Kiyohiko Sakata

DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors

CONTEXT Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs). OBJECTIVE The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively. DESIGN Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0. SUBJECTS Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available. RESULTS The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fishers exact test). CONCLUSIONS This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.

Acute focal demyelinating disease simulating brain tumors: histopathologic guidelines for an accurate diagnosis.

The object of the present study was to determine the histopathological guidelines for accurate diagnosis of cases of acute focal demyelinating disease that simulates brain tumors. The surgical pathology of three such cases is assessed. Histopathological keys to the diagnosis of such cases are as follows. First, a pattern of sheets of atypical gemistocytic astrocytes in the white matter that show well‐formed processes and that are adequately distanced from each other argues against a diagnosis of neoplasm. Second, uniform distribution of foamy macrophages aligned along axons, with occasional focal collections surrounding blood vessels and in the absence of any associated coagulative necrosis argues against the presence of a tumor. Third, perivascular chronic inflammatory infiltration, especially a mixture of lymphocytes and macrophages, favors the diagnosis of demyelination plaque. In such cases the lymphocytes will be predominantly T cells. Fourth, pleomorphic astrocytic proliferation with a lack of vascular endothelial proliferation should raise the suspicion that the lesion may not be a brain tumor. These diagnostic keys should be followed when diagnosing cases that are suspected to be demyelination processes rather than brain tumors. The presence of demyelination plaque should then be confirmed by imaging modalities such as staining with myelin‐and axon‐specific stains.

Leakage Sign for Primary Intracerebral Hemorrhage A Novel Predictor of Hematoma Growth

Background and Purpose— Recent studies of intracerebral hemorrhage treatments have highlighted the need to identify reliable predictors of hematoma expansion. Several studies have suggested that the spot sign on computed tomographic angiography (CTA) is a sensitive radiological predictor of hematoma expansion in the acute phase. However, the spot sign has low sensitivity for hematoma expansion. In this study, we evaluated the usefulness of a novel predictive method, called the leakage sign. Methods— We performed CTA for 80 consecutive patients presenting with spontaneous intracerebral hemorrhage. Two scans were completed: CTA phase and delayed phase (5 minutes after the CTA phase). By comparing the CTA phase images, we set a region of interest with a 10-mm diameter and calculated the Hounsfield units. We defined a positive leakage sign as a >10% increase in Hounsfield units in the region of interest. Additionally, hematoma expansion was determined on plain computed tomography at 24 hours in patients who did not undergo emergent surgery. Results— Positive spot signs and leakage signs were present in 18 (22%) patients and 35 (43%) patients, respectively. The leakage sign had higher sensitivity (93.3%) and specificity (88.9%) for hematoma expansion than the spot sign. The leakage sign, but not the spot sign, was significantly related with poor outcomes (severely disabled, vegetative state, and death) in all of the patients (P=0.03) and in patients with a hemorrhage in the putamen (P=0.0016). Conclusions— The results indicate that the leakage sign is a useful and sensitive method to predict hematoma expansion.

Sensitivity and usefulness of anti-phosphohistone-H3 antibody immunostaining for counting mitotic figures in meningioma cases

According to current World Health Organization (WHO) criteria, counting mitotic figures (MF), which is equal to the mitotic index (MI), on paraffin sections stained with hematoxylin and eosin (HE) is one of the recognized classification methods for meningiomas. However, it is not always easy to find the area of highest mitotic activity, and there are different perspectives among pathologists with regard to differentiating MF from non-MF, i.e., which are apoptotic figures and which are crushed or distorted cells. Moreover, there is an issue of overgrading in meningiomas with preoperative feeder embolization. Recently, anti-phosphohistone-H3 (PHH3) antibody has been reported as a mitosis-specific marker for meningioma grading. In this study, we attempted PHH3 immunostaining for our meningioma cases and verified not only the sensitivity of PHH3 immunostaining but also that of its usefulness in grading meningiomas. Forty-five initial histologically confirmed meningiomas (37 benign, 7 atypical, and 1 anaplastic) were reviewed according to current WHO criteria based on counting MF on HE-stained slides. PHH3-immunostained MF were counted in the same way, and the MIB-1 labeling index (LI) was calculated for each sample. PHH3-labeled MF were easily identified and permitted rapid recognition of the areas of highest mitotic activity. As a result, significant increase of PHH3 mitotic index (PHH3-MI) in comparison with HE mitotic index (HE-MI) and strong correlations with HE-MI to PHH3-MI as well as PHH3-MI to MIB-1 LI were demonstrated. Furthermore, no significant differences of PHH3-MI between cases with and without feeder embolization were demonstrated. As such, PHH3 may be a sensitive and useful marker for meningioma grading as based on the MF.

Sequential pathological changes during malignant transformation of a craniopharyngioma: A case report and review of the literature

Background: Malignant transformation of craniopharyngiomas is quite rare, and the etiology of transformation remains unclear. The prognosis of malignantly transformed craniopharyngiomas is very poor. Case Description: A 36-year-old male had five craniotomies, five transsphenoidal surgeries, and two radiation treatments until 31 years of age after diagnosis of craniopharyngioma at 12 years of age. All serial pathological findings indicated adamantinomatous craniopharyngioma including those of a surgery performed for tumor regrowth at 31 years of age. However, when the tumor recurred approximately 5 years later, the pathological findings showed squamous metaplasia. The patient received CyberKnife surgery, but the tumor rapidly regrew within 4 months. The tumor was resected with the cavernous sinus via a dual approach: Transcranial and transsphenoidal surgery with an extracranial-intracranial bypass using the radial artery. Pathologic examination of a surgical specimen showed that it consisted primarily of squamous cells; the lamina propria was collapsed, and the tumor cells had enlarged nuclei and clarification of the nucleolus. The tumor was ultimately diagnosed as malignant transformation of craniopharyngioma. After surgery, he received combination chemotherapy (docetaxel, cisplatin, and fluorouracil). The tumor has been well controlled for more than 12 months. Conclusion: Serial pathological changes of the craniopharyngioma and a review of the 20 cases reported in the literature suggest that radiation of the squamous epithelial cell component of the craniopharyngioma led to malignant transformation via squamous metaplasia. We recommend aggressive surgical removal of craniopharyngiomas and avoidance of radiotherapy if possible.

Primary meningeal melanocytoma of the sellar region: review of the literature and differential diagnosis with special reference to angiographical features

PurposePrimary intracranial melanocytomas are rare neoplasms, especially in the sellar region. Intracranial melanocytoma is usually a dural-based tumor, fed by dural arterial branches in a manner similar to meningioma. Primary sellar melanocytoma may be misdiagnosed as hemorrhagic pituitary macroadenoma, spindle cell oncocytoma, and intrasellar meningioma. These tumors differ in some radiological respects, but are difficult to differentiate preoperatively.MethodsOnly five cases of primary sellar/suprasellar melanocytic tumors, excluding melanomas have been reported thus far. In this paper, we report an instructive new case of a 31-year-old woman presenting with a 2-year history of amenorrhea and an intrasellar mass with suprasellar extension, suggestive of hemorrhagic pituitary adenoma.ResultsTranssphenoidal surgical excision was difficult due to extensive bleeding from the lesion, and at the time, the tumor could not be diagnosed histopathologically. Six years later, we operated again because of tumor regrowth. Angiography revealed a hypervascular tumor, which was fed from the dorsal sellar floor. We had difficulty resecting the tumor, but achieved total removal. Our case had typical radiographic characteristics of melanocytoma, revealed by both magnetic resonance imaging and angiography. However, it was difficult to reach a final diagnosis. Further histopathological examination, including immunohistochemical and ultrastructural studies, was helpful for diagnosis of melanocytoma.ConclusionsPrimary sellar melanocytic tumors are derived from melanocytes in the meningeal lining of the sellar floor or in the diaphragm sellae, based on both embryological assumptions and the clinical findings of our case. We discuss the problems of differential diagnosis and management of primary sellar melanocytic tumors.

Nontraumatic aneurysm rupture following an endoscopic third ventriculostomy and ventricular drainage: Case report of a rare complication

Background: Although endoscopic third ventriculostomy is a safe procedure, the authors report a case of aneurysmal subarachnoid hemorrhage as an unusual and serious complication of an endoscopic third ventriculostomy and ventricular drainage. Case Description: A 60-year-old male presented with obstructive hydrocephalus caused by midbrain tumors was admitted to our hospital. Endoscopic third ventriculostomy and external ventricular drainage were successfully performed. Two days after the operation, he became comatose, and a computed tomography (CT) scan revealed a diffuse subarachnoid hemorrhage. Emergency cerebral angiogram showed an aneurysm of the left internal carotid artery. Endovascular coil embolization of the ruptured aneurysm was then performed. Conclusion: The rupture of the aneurysm may have been induced by excessive cerebrospinal fluid drainage after the endoscopic third ventriculostomy. Planning for intracranial endoscopic procedures should consider that rupture of an unknown previously unruptured aneurysm is a possible complication.

Rare case of a rapidly enlarging symptomatic arachnoid cyst of the posterior fossa in an infant: A case report and review of the literature

Background: Intracranial arachnoid cysts are space-occupying lesions that typically remain stable or decrease in size over time. Cysts in infants younger than 1 year of age are remarkably different from those in older children and adults in terms of cyst localization and enlargement. Arachnoid cysts of the posterior fossa (PFACs) are very rare in infants and do not typically grow or present with clinical symptoms, such that surgical treatment is generally considered to be unnecessary. Here, we describe an extremely rare case of an infant with a rapidly enlarging symptomatic PFAC that was successfully treated with surgery. Case Description: A 4-month-old boy presented with increasing head circumference and a rapidly enlarging arachnoid cyst in the left posterior fossa with ventriculomegaly, which was documented using serial imaging over the preceding 2 months. We performed a microscopic resection of the cyst membrane to remove the mass effect as soon as possible and facilitate normal development. To confirm dural closure and prevent cerebrospinal fluid leakage, we also performed short-term (7 days) percutaneous long-tunneled external ventricle drainage after the surgery. Magnetic resonance imaging over a 4-year follow-up period revealed adequate reduction of the ventricle and cyst. The patient no longer exhibited progressive macrocrania and showed normal development. Conclusion: To our knowledge, this is the second successful case of surgical treatment of an enlarging symptomatic PFAC in an infant. Our surgical strategy for the treatment of this rare case can serve as a guide for surgeons in similar future cases.

Double pituitary adenomas associated with persistent trigeminal artery: a rare case report and the review of literature

Multiple pituitary adenomas are rare. We present a quite unique case of double pituitary adenomas associated with persistent trigeminal artery (PTA) treated by endoscopic surgery. To the best of our knowledge, this is the first report in the literature. A 64-year-old woman was referred to our hospital for suspicion of acromegaly. Preoperative magnetic resonance imaging revealed two separate intrasellar masses with intrasellar vascular structure. Right cerebral angiography showed medial-type PTA. The patient underwent endoscopic transsphenoidal surgery and both tumors were resected completely. Postoperative immunohistopathologic examination revealed two histologic types of adenoma: the first tumor was positive for growth hormone (GH), while the second was considered nonfunctioning. Postoperatively, the patient’s serum levels of GH and insulin-like growth factor-1 returned to normal. We observed an extremely rare case of double pituitary adenomas associated with PTA. Preoperative neuroimaging and modern endoscopic surgery are valuable to confirm diagnosis of double pituitary adenomas and identify anatomical localization of PTA.

Is hemifacial spasm affected by changes in the heart rate? A study using heart rate variability analysis

OBJECTIVE Hemifacial spasm (HFS) is caused by arterial conflict at the root exit zone of the facial nerve. As the offending artery is pulsatile in nature, this study investigated the association of heart rate fluctuation with HFS. METHODS Twenty-four preoperative patients underwent simultaneous recordings of facial electromyogram and electrocardiogram overnight. Series of R-wave to R-wave intervals (RRIs) in the electrocardiogram were analyzed across subjects in relation to HFS. The degree of heart rate fluctuation was quantified by analyzing the heart rate variability (HRV). The sleep stage was evaluated during the period of HFS. RESULTS A 0.1 Hz fluctuation in RRIs by 5% compared to the baseline preceded a few seconds the onset of the HFS, indicating that a significant increase in the heart rate coincided with HFS. HRV analysis demonstrated that fluctuations in the heart rate were significantly enhanced during HFS. Wake or light sleep stages were more often accompanied by HFS, suggesting an association with autonomic activities. CONCLUSION Our findings suggest that the etiology of HFS is more than just a mechanical compression of the facial nerve and may involve changes in pulsatile frequency in offending arteries. SIGNIFICANCE We propose the etiology of HFS from a unique standpoint.