Prolactin-cell adenoma with signet-ring cells: a case report.

OBJECTIVE: Signet-ring cell changes in the pituitary adenomas are extremely rare. To date, there have been only two reports documenting signet-ring cells in pituitary adenomas, one in a growth-hormone cell adenoma and the other in a nullcell adenoma. This report describes, for the first time, signet-ring cells in a prolactincell adenoma. CASE HISTORY: The patient is a 46-year-old male who presented with severe headache and acute on chronic visual loss. Radiographic studies demonstrated a large cystic pituitary lesion with evidence of pituitary apoplexy. Laboratory values were consistent with a prolactin-cell adenoma. The patient underwent transsphenoidal resection of the prolactin-cell adenoma with significant post-operative improvement. RESULTS: The tumor was composed of sheets of monomorphic round cells with conspicuous nuclei and granular cytoplasm, consistent with pituitary adenoma. Many cells had eccentric, often crescentic-shaped nuclei, imparting a signet-ring appearance and immunostaining was positive for prolactin, denoting an atypical prolactin-cell adenoma. The MIB-1 labeling index was slightly elevated. Electron microscopy demonstrated the presence of vacuolated areas in the cytoplasm that were not membrane bound and did not have specific inclusions. DISCUSSION: This case augments the literature on pituitary adenomas with signet-ring cells. The clinical significance of signet-ring cells in pituitary adenomas is unknown. Accumulation of clinical cases, together with the advances in molecular techniques and experimental models, may yield further insight.

Neurologic complications of inferior petrosal sinus sampling.

BACKGROUND AND PURPOSE: Inferior petrosal sinus sampling (IPSS) is a useful diagnostic technique in adrenocorticotropic hormone (ACTH)-dependent hypercortisolism with normal or equivocal MR imaging. The procedure is believed to be safe, with mostly minor complications. However, there are rare, but severe, neurologic complications that need to be considered. MATERIALS AND METHODS: We performed an institutional review board-approved retrospective review of our institutional IPSS experience from July 2001 to January 2007. IPSS was performed for the evaluation of Cushing disease. The end points of particular interest were the indications for IPSS and the incidence of associated complications. RESULTS: During the study period of 5(1/2) years, 44 patients underwent IPSS for evaluation of Cushing disease. There were 33 women and 11 men with a mean age of 43.1 years. Because of equivocal imaging and endocrine testing, 36 of 44 patients underwent IPSS, and 8 of 44 underwent IPSS after failed transsphenoidal exploration. The only complication was injury to the brain stem that occurred after an unremarkable procedure in a 42-year-old woman. She developed clinical evidence of pontomedullary dysfunction with MR imaging consistent with brain stem infarction. The cause of this injury is unclear, but a venous variant leading to transient venous hypertension or thrombosis is suspected. CONCLUSION: Neurologic injury is a rare but serious complication associated with IPSS. Despite this, if performed under a strict paradigm, IPSS is both accurate and safe and can be very useful in the management of Cushing disease.

Historical movements in transsphenoidal surgery.

Over the past century pituitary surgery has undergone multiple revolutions in surgical technique and technological advancements that have resulted in what is now recognized as modern transsphenoidal surgery. Although the procedure is well established in the current neurosurgical literature, the historical maze that led to its development continues to be of interest because it allows us to appreciate better the unique contributions made by the pioneers of the technique as well as the innovative spirit that continues to fuel neurosurgery. The early events in the history of transsphenoidal surgery have already been well documented. Therefore, the authors summarize the major early transitions along the timeline and then further describe more recent advancements in transsphenoidal surgery such as the surgical microscope, fluoroscopy, endoscopy, intraoperative neuroimaging, frameless image guidance, and radioimmunoassay. The story of these innovations is unique because each was developed as a response to certain needs of the surgeon. An understanding of these more recent contributions coupled with the early history provides a more complete perspective on modern transsphenoidal surgery.

Gender and age in the biochemical assessment of cure of acromegaly.

The principal biochemical criteria for cure in acromegaly are normalization of both glucose-suppressed GH levels and IGF-I levels. As we have reported previously, measurement of GH by highly sensitive assay in conjunction with IGF-I levels has led to a re-appraisal of "normal" GH suppression criteria during an OGTT in subjects with acromegaly. In some patients with active acromegaly, glucose-suppressed GH levels as measured by highly sensitive assay are much lower than could previously be appreciated with less sensitive GH assays and some other patients in apparent remission have subtle abnormalities of GH suppression. A question to arise is whether gender differences in glucose-suppressed GH levels as found by others in young healthy subjects should be considered in our interpretation of OGTT criteria for cure in acromegaly. Therefore, we have evaluated parameters of GH secretion in a larger number of subjects from our cohort of postoperative patients with acromegaly and in healthy subjects in order to determine if gender or age associated differences in these parameters exist. Ninety-two subjects with acromegaly (49 men, 43 women) and 46 age-matched healthy subjects (26 men, 20 women) were evaluated with baseline GH and IGF-I levels and nadir GH levels after a 100 g. OGTT. GH was assayed by highly sensitive IRMA (DSL). Basal GH levels were higher in female than in male healthy subjects, but the fall in GH from baseline (% suppression) was also greater in females resulting in no significant difference in mean nadir GH levels in female vs. male healthy subjects (0.09 vs. 0.08 microg/L). In the subjects with acromegaly, there were no significant gender differences in basal, %GH suppression or nadir GH levels. Basal and nadir GH levels correlated significantly only in subjects with active disease (r=0.84, p<.0001). Similarly, IGF-I levels correlated significantly with basal (r=0.573, p=.0012), and nadir (r=.702, p<.0001) GH levels only in subjects with active disease. Gender differences in IGF-I levels were not apparent in any group of subjects. As expected, IGF-I levels declined with age in those groups of subjects with normal IGF-I levels. Nadir GH levels did not vary with age. In conclusion, we have not found significant gender or age-related differences in nadir GH levels and thus our data does not support separate OGTT criteria for cure in men and women with acromegaly.

Primary intracerebral rosai-dorfman disease: a case report.

A 45-year-old woman presented with an isolated, contrast-enhancing brain lesion in white matter of the right frontal lobe, preoperatively thought to be either a primary brain neoplasm or metastasis. The lesion was demonstrated by histology and immunohistochemistry to be Rosai-Dorfman disease. Central nervous system (CNS) manifestations of this disease are rare. There have been 27 cases of intracranial involvement reported previously. All of them have been dural-based, where the disease clinically and radiologically resembles meningioma. To our knowledge, this is the first case of an isolated intraparenchymal CNS lesion without dural attachment, where the clinical and radiological features resembled an intraparenchymal glial neoplasm, lymphoma or metastatic tumor.

Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure.

Radiation therapy (RT) has traditionally been considered a useful additional therapy for patients with acromegaly not achieving biochemical remission after surgery. However, recent evidence has suggested that RT is not curative in most patients with acromegaly when normalization of the serum insulin-like growth factor I (IGF-I) level is used to define remission. Therefore, we evaluated the success of RT based on IGF-I level in the 47 patients who received RT as part of their treatment from the cohort of 161 patients with acromegaly seen by us between 1981 and 1999. Four patients in whom no post-RT IGF-I level was available were excluded from the analysis. Of the remaining 43 patients, 32 patients received external beam RT, 6 received fractionated stereotactic radiosurgery, 4 received gamma-knife RT, and 1 received proton beam RT. The most recent IGF-I levels in these 43 patients, obtained a mean of 5.2 yr post-RT (range, 0.8-13.2 yr), were compared to age-adjusted normal ranges. IGF-I levels were normal in 17 patients (39.5%) without the addition of medical therapy. The percentage of patients with a normal IGF-I level generally increased with time post-RT; 27% of patients less than 6 yr post-RT, but 69.2% of patients 6 yr or more post-RT had normal IGF-I levels. Using the more traditional criterion for cure, a random GH measurement, 74% of patients had a GH level below 5 ng/mL, and 44% had a GH level below 2.5 ng/mL and would have been considered in remission based on these criteria. We conclude that with time RT remains a useful adjunctive treatment for many patients with acromegaly. RT should be considered along with appropriate medical therapy in selected patients who do not achieve normalization of IGF-I level after surgery or for those resistant to medical therapy.

Absence of peritumoral Crooke's change is associated with recurrence in surgically treated Cushing's disease.

BACKGROUND: Pituitary surgery is the standard treatment for Cushing's disease but is complicated by a recurrence rate that ranges from 5.9 to 27%. Whereas some recurrences may be due to technical or anatomical factors resulting in subtotal resection of adenoma, clinical relapse after total tumor resection is a well-documented occurrence. The factors leading to such recurrences are unknown. METHODS: With the hypothesis that the pathology of the nontumoral adenohypophysis is important in predicting relapse, we undertook a study to determine if the absence of Crooke's change (CC), thought to be an indicator of nontumoral corticotroph inhibition, was associated with unexpected clinical recurrence. Twenty-one patients with Cushing's disease, with gross total resection of intrasellar corticotroph microadenoma, were reviewed independently by 2 neuropathologists for the presence of CC in adjacent adenohypophysis. All tumors were stained with H&E, PAS/orange-G and immunohistochemistry for ACTH. Clinical relapse was determined by chart reviews and defined as serum ACTH > 15 pg/ml, clinically Cushingoid, and/or radiographic evidence of recurrent tumor. RESULTS: Seven of 21 patients recurred; 3 did not have CC in their initial resection specimen. All 3 of these patients had unexpected recurrences at 6 to 48 months post-op. Two patients with CC recurred at one year follow-up, 1 after 4 years and 1 after 5 years. All specimens from patients with long-term cure (follow-up from 9-72 months) contained CC. In this study, the absence of CC in peritumoral adenohypophysis was associated with unexpected recurrence of Cushing's disease (p = 0.0214). CONCLUSIONS: We conclude that absence of CC in peritumoral adenohypophysis may be of some assistance in predicting recurrence of Cushing's disease after adequate resection of intrasellar microadenoma.

Clinical use of the optical digitizer for intracranial neuronavigation.

OBJECTIVE: Computer-assisted frameless navigation techniques are used in many centers for intracranial neurosurgical procedures. In this study, we assessed the accuracy and the clinical usefulness of a frameless system based on the optical digitizer in a variety of intracranial procedures. METHODS: The optical digitizer (StealthStation, Sofamor Danek, Memphis, TN) was used to perform 170 neurosurgical operations. Its accuracy was judged before and after each operation by comparing the computer-estimated error with the real estimated error measured on the patient's anatomy. Several objective factors were evaluated to assess the clinical usefulness of the optical digitizer. For craniotomies, the intraoperative extent of resection based on computer-generated images was compared with that on postoperative images, and the length of hospital stay of patients undergoing frameless procedures was compared with that of patients undergoing conventional procedures. For needle biopsies, clinical usefulness was based on the rate of success in establishing a histological diagnosis. RESULTS: The optical digitizer was accurate to within 2 mm for all procedures. The computer-estimated error was not significantly different from the real estimated error. The intraoperative extent of resection was accurate in 58 of 60 tumor resection patients, as confirmed on postoperative images. Patients undergoing frameless procedures had a significantly shorter hospital stay than those undergoing conventional procedures (7.5 +/- 1 versus 10.8 +/- 1.3 d, P < 0.05). All biopsies were diagnostic. CONCLUSION: The optical digitizer is an accurate frameless device that offers clinical benefits. These include precise surgical resection, decreased hospitalization time, and accurate tissue diagnosis.

Endoscopic resection of colloid cysts: surgical considerations using the rigid endoscope.

OBJECTIVE: Colloid cysts of the third and lateral ventricles have traditionally been treated by transfrontal and transcallosal microsurgical resection or by stereotactic aspiration. Recently, rigid and flexible ventricular endoscopic techniques have been used to treat these lesions. Our study was undertaken to examine the efficacy of rigid endoscopy in the resection of colloid cysts. METHODS: Fifteen patients with a radiological diagnosis of colloid cysts were given the option of undergoing either endoscopic surgery or craniotomy. The average tumor size was 1.43 cm. Fourteen patients underwent planned endoscopic resections, and a craniotomy was performed initially in one patient. RESULTS: Entire tumor resection was achieved with the endoscope in 12 patients (86%). A craniotomy was required for two colloid cysts that could not be resected endoscopically. In total, complete radiographic resections were achieved in 14 patients (93%). There were no permanent complications, although postoperative deficits included short-term memory loss and hemiparesis, each in one patient. CONCLUSION: Rigid endoscopy affords good optical resolution, high magnification, and excellent illumination. Total or near total resection of colloid cysts should be the goal for all patients and can be achieved using the rigid endoscope, with little morbidity, shortened operative time, reduced length of stay, and resolution of symptoms. Although long-term follow-up is needed, we think that endoscopy should be considered as a primary treatment for most patients.

Differential diagnosis of sellar masses.

The differential diagnosis of nonpituitary sellar masses is broad; differentiating among potential etiologies may not always be straightforward because many of these lesions, tumorous and nontumorous, may mimic the clinical, endocrinologic, and radiologic presentations of pituitary adenomas. This article provides an overview of the clinical and radiographic characteristics of both pituitary tumors and the nonpituitary lesions found in the sellar/parasellar region and discusses, in detail, the specific nonpituitary origins of the sellar masses.

Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly.

Traditionally, suppression of GH measured by polyclonal RIA to less than 2.0 microg/L after oral glucose was accepted as evidence of remission after transsphenoidal surgery for acromegaly. Recently, with newer, more sensitive GH assays, a cut-off of less than 1.0 microg/L has been suggested. With the development of accurate insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) assays, additional tools are now available for assessing postoperative GH secretion. There has, however, never been a systematic comparison of sensitive GH, IGF-I, and IGFBP-3 assays in defining disease status in a large cohort of postoperative patients with acromegaly. Therefore, we evaluated how the use of modern assays impacts on our assessment of disease activity in these patients. Sixty postoperative subjects with acromegaly and 25 age-matched healthy subjects were evaluated with nadir GH levels after 100 g oral glucose as well as baseline IGF-I and IGFBP-3 levels. GH was assayed by polyclonal RIA, sensitive immunoradiometric assay (IRMA), and highly sensitive enzyme-linked immunosorbent assay. The mean nadir GH determined by IRMA was 0.09 +/- 0.004 microg/L in the healthy subjects, with the upper limit of the normal nadir being 0.14 microg/L (mean + 2 SD). Subjects with acromegaly were divided into those with active disease (n = 22), defined by elevated IGF-I levels, and those in remission (n = 38), defined by normal IGF-I levels. GH determined by IRMA failed to suppress into the normal range defined by our healthy subjects in all patients with active disease; nadir GH determined by IRMA ranged from 0.33-5.0 microg/L in this group. In 50% of the active group, nadir GH levels determined by IRMA were less than 1.0 microg/L, a GH nadir previously considered normal by strict criteria. When nadir GH levels in the subjects with active disease were measured by polyclonal RIA, there was overlap with the range of RIA values in the healthy subjects. Thus, the IRMA was superior to the RIA in that the overlap between these two groups was eliminated. Subjects with acromegaly in remission included those with normal GH suppression (n = 23; mean nadir GH by IRMA, 0.10 +/- 0.006 microg/L) and others with abnormal GH suppression by IRMA (n = 15; mean nadir GH by IRMA, 0.35 +/- 0.07 microg/L). The latter group may have persistent GH dysregulation detected by the sensitive IRMA. GH levels measured by enzyme-linked immunosorbent assay confirmed the IRMA results. IGFBP-3 levels were significantly higher in subjects with active acromegaly (4940 +/- 301 microg/L) vs. those in healthy subjects (2887 +/- 153 microg/L; P < 0.0001) and those in the subjects in remission (2966 microg/L; P < 0.0001). IGFBP-3 levels correlated overall with IGF-I levels (r = 0.765; P < 0.0001), but IGFBP-3 levels were not predictive of disease status because 32% of the subjects with active acromegaly had normal IGFBP-3 levels. In addition, failure of GH to suppress adequately was not associated with a higher IGFBP-3 level among the subjects in remission. These data indicate that the IRMA is superior to the RIA in distinguishing between patients with active disease (defined by elevated IGF-I levels) and healthy subjects. We also show that GH levels after oral glucose measured with highly sensitive GH assays can be much lower in subjects with active disease than previously believed; values less than 1.0 microg/L may be found in up to 50% of patients. In addition, in 39% of patients in apparent remission with normal IGF-I levels, GH determined by highly sensitive assays fails to suppress normally; it remains to be determined whether these patients are at higher risk for recurrence of active disease.

Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly.

OBJECT: The results of surgical therapy for acromegaly were assessed using carefully conducted endocrinological testing in 115 patients who underwent transsphenoidal surgery from 1981 to 1995. METHODS: Ninety-nine of the 115 patients could be contacted for follow-up review; in 57 of the patients an endocrinological assessment was performed by the authors. Biochemical cure was strictly defined as a normalization of the insulin-like growth factor(IGF)-I level (obtained in 100 patients) and/or a basal or glucose-suppressed growth hormone (GH) level of 2 ng/ml or less. The mean length of follow up from transsphenoidal surgery to laboratory testing was 5.4 years with a maximum of 15.7 years. After transsphenoidal surgery alone, 61% of the patients achieved a biochemical remission; the remission rate was 88% for patients with microadenomas and 53% for those with macroadenomas. Tumor size and preoperative GH level tended to correlate negatively with outcome of surgery. Early postoperative GH level tended to correlate with long-term outcome; in cases in which the early postoperative GH level was lower than 3 ng/ml, the chance of long-term remission was 89%. Thirty-two patients received postoperative radiotherapy: in 10 (31%) of these patients the disease is currently in remission after surgery and radiotherapy only and in three others the disease is in remission with the addition of medical therapy. The overall complication rate was 6.9% with no cerebrospinal fluid leaks, meningitis, permanent diabetes insipidus, or new hypopituitarism. The overall recurrence rate was low at 5.4%. CONCLUSIONS: This series shows, based on IFGF-I measurements and strict GH suppression criteria to define remission, that transsphenoidal surgery provides an excellent chance for long-term cure in patients with microadenomas. Surgery alone is successful in most patients with noninvasive macroadenomas; however, most patients with invasive macroadenomas will require adjunctive therapy. Recurrences are uncommon when biochemical remission is clearly documented postoperatively.

Frequent inactivation of the p16 gene in human pituitary tumors by gene methylation.

Rodent models of pituitary tumorigenesis have implicated the retinoblastoma (Rb) pathway in the development of pituitary tumors. Previously, we reported that loss of p16 expression rather than loss of Rb occurs in most human pituitary adenomas. This alteration in these tumors is not associated with p16 mutation or frequent homozygous p16 gene loss. Our laboratory has now demonstrated that in most human pituitary tumors, the 5' CpG island of the p16 gene is extensively methylated. The high frequency of p16 gene methylation in human pituitary tumors suggests that this alteration is an early and perhaps required event in pituitary cell transformation.

Craniopharyngioma arising de novo in middle age. Case report.

The authors report the case of a 55-year-old woman who developed a symptomatic craniopharyngioma within 2 years of obtaining a normal magnetic resonance image of her brain. Craniopharyngiomas are histologically benign tumors. They are thought to arise from embryonic remnants of Rathke's pouch and sac and to manifest themselves clinically after a steady growth that commences in fetal life. To the authors' knowledge, this is the first report that documents a tumor arising de novo in the sixth decade of life. This report appears to challenge the concept of the origin and natural history of craniopharyngiomas.

Intracerebral hemorrhage occurring remote from the craniotomy site.

OBJECTIVE: The purpose of this study was to analyze the available clinical data on postoperative intracerebral hemorrhages that occur in locations remote from the sites of craniotomy. METHODS: The findings of 37 cases of postoperative intracerebral hemorrhages occurring remote from the craniotomy sites were reviewed (5 from our records and 32 from the literature). RESULTS: Remote postoperative intracerebral hemorrhages presented within the first few hours postoperatively in 78% of the patients and were not related to the types of lesions for which the craniotomies were performed. Supratentorial procedures that produced infratentorial hemorrhages involved operations in the deep sylvian fissure and paraclinoid region in 81% of the patients and hemorrhages in the cerebellar vermis in 67% of the patients. Infratentorial procedures that produced supratentorial hemorrhages were performed with the patient in the sitting position for 87% of the patients. The remote supratentorial hemorrhages that occurred were superficial and lobar in 84% of the patients, as opposed to deep and basal ganglionic, which are classic locations for hypertensive hemorrhages. Remote intracerebral hemorrhages occurring after craniotomies were not associated with hypertension, coagulopathy, cerebrospinal fluid drainage, or underlying occult lesions. These hemorrhages commonly led to significant complications; 5 of 37 patients (14%) were left severely disabled, and 12 of 37 patients (32%) died. CONCLUSIONS: Remote intracerebral hemorrhage is a rare complication of craniotomy with significant morbidity and mortality. Such hemorrhages likely develop at or soon after surgery, tend to occur preferentially in certain locations, and can be related to the craniotomy site, operative positioning, and nonspecific mechanical factors. They do not seem to be related to hypertension, coagulopathy, cerebrospinal fluid drainage, or underlying pathological abnormalities.

Symptoms of pituitary apoplexy rapidly reversed with bromocriptine. Case report.

Macroprolactinomas rarely present with apoplexy. The authors describe a patient with a macroprolactinoma who presented with apoplexy and rapid progression of a third nerve palsy. The patient was managed expectantly with bromocriptine, and within 48 hours, the patient's third nerve palsy had completely resolved. The authors suggest that all patients who present with pituitary apoplexy in the presence of a pituitary tumor receive an immediate course of bromocriptine and steroid therapy until the prolactin level can be determined. Emergency surgery is indicated if visual function is abnormal and the tumor is not a prolactinoma.

Prevention of headache after retrosigmoid removal of acoustic tumors.

OBJECTIVE: To demonstrate a causal relationship between bone dust and the development of headache after retrosigmoid removal of acoustic neuromas. STUDY DESIGN: The study design was both retrospective (group I) and prospective (groups 2 and 3). SETTING: Tertiary Care Referral Center/Outpatient Data Collection. PATIENTS: Eighty-four consecutive patients underwent surgery at the Mount Sinai Medical Center in New York by the same surgical team. INTERVENTION: All patients underwent retrosigmoid removal of acoustic neuromas via the following methods: group 1, standard excision; group 2, excision and cranioplasty; group 3, excision, cranioplasty, and residue trapping. MAIN OUTCOME MEASURE: Presence or absence of postoperative headache. RESULTS: In all, 43 patients (51%) reported postoperative headache. By groups, headache incidence was 64% for group 1 (43% grade 3-4), 81% for group 2 (37% grade 3-4), and 10% (all grade 1) for group 3. Differences with respect to headache incidence and severity were statically significant between groups 1 and 3, and between groups 2 and 3 (p < 0.001). CONCLUSIONS: Free circulation of bone dust into the posterior fossa during intradural drilling of the internal auditory canal may be the most important factor in the development of headache after this surgical procedure.

Abundance and state of phosphorylation of the retinoblastoma gene product in human pituitary tumors.

Targeted disruptions of the retinoblastoma (Rb) gene result in a high frequency of pituitary tumors in heterozygous mice. While our group and others have reported that loss of heterozygosity (LOH) at the Rb locus in human pituitary tumors is rare, these studies have not excluded small inactivating Rb-gene abnormalities more frequently found in human tumors and undetectable by LOH-PCR assays. As a more sensitive means of detecting evidence of these lesions, we have performed Western-blot analysis of several human pituitary tumors to identify Rb loss at the protein level as well as truncated forms of the Rb protein frequently associated with Rb-gene mutations. In 24 tumors, Rb protein was detected at levels 1.4- to 3.9-fold those detected in normal postmortem pituitary. There was no evidence of truncated forms of the Rb protein and only the hypophosphorylated (active) form of the protein was detected in normal and in pituitary tumor specimens. To investigate the possibility of loss of function mutations in certain tumors resulting in the expression of stable, mutant, hypophosphorylated Rb protein, we further performed SSCP analysis of exons 20 through 24 corresponding to the pocket domain of the Rb protein. Of 20 pituitary tumors examined, no mobility shifts could be demonstrated in this analysis. Our findings provide further evidence that primary Rb inactivation is not common in human pituitary tumors. Our detection of only the hypophosphorylated form of the Rb protein probably reflects the low proliferative state of these tumors.