Placental alkaline phosphatase levels in cerebrospinal fluid can have a decisive role in the differential diagnosis of intracranial germ cell tumors.

OBJECTIVE: Placental alkaline phosphatase (PLAP) in CSF can provide a very high diagnostic value in cases of intracranial germ cell tumors (GCTs), especially in pure germinomas, to the level of not requiring histological confirmation. Unlike other tumor markers, reliable data analysis with respect to the diagnostic value of PLAP serum or CSF levels has not been available until now. This is the first systematic and comprehensive study examining the diagnostic value of CSF PLAP in patients with intracranial GCTs. METHODS: From 2004 to 2014, 74 patients (average age 19.6 ± 10.6 years) with intracranial GCTs were evaluated using PLAP from their CSF and histological samples. Chemiluminescent enzyme immunoassay was utilized to measure CSF PLAP in the following tumor sites: pineal (n = 32), pituitary stalk, suprasellar (n = 16), basal ganglia (n = 15), intraventricular (n = 9), and cerebellar (n = 5) regions. In addition to classifying GCT cases, all patients underwent tumor biopsy for correlation with tumor marker data. RESULTS: PLAP in combination with other tumor markers resulted in extremely high sensitivity and specificity of the diagnostic value of intracranial GCTs. Intracranial GCT cases were classified into 1) germinomas, both "pure" and syncytiotrophoblastic giant cell types (n = 38); 2) nongerminomatous GCTs, choriocarcinomas (n = 9) and teratomas (n = 4); and 3) nongerminomas, other kinds of tumors (n = 23). Consequently, all patients received chemoradiation therapy based on elevation of PLAP and the histopathological results. It was also speculated that the level of PLAP could show the amount of intracranial germ cell components of a GCT. PLAP was 100% upregulated in all intracranial germinoma cases. The absence of CSF PLAP proved that the tumor was not a germinoma. CONCLUSIONS: The current study is the first systematic and comprehensive examination of the diagnostic value of the tumor marker PLAP in pediatric patients with intracranial GCT. Using the level of PLAP in CSF, we were able to detect the instances of intracranial germinoma with very high reliability, equivalent to a pathological diagnosis.

Primary Intracranial Malignant Melanoma with Extracranial Metastasis.

We report a case of primary intracranial malignant melanoma (PIMM) with extracranial metastases. The patient was an 82-year-old woman diagnosed with PIMM under the left cerebellar tentorium. We performed a tumor resection followed by gamma knife surgery. An magnetic resonance imaging at 11 months after surgery showed a local intracranial recurrence. At 12 months, vertebral metastasis was suspected, and 2-[fluorine-18]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) showed multiple extracranial metastases. She died at 13 months after surgery. Although extracranial metastases of PIMM are extremely rare, we should carefully follow up extracranial metastases together with intracranial ones, especially by FDG-PET/CT, even at an early asymptomatic stage.

[Two Cases of Primary Intracranial Solitary Fibrous Tumor:Genetic Examination of NAB2-STAT6 Fusion and Its Association with Hemangiopericytoma].

Using whole exome and transcriptome sequencing, NAB2-STAT6 gene fusions have recently been identified in patients with solitary fibrous tumors (SFT). We report two cases of SFT in which NAB2-STAT6 fusions were identified. The patients were a 32-year-old man with a parasagittal tumor involving the superior sagittal sinus, and a 40-year-old man with a cerebellar convexity tumor partially involving the transverse sinus. Their tumors were gross totally resected and diagnosed to be SFT according to the following pathological findings:the tumors were composed of spindle cells with a patternless architecture, with prominent stromal collagen and staghorn vessels. An immunohistochemical study yielded positive results for CD34, CD99, and Bcl-2 and negative results for EMA, GFAP, and S100. The MIB-1 indexes were 13 and 7%, respectively. NAB2-STAT6 fusions were detected in both cases with a common fusion variant, NAB2ex6-STAT6ex16/17. We also identified NAB2-STAT6 fusions in two hemangiopericytomas diagnosed in the past with a common variant of NAB2ex6-STAT6ex16/17. These findings suggest that solitary fibrous tumor and hemangiopericytoma may be diagnosed based on the presence of NAB2-STAT6 fusion, and not classified separately because of the same genetic background.

Cranial molding helmet therapy and establishment of practical criteria for management in Asian infant positional head deformity.

BACKGROUND: The growing number of infants with deformational plagiocephaly (DP) has raised clinical questions about which children, at what age, and how molding helmet therapy (MHT) should be performed especially in Japan. METHODS: A total of 1,011 Japanese pediatric head deformity infants had undergone MHT after being diagnosed with non-synostotic DP. Three ratios of left to right comparison (anterior, posterior, and overall) were created and analyzed comparing age of starting treatment, helmet wearing period, and severity of skull deformity before with after MHT. RESULTS: The averages of head symmetry ratios after treatment in all groups (for the occipital region) showed apparent improvement; t(930) = -60.86, p = 0.000. (t(932) = -57.8, p = 0.000.) In the "severe" deformation group, the earlier the treatment was started, the higher symmetry ratio recovery was obtained. Treatment was especially effective when started in 4-month-old infants. In contrast to the "severe" group, the "mild" deformation group showed that MHT was most effective if treatment started before 6 months of age. Again, the earlier the treatment was started, the higher symmetry ratio was achieved, but compared to the "severe" group, it had a modest effect when treatment was started in infants older than 8 months. CONCLUSION: This is the first large-scale molding helmet study reporting the method and efficacy in Japanese infants. It demonstrated that despite the structural and physiological differences from infants of other races, molding helmet therapy is effective in Asian-born infants, provided that intervention timing and recognition conditions are met.

[A case of cavernous sinus epidermoid: anatomical classification and surgical approach].

Epidermoid rarely appears in the cavernous sinus. We encountered a 41-year-old man with left abducens nerve palsy. A round-shaped, low-density lesion on CT was located lateral to the left cavernous sinus with a compressed and thinned lateral wall of the sphenoid sinus. We could not identify cranial nerves in the cavernous sinus, which was found to be packed with a non-enhanced, high-intensity tumor on both T1 and T2 MRI. Part of the tumor capsule and its pearly contents were removed with an intradural subtemporal approach, and an inner membranous layer with cranial nerves and a tumor capsule were seen at the bottom of the tumor cavity. Postoperatively, complete cure was achieved. Reviewing similar cases, we found 18 cavernous sinus epidermoids:extracavernous type in 5;interdural in 10;and intracavernous in 3. The interdural type could be further divided into two subtypes:superficial cavernous sinus and inner membranous types. The present case belongs to the former. Frontotemporal and subtemporal procedures via both intra- and extradural approaches are relatively safe for lesions except for the intracavernous type, because cranial nerves are not located in the lateral wall of the tumor. MRI provides more useful information on cranial nerves and aid in choosing a better treatment strategy.

Clinicopathological features of sellar region xanthogranuloma: correlation with Rathke's cleft cyst.

Xanthogranuloma of the sellar region is a rare clinical observation. Although it was included in the World Health Organization (WHO) brain tumor classification in 2000, its clinical features and pathogenesis remain uncertain. We report herein seven cases of xanthogranuloma of the sellar region who underwent transsphenoidal surgery at Tokyo Women's Medical University between 2005 and 2011, and discuss the clinical characteristics of this tumor. Six out of these 7 patients (86 %) presented with endocrinological dysfunction, six (86 %) had headaches, five (71 %) had visual field disturbances, and three (43 %) had diplopia including two with unilateral ptosis. Pathological findings revealed cholesterol clefts, hemosiderin deposits, chronic inflammatory infiltrates, multinucleated giant cells, macrophages, and fibrous proliferation. Of these seven cases, components of Rathke's cleft cyst were observed for six. Xanthogranuloma in the sellar region is suspected of being a terminal stage resulting from a secondary reaction caused by repeated inflammatory change, hemorrhage, and degeneration of a Rathke's cleft cyst.

Histological characteristics of incidentally-found growing meningiomas.

OBJECT: With the wider use of CT and MRI, many meningiomas are discovered as incidental findings during diagnostic work-up for unrelated symptoms. The majority shows no or minimal growth. The purpose of this study was to distinguish pathological features of incidentally-found growing meningiomas by comparing incidentally-found with symptomatic meningiomas. METHODS: One hundred and thirty two consecutive non-recurrent surgically-treated meningiomas treated between 2005 and 2007 were divided into three categories: 19 incidentally-found growing meningiomas (IG), 50 incidentally-found meningiomas (I), and 63 symptomatic (S) meningiomas. The average follow-up period for the IG meningiomas was 3.7 years. Six out of 19 patients of the IG meningiomas became symptomatic during observation. RESULTS: There is a significant difference of the incidence of WHO grades I, II, and III between all three groups (p=0.035). The incidence of WHO grades II and III in groups IG, I, and S were 26%, 2%, and 10%, respectively. We compare MIB-1 staining index between three groups: an average was 3.8% in IG, 1.3% in I, and 2.4% in S meningiomas. CONCLUSIONS: Incidentally-found meningiomas need careful follow-up. One fourth of the meningiomas that showed signs of growing belonged to the atypical or malignant grade.

Technical options for the surgical management of extracranial carotid artery aneurysms. Three case reports.

Three cases of extracranial carotid artery (ECA) aneurysm were treated with various surgical options. Two female patients (74 and 37-year-old women) presented with pulsatile masses in their necks, which were confirmed as ECA aneurysms. Another 65-year-old woman presented with a calcified mass in her neck caused by an ECA aneurysm. The first case was treated with aneurysmorrhaphy with primary closure, the second with replacement of the involved site with vascular prosthesis, and the third with a high flow bypass with proximal ligation of the internal carotid artery. All three different surgical techniques were successful. ECA aneurysms are rare and require careful selection of the surgical method according to etiology, shape, and location of the ECA aneurysm. Proficiency in various vascular reconstruction techniques is a desirable prerequisite for the surgeon in-charge.

[A case of cerebral infarction treated with tissue-plasminogen activator exhibiting prolonged cerebral edema for more than 1 month].

A 62-year-old man with hypertension and diabetes mellitus controlled by medication suddenly noticed slight hemiparesis and was admitted to our hospital. Tissue-plasminogen activator (t-PA) was administered as his NIHSS was 6 and there were no contraindications. His symptoms completely resolved after t-PA injection. He was discharged on Day 9 without neurological deficits despite minor bleeding being detected in a small, low-density area in the right post-central region on CT. However, the hemiparesis gradually recurred subsequently and the low-density area had increased. He was readmitted on Day 38 due to deterioration of symptoms and enhanced CT imaging exhibited a large, low-density area in the central parasagittal region with enhancement was seen. An open biopsy was performed on Day 52 for diagnostic purposes. Histology demonstrated increased small vessels surrounded by many non-specific inflammatory cells and abundant reactive astrocytes. To date, reports of prolonged cerebral edema lasting more than 1 month after cerebral infarction are rare. This condition may be due to angiogenesis induced by t-PA. Another reason may have been the location, i.e., the parasagittal region, which is the most common area for severe cerebral edema after gamma knife surgery.

A highly sensitive and specific chemiluminescent enzyme immunoassay for placental alkaline phosphatase in the cerebrospinal fluid of patients with intracranial germinomas.

BACKGROUND: Placental alkaline phosphatase (PLAP) in cerebrospinal fluid (CSF) has been proposed as a tumor marker for intracranial germinomas. The purpose of the present study was to develop a sensitive assay for measuring CSF PLAP and to evaluate the clinical significance of PLAP in patients with germinomas. METHODS: A chemiluminescent enzyme assay for PLAP was developed using an anti-human-PLAP monoclonal antibody. PLAP concentrations were determined in 37 controls, 36 germinomas, 3 nongerminomatous germ cell tumors, 21 gliomas and 12 other brain tumors. RESULTS: The assay detection limit was 5 pg/ml. The median PLAP concentration in the control group was below the detection limit. Significantly higher PLAP levels were detected in all 36 germinoma patients, with values ranging from 16 to 3,700 pg/ml. The high PLAP concentrations of 17 germinoma patients decreased to below the detection limit after complete remission had been achieved with radiochemotherapy. The sensitivity and specificity of PLAP for germinomas were 94 and 97%, respectively, with a cutoff value of 30 pg/ml. CONCLUSIONS: The results of this study suggest that the determination of CSF PLAP by the chemiluminescent method described here provides a clinically useful tumor marker for the diagnosis and monitoring of intracranial germinomas.

A case of TSH-producing adenoma treated with octreotide in combination with thiamazole for the control of TSH and thyroid hormones after trans-sphenoidal neurosurgery.

While TSH-producing adenoma (TSHoma) is rare, the diagnosis is often delayed because the clinical features are heterogeneous. The patient was a 69-year-old woman who had been referred to the Yachiyo Medical Center in August 2008, because of dyspnea, loss of appetite, weight loss of 10 kg, and diarrhea that lasted 4 years. We diagnosed this patient with pituitary TSH-producing macroadenoma. Thyroid hormone concentration was increasing although the serum TSH level was within a normal range after trans-sphenoidal surgery. We considered that because of enlargement of the thyroid gland due to long-term stimulation by TSH, a low concentration of TSH could stimulate the thyroid gland to produce excess T3 or T4. The somatostatin analogue, octreotide was used to control the TSHoma and serum TSH concentration but not thyroid hormone. The octreotide in combination with thiamazole treatment for 14 months controlled thyroid hormone concentration and decreased the thyroid mass, and ultimately, the thiamazole could be stopped. To date, the use of combination therapy of octreotide with thiamazole in patients with remaining TSH-producing adenoma without Basedow's disease is rare, and we suggest that this treatment is one of the therapeutic means to treat recurrence of TSH-producing adenoma after surgery with progressive complications or large thyroid gland.

High-dose chemotherapy followed by autologous and allogeneic peripheral blood stem cell transplantation for recurrent disseminated trilateral retinoblastoma.

INTRODUCTION: Trilateral retinoblastoma (TRb) is an intracranial neurogenic tumor associated with unilateral or bilateral retinoblastoma and has very poor prognosis. Patients typically die from leptomeningeal tumor dissemination. CASE REPORT: A 3-year-old girl who had been diagnosed with TRb had a disseminated relapse after a tumorectomy, cerebrospinal irradiation, and conventional chemotherapy. The disseminated tumor disappeared after the first autologous peripheral blood stem cell transplantation (PBSCT) with high-dose melphalan and thiotepa. During the second complete remission, a second autologous PBSCT with high-dose busulfan and melphalan was performed. Seven months after the first PBSCT, the second relapse occurred, and we subsequently performed an allogeneic PBSCT with myeloablative chemotherapy consisting of melphalan, thiotepa, and cyclophosphamide. The patient showed clinical improvement after the allogeneic PBSCT. CONCLUSION: Although high-dose chemotherapies have a curative effect for some patients with TRb, the prognoses of disseminated tumors are still poor. Further examination of the high-dose chemotherapy is necessary for the time, the conditioning drugs, and the hematopoietic stem cell sources.

Meningioma of the internal auditory canal with rapidly progressive hearing loss: case report.

A 38-year-old male presented with a meningioma within the internal auditory canal (IAC) manifesting as rapidly progressive hearing loss over a period of one month. He had a 2-year history of tinnitus. Magnetic resonance imaging revealed a 10-mm intracanalicular tumor, which was surgically resected by a retrosigmoid lateral suboccipital approach. The histological findings showed meningothelial meningioma. The patient had no facial palsy after surgery, but his cochlear function did not recover. Common symptoms of IAC meningiomas are tinnitus and hearing loss, but rapidly progressive hearing loss is very rare. IAC meningioma is rare but should be taken into consideration as a cause of rapidly progressive hearing loss.

Shared molecular targets in pediatric gliomas and ependymomas.

BACKGROUND: Recent advances in multidisciplinary treatment approaches have improved the overall prognosis of pediatric brain tumors, but some patients remain refractory to treatment and do poorly. Several molecularly targeted therapies are under development for the treatment of brain tumors, and high-grade gliomas in adults are a particular area of study. PROCEDURE: To better understand if these new therapies can be used in pediatric populations, we examined the expression of the following seven marker genes involved in signaling pathways targeted by new therapies: ß-catenin, suppressor of fused (SUFU), erythroblastic leukemia viral oncogene homolog (ERBB) 2, platelet-derived growth factor receptorα (PDGFRα), proliferating cell nuclear antigen (PCNA), secreted protein acid and rich in cysteine (SPARC), and granulocyte colony-stimulating factor receptor (G-CSFR). Samples from 27 patients with the primitive neuroectodermal tumor (PNET)/medulloblastomas (MBs) (n = 8), ependymomas (n = 5), or gliomas (n = 14) were assessed by quantitative real-time PCR. [Correction made here after initial online publication]. We assigned an EXP score to compare across samples and determined the levels of gene expression among tumor cell types. RESULTS: Gene expression varied among the different tumors, but, within a tumor type, clear expression patterns were seen. The expression of SUFU, ERBB2, and PCNA in metastatic MBs were greater than that seen in non-metastatic MBs. Most glioma cases highly expressed PDGFRα and G-CSFR. Additionally, the expression patterns of gliomas and ependymomas were similar (r = 0.77, P = 0.04), but PNET/MBs substantially differed from gliomas (r = -0.37, P = 0.41) or ependymomas (r = 0.23, P = 0.62). CONCLUSIONS: The development of new drugs targeting up-regulated pathways may be useful for the treatment of pediatric brain tumors. As new drugs are developed, gliomas and ependymomas may be treated with similar compounds.

A case-case study of mobile phone use and acoustic neuroma risk in Japan.

Results of case-control studies of mobile phone use and acoustic neuroma have been inconsistent. We conducted a case-case study of mobile phone use and acoustic neuroma using a self-administered postal questionnaire. A total of 1589 cases identified in 22 hospitals throughout Japan were invited to participate, and 787 cases (51%) actually participated. Associations between laterality of mobile phone use prior to the reference dates (1 and 5 years before diagnosis) and tumor location were analyzed. The overall risk ratio was 1.08 (95% confidence interval (CI), 0.93-1.28) for regular mobile phone use until 1 year before diagnosis and 1.14 (95% CI, 0.96-1.40) for regular mobile phone use until 5 years before diagnosis. A significantly increased risk was identified for mobile phone use for >20 min/day on average, with risk ratios of 2.74 at 1 year before diagnosis, and 3.08 at 5 years before diagnosis. Cases with ipsilateral combination of tumor location and more frequently used ear were found to have tumors with smaller diameters, suggesting an effect of detection bias. Furthermore, analysis of the distribution of left and right tumors suggested an effect of tumor-side-related recall bias for recall of mobile phone use at 5 years before diagnosis. The increased risk identified for mobile phone users with average call duration >20 min/day should be interpreted with caution, taking into account the possibilities of detection and recall biases. However, we could not conclude that the increased risk was entirely explicable by these biases, leaving open the possibility that mobile phone use increased the risk of acoustic neuroma.

A case of corticotroph carcinoma that caused multiple cranial nerve palsies, destructive petrosal bone invasion, and liver metastasis.

A 52-year-old woman experienced sudden onset of double vision due to a right abducens nerve palsy and was diagnosed as having a pituitary macroadenoma that invaded into the right cavernous sinus. Otherwise, she was asymptomatic despite marked elevation of ACTH (293 pg/ml) and cortisol (24.6 µg/dl) levels. The patient underwent transsphenoidal surgery followed by γ-knife radiosurgery (GKR), which healed the diplopia and ameliorated the hypercortisolemia. The excised tumor was diffusely stained for ACTH with a high (15%) Ki-67 labeling index. Early tumor recurrence occurred twice thereafter, producing right lower cranial nerve palsies with petrosal bone destruction at 8 months and an ipsilateral oculomotor nerve palsy at 12 months after GKR; all palsies resolved completely with the second and third GKRs. Hypercortisolemia worsened rapidly soon after the third GKR, and the patient developed marked weight gain, hypokalemia, and hypertension. Multiple liver lesions were incidentally detected with computer tomography and identified as metastatic pituitary tumor on immunohistochemistry. An ACTH-producing adenoma should be followed carefully for early recurrence and/or metastatic spread when the tumor is an invasive macroadenoma with a high proliferation marker level. The unique aggressive behavior and high potential for malignant transformation of this case are discussed.

Precise comparison of protoporphyrin IX fluorescence spectra with pathological results for brain tumor tissue identification.

Photodynamic diagnosis is used during glioma surgery. Although some studies have shown that the spectrum of fluorescence was efficient for precise tumor diagnosis, previous methods to characterize the spectrum have been problematic, which can lead to misdiagnosis. In this paper, we introduce a comparison technique to characterize spectrum from pathology and results of preliminary measurement using human brain tissues. We developed a spectrum scanning system that enables spectra measurement of raw tissues. Because tissue preparations retain the shape of the device holder, spectra can be compared precisely with pathological examination. As a preliminary analysis, we measured 13 sample tissues from five patients with brain tumors. The technique enabled us to measure spectra and compare them with pathological results. Some tissues exhibited a good relationship between spectra and pathological results. Although there were some false positive and false negative cases, false positive tissue had different spectra in which intensity of short-wavelength side was also high. The proposed technique provides an accurate comparison of quantitative fluorescence spectra with pathological results. We found that spectrum analysis may reduce false positive errors. These results will increase the accuracy of tumor tissue identification.

¹H-MRS of intracranial meningiomas: what it can add to known clinical and MRI predictors of the histopathological and biological characteristics of the tumor?

OBJECTIVE: The main goal of the present study was evaluation of proton magnetic resonance spectroscopy (¹H-MRS) in diagnosis of histopathologically aggressive intracranial meningiomas. METHODS: Single-voxel ¹H-MRS of 100 intracranial meningiomas was performed before their surgical resection. Investigated metabolites included mobile lipids, lactate, alanine, N-acetylaspartate (NAA), and choline-containing compounds (Cho). According to criteria of World Health Organization (WHO) 82 meningiomas were assigned histopathological grade I, 11 grade II, and 7 grade III. The MIB-1 index varied from 0% to 27.3% (median, 1.6%). In 43 cases tight adhesion of the tumor to the pia mater or brain tissue was macroscopically identified at surgery. The consistency of 49 meningiomas was characterized as soft, 26 as hard, and 25 as mixed. RESULTS: No one metabolic parameter had statistically significant association with histopathological grade and subtype, invasive growth, and consistency of meningioma. Univariate statistical analysis revealed greater ¹H-MRS-detected Cho content (P=0.0444) and lower normalized NAA/Cho ratio (P=0.0203) in tumors with MIB-1 index 5% and more. However, both parameters lost their statistical significance during evaluation in the multivariate model along with other clinical and radiological variables. It was revealed that non-benign histopathology of meningioma (WHO grade II/III) is mainly predicted by irregular shape (P=0.0076) and large size (P=0.0316), increased proliferative activity by irregular shape (P=0.0056), and macroscopically invasive growth by prominent peritumoral edema (P=0.0021). CONCLUSION: While ¹H-MRS may be potentially used for the identification of meningiomas with high proliferative activity, it, seemingly, could not add substantial diagnostic information to other radiological predictors of malignancy in these tumors.

Double high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation for primary disseminated medulloblastoma: a report of 3 cases.

We performed double high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT) in 3 children with medulloblastoma and primary leptomeningial dissemination, including spinal metastasis. After resection of the main tumor mass, 30.6 Gy whole craniospinal radiation therapy and 4 or 5 courses of conventional chemotherapy with vincristine (1.5 mg/m), carboplatin (560 mg/m), ifosfamide (9000 mg/m), and etoposide (500 mg/m), and 2 courses of high-dose thiotepa (680 mg/m) and melphalan (240 mg/m) therapy with PBSCT were administered. Two patients with low erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene expression achieved long-term survival (41 mo and 40 mo) but the patient with high ERBB2 expression relapsed 9 months after the second PBSCT.