[Solitary fibrous tumor/hemangiopericytoma of central nervous system: a clinicopathological analysis of 60 cases].

Objective: To investigate the clinical manifestations, imaging features, clinicopathologic features, and differential diagnosis of solitary fibrous tumors/anginoblastomas (SFT/HPCs) originating in the central nervous system. Methods: Sixty cases of SFT/HPCs originating in the central nervous system were collected at Nanjing Jinling Hospital, from January 1, 2008 to December 31, 2016. The clinical data, imaging data, histomorphologic changes and immunohistochemical finding were analyzed in the sixty cases. Results: The 60 cases included 26 males and 34 females, aged 14 to 85 (median 49) years. The main clinical manifestations were headache, dizziness with nausea and vomiting. Radiologically, the tumors were large, enhancing, solid and cystic masses attached to the dura. Histopathologically, the neoplasms were composed of spindle cells with oval nuclei, inconspicuous nucleoli and moderate amount of eosinophilic cytoplasm arranged in fascicles with areas of hyalinized stroma, myxoid changes and a staghorn vascular pattern. Immunohistochemically, tumor cells of all cases were positive for vimentin (100.0%, 60/60), STAT6 (98.3%, 59/60), CD34 (61.7%, 37/60), and the tumor cells were typically positive for CD99, bcl-2, EMA and SSTR2 as well.Negative for S-100 protein, SOX10, E-cadherin, GFAP. Ki-67 index ranged from 1% to 50%. Forty cases were followed up for 6 to 82 months with average of 40 months, 30 patients were alive and 10 patients died. Conclusions: Central nervous system SFT/HPCs can be aggressive and relapses may occur several years after diagnosis. STAT6 is highly sensitive and specific for the diagnosis. Complete tumor resection is optional treatment followed by radiotherapy and chemotherapy. There is a correlation between the prognosis and the location of the disease, the histological grade, Ki-67 index, and fusion gene variants.

Near-Infrared Triggered Decomposition of Nanocapsules with High Tumor Accumulation and Stimuli Responsive Fast Elimination.

A near-infrared (NIR) induced decomposable polymer nanocapsule is demonstrated. The nanocapsules are fabricated based on layer-by-layer co-assembly of azobenzene functionalized polymers and up/downconversion nanoparticles (U/DCNPs). When the nanocapsules are exposed to 980 nm light, ultraviolet/visible photons emitted by the U/DCNPs can trigger the photoisomerization of azobenzene groups in the framework. The nanocapsules could decompose from large-sized nanocapsule to small U/DCNPs. Owing to their optimized original size (ca. 180 nm), the nanocapsules can effectively avoid biological barriers, provide a long blood circulation (ca. 5 h, half-life time) and achieve four-fold tumor accumulation. It can fast eliminate from tumor within one hour and release the loaded drugs for chemotherapy after NIR-induced dissociation from initial 180 nm capsules to small 20 nm U/DCNPs.

[Solitary fibrous tumor/hemangiopericytoma of central nervous system: a clinicopathologic analysis of 71 cases].

Objective: As solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) share the same molecular genetics features, the 2016 WHO classification of central nervous system (CNS) tumors had created the combined term SFT/HPC and assigns three grades. This study aims to investigate the clinicopathologic characteristics, diagnosis, differential diagnosis and prognosis of CNS SFT/HPC. Methods: Seventy-one cases of CNS SFT and HPC were retrospectively reclassified and studied. Histopathological, immunohistochemical and imaging features were analyzed. The follow-up data were analyzed. Results: There were 37 male and 34 female patients. The median age was 48 years (range, 3-77 years). Twelve cases (17%) were WHO grade Ⅰ, 26 (37%) were WHO grade Ⅱ and 33 (46%) were WHO grade Ⅲ. Microscopically the tumor could show traditional SFT phenotype, HPC phenotype or mixed phenotype. Immunochemically, 97%(69/71) were positive for STAT6, with 96%(66/69)showing diffuse strong staining. Approximately 90% were diffusely positive for bcl-2, CD99 and vimentin. The expression rate of CD34 decreased with increasing tumor grade, and the mean expression rate was 78%. SSTR2a was variably expressed in 10% (7/71) of cases including one case showing strong cytoplasmic staining. A few cases expressed EMA, CD57 and S-100 focally. The Ki-67 index ranged from 1% to 50%. Thirty four patients were followed up for 8-130 months; 12 patients(35%)had recurrences, and two (6%) had liver metastases. Conclusions: CNS SFT/HPC is relatively uncommon. There was significant morphological overlap or transition between different grades. STAT6 is a specific marker for the diagnosis of this tumor. Surgical resection is the preferred treatment. WHO grade Ⅱ and Ⅲ SFT/HPC show rates of local recurrence and systemic metastasis, with liver being the most common site of extracranial metastasis.

The "Liquid Biopsy": the Role of Circulating DNA and RNA in Central Nervous System Tumors.

The detection of tumor-derived circulating nucleic acids in patients with cancer, known as the "liquid biopsy," has expanded from use in plasma to other bodily fluids in an increasing number of malignancies. Circulating nucleic acids could be of particular use in central nervous system tumors as biopsy carries a 5-7 % risk of major morbidity. This application presents unique challenges that have limited the use of cell-free DNA and RNA in the diagnosis and monitoring of CNS tumors. Recent work suggests that cerebrospinal fluid may be a useful source of CNS tumor-derived circulating nucleic acids. In this review, we discuss the available data and future outlook on the use of the liquid biopsy for CNS tumors.

[Primary central nervous system diffuse large B cell lymphoma: a clinicopathologic and molecular study].

Objective: To investigate clinicopathologic characteristics, immunophenotype and EB virus-related molecular genetic alterations in primary central nervous system diffuse large B cell lymphoma (DLBCL) along with correlation with clinical prognosis. Methods: A total of 30 cases of primary central nervous system DLBCL were retrospectively studied by retrieving clinical data, histological evaluation and immunophenotyping by EnVision two steps methods. The expression of EBER mRNA was detected by in situ hybridization and bcl-2, bcl-6 and C-MYC gene abnormalities were analyzed by interphase fluorescence in situ hybridization. Results: The cases included 18 males and 12 females (sex ratio of 1.5∶1.0) with an age ranging from 24 to 78 years (average age of 52 years, the median age of 53 years). The single primary clinical presentation was focal neurologic deficits. Tumor locations were supratentorial (21 cases), subtentorial (7 cases), involving both locations in 2 cases. Diffuse growth pattern was observed with large lymphoid cells mostly resembling centroblasts with abundant basophilic cytoplasm with oval to round, vesicular nuclei containing fine chromatin. An angiocentric and angiodestructive growth pattern was also present. Other features included perivascular space invasion. Immunohistochemical staining using a panel of CD10, bcl-6 and MUM1, six cases were germinal center-like (GCB) and 24 cases were non-germinal central-like (non-GCB). The positive rates of bcl-2, bcl-6 and C-MYC were 53.3% (16/30), 80.0% (24/30) and 20.0% (6/30), respectively. Genetic alterations were detected by FISH and the gene arrangement rates of bcl-2, bcl-6 and C-MYC were 3.3% (1/30), 16.7% (5/30) and 3.3% (1/30), respectively. There were 19 cases in stage 0-1 disease and 11 cases had stage 2-3 disease. Postoperative follow-up for average 13.6 months showed the median survival of 10 months, one-year survival of 46.7% and 16 patients died within a year. Conclusions: The clinical prognosis of primary central nerve system DLBCL depends on age, clinical performence status score, IPI score, immune classification and treatment. Patients typically progress rapidly with the high mortality within one year of diagnosis. Surgical resection combined with high-dose methotrexate or cytarabine chemotherapy offer the best treatment option.

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL).

BACKGROUND: Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. PATIENTS AND METHODS: A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. RESULTS: None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.

Primary CNS lymphoma.

PURPOSE OF REVIEW: Despite recent progress, the diagnosis of primary CNS lymphoma (PCNSL) remains a challenge and is often delayed by several months. Treatment options are still debated and the prognosis of PCNSL lymphoma is poor for most patients. This review will describe recent progress and future orientations for diagnosis of PCNSL and report on the recent trends regarding therapeutic options. RECENT FINDINGS: PCNSL must be suspected in cases of chronic posterior uveitis, especially in patients over 50 years old. Diagnosis is based on cytology and molecular analysis of clonality of vitreous samples. Intraocular interleukin (IL)-10 level has proved to be a valuable tool for screening purposes in cases where there is a suspicion of primary vitreoretinal lymphoma. Intraocular cytokine dosage could also be a useful marker to follow the therapeutic response of patients with PCNSL. Treatment of PCNSL remains under debate. SUMMARY: Diagnosis of PCNSL is challenging. Suspicion relies on clinical history and on IL-10 and IL-6 levels in ocular fluid samples. Definite diagnosis is based on cytology and molecular analysis of clonality. New diagnostic and prognostic markers are currently evaluated. Whether isolated vitreoretinal lymphoma should be treated locally or with systemic treatment remains highly controversial.

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart.

ABSTRACT: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.

Solitary fibrous tumor of the central nervous system: a clinicopathologic study of 24 cases.

OBJECTIVE: Solitary fibrous tumor is a rare, spindle-cell benign mesenchymal neoplasm and has a high recurrence rate. In this study, we reviewed our experience in the diagnosis and treatment of 24 patients with central nervous system solitary fibrous tumors. METHODS: Clinical data were retrieved from the medical records. Prognosis was assessed by clinic service and telephone interview. The specimens were stained with hematoxylin and eosin. Immunohistochemistry for CD34, CD99, EMA, HMB-45, Bcl-2, vimentin, GFAP, S-100, MBP, CK and MIB-1 was performed in all cases. Distributions of time to progression and recurrence were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: The 24 patients included 13 men and 11 women with a median age of 49.0 years. The most frequent initial symptoms were headache, dizziness, unstable walk and hearing loss. The most common location was cerebellar pontine angle (n = 6). Surgery reached gross total removal for 18 patients but subtotal removal for six patients on initial operation. Histopathologic examination showed spindle to oval cells were disposed in wavy fascicles between prominent, eosinophilic bands of collagen. Dense bands of collagen appeared in cross section as minute nodules that separated individual tumor cells. Cellular areas with a partial hemangiopericytoma pattern were noted in six cases. Atypical presentations were shown on initial operation in three cases. CD34, CD99 and vimentin were 100% positive; but EMA, CK, MBP, HBM-45 and GRAP were 100% negative. The positive in Bcl-2, RF and S-100 was 89%, 85% and 26%, respectively. Follow-up information was available for 23 patients. The median follow-up period was 36.0 months. Nine patients recurred and one patient died from the progression. Incomplete surgical resection was significantly associated with recurrence (p = 0.010). MIB-1 labeling index in recurrence was higher than in no recurrence (6.0% versus 3.4%, p = 0.029). All treated with subtotal removal only had subsequent tumor recurrence or progression; however, the two patients who were administered adjuvant radiosurgery after subtotal removal did not recur or progress. Adjuvant radiosurgery seemed to improve the prognosis (p = 0.028). CONCLUSIONS: Solitary fibrous tumor is a rare mesenchymal tumor with a propensity to recur. The most affected area is the cerebellopontine angle. Immunohistochemistry should be used to differentiate solitary fibrous tumor from other tumors. The extent of resection, MIB-1 labeling index and some anaplastic features might be predictive for recurrence. Postoperative radiosurgery might be an option in incompletely resected solitary fibrous tumor. Regular and long-term follow-up remains mandatory to monitor recurrence.

[Guidelines for adult diffuse gliomas WHO grade II, III and IV: pathology and biology. Société franc¸aise de neuropathologie . Réseau de neuro-oncologie pathologique]. / Référentiel gliomes diffus de l'adulte de grade OMS II, III et IV : anatomie pathologique et biologie.

Pathological diagnosis plays a major role in the therapeutic management of adult diffuse gliomas. It is based on the histopathological analysis of a representative specimen. Therefore pathologists might be aware of the neuroradiological features of the lesions. Pathologists play a major role in the management of biological resources. Pathologists should classify adult gliomas according to WHO 2007 classification (histological subtype and grade). In addition, in order to provide the histomolecular classification of adult gliomas, search for molecular markers of diagnostic, prognostic or predictive of therapeutic responses must be performed by appropriate and validated immunohistochemical and molecular techniques. In all diffuse gliomas, whatever their grade, search for IDH1 R132H and P53 expression is required. Search for IDH1 minor mutations and IDH2 mutations is required in grade II and III IDH1 R132H negative gliomas whereas 1p19q codeletion should be searched for in grade II and III gliomas with an oligodendroglial component. Search for EGFR amplification and MGMT promoter methylation is recommended. It is strongly recommended to fill the standardized form for pathology and molecular features (validated by the French Society of Neuropathology) in all adult diffuse gliomas.

Cytology of Extraneural Metastases of Nonhematolymphoid Primary Central Nervous System Tumors: Six Cases with Histopathological Correlation and Literature Update.

INTRODUCTION: Extraneural/-cranial metastases (ENM) of primary central nervous system (CNS) tumors are rare and may be diagnostically challenging. We describe the cytomorphological and pertinent clinical features of ENM in a case series assessed by fine-needle aspiration (FNA). A search of the laboratory information systems of 2 tertiary care centers in Toronto (2000-2015) was performed. Cases with direct extracranial/-spinal extension of CNS neoplasms were excluded. Microscopic slides of FNA and surgical specimens were reviewed. Demographic and clinicopathological data were retrieved. CASE PRESENTATION: Six cases were identified with the original diagnoses of glioblastoma, glioblastoma with primitive neuroectodermal tumor-like components, anaplastic ependymoma, myxopapillary ependymoma, atypical meningioma, and hemangiopericytoma. Median patient age at first diagnosis was 44 years (range 22-56). The time interval between initial diagnosis and first metastatic disease manifestation was 3 months to 19 years. All FNA diagnoses were rendered correctly. In 4 cases, immunohistochemistry was used to support the diagnosis. All cases had prior surgical intervention at the primary tumor site. In 4 cases, the ENM location was the ipsilateral parotid or buccal area. Two primary tumors in midline location developed ENM in the scapular area. DISCUSSION/CONCLUSION: ENM are a rare manifestation of a range of different primary CNS tumors and may involve the ipsilateral head and neck mimicking clinically a salivary gland neoplasm. FNA can rapidly discriminate ENM from other, potentially more indolent conditions. Awareness of the clinical history is paramount to avoid diagnostic confusion.

Histological and immunohistochemical characterization of AT/RT: a report of 15 cases from India.

Atypical teratoid rhabdoid tumor (AT/RT) is a highly malignant embryonal CNS tumor, generally unresponsive to any form of therapy, uniformly fatal within 1 year. We report 15 cases of AT/RT diagnosed at our center over a period of 5 years (2003-08). Tumors were located in different sites of the neuraxis, posterior fossa being the most common (n = 10) followed by cerebral lobes (n = 3). There was one each at the supra sellar and cervical spinal regions, respectively. Radiologically most of the tumors were heterodense and enhancing heterogeneously. The tumors exhibited diverse histological profile that included rhabdoid and PNET areas in all cases, mesenchymal and epithelial areas in 73.3% and 53.3% cases, respectively. Necrosis was evident in all cases and one showed calcification. Tumor cells displayed a polyphenotypic immunoprofile. All cases were consistently positive for vimentin and epithelial membrane antigen and were negative for desmin. Variable positivity was seen for other markers. The number of cases positive for these were: CK (53%), SMA (60%), synaptophysin (66%), NFP (33.3%) and GFAP (85%). CK staining was prominent in epithelial areas, while PNET cells labeled prominently with synaptophysin. There was lack of INI1 expression in all cases. Follow-up was available in 46.6% of cases which revealed a uniform poor prognosis.

Primary central nervous system lymphoma: immunohistochemical profile and prognostic significance.

Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma (NHL) with extranodal location affecting only the CNS, meninges and eye, without visceral or lymph node involvement. Its incidence has increased sharply over the past three decades, especially in immunocompetent subjects. Most PCNSL cases are diffuse large B-cell lymphomas (DLBCLs). However, it differs from nodal DLBCL in that it has a worse prognosis. DLBCLs are a heterogeneous entity and according to new genomic discoveries, classifications into prognostic subgroups have been embarked upon. Two prognostic algorithms were then prepared using a panel of immunohistochemical markers (CD10, Bcl6, MUM1/IRF-4, and Bcl2), thus categorizing DLBCL into two subgroups, GCB (germinal centre B-cell-like) or non-GCB, and into Group 1 or Group 2. Our goal is to apply both of these two sub-classifications to 39 PCNSLs, in order to assess their usefulness and prognostic relevance. 74.3% of our PCNSLs were of a non-GCB phenotype, corresponding to an activated postgerminal origin. They were evenly distributed across G1 and G2. Two- and 5-year overall survival rates were 34.8% and 19.6%, respectively. Younger age (<65) and a therapeutic combination of chemotherapy and radiotherapy significantly improved our patients' survival rates. The other clinical or biological markers tested had no prognostic impact. The two classifications did not reveal any significant survival difference. The recent discovery of a specific "transcriptional signature" of PCNSL, marking them out of DLBCL could account for the irrelevance of such prognostic classifications to PCNSL.

Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: a study of 77 cases.

Primary germ cell tumors of the central nervous system (CNS) sometimes pose diagnostic difficulty. In this study we analyzed the diagnostic utility of a novel marker, SALL4, in 77 such tumors (59 pure and 18 mixed) consisting of the following tumors/tumor components: 49 germinomas, 7 embryonal carcinomas, 27 yolk sac tumors, 3 choriocarcinomas, and 14 teratomas. We also stained SALL4 in 99 primary non-germ cell tumors to test SALL4 specificity. We compared SALL4 with OCT4 in all germ cell tumors and compared SALL4 with alpha-fetoprotein and glypican-3 in all yolk sac tumors. The staining was semiquantitatively scored as 0 (no staining), 1+ (90%). Strong SALL4 staining was observed in all 49 germinomas (4+ in 48, 3+ in 1), 7 embryonal carcinomas (all 4+), and 27 yolk sac tumors (1+ in 1, 2+ in 2, 3+ in 7, 4+ in 17). SALL4 staining, 1+ weak to focally strong, was observed in 2 of 3 choriocarcinomas (in mononucleated trophoblasts) and in 9 of 14 teratomas (in primitive neuroepithelium and teratomatous glands). All germinomas and embryonal carcinomas showed strong OCT4 staining (4+ in all except 1 germinoma with 3+), whereas other germ cell tumors were negative. Out of 27 yolk sac tumors, 26 showed positive alpha-fetoprotein staining (1+ in 9, 2+ in 7, 3+ in 5, and 4+ in 5). All yolk sac tumors showed positive glypican-3 staining (1+ in 6, 2+ in 6, 3+ in 7, and 4+ in 8). The mean percentage of yolk sac tumor cells stained was 84% with SALL4, 45% with alpha-fetoprotein, and 63% with glypican-3 (P<0.01). No non-germ cell tumors showed SALL4 staining. Our results indicate that SALL4 is a novel sensitive diagnostic marker for primary germ cell tumors of the CNS with high specificity. SALL4 is a more sensitive marker than alpha-fetoprotein and glypican-3 for yolk sac tumors.

Oligodendrocyte lineage transcription factor 2 inhibits the motility of a human glial tumor cell line by activating RhoA.

The basic helix-loop-helix transcription factor, oligodendrocyte lineage transcription factor 2 (OLIG2), is specifically expressed in the developing and mature central nervous system and plays an important role in oligodendrogenesis from neural progenitors. It is also expressed in various types of glial tumors, but rarely in glioblastoma. Although we previously showed that OLIG2 expression inhibits glioma cell growth, its role in tumorigenesis remains incompletely understood. Here, we investigated the effect of OLIG2 expression on the migration of the human glioblastoma cell line U12-1. In these cells, OLIG2 expression is controlled by the Tet-off system. Induction of OLIG2 expression inhibited both the migration and invasiveness of U12-1 cells. OLIG2 expression also increased the activity of the GTPase RhoA as well as inducing the cells to form stress fibers and focal adhesions. Experiments using short interfering RNA against p27(Kip1) revealed that up-regulation of the p27(Kip1) protein was not essential for RhoA activation, rather it contributed independently to the decreased motility of OLIG2-expressing U12-1 cells. Alternatively, semiquantitative reverse transcription-PCR analysis revealed that mRNA expression of RhoGAP8, which regulates cell migration, was decreased by OLIG2 expression. Furthermore, expression of C3 transferase, which inhibits Rho via ADP ribosylation, attenuated the OLIG2-induced inhibition of cell motility. Imaging by fluorescence resonance energy transfer revealed that in U12-1 cells lacking OLIG2, the active form of RhoA was localized to protrusions of the cell membrane. In contrast, in OLIG2-expressing cells, it lined almost the entire plasma membrane. Thus, OLIG2 suppresses the motile phenotype of glioblastoma cells by activating RhoA.

Central Nervous System-type Neuroepithelial Tumors and Tumor-like Proliferations Developing in the Gynecologic Tract and Pelvis: Clinicopathologic Analysis of 23 Cases.

Central nervous system (CNS)-type tumors and tumor-like proliferations arising in the gynecologic tract and pelvis are rare. Clinicopathologic features of 23 cases are reported using the current WHO classification system for CNS tumors, with selected relevant immunohistochemical and molecular genetic analyses when possible. There were 12 embryonal tumors, including 7 medulloepitheliomas, 2 embryonal tumors (not otherwise specified), 1 embryonal tumor with multilayered rosettes, 1 embryonal tumor with features of nodular desmoplastic medulloblastoma, and 1 medulloblastoma with extensive nodularity, with primary sites including ovary (7), uterus/endometrium (3), and pelvis (2). Six ovarian tumors had associated germ cell tumors (3 immature teratomas [1 also with yolk sac tumor], 2 mature cystic teratomas, and 1 yolk sac tumor). These tumors typically had some expression of synaptophysin (10/10), GFAP (5/9), S100 (3/6), and NeuN (3/3) and were negative for C19MC amplicon by fluorescence in situ hybridization (0/5). There were 6 glial tumors, including 3 ependymomas (1 anaplastic), 1 oligodendroglioma, not otherwise specified, 1 pilocytic astrocytoma, and 1 atypical glial proliferation after therapy of a high-grade high-stage immature teratoma, with primary sites including ovary (4), fallopian tube (1), and pelvic sidewall (1). Four ovarian tumors had associated teratomas (2 immature and 2 mature). These tumors expressed GFAP (5/6), OLIG2 (2/3), and S100 (1/1), and the pilocytic astrocytoma was negative for BRAF (V600E) mutant protein. There were 4 neuronal or mixed glioneuronal tumors, including 3 neurocytomas and 1 malignant (high-grade) glioneuronal neoplasm, all primary ovarian and associated with teratomas (3 mature, 1 immature). These tumors expressed synaptophysin (4/4), GFAP (1/3), NeuN (1/2), and OLIG2 (1/2). Single-nucleotide polymorphism microarray analysis of the malignant glioneuronal neoplasm demonstrated a partial deletion at location (1)(p36.23p35.2) on chromosome 1p, and 2 regions of deletion at locations (19)(q11q13.12) and (19)(q13.41qter) on 19q. One neurocytoma had no 1p and 19q co-deletions. There was 1 meningioma in the pelvis. For 10 patients with embryonal tumors and follow-up, 5 were alive with no evidence of disease (mean/median: 60/52 mo), 4 were alive with recurrent disease (mean/median: 32/31 mo), and 1 died of disease (13 mo). For 5 patients with other tumor types and follow-up, all were alive without evidence of disease (mean/median: 33/30 mo). Diagnostic evaluation and classification per systems used for primary CNS tumors are recommended for the wide spectrum of CNS-type neuroepithelial tumors that can occur in the female genital tract and pelvis.

Prognostic significance of O6-methylguanine-DNA methyltransferase protein expression in patients with recurrent glioblastoma treated with temozolomide.

BACKGROUND: Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O(6)-methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to TMZ and nitrosoureas. We evaluated the efficacy and safety of the standard 5-day TMZ regimen in patients with recurrent GBM after initial therapy including nitrosourea-based chemotherapy, in conjunction with an analysis of the prognostic value of MGMT protein expression regarding response to TMZ and survival. METHODS: From September 2003 to January 2007, 30 patients having recurrent GBM received 150-200 mg/m(2)/day of TMZ for five consecutive days every 28 days. Tumor tissue from 19 patients was analysed for MGMT protein expression using western blotting, and 17 of them were assessable for a response. RESULTS: The overall response rate was 23.5% (one complete response and three partial responses). Six patients had stable disease (35.3%). Median progression-free survival (PFS) time was 2.2 months, and median overall survival (OS) time was 9.9 months from the initiation of TMZ therapy. Patients with low MGMT protein expression had a significantly improved PFS (P = 0.016) and OS (P = 0.019) compared to those with high expression. Both low MGMT expression (P = 0.040) and re-resection at relapse (P = 0.014) persisted as significant independent favorable prognostic factors for OS. The most common grade 3 and 4 hematological toxicity was lymphopenia (22.2%). CONCLUSIONS: The standard 5-day TMZ regimen resulted in moderate antitumor activity with an acceptable safety profile in patients with nitrosourea-pretreated recurrent GBM, and protein expression of MGMT is an important prognostic factor for patients treated with TMZ even after recurrence.

Programmed Cell Death Ligand 1 Expression in Primary Central Nervous System Lymphomas: A Clinicopathological Study.

BACKGROUND/AIM: Programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) have been shown to predict response to PD-L1/PD-1-targeted therapy. We analyzed PD-L1 expression in primary central nervous system lymphomas (PCNSLs). MATERIALS AND METHODS: PD-L1 protein and mRNA expression were evaluated in 64 PCNSL tissue samples. IFN-γ, IL-10, CD4, and CD8 mRNA expression was also evaluated. RESULTS: PD-L1 protein was detected in tumor cells in 2 (4.1%) cases and in tumor microenvironments in 25 (52%) cases. PD-L1 mRNA positively correlated with IFN-γ (p=0.0024) and CD4 (p=0.0005) mRNA expression. IFN-γ mRNA positively correlated with CD8 mRNA expression (p=0.0001). Furthermore, tumor cell PD-L1 expression correlated positively with overall survival (p=0.0177), whereas microenvironmental PD-L1 expression exhibited an insignificant negative trend with overall survival (p=0.188). CONCLUSION: PD-L1 was expressed on both tumor and/or tumor-infiltrating immune cells in PCNSL. The biological roles of this marker warrant further investigation.

B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry.

In this retrospective study from one institution, we performed a clinicopathological study of a cohort of patients with posttransplant lymphoproliferative disorder (PTLD) confined to the central nervous system. We also identified a comparison cohort of patients with de novo primary diffuse large B-cell lymphoma of the central nervous system. We performed a detailed morphologic review, evaluated Epstein-Barr virus (EBV) by in situ hybridization, and interpreted a panel of immunohistochemical stains in a subset of cases including Hans classification markers (CD10, BCL6, MUM1), p53, CD30, Myc, and BCL2. All 17 of the posttransplant and none of 11 de novo cases were EBV positive (P < .005). Morphologic patterns identified in the PTLD cases were monomorphic diffuse large B-cell lymphoma pattern (10 patients) and "T-cell-rich" pattern (7 patients). The monomorphic posttransplant cases were more likely to be Myc negative (P = .015) and CD30 positive (P < .005) than the de novo cases, and showed a similarly low rate of p53 positivity by immunohistochemistry. No prognostic factors for overall survival were identified. Central nervous system PTLD is EBV positive, typically lacks p53 and Myc expression by immunohistochemistry, and can present with numerous background T lymphocytes.