Anterior pituitary function in Rathke's cleft cysts versus nonfunctioning pituitary adenomas.

Although Rathke's cleft cysts (RCCs) are common sellar/parasellar lesions, studies examining pituitary function in patients with nonsurgical RCC are limited. This study aimed to clarify the importance of RCCs, including small nonsurgical ones, as a cause of hypopituitarism by determining the prevalence of pituitary hormone secretion impairment and its relationship to cyst/tumor size in patients with RCC and in those with nonfunctioning pituitary adenoma (NFA). We retrospectively investigated the basal levels of each anterior pituitary hormone, its responses in the stimulation test(s), and cyst/tumor size in patients with RCC (n = 67) and NFA (n = 111) who were consecutively admitted to our hospital for endocrinological evaluation. RCCs were much smaller than NFAs (median height, 12 vs. 26 mm). The prevalence of gonadotropin, PRL, and GH secretion impairment in RCC was lower in comparison to NFA (19% vs. 44%, 34% vs. 61%, and 24% vs. 46%, respectively), whereas the prevalence of TSH and ACTH secretion impairment was comparable (21-27% and 17-24%, respectively). A significant positive relationship between cyst/tumor size and number of impaired hormones was observed in both groups, but smaller cysts could cause hormone secretion impairment in RCC. Stimulation tests suggested that most hormone secretion impairment was attributable to the interrupted hypothalamic-pituitary axis in both groups. Therefore, RCC, even small ones, can cause pituitary dysfunction. Different mechanisms may underlie hypothalamic-pituitary interruption in RCC and NFA.

A case series of atypical features of patients with biopsy-proven isolated IgG4-related hypophysitis and normal serum IgG4 levels.

BACKGROUND: IgG4-related hypophysitis is a rare clinical entity that forms part of an emerging group of multi-organ IgG4-related fibrosclerotic systemic diseases. The rare prevalence of the disease, presenting features that overlap with other sellar pathologies, and variable imaging features can make preoperative identification challenging. PURPOSE AND METHODS: We report three cases of isolated IgG4-related hypophysitis with atypical clinical and imaging features that mimicked those of pituitary apoplexy and other sellar lesions. Additionally, we review the literature of IgG4-related hypophysitis to provide context for individual patient data described herein. RESULTS: All patients presented with symptoms that mimicked those of pituitary apoplexy and visual disturbance, and MRI findings suggestive of pituitary macroadenoma, Rathke's cleft cyst and craniopharyngioma. The clinical presentation warranted surgical decompression, resulting in rapid symptomatic improvement. Preoperative high-dose followed by postoperative low-dose glucocorticoid replacement therapy was administered in all cases. Histopathology showed dense infiltrate of IgG4 cells. Post-operative follow-up monitoring for 12-26 months revealed normal serum IgG4 levels with no other organ involvement, while endocrinological testing revealed persistent pituitary hormone deficiencies. CONCLUSIONS: Our cases highlight the importance of considering IgG4-related hypophysitis in the differential diagnosis of solid and cystic sellar lesions presenting acutely with pituitary apoplexy symptoms. Existing diagnostic criteria may not be sufficiently precise to permit rapid and reliable identification, or avoidance of surgery in the acute setting. In contrast to other reports of the natural history of this condition, despite the severity of presenting features, the disease in our cases was pituitary-restricted with normal serum IgG4 levels.

Central hypoadrenocorticism associated with Rathke's cleft cyst.

Rathke's cleft cysts (RCCs) are non-neoplastic, sellar or suprasellar epithelium-lined cysts originating from Rathke's pouch in the pituitary gland. Patients with RCCs are usually asymptomatic, but some have only been identified when symptoms manifested in middle age. The characteristics of these patients during childhood or adolescence remains unknown. We describe an 18-year-old girl who had occasionally suffered from malicious fatigue in the morning since her early teens. Brain magnetic resonance imaging (MRI) revealed T1 hyperintense/T2 hypointense signals between the anterior and posterior pituitary glands, indicating the presence of RCC. Based on an authentic endocrinological evaluation, her adrenal function seemed normal; nevertheless, her serum cortisol level strangely dropped around noon. Furthermore, daily supplementation of oral hydrocortisone bizarrely suppressed ACTH secretion to below the detection range in the morning. These data appeared compatible with the presence of central adrenal dysfunction. We also review the literature for previously reported cases. In conclusion, the symptoms and endocrinological data for dysfunction of the hypothalamic pituitary system might be non-specific and vary among patients, especially in teenagers. Brain MRI and daily cortisol profiling in blood are key to obtaining a diagnosis of an impaired hypothalamic adrenal function due to RCC.

Assessment of pre- and postoperative endocrine function in 94 patients with Rathke's cleft cyst.

We reviewed 94 patients with Rathke's cleft cyst (RCC) who were surgically treated at Nippon Medical School Hospital between December 1995 and July 2009 to clarify the effect of surgery on their endocrine function. In our statistical analysis we considered their age and sex, the cyst volume, and preoperative MRI findings. Using simple linear- and multiple regression analysis we evaluated the association between these factors and their preoperative hormone baseline levels. To assess pre- and postoperative anterior pituitary function we subjected the results of various hormone loading tests to the Wilcoxon rank sum test. Surgery improved headache and visual impairment in most patients and elevated PRL levels were significantly normalized after surgery (p = 0.004). However, pre- and postoperative anterior pituitary hormone loading tests revealed that the levels of GH, TSH, LH, and FSH were not improved significantly by surgery. Although the ACTH loading test showed postoperative improvement, the change was not statistically significant. We suggest that RCC patients with headache or visual impairment are good candidates for surgery. We also recommend that patients with hyperprolactinemia and those with ACTH deficiency whose MRI findings reveal low-intensity on T1WI and high-intensity on T2WI are likely to benefit from surgery. In contrast, RCC patients with other hormone dysfunctions do not appear to benefit from surgical intervention.

Early morning cortisol levels as predictors of short-term and long-term adrenal function after endonasal transsphenoidal surgery for pituitary adenomas and Rathke's cleft cysts.

OBJECTIVE: Patients undergoing pituitary adenoma or Rathke cleft cyst (RCC) removal are often administered perioperative glucocorticoids regardless of lesion size and preoperative adrenocorticotropic hormone/cortisol levels. To minimize unnecessary glucocorticoid therapy, we describe a protocol in which patients with normal preoperative serum cortisol and adrenocorticotropic hormone levels are given glucocorticoids only if postoperative day 1 or 2 (POD1 or POD2) cortisol levels decrease below normal. METHODS: A total of 207 consecutive patients undergoing endonasal surgery for an adenoma or RCC were considered for study. Of these, 68 patients with preoperative adrenal insufficiency or Cushing disease were excluded. Glucocorticoids were withheld unless POD1 or POD2 morning cortisol values were below normal (≤4 µg/dL). Subsequent adrenal status was assessed through follow-up biochemical and clinical evaluations. RESULTS: The 139 patients included 119 with macroadenomas, 14 microadenomas, and 6 RCCs (follow-up, 3-41 months; median, 10 months). Nine patients (6.5%), all with macroadenomas (mean diameter, 26 ± 10 mm) had low POD1 or POD2 cortisol values and received glucocorticoids; of these, five patients were weaned off within 3-28 weeks of surgery. Overall, 12 of 139 patients (8.6%) were treated for early (n = 9) or delayed (n = 3) adrenal insufficiency but only 5 patients (3.6%) remain on glucocorticoid replacement. No patient experienced an adrenal crisis. Using morning POD1 or POD2 cortisol values >4 µg/dL as a measure of adequate hypothalamic-pituitary-adrenal axis function, yields a sensitivity of 96%, a specificity of 57%, and a positive predictive value of 98%. CONCLUSIONS: In patients with normal preoperative cortisol levels undergoing endonasal removal of a pituitary adenoma or RCC, normal morning cortisol values on POD1 and POD2 reliably predicts adequate and safe adrenal function in 98% of patients. This simple protocol of withholding postoperative glucocorticoids avoids unnecessary steroid exposure and poses minimal risk to the well-informed closely monitored patient.

Edema is a precursor to central nervous system peritumoral cyst formation.

Despite the common occurrence and frequent clinical effects of peritumoral cysts in the central nervous system (CNS), the mechanism underlying their development and evolution is not understood. Because they commonly produce peritumoral cysts and because serial magnetic resonance imaging (MRI) is obtained in von Hippel-Lindau disease patients, hemangioblastomas provide an opportunity to examine the pathophysiology of CNS peritumoral cyst formation. Serial MRI was correlated with the clinical findings in 16 von Hippel-Lindau disease patients with 22 CNS hemangioblastomas (11 spinal cord; 11 cerebellar) that were associated with the appearance and evolution of peritumoral cysts. Hemangioblastoma-associated cyst wall histomorphological analysis was performed on postmortem tissues from three von Hippel-Lindau disease patients (not in the clinical series). Comparative proteomic profiling was performed on peritumoral cyst fluid and serum. Vascular endothelial growth factor levels were determined in peritumoral cysts. MRI clearly showed peritumoral edema that developed and slowly and progressively evolved into enlarging hemangioblastoma-associated cysts in all tumors (mean follow-up, 130 +/- 38 months; mean +/- standard deviation). Postcontrast MRI demonstrated convective leakage of gadolinium into cysts. Mean time required for edema to evolve into a cyst was 36 +/- 23 months (range, 8-72 months). Thirteen (59%) hemangioblastoma-cysts became symptomatic (mean time to symptom formation after cyst development, 35 +/- 32 months; range, 3-102 months) and required resection. Protein profiles of cyst fluid and serum were similar. Mean cyst fluid vascular endothelial growth factor concentration was 1.5 ng/ml (range, 0-5.4 ng/ml). Histology of the cyst walls was consistent with reactive gliosis. CNS peritumoral cyst formation is initiated by increased tumor vascular permeability, increased interstitial pressure in the tumor, and plasma extravasation with convective distribution into the surrounding tissue. When the delivery of plasma from the tumor exceeds the capacity of the surrounding tissue to absorb the extravasated fluid, edema (with its associated increased interstitial pressure) and subsequent cyst formation occur.

Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and correlates with tumor progression.

Vascular endothelial growth factor (VEGF), a key regulatory protein in neoangiogenesis, is strongly expressed in a variety of primary brain tumors, particularly malignant gliomas. In previous studies, high levels of VEGF were also reported in tumor cysts of glioblastomas. Using an ELISA method we measured the concentration of VEGF in matched samples of aspiration fluid from tumor cysts and serum. Samples were collected from 14 patients with primary brain tumors of various histology (six glioblastomas, one protoplasmatic astrocytoma, two pilocytic astrocytomas, one ependymoma, one meningioma, and three craniopharyngiomas) and two patients with solitary cystic brain metastases from adenocarcinomas of the lung. Aspiration fluids of tumor cysts from all patients revealed high VEGF levels ranging between 882 and 1,263,000 pg/ml, which were 2 to more than 2,000 times higher than the corresponding serum levels. Maximum VEGF levels were detectable in cyst fluids from recurrent glioblastoma. Serum VEGF levels ranged between 125 and 716 pg/ml and did not differ from serum levels in 145 healthy volunteers. In a single patient with metastatic lung cancer the concentration of VEGF in serum and cyst fluid was determined during disease progression. During 60 days of follow-up VEGF concentrations in the cyst fluid collected by puncture of an Ommaya reservoir increased 650-fold, while serum levels remained rather constant. These findings indicate that immunoreactive VEGF is produced at the tumor site and abundantly released into the cyst fluid of primary and metastatic brain tumors. Interestingly, this abundant local release is not reflected in serum VEGF levels, even in the case of very high VEGF concentrations in tumor cysts. Thus, VEGF may be biologically relevant for the formation of tumor cysts in brain tumors and correlates with local disease progression.