[Prognostic value of granular pattern of growth hormone secreting tumors]. / Caracterización de tumores secretores de hormona de crecimiento de acuerdo al patrón granular y su rol en el pronóstico.

BACKGROUND: Classification of growth hormone (GH) - secreting tumors by the granular pattern might predict their clinical behavior in acromegalic patients. There are several other prognostic factors. AIM: To compare the features at presentation and cure rates of patients with GH secreting tumors according to the granular pattern, and to define independent prognostic factors for surgical treatment in these patients. MATERIAL AND METHODS: A retrospective, observational study of 85 active acromegalic patients surgically treated in two medical centers. RESULTS: Seventy-four patients (87%) were classified as having densely granulated (DG) and 11 (13%) as sparsely granulated (SG) tumors. The latter were less active biochemically, had a higher rate of macroadenoma and cavernous sinus invasion and had a lower rate of biochemical cure than the DG group. Several characteristics were associated with disease persistence but only age (Odds ratio (OR) = 0.93) and cavernous sinus invasion (OR = 21.7) were independently associated in the logistic regression model. CONCLUSIONS: The sparsely granulated pattern is associated with a more aggressive behavior, but the main determinants of prognosis are age and cavernous sinus invasion.

Caracterización de tumores secretores de hormona de crecimiento de acuerdo al patrón granular y su rol en el pronóstico / Prognostic value of granular pattern of growth hormone secreting tumors

Background: Classification of growth hormone (GH) - secreting tumors by the granular pattern might predict their clinical behavior in acromegalic patients. There are several other prognostic factors. Aim: To compare the features at presentation and cure rates of patients with GH secreting tumors according to the granular pattern, and to define independent prognostic factors for surgical treatment in these patients. Material and Methods: A retrospective, observational study of 85 active acromegalic patients surgically treated in two medical centers. Results: Seventy-four patients (87%) were classified as having densely granulated (DG) and 11 (13%) as sparsely granulated (SG) tumors. The latter were less active biochemically, had a higher rate of macroadenoma and cavernous sinus invasion and had a lower rate of biochemical cure than the DG group. Several characteristics were associated with disease persistence but only age (Odds ratio (OR) = 0.93) and cavernous sinus invasion (OR = 21.7) were independently associated in the logistic regression model. Conclusions: The sparsely granulated pattern is associated with a more aggressive behavior, but the main determinants of prognosis are age and cavernous sinus invasion.

Usefulness and Pitfalls in Sodium Intake Estimation: Comparison of Dietary Assessment and Urinary Excretion in Chilean Children and Adults.

BACKGROUND: High sodium intake has been associated with various noncommunicable disease like hypertension, cardiovascular disease, or stroke. To estimate accurately sodium intake is challenging in clinical practice. We investigate the usefulness and limitations of assessing sodium intake simultaneously by dietary assessment and urinary samples in both children and adults. METHODS: We used a cross-sectional study design inviting 298 Chilean subjects (74 children and 222 adults) aged between 9 and 66 years of both genders. Sodium intake by dietary assessment was obtained from Chilean food composition data, based on FAO tables. Sodium and creatinine excretion were measured in 24-hour urine samples, in all participants. RESULTS: Adequate urinary collection was obtained in 81% of children (59/74) and 61% of adults (135/222). The mean sodium intake by dietary assessment was similar to the sodium excretion in 24 hours (3,121±1,153mg/d vs. 3,114±1,353mg/24h, P = nonsignificant) in children but was significantly lower (3,208±1,284mg/d vs. 4,160±1,651mg/24h, P < 0.001) in adults. In both children and adults, sodium intake correlated with urinary sodium excretion (r = 0.456, P < 0.003 and r = 0.390, P < 0.001, respectively). Secondary analyses also suggested that the dietary assessment was more inaccurate in overweight adult subjects. CONCLUSIONS: Our results showed that average sodium intake was higher than recommended in both children and adults (WHO ≤2,000mg/d). The sodium intake estimated by dietary assessment correlated with urinary excretion in all subjects, but in obese adults was more inaccurate than in children. Future studies to validate the appropriate test to assess sodium intake by age and nutritional status are warranted.

Hormonal, Radiological, NP-59 Scintigraphy, and Pathological Correlations in Patients With Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease (PPNAD).

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing's syndrome that may occur in an isolated form or as part of Carney complex. The diagnosis of this disease can be difficult preoperatively because computed tomography (CT) scan can be normal or suggest unilateral adrenal lesion, which can impede the correct diagnosis of bilateral adrenal disease. OBJECTIVE: The aim of our study was to describe the results of preoperative imaging (adrenal [6ß-(131)I]iodomethyl-19-norcholesterol] [NP-59] scintigraphy and standard adrenal CT scan) and their correlations with clinical, pathological, and genetics investigations in patients with PPNAD. PATIENTS AND METHODS: Seventeen patients with ACTH-independent syndrome due to PPNAD were investigated with a standard adrenal CT scan and NP-59 scintigraphy. Hormonal, pathological, and genetics data were analyzed. RESULTS: Four males and 13 females (median age, 27 y) were included. PPNAD was isolated in 11 patients (with PRKAR1A mutation, n = 7; and without PRKAR1A mutation, n = 4) and was associated with extra-adrenal manifestations of Carney complex in six patients (with PRKAR1A mutation, n = 4; and without PRKAR1A mutation, n = 2). Standard adrenal CT scan revealed micronodules in 11 patients, macronodules in three patients, and was normal in three patients. All patients demonstrated bilateral adrenal radiocholesterol uptake. Adrenal uptake was asymmetrical in 10 of 17 patients (59%). Asymmetrical uptake correlated with the presence of macronodules at pathological analysis (P = .03). CONCLUSION: Standard adrenal CT scan most often reveals micronodules but there is no specific CT imaging. NP-59 scintigraphy always shows a bilateral adrenal uptake confirming the bilateral nature of the disease, but asymmetrical scintigraphic uptake can be observed in patients with macronodules.

[Selective use of glucocorticoids during the perioperative period of transsphenoidal surgery for pituitary tumors]. / Criterios para la indicación selectiva de glucocorticoides en pacientes con tumores hipofisiarios sometidos a cirugía transesfenoidal.

BACKGROUND: There is consensus in promoting the selective use of glucocorticoids (GC) in the peri-operative period of transsphenoidal surgery (TE) for pituitary adenomas (PA). AIM: To evaluate the safety of a selective glucocorticoid administration protocol and the usefulness of immediate postoperative cortisol levels as a predictor of final eucortisolism. PATIENTS AND METHODS: Clinical and biochemical data from 40 patients aged 27 to 78 years (65% males) were prospectively collected. Exclusion criteria were previous use of GC, apoplexy and Cushing disease. Patients with pre-operative short synthetic ACTH test (SST) > 18 µg/dl or basal cortisol > 15 µg/dl did not receive GC. A morning serum cortisol (SC) threshold of 10 µg/dl in postoperative days one to three was used to decide a discharge without GC. Hypotension, dizziness or nausea, requirement of increased dose of corticosteroids, hospitalizations and emergency service visits were investigated, as well as surgical and endocrinological complications. Corticotropic status was evaluated three months after surgery. RESULTS: Macroadenomas were present in 87% of patients. Median hospital stay was 4 days and follow up lasted 9 months. No differences were found in gender, age or tumor size between patients who received or not GC (35 and 65% respectively). Eighty five percent of patients were discharged without GC and all of them had normal corticotropic function three months after surgery. A SC ≥ 15 µg/dl had 100% specificity to predict eucortisolism. CONCLUSIONS: Selective glucocorticoid administration is safe. A normal corticotropic function before surgery and in the immediate postoperative period are useful to identify patients who do not need GC.

Criterios para la indicación selectiva de glucocorticoides en pacientes con tumores hipofisiarios sometidos a cirugía transesfenoidal / Selective use of glucocorticoids during the perioperative period of transsphenoidal surgery for pituitary tumors

Background: There is consensus in promoting the selective use of glucocorticoids (GC) in the peri-operative period of transsphenoidal surgery (TE) for pituitary adenomas (PA). Aim: To evaluate the safety of a selective glucocorticoid administration protocol and the usefulness of immediate postoperative cortisol levels as a predictor of final eucortisolism. Patients and Methods: Clinical and biochemical data from 40 patients aged 27 to 78 years (65% males) were prospectively collected. Exclusion criteria were previous use of GC, apoplexy and Cushing disease. Patients with pre-operative short synthetic ACTH test (SST) > 18 µg/dl or basal cortisol > 15 µg/dl did not receive GC. A morning serum cortisol (SC) threshold of 10 µg/dl in postoperative days one to three was used to decide a discharge without GC. Hypotension, dizziness or nausea, requirement of increased dose of corticosteroids, hospitalizations and emergency service visits were investigated, as well as surgical and endocrinological complications. Corticotropic status was evaluated three months after surgery. Results: Macroadenomas were present in 87% of patients. Median hospital stay was 4 days and follow up lasted 9 months. No differences were found in gender, age or tumor size between patients who received or not GC (35 and 65% respectively). Eighty five percent of patients were discharged without GC and all of them had normal corticotropic function three months after surgery. A SC ≥ 15 µg/dl had 100% specificity to predict eucortisolism. Conclusions: Selective glucocorticoid administration is safe. A normal corticotropic function before surgery and in the immediate postoperative period are useful to identify patients who do not need GC.

The role of primary pharmacological therapy in acromegaly.

BACKGROUND AND OBJECTIVES: Primary pharmacological therapy may be the only viable treatment option for many patients with acromegaly, especially those presenting with advanced disease with large inoperable tumors. Long-acting somatostatin analogs are currently the first-line treatment of choice in this setting, where they provide biochemical control and reduce tumor size in a significant proportion of patients. We herein present a brief overview of the role of primary pharmacological therapy in the treatment of acromegaly within the context of Latin America and support this with a representative case study. CASE DESCRIPTION: A 20 year old male presented with clinical and biochemical evidence of acromegaly. The glucose-suppressed growth hormone (GH) was 5.3 µg/L, his insulin-like growth factor-1(IGF-1) was 3.5 times the ULN and serum prolactin greater than 4,000 µg/L. Pituitary MRI revealed a large and invasive mass, extending superiorly into the optic chiasm and laterally into the left cavernous sinus. He was treated with a combination of octreotide and cabergoline with remarkable clinical improvement, normalization of GH and IGF-1 values and striking shrinkage of the adenoma. CONCLUSION: This case illustrates how effective the pharmacological therapy of acromegaly can be and yet at the same time, raises several important issues such as the need for life-long treatment with costly medications such as the somatostatin analogs. Access to these agents may be limited in regions where resources are restricted and clinicians face challenges in order to make the most efficient use of available options.

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.

Primary pituitary lymphoma in immunocompetent patient: diagnostic problems and prolonged follow-up.

Primary pituitary lymphoma in immunocompetent patients is a rare disease and has been described in less than 20 cases. Moreover, low-grade lymphomas constitute only 3% of all primary central nervous system lymphoma. The objective of this report is to report a low-grade primary pituitary lymphoma, diagnostic problems and to give more evidence about the evolution of this rare disease. A 49 y.o. woman was referred to our clinic with symptoms of hypopituitarism. A diagnostic work-up showed mild anemia, an erythrocyte sedimentation rate of 122 mm/h and a negative Elisa test for HIV. Panhypopituitarism was confirmed and the MRI showed a 20 mm sellar and suprasellar enhancing mass with a thickening of the pituitary stalk, chiasmal compression and bitemporal hemianopsia. She underwent transsphenoidal resection only 10 months later for non medical reasons. During this period she was clinically asymptomatic on hormonal replacement therapy. A new MRI showed regression of the suprasellar extension and invasion to the left cavernous sinus. A firm and infiltrative mass was found during transsphenoidal surgery, and only partial resection was performed. Biopsy showed a low-grade lymphoplasmacytic lymphoma. Staging was negative for other localizations. She was given chemotherapy and localized radiotherapy. Four years after surgery, the sellar MRI showed a 10 mm residual sellar mass with the persistence of a cavernous sinus invasion and she is considered to be in remission. The neurosurgeon and clinician should consider primary pituitary lymphoma as a potential cause of a sellar mass, especially in the presence of diabetes insipidus and an enhancing invasive mass. Neurosurgical biopsy is crucial for a correct diagnosis and prognosis could be better than classic CNS primary lymphomas.

Midnight salivary cortisol determination for assessing the outcome of transsphenoidal surgery in Cushing's disease.

CONTEXT: Midnight salivary cortisol (MSC) is now recognized as a reliable index for Cushing's syndrome diagnosis but has to be validated for the follow-up of treated patients. OBJECTIVE: Our objective was to evaluate MSC for assessing the outcome of transsphenoidal surgery (TSS) in patients with Cushing's disease (CD). DESIGN: We conducted a retrospective cohort study in a single center. PATIENTS AND METHODS: Sixty-eight patients treated by TSS between 1996 and 2006 and followed for at least 6 months with postoperative MSC were included. Mean follow-up (+/- sd) was 45 +/- 31 months. Morning plasma cortisol was determined 5 d after TSS, and MSC and urinary cortisol (UC) were determined 6-12 months after surgery. The remission group included hypocortisolic (morning plasma cortisol < 50 ng/ml and/or insufficient response to cosyntropin) and eucortisolic (midnight plasma cortisol < 75 ng/ml and normal UC) patients. Patients in the treatment failure group had high midnight plasma cortisol and UC concentrations. RESULTS: Fifty patients (74%) were in remission. Mean MSC was 0.7 +/- 0.4 ng/ml (range, 0.4-2.1 ng/ml) and 6.5 +/- 6.5 ng/ml (range, 2.1-27.2 ng/ml) for the remission and treatment failure groups, respectively (P = 0.001). A cutoff of 2 ng/ml for MSC gave a sensitivity of 100% and a specificity of 98% for treatment failure diagnosis, whereas UC less than 90 microg/d had a sensitivity of 71% and specificity of 98%. Postsurgical morning plasma cortisol less than or equal to 18 ng/ml had a sensitivity of 93% and specificity of 74%. CONCLUSIONS: MSC is a simple, robust marker of remission after TSS for CD.

Melanotic nonpsammomatous trigeminal schwannoma as the first manifestation of Carney complex: case report.

OBJECTIVE: Melanotic schwannoma is a rare neoplasm, classifiable as a peripheral nerve sheath tumor, and differentiated from a typical schwannoma by heavy pigmentation. Psammoma bodies can be visualized in more than 50% of melanotic schwannomas. Half of patients with such "psammomatous melanotic schwannomas" have Carney complex, a dominantly transmitted autosomal disorder. Most recently, the tumor suppressor gene, PRKAR1A, coding for the Type 1alpha regulatory subunit of protein kinase A was found to be mutated in approximately half of the known Carney complex families. Although cranial schwannomas have been described in patients with Carney complex, their numbers are too small to be considered a definite part of the syndrome. Furthermore, only melanotic schwannomas with psammoma bodies are included as diagnostic criteria for Carney complex. The objective of this report is to communicate a case of trigeminal nonpsammomatous melanotic schwannoma as the first manifestation of Carney complex. CLINICAL PRESENTATION: A 34-year-old woman presented with odontalgia, right V3 hypoesthesia, V2 paresthesia, and diplopia. Magnetic resonance imaging scans of the brain revealed a small tumor with homogenous contrast in the right trigeminal pathway. INTERVENTION: We performed an extradural approach to the right cavernous sinus by a middle fossa approach. The lateral wall was opened between the cranial nerves, and a soft and black tumor was resected in a piecemeal fashion. Histology and immunohistochemical analysis of the tumor were compatible with melanotic schwannoma, but no psammomatous bodies were identified. Endocrine evaluation showed that this patient's symptoms fulfilled the diagnostic criteria of Carney complex, with lentiginosis, multiple breast ductal adenomas, multiple hypoechoic nodules on thyroid ultrasonography, and a 4 x 5-cm asymptomatic atrial cardiac myxoma, which was removed 15 days after the neurosurgery. Three months later, a recurrence of melanotic schwannoma was identified. Molecular analyses of genomic and somatic deoxyribonucleic acid from the patient found a 578 to 579delTG mutation of PRKAR1A. CONCLUSION: We present the unusual case of a nonpsammomatous trigeminal melanotic schwannoma associated with Carney complex, with confirmed PRKAR1A gene mutation. Our case highlights that neurosurgeons, in the presence of a melanotic schwannoma, should be aware of the features of the Carney complex because, in such cases, pre- and postoperative management is significantly affected. We also postulate that the absence of psammoma bodies or cranial localization do not exclude this diagnosis.

Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism.

Primary hyperparathyroidism may occur as part of hereditary syndromes, including multiple endocrine neoplasia types 1 and 2A (MEN1 and MEN2A), hyperparathyroidism-jaw tumor syndrome, and the familial isolated hyperparathyroidism (FIHP). It is unclear whether FIHP corresponds to a different genetic entity or a variant of MEN1 (or hyperparathyroidism-jaw tumor syndrome). We report a patient and 11 family members with FIHP in whom we identified a heterozygous G-to-A mutation at nucleotide 7361 of tumor suppressor MEN1 gene. This mutation is located in the first base of intron 9 (IVS9 + 1 G>A). All the family members with hyperparathyroidism were heterozygous for the intronic mutation. In vitro studies were performed in COS cells transfected with minigenes carrying the coding regions spanning exon-intron 9 and 10 with the mutant and the wild-type sequences. RT-PCR analyses showed an abnormal mRNA of greater size (829 bp) in the mutated MEN1 gene than the normal transcript (629 bp). The longer PCR product includes the exon 9, the unspliced intron 9, and part of exon 10. RT-PCR of MEN1 mRNA from patient's blood confirmed the existence of unspliced intron 9 in mature mRNA. In summary, we report a case of FIHP associated with a new intronic heterozygous germline mutation (IVS9 + 1 G>A) of MEN1 gene. This mutation produces an aberrant splicing of mRNA that could lead to a truncated protein, without activity, explaining the clinical picture of this patient and his family.