiple systems and organs. We designed a new informatics tool to study data from patients with acromegaly, the Liege Acromegaly Survey (LAS). This relational database permits the inclusion of anonymous historical and prospective data on patients and includes pathophysiology, clinical features, responses to therapy and long term outcomes of acromegaly. We deployed the LAS in a validation study at a single center in order to study the characteristics of patients with acromegaly diagnosed at our center from 1970-2011. A total of 290 patients with acromegaly were included (147 males and 143 females). There was a linear relationship between age at diagnosis and the date of diagnosis, indicating that older patients are being diagnosed with acromegaly more frequently. A majority presented with macroadenomas (77.5%) and the median diameter was 14 mm. Patients with macroadenomas were significantly younger than patients with microadenomas (P=0.01). GH values at diagnosis decreased with the age of the patients (P=0.01) and there was a correlation between GH values and tumor size at diagnosis (P=0.02). No correlation existed between insulin-like growth factor 1 (IGF-1) levels and tumor characteristics. The prevalence of diabetes was 21.4% in this population and 41.0% had hypertension. The presence of hypertension and diabetes were significantly associated with one another (P<0.001). There was a linear relation between initial GH and IGF-1 levels at diagnosis and those obtained during SSA analog treatment and the lowest GH and IGF-1 values following SSA therapy were obtained in older patients (GH: P<0.001; IGF-1: P<0.001). The LAS is a new relational database that is feasible to use in the clinical research setting and permits ready pooling of anonymous patient data from multiple study sites to undertake robust statistical analyses of clinical and therapeutic characteristics.

A prospective analysis of 151 cases of patients with acromegaly operated by one neurosurgeon: a follow-up of more than 23 years.

BACKGROUND: Transsphenoidal adenomectomy has been the accepted surgical management for treatment of growth hormone (GH)-secreting pituitary adenomas. Although the goal of treatment might be to keep the GH level in the reference range, the actual definition of success in control of acromegaly is not yet clear. METHODS: The aim of this study was to analyze prospectively the result of transsphenoidal adenoctomy performed over 23-year period by a single neurosurgeon in one center. The analysis has been performed to determine which preoperative factor could significantly influence the long term outcome. This series consisted of 151 patients. The preoperative hormonal studies documenting the high GH and/or insulin-like growth factor were available in all the cases. At least 1 laboratory report documenting the postoperative level of hormones was also available for all of them. Transsphenoidal microsurgical adenomectomy was performed in all the cases. RESULTS: There were 90 patients with pure GH-secreting adenoma (59.6%) with the highest GH level of 235 mU/L. A second group of 12 patients had normal GH level but elevated serum level of insulin-like growth factor 1 (8%). The group with mixed secretion of GH and prolactin included 49 cases (32.4%). There was no postoperative mortality. Cerebrospinal fluid leakage occurred in 12 patients. Transient diabetes insipidus was encountered in 19 cases (12.6%) and long lasting diabetes insipidus in 2 patients (1.3%). Early and minor hypopituitarism was encountered in 14 patients, whereas a persistent condition occurred mainly after irradiation in 14 other cases. Normal postoperative serum GH level could be achieved in 98 patients (94.2%) of 104 cases with full follow-up. CONCLUSION: In the developing countries, early diagnosis and proper surgical extirpation of the GH-secreting adenoma by an experienced and dedicated pituitary surgeon is mandatory to reduce the mortality and increase the chance of cure of this rather mortal endocrionopathy.

[Predictive value of the Knosp classification in grading the surgical resection of invasive pituitary macroadenomas. A prospective study of 23 cases]. / Valor predictivo de la clasificación de Knosp en el grado de resección quirúrgica de los macroadenomas invasivos. Estudio prospectivo de una serie de 23 casos.

OBJECTIVE: To evaluate our experience regarding the treatment of pituitary macroadenomas with cavernous sinus invasion in a series of 23 cases of transphenoidal resection. MATERIALS, METHODS AND RESULTS: Twenty two patients, fifteen males and seven females, with ages ranging from 27 to 75 (mean of 48), were operated under protocol by a single surgeon between May of 2002 and December of 2004. Preoperatively all lesions were diagnosed by MRI and staged according to the Knosp classification. All tumors had extension to one or both cavernous sinuses. Four patients were considered to be grade 1, two grade 2, one grade 3 and sixteen grade 4. Twenty three operations were performed on twenty-two patients. Twenty cases were the standard transsphenoidal approach, and three were endoscopic. Postoperatively, the excision was classified as Complete or Total, Subtotal or Partial. Mean follow up was 15 months. The variables considered for analysis include invasion and resection grades. All six patients with graded 1 and 2 lesions and two patients with grade 4 lesions underwent a complete resection. Subtotal (greater than 80%) excision was achieved in one patient with a grade 3 tumor and six patients with grade 4 tumors. The remaining seven patients with grade 4 adenomas had a Partial (less than 80%) excision. We compare de resection grade versus invasion grade with exact Fisher test. And there is not estadistical difference (p=0.12). CONCLUSION: The Knosp classification alone cannot predict the behavior of these tumors. In our experience, despite tumor extension to the cavernous sinus, pituitary macroadenomas can be safely resected with low morbidity and mortality.

[Cushing's disease and corticotrophic adenoma: results of pituitary microsurgery]. / Maladie de Cushing et adenome corticotrope: resultats de la microchirurgie hypophysaire.

Between November 1994 and June 2001, 194 patients with Cushing's disease underwent transsphenoidal surgery: 167 patients had adenomectomy, 14 had ante hypophysectomy, 5 had subtotal hypophysectomy, 4 had hemihypophysectomy 4 had central hypophysectomy. Complications occurred in 18 patients (9.3%), including 4 deaths (three were apparently not related to surgery). Remission of disease was achieved in 162 of 190 (85.3%) patients analyzed. Surgical failures were associated with lack of pituitary adenoma, size of the tumor and invasiveness. Among patients with confirmed adenomas, the rate of remission was significantly higher (p<0.01) in patients with microadenomas (92.6%) than in patients with macroadenomas (66.7%). Reoperation in 6 failures was followed by remission in 4 cases. The overall remission rate was 87.4%. In the 162 patients with immediate success, duration of follow-up was 10.0 +/- 5.9 years (m +/- DS; median=10.0). Recurrence of the disease occurred in 24 (14.8%) of 162 patients at a mean 4.8 years (range: 0.8-12.0 years). Our longest sustained remission is 25.6 years. Actuarial analysis indicates that the probability of a patient remaining well 12 years after surgery is 80.0%. It is 86.2% in microadenomas versus 52.5% in macroadenomas and 94.5% in the patients with postoperative hypocortisolism versus 59.2% in the others.

[Indications for total hypophysectomy in Cushing's disease]. / Place de l'antéhypophysectomie totale dans le traitement de la maladie de Cushing.

OBJECTIVE: Transsphenoidal selective adenomectomy is the treatment of choice for Cushing's disease. In some patients, magnetic resonance imaging (MRI) fails to detect small pituitary ACTH-secreting adenomas. Total hypophysectomy can be performed when MRI appears normal. The aim of this paper is to study results and complications after total hypophysectomy for Cushing's disease. METHODS: Between July 1988 and May 1999, 49 patients underwent transsphenoidal surgery for Cushing's disease at our institution. The criteria for inclusion in this study were clinical and biochemical studies strongly suggestive of Cushing's disease with normal MRI. Total hypophysectomy was performed in 7 patients who fulfilled these criteria. Their results were analyzed retrospectively. RESULTS: The average age of the patients was 43 years; there were 7 women. Five adrenocorticotrophic hormone-secreting adenomas were proven histologically. Complications occurred in 6 patients (cerebrospinal fluid fistulas in 6 patients, loss of vision in 1 patient, meningitis in 5 patients, anterior pituitary insufficiency in 5 patients, diabetes insipidus in 5 patients). Six patients had sustained remission 36 months after surgery. CONCLUSION: Total hypophysectomy can be perform ed for Cushing's disease with normal MRI. Complications occurs frequently, especially cerebrospinal fluid fistulas. Inferior petrosal sinus sampling can be helpful in localizing the adenoma allowing hemihypophysectomy and thus reduced morbidity.

Transsphenoidal hypophysectomy through the external rhinoplasty approach.

The external rhinoplasty approach is a refinement of the well-recognized sublabial transseptal technique for transsphenoidal hypophysectomy first introduced by Cushing in 1910. This article relates our experience with 111 cases of transsphenoidal hypophysectomy performed during a 10-year period (1982-1992) and includes a detailed description of our use of the external technique. Fifty-one patients were male, and 60 were female. Ages ranged from 12 years to 80 years, with an average of 46 years. One hundred one patients had pituitary adenomas, four had craniopharyngiomas, two had inverting papillomas, and there was one each of lymphoma, metastatic prostate cancer, pituitary abscess, and posttraumatic cerebrospinal fluid leak. Nine of the operations were for recurrent adenomas. Complications included 8 symptomatic anterior septal perforations and 13 asymptomatic posterior perforations. Five had transient cerebrospinal fluid rhinorrhea, five had perioperative hemorrhages, two had minor postoperative columellar deformities, and one had injury to the internal carotid artery requiring embolization. We have found the external technique for transsphenoidal hypophysectomy to be a reliable and facile means for nasal exposure of the sphenoid sinus and pituitary gland without loss of nasal tip projection or significant cosmetic deformity.

[The value of MR tomography after transsphenoidal hypophyseal resection. A retrospective comparison between endocrinology, operation and MRT]. / Wertigkeit der MR-Tomographie nach transsphenoidaler Hypophysenresektion. Retrospektiver Vergleich zwischen Endokrinologie, Operation und MRT.

Postoperative magnetic resonance images of 40 patients after transsphenoidal surgery for pituitary adenoma were evaluated retrospectively. The signal intensities of packing material and residual tumour were analysed. T1-weighted spin-echo sequences were obtained in coronal and sagittal views with and without intravenous injection of contrast media. Residual tumour demonstrated homogeneous or inhomogeneous signal intensity on the native scan with homogeneous or inhomogeneous enhancement. Packing material demonstrated a homogeneous signal intensity on the images obtained without injection of contrast media with a peripheral enhancement or alternate layers of low and intermediate signal intensity with alternate enhancement after injection of contrast media. In 5 of 54 examinations different results were found in MRI, endocrinology and surgery (two false negative and one false positive MRI in correlation with endocrinology; two residual tumours on MRI where surgery was supposed to be complete). Application of intravenous contrast media facilitates the interpretation of postoperative examination of the pituitary gland as well as comparison with preoperative examinations and the knowledge of the intraoperative procedure.