Central nervous system tumor guidelines

Central nervous system tumor guidelines

The NCCN Guidelines for Central nervous system tumor focus on the management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 Oligodendroglioma IDH-mutant and 1p/19q-codeleted, WHO grade 2-4 Astrocytoma IDH-mutants, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastasesleptomeningeal metastases, non-AIDS-related Primary central nervous system lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers is designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of glioma1)

Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS).

The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice.

This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low-grade gliomas, vestibular schwannomas, and metastatic brain tumors 2).


1)

Horbinski C, Nabors LB, Portnow J, Baehring J, Bhatia A, Bloch O, Brem S, Butowski N, Cannon DM, Chao S, Chheda MG, Fabiano AJ, Forsyth P, Gigilio P, Hattangadi-Gluth J, Holdhoff M, Junck L, Kaley T, Merrell R, Mrugala MM, Nagpal S, Nedzi LA, Nevel K, Nghiemphu PL, Parney I, Patel TR, Peters K, Puduvalli VK, Rockhill J, Rusthoven C, Shonka N, Swinnen LJ, Weiss S, Wen PY, Willmarth NE, Bergman MA, Darlow S. NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022. J Natl Compr Canc Netw. 2023 Jan;21(1):12-20. doi: 10.6004/jnccn.2023.0002. PMID: 36634606.
2)

Redjal N, Venteicher AS, Dang D, Sloan A, Kessler RA, Baron RR, Hadjipanayis CG, Chen CC, Ziu M, Olson JJ, Nahed BV. Guidelines in the management of CNS tumors. J Neurooncol. 2021 Feb;151(3):345-359. doi: 10.1007/s11060-020-03530-8. Epub 2021 Feb 21. PMID: 33611702.

Primary central nervous system ALK-negative anaplastic large cell lymphoma

Primary central nervous system ALK-negative anaplastic large cell lymphoma

see also Primary central nervous system ALK-positive anaplastic large cell lymphoma


Primary central nervous system anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an extremely rare type of primary central nervous system lymphoma (PCNSL).

There are only nine cases reported in the literature to date, most of which have an overall survival time of no more than 8 months. Yuan et al. reported such a rare case that has a good outcome with the longest survival time and performed a literature review 1).


George et al. reported four new cases of primary central nervous system ALCL from the Mayo Clinic and incorporated additional data from five previously published cases. ALK-1 expression was determined in all nine tumors. Patient age was 4-66 years (mean 29 years) with a bimodal distribution: 6 < or = 22 years, 3 > or = 50 years. Six were female. Tumors were mostly supratentorial, five were multifocal, and seven had involvement of dura or leptomeninges. Seven tumors were T cells, two were null cells, and five of nine were ALK-1 immunopositive. Total mortality was six of nine. Three patients, 4-18 years of age (mean 13 years), were alive at 4.8-6.1 years postdiagnosis; these tumors were all ALK-positive. Five patients, 13-66 years of age (mean 43 years), died of tumor 4 days to 11 weeks postdiagnosis; four of five of these tumors were ALK-negative. One 10-year-old child with an ALK-positive tumor died of sepsis, but in remission. The central nervous system ALCL is aggressive. The study suggests that a better outcome may be associated with young age and ALK-1 positivity, prognostic parameters similar to systemic ALCL 2).


A review demonstrated that ALK-negative ALCL exhibits a poor prognosis and is very often fatal. The majority of ALK-negative patients were treated with radiotherapy or supportive care, due to their older age or poor PS. As ALK-negative ALCL tends to occur in older individuals, similar to PCNSL and DLBCL, chemoradiotherapy including HD-MTX should be initiated earlier.

In conclusion, findings indicate that the prognosis of ALCL of the CNS is correlated with ALK positivity and patient age of <40 years. Chemoradiotherapy with MTX is recommended as the standard treatment for ALCL. However, additional multicenter studies including large numbers of cases are required 3).

A 19-year-old male patient was admitted to the hospital complaining of dizzinessCT and MRI imaging showed a heterogeneous enhanced lesion in the left parieto-occipital lobe and the leptomeninges of the occipital lobe and the cerebellum. The lesion was resected and confirmed to be ALK-negative ALCL by pathological examination. Then, the patient received 10 cycles of chemotherapy with high-dose methotrexate (HD-MTX) and whole brain radiotherapy. The patient recovered well and was regularly followed up. He was free of symptoms without recurrence on imaging examination 3 years later. ALCL is a rare type of PCNSL. HD-MTX combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify the biological characteristics of this rare type of PCNSL 4).


1) , 4)

Yuan C, Duan H, Wang Y, Zhang J, Ou J, Wang W, Zhang M. Primary central nervous system ALK-negative anaplastic large cell lymphoma: a case report and literature review. Ann Palliat Med. 2021 Jul 1:apm-21-557. doi: 10.21037/apm-21-557. Epub ahead of print. PMID: 34263607.
2)

George DH, Scheithauer BW, Aker FV, Kurtin PJ, Burger PC, Cameselle-Teijeiro J, McLendon RE, Parisi JE, Paulus W, Roggendorf W, Sotelo C. Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression. Am J Surg Pathol. 2003 Apr;27(4):487-93. doi: 10.1097/00000478-200304000-00008. PMID: 12657933.
3)

Nomura M, Narita Y, Miyakita Y, Ohno M, Fukushima S, Maruyama T, Muragaki Y, Shibui S. Clinical presentation of anaplastic large-cell lymphoma in the central nervous system. Mol Clin Oncol. 2013 Jul;1(4):655-660. doi: 10.3892/mco.2013.110. Epub 2013 Apr 30. PMID: 24649224; PMCID: PMC3915681.

Primary Central Nervous System Angiosarcoma

Primary Central Nervous System Angiosarcoma

Angiosarcoma is an infrequent tumor among sarcomas, especially presenting as a primary tumor within the central nervous system, which can lead to rapid neurological deterioration and death in few months.

Mena et al. reported in 1991 eight patients with primary angiosarcoma of the central nervous system these included five males and three females ranging in age from 2 weeks to 72 years (mean 38 years). Of the eight neoplasms, six were located in the cerebral hemispheres and one was in the meninges; the site was unknown in the other. All patients underwent surgical resection. Five of the eight patients died, four within 4 months after surgery and one after 30 months. Two of the remaining three patients were 17 and 27 years old at the time of diagnosis and were alive at follow-up review 39 and 102 months after surgery, respectively. One patient was lost to follow-up monitoring. Microscopically, all eight tumors demonstrated a well-differentiated pattern with irregular vascular channels and intraluminal papillae; in addition, four showed poorly differentiated solid areas. Immunohistochemical staining of neoplastic cells to factor VIII-related antigen and Ulex europaeus agglutinin I was performed in five tumors and was focally positive in four. No correlation could be shown between the histological features and the growth and biological behavior of the tumors 1)

Valera-Melé et al. presented a 41-year old man with a right frontal enhancing hemorrhagic lesion. Surgery was performed with histopathological findings suggesting a primary central nervous system angiosarcoma. He was discharged uneventfully and received adjuvant chemotherapy and radiotherapy. At 5 months, the follow-up MRI showed two lesions with an acute subdural hematoma, suggesting a relapse. Surgery was again conducted finding tumoral membranes attached to the internal layer of the dura mater around the right hemisphere. The patient died a few days later due to the recurrence of the subdural hematoma. This case report illustrates a rare and lethal complication of an unusual tumor. The literature reviewed shows that gross-total resection with adjuvant radiotherapy seems to be the best treatment of choice 2).


Gao M, Li P, Tan C, Liu J, Tie X, Pang C, Guo Z, Lin Y. Primary Central Nervous System Angiosarcoma. World Neurosurg. 2019 Dec;132:41-46. doi: 10.1016/j.wneu.2019.08.128. Epub 2019 Aug 27. PubMed PMID: 31470162 3).


report a case of intracranial angiosarcoma in a Caucasian male and present a review of the imaging features in the recent literature. The tumor mostly presents as a well-demarcated, heterogeneous, moderately to strongly enhancing lesion with signs of intratumoral bleeding and surrounding vasogenic edema. The differential imaging features of common hemorrhagic intracranial tumors are discussed 4).


Two cases of primary angiosarcoma of the brain are well characterized by imaging, histopathology, and immunohistochemistry. Case 1: The first patient was a 35-year-old woman who developed exophthalmos. Subtotal resection of a left extra-axial retro-orbital mass was performed.

Case 2: our second patient was a 47-year-old man who presented with acute visual loss, word-finding difficulty, and subtle memory loss. A heterogeneously-enhancing left sphenoid wing mass was removed. We also review the literature aiming at developing a rational approach to diagnosis and treatment, given the rarity of this entity.

Gross total resection is the standard of care for primary angiosarcoma of the brain. Adjuvant radiation and chemotherapy are playing increasingly recognized roles in the therapy of these rare tumors 5).


1)

Mena H, Ribas JL, Enzinger FM, Parisi JE. Primary angiosarcoma of the central nervous system. Study of eight cases and review of the literature. J Neurosurg. 1991 Jul;75(1):73-6. doi: 10.3171/jns.1991.75.1.0073. PMID: 2045922.
2)

Valera-Melé M, Darriba Allés JV, Ruiz Juretschke F, Sola Vendrell E, Hernández Poveda JM, Montalvo Afonso A, Casitas Hernando V, García Leal R. Primary central nervous system angiosarcoma with recurrent acute subdural hematoma. Neurocirugia (Astur). 2021 Mar 22:S1130-1473(21)00027-0. English, Spanish. doi: 10.1016/j.neucir.2021.02.002. Epub ahead of print. PMID: 33766476.
3)

Gao M, Li P, Tan C, Liu J, Tie X, Pang C, Guo Z, Lin Y. Primary Central Nervous System Angiosarcoma. World Neurosurg. 2019 Dec;132:41-46. doi: 10.1016/j.wneu.2019.08.128. Epub 2019 Aug 27. PubMed PMID: 31470162.
4)

Jerjir N, Lambert J, Vanwalleghem L, Casselman J. Primary Angiosarcoma of the Central Nervous System: Case Report and Review of the Imaging Features. J Belg Soc Radiol. 2016 Oct 10;100(1):82. doi: 10.5334/jbr-btr.1087. PMID: 30151480; PMCID: PMC6100495.
5)

Hackney JR, Palmer CA, Riley KO, Cure JK, Fathallah-Shaykh HM, Nabors LB. Primary central nervous system angiosarcoma: two case reports. J Med Case Rep. 2012 Aug 21;6:251. doi: 10.1186/1752-1947-6-251. PMID: 22909122; PMCID: PMC3459733.

Methotrexate for Primary central nervous system lymphoma

In neurooncology and onco-hematology, intraventricular injection of chemotherapeutic agents (most typically, methotrexate) is an inevitable part of many protocols for treating patients with malignant tumors of the CNS, neuroleukemia, CNS lymphomas and some other disorders.


High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 1).


MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 2).


The addition of intraventricular MTX (rather than just intrathecal via LP) delivered through a Ommaya reservoir (6 doses of 12 mg twice a week, with IV leucovorin rescue) may result in even better survival 3)

In the event of an intrathecal MTX overdose (OD), interventions recommended 4) :

ODs of up to 85 mg can be well tolerated with little sequelae; immediate LP with drainage of CSF can remove a substantial portion of the drug (removing 15 ml of CSF can eliminate ≈ 20–30% of the MTX within 2 hrs of OD). This can be followed by ventriculolumbar perfusion over several hours using 240 ml of warmed isotonic preservative-free saline entering through the ventricular reservoir and exiting through a External lumbar cerebrospinal fluid drainage. For major OD of > 500 mg, add intrathecal administration of 2,000 U of carboxypeptidase G2 (an enzyme that inactivates MTX). In cases of MTX OD, systemic toxicity should be prevented by treating with IV dexamethasone and IV (not IT) leucovorin.


Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. 5).


A study provides Class III evidence that in immunocompetent patients with primary CNS lymphomas (PCNSLs), high-dose methotrexate (HD-MTX) plus rituximab compared with HD-MTX alone improves complete response (CR) and overall survival rates 6).

Case series

Yoon et al. presented the experiences with high-dose methotrexate (HD-MTX) monotherapy for immunocompetent patients with PCNSL at three institutions and investigate factors related to survival.

PCNSL patients, who were histologically confirmed with diffuse large B cells and treated with HD-MTX monotherapy from 2001 to 2016, were retrospectively reviewed. Patients underwent induction chemotherapy with 8 g/m2 of MTX every 10 days (maximum three cycles). Maintenance chemotherapy of 3.5 g/m2 of MTX (maximum six cycles) was selectively performed depending on the response to induction chemotherapy.

A total of 67 patients were included. Although seven patients discontinued induction chemotherapy because of MTX toxicity, 40 (59.7%) patients showed a complete response (CR) to induction chemotherapy. Twenty-six (38.8%) and three (4.5%) patients showed a CR and partial response, respectively, after maintenance chemotherapy. Forty-one patients with recurrence or progression following HD-MTX underwent second-line treatment. Progression-free survival rates were 43% and 24% at 1 and 2 years, respectively. The median overall survival was 40.3 months. In a multivariate analysis, a radiological CR to induction chemotherapy was a significant factor related to prolonged progression-free survival and overall survival (P < 0.05).

MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 7).


A single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL 8).


Zhu et al. studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. They identified 31 patients diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survivals were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 9).

References

1) , 9)

Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT. High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol. 2009 Apr;11(2):211-5. doi: 10.1215/15228517-2008-067. Epub 2008 Aug 29. PMID: 18757775; PMCID: PMC2718993.
2) , 7)

Yoon WS, Park JS, Kim YI, Chung DS, Jeun SS, Hong YK, Yang SH. High-dose methotrexate monotherapy for newly diagnosed primary central nervous system lymphoma: 15-year multicenter experience. Asia Pac J Clin Oncol. 2020 Sep 25. doi: 10.1111/ajco.13427. Epub ahead of print. PMID: 32978898.
3)

DeAngelis LM, Yahalom J, Thaler HT, Kher U. Com- bined Modality Therapy for Primary CNS Lympho- mas.JClinOncol.1992;10:635–643
4)

O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful Treatment of Intrathecal Methotrexate Overdose by Using Ventriculolumbar Perfusion and Intrathecal Instillation of Carboxypeptidase G2. Mayo Clin Proc. 1996; 71:161–165
5)

Tempaku A, Takahashi Y, Kamada H. Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. Acta Haematol. 2019 May 21:1-2. doi: 10.1159/000499100. [Epub ahead of print] PubMed PMID: 31112947.
6)

Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, Grossman SA, Ye X. High-dose methotrexate with or without Rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014 Jul 15;83(3):235-9. doi: 10.1212/WNL.0000000000000593. Epub 2014 Jun 13. PubMed PMID: 24928128; PubMed Central PMCID: PMC4117362.
8)

Ly KI, Crew LL, Graham CA, Mrugala MM. Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience. Oncol Lett. 2016 May;11(5):3471-3476. doi: 10.3892/ol.2016.4393. Epub 2016 Mar 30. PMID: 27123138; PMCID: PMC4840907.

Primary central nervous system lymphoma MRI

Primary central nervous system lymphoma MRI

Reported signal characteristics include:

T1

Typically hypointense to grey matter

T1 C+ (Gd)

typical high-grade tumours show intense homogeneous enhancement while low-grade tumours have absent to moderate enhancement

Peripheral ring enhancement may be seen in immunocompromised patients (HIV/AIDS)

T2

Variable

Majority are iso to hypointense to grey matter

Isointense: 33%

Hypointense: 20% 9 – when present this is a helpful distinguishing feature

Hyperintense: 15-47%, more common in tumours with necrosis

DWI/ADC

Restricted diffusion with ADC values lower than normal brain, typically between 400 and 600 x 10-6 mm2/s (lower than high-grade gliomas and metastases)

A number of studies have suggested that the lower the ADC values of the tumour the poorer the response to tumour and higher likelihood of recurrence

AADC is particularly useful in assessing response to chemotherapy, with increases in ADC values to above those of normal brain predictive of complete response

MR spectroscopy

Large choline peak

Reversed choline/creatinine ratio

Markedly decreased NAA

Lactate peak may also be seen

MR perfusion

Only modest if any increase in rCBV (much less marked than in high-grade gliomas, where angiogenesis is a prominent feature).

Volume

Precise volumetric assessment of brain tumors is relevant for treatment planning and monitoring. However, manual segmentations are time-consuming and impeded by intra- and inter rater variabilities.

To investigate the performance of a deep learning model (DLM) to automatically detect and segment primary central nervous system lymphoma (PCNSL) on clinical MRI.

Study type: Retrospective.

Population: Sixty-nine scans (at initial and/or follow-up imaging) from 43 patients with PCNSL referred for clinical MRI tumor assessment.

Field strength/sequence: T1 weighted image -/T2 weighted image, T1 -weighted contrast-enhanced (T1 CE), and FLAIR at 1.0, 1.5, and 3.0T from different vendors and study centers.

Fully automated voxelwise segmentation of tumor components was performed using a 3D convolutional neural network (DeepMedic) trained on gliomas (n = 220). DLM segmentations were compared to manual segmentations performed in a 3D voxelwise manner by two readers (radiologist and neurosurgeon; consensus reading) from T1 CE and FLAIR, which served as the reference standard.

Statistical tests: Dice similarity coefficient (DSC) for comparison of spatial overlap with the reference standard, Pearson’s correlation coefficient ® to assess the relationship between volumetric measurements of segmentations, and Wilcoxon rank-sum test for comparison of DSCs obtained in initial and follow-up imaging.

The DLM detected 66 of 69 PCNSL, representing a sensitivity of 95.7%. Compared to the reference standard, DLM achieved good spatial overlap for total tumor volume (TTV, union of tumor volume in T1 CE and FLAIR; average size 77.16 ± 62.4 cm3 , median DSC: 0.76) and tumor core (contrast enhancing tumor in T1 CE; average size: 11.67 ± 13.88 cm3 , median DSC: 0.73). High volumetric correlation between automated and manual segmentations was observed (TTV: r = 0.88, P < 0.0001; core: r = 0.86, P < 0.0001). Performance of automated segmentations was comparable between pretreatment and follow-up scans without significant differences (TTV: P = 0.242, core: P = 0.177).

Data conclusion: In clinical MRI scans, a DLM initially trained on gliomas provides segmentation of PCNSL comparable to manual segmentation, despite its complex and multifaceted appearance. Segmentation performance was high in both initial and follow-up scans, suggesting its potential for application in longitudinal tumor imaging.

Level of evidence: 3 TECHNICAL EFFICACY STAGE: 2 1).

1)

Pennig L, Hoyer UCI, Goertz L, et al. Primary Central Nervous System Lymphoma: Clinical Evaluation of Automated Segmentation on Multiparametric MRI Using Deep Learning [published online ahead of print, 2020 Jul 13]. J Magn Reson Imaging. 2020;e27288. doi:10.1002/jmri.27288

Fungal Infections of the Central Nervous System Pathogens, Diagnosis, and Management

Fungal Infections of the Central Nervous System Pathogens, Diagnosis, and Management

by Mehmet Turgut (Editor), Sundaram Challa (Editor), Ali Akhaddar (Editor)

List Price:$199.99

Buy

This book provides comprehensive information on fungal infections of the central nervous system (CNS). Fungal infections are still a major public health challenge for most of the developing world and even for developed countries due to the rising numbers of immune compromised patients, refugee movements, and international travel. Although fungal infections involving the CNS are not particularly common, when they do occur, the results can be devastating in spite of recent advances and currently available therapies. Further, over the past several years, the incidence of these infections has seen a steep rise among immunodeficient patients. In this context, aggressive surgery remains the mainstay of management, but conservative antifungal drug treatment complemented by aggressive surgical debridement may be necessary. Yet the optimal management approach to fungal infections of the CNS remains controversial, owing to the limited individual experience and the variable clinical course of the conditions. Addressing that problem, this comprehensive book offers the ideal resource for neurosurgeons, neurologists and other specialists working with infectious diseases.

Primary central nervous system lymphoma diagnosis

Diagnosing central nervous system (CNS) lymphoma remains a challenge. Most patients have to undergo brain biopsy to obtain tissue for diagnosis, with associated risks of serious complications. Diagnostic markers in blood or cerebrospinal fluid (CSF) could facilitate early diagnosis with low complication rates.


In a retrospective study of patients with Primary central nervous system lymphoma (PCNSL) treated between January 2001 and December 2011 at the Navy General Hospital (Beijing). All included patients were pathologically diagnosed with PCNSL. Specimens were obtained by stereotactic biopsy and diagnosed by pathological examination. Serological panel had to be negative for HIV.

Out of the 118 patients, 73 (61.9%) were male and 45 (38.1%) were female. Median age was 54 (range 11-83) years. All patients had B cell lymphoma. The lesions showed slightly hyperdense shadows on computed tomography (CT) images, and mostly hyperintense T1 and iso- or hyperintense T2 signals on magnetic resonance imaging (MRI). Most lesions showed patchy enhancement after enhanced scanning, and some had the characteristic “butterfly sign” on enhanced MRI. The magnetic resonance spectroscopy of PCNSL manifested as increased Cho peak, moderately decreased NAA peak, and slightly decreased Cr peak. Positron emission tomography indicated high metabolism of 18F-FDG in PCNSL lesions.

MRI is important in the diagnosis of PCNSL. Understanding the imaging features of PCNSL will help improve its diagnosis in clinics 1).


van Westrhenen et al., performed a systematic review literature search for studies on markers in blood or cerebrospinal fluid for the diagnosis CNS lymphoma and assessed the methodological quality of studies with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2).

They evaluated diagnostic value of the markers at a given threshold, as well as differences between mean or median levels in patients versus control groups. Twenty-five studies were included, reporting diagnostic value for 18 markers in CSF (microRNAs -21, -19b, and -92a, RNU2-1f, CXCL13, interleukins -6, -8, and -10, soluble interleukin-2-receptor, soluble CD19, soluble CD27, tumour necrosis factor-alfa, beta-2-microglobulin, antithrombin III, soluble transmembrane activator and calcium modulator and cyclophilin ligand interactor, soluble B cell maturation antigen, neopterin and osteopontin) and three markers in blood (microRNA-21 soluble CD27, and beta-2-microglobulin). All studies were at considerable risk of bias and there were concerns regarding the applicability of 15 studies. CXCL13, beta 2 microglobulin and neopterin have the highest potential in diagnosing CNS lymphoma, but further study is still needed before they can be used in clinical practice 2).

Radiographic features

The most helpful imaging pattern presents mainly in untreated non-immunocompromised patients is of a CT hyperdense avidly enhancing mass, with MRI T1 hypointense, T2 iso- to hypointense, vivid homogeneous gadolinium-enhancing lesion/s with restricted diffusion, subependymal extension, and crossing of the corpus callosum. Unfortunately, this pattern is not always present.

Typically PCNSL are supratentorial (75-85%) and appear as a mass or multiple masses (11-50%) that are usually in contact with the subarachnoid/ependymal surfaces. Crossing the corpus callosum is not infrequently seen. Enhancement on both CT and MRI is pronounced and usually homogeneous. Even with larger lesions, there is little mass effect for size and limited surrounding vasogenic oedema.

Low-grade tumours differ from the more common high-grade PCNSL in several ways:

Deep locations and spinal involvement is more common

Contrast enhancement is absent, irregular or only mild

Disseminated meningeal/intraventricular disease is uncommon, it is seen in ~5% (range 1-7%) of cases at presentation and usually in high-grade cases.

It should be noted that in patients who are immunocompromised (typically HIV/AIDS or post-transplant) appearances are more heterogeneous, including central non-enhancement/necrosis and haemorrhage, although the latter is still uncommon

CT

Most lesions are hyperattenuating (70%) 3

Shows enhancement

Haemorrhage is distinctly uncommon

There are often multiple lesions in patients with HIV/AIDS

MRI

Scintigraphy

Thallium 201

Shows increased uptake

C11 Methionine PET

Shows increased uptake 3).

Flow cytometry

Flow cytometry has a high specificity and can confirm the diagnosis of a lymphoma significantly faster than immunohistochemistry. This allows for rapid initiation of treatment in this highly aggressive tumor. However, since its sensitivity is less than 100%, van der Meulen et al., recommend to perform histology plus immunohistochemistry in parallel to flow cytometry 4).

References

1)

Cheng G, Zhang J. Imaging features (CT, MRI, MRS, and PET/CT) of primary central nervous system lymphoma in immunocompetent patients. Neurol Sci. 2018 Dec 22. doi: 10.1007/s10072-018-3669-7. [Epub ahead of print] PubMed PMID: 30580380.
2)

van Westrhenen A, Smidt LCA, Seute T, Nierkens S, Stork ACJ, Minnema MC, Snijders TJ. Diagnostic markers for CNS lymphoma in blood and cerebrospinal fluid: a systematic review. Br J Haematol. 2018 May 29. doi: 10.1111/bjh.15410. [Epub ahead of print] PubMed PMID: 29808930.
4)

van der Meulen M, Bromberg JEC, Lam KH, Dammers R, Langerak AW, Doorduijn JK, Kros JM, van den Bent MJ, van der Velden VHJ. Flow cytometry shows added value in diagnosing lymphoma in brain biopsies. Cytometry B Clin Cytom. 2018 May 10. doi: 10.1002/cyto.b.21641. [Epub ahead of print] PubMed PMID: 29747221.

Update: Central nervous system high grade neuroepithelial tumor with BCOR alteration

Central nervous system high grade neuroepithelial tumor with BCOR alteration

Central nervous system high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3′ end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features.

CNS HGNET-BCOR display pathological overlap with CNS-PNET and other histological entities 1).

The high expression of IGF-2 may be a common feature of HGNET-BCOR and ependymoma and may represent a target for new approaches. Several monoclonal antibodies and TKIs for IGF1R are being tested in preclinical and early phase clinical studies and may become relevant in the management of this new and aggressive tumor entity 2).

High expression of altered BCOR transcripts in CNS HGNET-BCOR tumors suggests a different mechanism from BCOR loss-of-function mutations reported in other malignancies, such as medulloblastoma 3) 4).

Yoshida et al., performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS 5).

Kirkman et al., describe a pediatric male patient with CNS HGNET-BCOR who developed seeding of the tumor into the site of the surgical wound within months of surgery for resection of a residual posterior fossa tumor.

This case emphasises three important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiological surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinised to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques 6).

Appay et al., reported in 2017, 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecantemozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of “embryonal tumors” or within the category of “mesenchymal, nonmeningothelial tumors” remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity 7).

1)

Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I, Ryzhova M, Koelsche C, Pfaff E, Allen SJ, Balasubramanian G, Worst BC, Pajtler KW, Brabetz S, Johann PD, Sahm F, Reimand J, Mackay A, Carvalho DM, Remke M, Phillips JJ, Perry A, Cowdrey C, Drissi R, Fouladi M, Giangaspero F, Łastowska M, Grajkowska W, Scheurlen W, Pietsch T, Hagel C, Gojo J, Lötsch D, Berger W, Slavc I, Haberler C, Jouvet A, Holm S, Hofer S, Prinz M, Keohane C, Fried I, Mawrin C, Scheie D, Mobley BC, Schniederjan MJ, Santi M, Buccoliero AM, Dahiya S, Kramm CM, von Bueren AO, von Hoff K, Rutkowski S, Herold-Mende C, Frühwald MC, Milde T, Hasselblatt M, Wesseling P, Rößler J, Schüller U, Ebinger M, Schittenhelm J, Frank S, Grobholz R, Vajtai I, Hans V, Schneppenheim R, Zitterbart K, Collins VP, Aronica E, Varlet P, Puget S, Dufour C, Grill J, Figarella-Branger D, Wolter M, Schuhmann MU, Shalaby T, Grotzer M, van Meter T, Monoranu CM, Felsberg J, Reifenberger G, Snuderl M, Forrester LA, Koster J, Versteeg R, Volckmann R, van Sluis P, Wolf S, Mikkelsen T, Gajjar A, Aldape K, Moore AS, Taylor MD, Jones C, Jabado N, Karajannis MA, Eils R, Schlesner M, Lichter P, von Deimling A, Pfister SM, Ellison DW, Korshunov A, Kool M. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell. 2016 Feb 25;164(5):1060-1072. doi: 10.1016/j.cell.2016.01.015. PubMed PMID: 26919435; PubMed Central PMCID: PMC5139621.
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Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012 Aug 2;488(7409):100-5. doi: 10.1038/nature11284. PubMed PMID: 22832583; PubMed Central PMCID: PMC3662966.
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Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jäger N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012 Aug 2;488(7409):106-10. doi: 10.1038/nature11329. PubMed PMID: 22820256; PubMed Central PMCID: PMC3413789.
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Yoshida Y, Nobusawa S, Nakata S, Nakada M, Arakawa Y, Mineharu Y, Sugita Y, Yoshioka T, Araki A, Sato Y, Takeshima H, Okada M, Nishi A, Yamazaki T, Kohashi K, Oda Y, Hirato J, Yokoo H. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol. 2017 Dec 11. doi: 10.1111/bpa.12585. [Epub ahead of print] PubMed PMID: 29226988.
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Monitoring the Nervous System for Anesthesiologists and Other Health Care Professionals

Monitoring the Nervous System for Anesthesiologists and Other Health Care Professionals

Monitoring the Nervous System for Anesthesiologists and Other Health Care Professionals
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This widely praised, first-of-its-kind book has been thoroughly updated, expanded, and enriched with extensive new case material, illustrations, and link-outs to multimedia, practice guidelines, and more. Written and edited by outstanding world experts, this was the first and remains the leading single-source volume on intraoperative neurophysiological monitoring (IOM). It is aimed at graduate students and trainees, as well as members of the operative team, including anesthesiologists, technologists, neurophysiologists, surgeons, and nurses.
Now commonplace in procedures that place the nervous system at risk, such as orthopedics, neurosurgery, otologic surgery, vascular surgery, and others, effective IOM requires an unusually high degree of coordination among members of the operative team. The purpose of the book is to help students, trainees, and team members acquire a better understanding of one another’s roles and thereby to improve the quality of care and patient safety.From the reviews of the First Edition:
“A welcome addition to reference works devoted to the expanding field of nervous system monitoring in the intraoperative period… will serve as a useful guide for many different health care professionals and particularly for anesthesiologists involved with this monitoring modality…An excellent reference…[and] a helpful guide both to the novice and to the developing expert in this field.” ‐‐Canadian Journal of Anesthesia
“Impressive… [The book] is well written, indexed, and illustrated…The chapters are all extensively referenced. It is also very good value at the price….I would recommend this book to all residents and especially to all neuroanesthesiologists. It will make a worthwhile addition to their library.” ‐‐Journal of Neurosurgical Anesthesiology


Product Details

  • Published on: 2017-06-13
  • Original language: English
  • Number of items: 1
  • Dimensions: 10.00″ h x .0″ w x 7.00″ l, .0 pounds
  • Binding: Paperback
  • 718 pages