Kenichi Oyama

High incidence of low O6-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease

CONTEXT Crookes cell adenoma (CCA), characterized by massive Crookes hyaline change in corticotroph adenoma, causes a rare subtype of Cushings disease. In contrast to ordinary corticotroph adenomas, CCAs are generally aggressive and present as invasive macroadenomas, which are refractory to both surgery and radiotherapy and have a high-recurrence rate. Moreover, some patients with CCA present with distant or craniospinal metastases. Currently, there are no effective standard therapies for CCA. OBJECTIVE We report a patient with Crookes cell carcinoma who presented with local invasion and liver metastases, which was refractory to conventional therapeutic modalities including transsphenoidal surgery, radiosurgery, medications, and hepatic transcatheter arterial embolization. After all these treatments failed, the patient had monthly temozolomide administrations, resulting in gradual clinical improvement and biochemical data that were consistent with tumor shrinkage. In glioblastoma, low O(6)-methylguanine DNA methyltransferase (MGMT) expression is associated with epigenetic gene silencing and predicts a better response to temozolomide. METHODS We thus investigated MGMT expression, immunohistochemically, in seven CCAs (five invasive macroadenomas and two invasive microadenomas) and 17 ordinary-type adenomas (OTAs; three noninvasive macroadenomas, 12 noninvasive microadenomas, and two invasive microadenomas) from patients with Cushings disease. RESULTS In seven CCAs, all five invasive macroadenomas exhibited low MGMT expression, defined as <5% nuclear MGMT staining. In 17 OTAs, only one adenoma showed low MGMT expression. CONCLUSION In Cushings disease, invasive macroadenomas including CCA usually have low-MGMT expression. Temozolomide thus may be a new therapeutic option for invasive macroadenomas such as CCA particularly when conventional treatments are ineffective.

Surgical outcome in 90 patients with craniopharyngioma: an evaluation of transsphenoidal surgery.

OBJECTIVE To analyze surgical outcomes in 90 patients with craniopharyngioma treated by standard transsphenoidal surgery (TSS) or extended transsphenoidal surgery (eTSS). METHODS From 1990-2008, 90 patients (64 adults and 26 children) underwent TSS for craniopharyngioma (34 subdiaphragmatic and 56 supradiaphragmatic). TSS was performed as the initial surgery in 62 patients and as the second procedure in 28 patients. RESULTS Total tumor removal was achieved in 70 (77.8%) patients, subtotal removal was achieved in 17 (18.9%), and partial removal was achieved in 3 (3.3%). Total removal was more often accomplished in initial surgery (56 of 62 [90.3%]) than second surgery (14 of 28 [50.0%]). Postoperative deterioration of anterior pituitary hormones developed in 31 of 47 (66.0%) patients with preoperative normal function or partial anterior pituitary loss. New-onset postoperative diabetes insipidus (DI) developed in 35 of 67 (52.2%) patients. Of 61 patients with preoperative visual loss, 55 (90.2%) noted some degree of visual improvement after surgery. The early postoperative mortality rate was 2.2% (2 of 90 patients). Cerebrospinal fluid (CSF) leakage occurred in 11 patients (12.2%), and 5 patients required surgical repair of the leak. Tumor recurrence was observed in seven (7.8%) patients during a mean follow-up period of 4.6 years. CONCLUSIONS Most craniopharyngiomas including the supradiaphragmatic type can be removed safely by TSS with a good outcome, although endocrine function frequently worsens after surgery. Dural fascia graft is a very effective technique to prevent CSF leaks, especially after eTSS.

Repeat transsphenoidal surgery for the treatment of remaining or recurring pituitary tumors in acromegaly.

BACKGROUND:Acromegaly is a disorder characterized by hypersecretion of growth hormone caused by a growth hormone–secreting pituitary adenoma. OBJECTIVE:To evaluate the long-term efficacy and safety of repeat transsphenoidal surgery for persistent or recurrent acromegaly. METHODS:We retrospectively reviewed records for 53 acromegalic patients who underwent repeat transsphenoidal surgery for persistent or progressive acromegaly at Toranomon Hospital between 1987 and 2006. Multivariate logistic regression was performed to evaluate preoperative factors influencing the surgical outcome. RESULTS:Thirty-one patients (58.5%) met the criteria for cure on long-term follow-up endocrine findings. Furthermore, 17 patients were well controlled with normal insulin-like growth factor I levels without (2 patients) or with medication (15 patients), whereas insulin-like growth factor I levels were still above normal in 5 patients after postoperative adjuvant therapy. Only 1 patient was undergoing additional hormonal replacement after surgery, although transient cerebrospinal fluid leak, transient abducens nerve palsy, severe nasal bleeding, and pituitary abscess occurred in each patient, respectively. Multivariate analysis clarified that a favorable surgical outcome was achieved in patients without cavernous sinus invasion (hazard ratio 12.56), tumor segmentation (hazard ratio 5.82), or in those older than 40 years old (hazard ratio 3.21). CONCLUSION:Repeat surgery can be performed safely with an approximately 60% long-term cure rate in this series. Reoperation should therefore be considered for persistent or recurrent disease in acromegalic patients in whom adjuvant therapy is not effective enough or cannot be accepted. The careful study of initial or preoperative magnetic resonance imaging and the use of micro-Doppler, endoscope, and eye movement monitoring device during surgery can help increase cure rate with a lower complication rate.

Petrous apex cholesterol granuloma treated via the endoscopic transsphenoidal approach

SummaryNumerous surgical approaches have been used to treat petrous apex cholesterol granulomas. They are usually treated via the transtemporal- or middle fossa approach; some are managed endoscopically. We present a patient treated by the endoscopic transsphenoidal approach and review the literature.

Expression of interleukin-6, interleukin-6 receptor (gp80), and the receptor's signal-transducing subunit (gp130) in human normal pituitary glands and pituitary adenomas.

Interleukin-6 (IL-6) is an important cytokine in cell proliferation and differentiation in several organs. It has also been reported that IL-6 plays a role in secretion or release of pituitary hormones in pituitary hormone–secreting cells and pituitary adenomas, but convincing data in situ have not yet been reported. In this study, we examined the participation of IL-6 in the production of pituitary hormones and the differences between human normal pituitary glands and pituitary adenomas by determination of the localization or expression of IL-6, IL-6 receptor (IL-6R, gp80), and the signal-transducing subunit (gp130) of the receptor using immunohistochemical staining and RT-PCR. IL-6 was mainly expressed in ACTH- and FSH/LH-secreting cells in normal pituitary glands, as shown by double staining. gp 80 and gp130 were coexpressed in almost all GH- and PRL-secreting cells and in approximately 30% of FSH/LH-secreting cells. RT-PCR showed that IL-6 mRNA was expressed in only one of all the pituitary adenomas examined, whereas gp 80 and gp 130 mRNAs were detected in all these pituitary adenomas. In conclusion, IL-6 was mainly expressed in ACTH- and FSH/LH-secreting cells, and the receptors were expressed in GH-, PRL- and FSH/LH-secreting cells in human normal pituitary glands. Furthermore, our data emphasized that the mechanism of IL-6 function in human pituitary adenoma cells is distinct from that in normal pituitary cells.

Expression of proliferation markers in human pituitary incidentalomas.

This study aimed to immunohistochemically assess the proliferation activity of pituitary incidentalomas. A series of 52 incidentalomas studied included 22 gonadotroph cell adenomas, 21 null cell adenomas, and 9 clinically silent adenomas (identified as functioning by immunohistochemistry). We also analyzed the differences in proliferation activity between 43 non-functioning pituitary incidentalomas (not including 9 silent adenomas) and 43 symptomatic non-functioning adenomas (NFAs) that caused visual disturbance. Cell proliferation markers were immunostained using monoclonal Ki-67 (MIB-1) antibody and monoclonal anti-topoisomerase II alpha (Topo-II alpha) antibody. The average of MIB-1 labeling indices in pituitary incidentalomas was 0.61%±0.06%. Overall, both MIB-1 and Topo-II alpha labeling indices of the incidentalomas were significantly lower than those of symptomatic NFAs. There were no significant differences in immunopositivity between the two groups based on gender, age, or subtype. The MIB-1 index of the smallest adenoma group in pituitary incidentalomas was significantly lower than in symptomatic NFAs, while the Topo-II alpha incidentaloma was significantly lower than in symptomatic NFas. Our findings suggest that small or less invasive pituitary incidentalomas should be observed with follow-up MRI. Large or invasive incidentalomas should be surgically treated if the patients show visual disturbances, hypopituitarism, or pituitary apoplexy during the follow-up period.

Sellar Neuroblastoma Mimicking Pituitary Adenoma

Abstract.Objective and importance: Primary intracranial neuroblastomas are rare. They generally arise in the supratentorial parenchyma or paraventricular region. Even more rare are primary sellar neuroblastomas. We present a neuroblastoma that arose in the sellar region and mimicked a non-functioning pituitary adenoma. Clinical presentation: This 33-year-old man presented with bitemporal hemianopsia. MRI showed a sellar mass with suprasellar extension mimicking a pituitary adenoma. Intervention: Because of tumor recurrence and dissemination to the cervical region, he underwent 6 operations and radiosurgery. Detailed histologic examination confirmed the diagnosis of neuroblastoma. Postoperative conventional radiotherapy was effective in reducing the size of the tumor. Conclusion: Neuroblastoma should be considered in the differential diagnosis of patients with sellar lesions.

Immunohistochemical Analysis of RCAS1 in Human Pituitary Adenomas

It has been reported that RCAS1 (receptor-binding cancer antigen expressed on SiSO cells) acts as a ligand for a receptor present on normal peripheral lymphocytes and induces apoptotic cell death. It is expressed in uterine and ovarian carcinomas, especially in invasive cancers. This immunohistochemical study is aimed to elucidate the expression of RCAS1 in human pituitary adenomas in order to clarify its role in their proliferative regulation and invasiveness. Five normal pituitary glands, 50 human pituitary adenomas, and one malignant glioma were subjected to immunohistochemical studies. In normal pituitary glands, immunostaining of RCAS1 and MIB-1 was not found. In malignant glioma, large numbers of cell nuclei were positive for MIB-1 (MIB-1 index: 28%), and RCAS1 was detected both in the cytoplasm and on the membrane of the tumor cells. Expression of RCAS1 was noted in 48% of pituitary adenomas immunohistochemically (60.0% of growth hormone-secreting adenomas, 60.0% of prolactin-secreting adenomas, 42.9% of adrenocorticotrophin-secreting adenomas, 40.0% of thyroid-stimulating hormone-secreting adenomas, 33.3% of nonfunctioning adenomas, and 44.4% of gonadotropin-subunit-positive adenomas). It showed no correlation with tumor type, size, and invasiveness. The statistically significant relationship between RCAS1 and MIB-1 positivity was identified in our study. These results suggest that expression of RCAS1 as well as MIB-1 positivity predict the growth potential of individual pituitary adenomas.

Easy slip-knot: a new simple tying technique for deep sutures

BackgroundKnot-tying in the deep operative field is very complicated because of the narrow working space during endoscopic transsphenoidal surgery. We present a novel technique for tying deep knots called the “easy slip-knot,” which was developed from a knot used to tie fishing lines.MethodAfter threading the dura, an easy slip-knot is made outside the nostril. One end of the string is pulled, the knot then naturally slips, and should reach the operative field without needing a knot-pusher.FindingsThis method is not complicated, is easily applied to the operative field by slipping the knot into position, and is able to tie sutures securely.ConclusionsThe easy slip-knot should be useful for endoscopic surgery.

Diagnostic value of 18F-dihydroxyphenylalanine positron emission tomography for growth hormone-producing pituitary adenoma

A 55-year-old woman with signs of acromegaly was referred to our hospital. Endocrinological examinations showed that she had high levels of growth hormone (GH; 5.54 ng ml(-1); normal range: 0.66-3.68 ng ml(-1)) and insulin-like growth factor-I (IGF-I; 508 ng ml(-1); normal range: 37-266 ng ml(-1)) levels, incomplete suppression of serum GH following a 75-gram oral glucose tolerance test (oGTT; trough GH 3.66 ng ml(-1)), and paradoxical GH responses to a TRH provocation test (peak GH 38.9 ng ml(-1)). Dynamic magnetic resonance imaging (MRI) suggested the presence of an intrasellar mass lesion (5.9 x 2.8 mm) in the left part of her pituitary gland (Fig. 1a, upper panel). F-18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) imaging clearly showed focal but remarkable FDG uptake (Fig. 1a, lower panel), consistent with the localization of the tumor suspected on MRI. The tumor was removed by transsphenoidal surgery. Subsequent histological analysis confirmed the diagnosis of a GH-producing pituitary adenoma. After removal, serum IGF-I levels decreased to a normal range (178 ng ml(-1)), and serum GH was appropriately suppressed during oGTT (trough GH 0.30 ng ml(-1)), suggesting that complete resection was obtained [1]. While postsurgical changes made it difficult to detect any residual lesion on MRI (Fig. 1b, upper panel), abnormal FDG uptake was not seen on FDG-PET after surgery (Fig. 1b, lower panel). PET scans are reported to be a valuable tool for the detection of pituitary adenomas [2-4]. This case clearly showed that FDG-PET is also useful for re-evaluation of the disease after surgery. PET scans are recommended for patients with equivocal pituitary mass lesions on conventional MRI, and for follow-up examinations after surgery.