diffuse

Diffuse midline glioma H3 K27M-altered case series

Diffuse midline glioma H3 K27M-altered case series

2022

Forty-one cases of childhood Diffuse midline glioma H3 K27-altered were collected at Children’s Hospital of Fudan University (39 cases) and Xi’an Children’s Hospital (2 cases), from July 2016 to July 2020. The clinical manifestations, imaging data, histopathology, immunohistochemical phenotype and molecular genetics features, tumor size, site and histological grading were evaluated. Among the 41 cases, 21 were males and 20 females, the age of onset was 3-14 years, the average and median age was 7.6 years and 7.0 years, respectively. The tumor sites were brain stem (n=36) and other locations (n=5). The clinical manifestations were dizziness, gait disturbance, and limb weakness, etc. The MRI features were variable. The histology varied from low-grade to high-grade glioma with neuron differentiation. Immunohistochemistry showed that the tumor cells expressed H3K27M, GFAP, and Olig2. Genetic study showed that 76% (16/21) of tumors had H3F3A gene mutation, mostly accompanied by TP53 (62%, 13/21) missense mutation; five tumors (24%, 5/21) had HIST1H3B gene mutation, accompanied by missense mutations in ACVR1 and PI3K pathway-related gene PIK3CA (4/5) and PIK3R1 (1/5) mutations. The prognosis was dismal with only one alive and others died. The average and median overall survival time was 7 months and 4 months, respectively. Cox multivariate regression analysis showed that age, tumor location, radiologically maximum tumor diameter, histologic grading, and surgical methods were not significantly associated with overall survival rate (P>0.05). Pediatric diffuse midline gliomas with H3K27 alteration have unique clinicopathological and genetic characteristics. The prognosis is poor. The tumor location and histopathologic grading are not related to prognosis. New specific drugs and comprehensive treatment are needed to improve the prognosis 1).

2019

Piccardo et al., from Genoa, Italy. retrospectively analyzed 22 pediatric patients with DMG histologically proved and molecularly classified as H3K27M-mutant (12 subjects) and wild-type (10 subjects) who underwent DWI, Proton magnetic resonance spectroscopic imaging, and ASL performed within 2 weeks of 18F-FDOPA PET. DWI-derived relative minimum apparent diffusion coefficient (rADC min), 1H-MRS data choline/N-acetylaspartate (Cho/NAA), choline/creatine (Cho/Cr), and presence of lactate and relative ASL-derived cerebral blood flow max (rCBF max) were compared with 18F-DOPA uptake Tumor/Normal tissue (T/N) and Tumor/Striatum (T/S) ratios, and correlated with histological and molecular features of DMG. Statistics included Pearson’s chi-square and Mann-Whitney U tests, Spearman’s rank correlation and receiver operating characteristic (ROC) analysis.

The highest degrees of correlation among different techniques were found between T/S, rADC min and Cho/NAA ratio (p < 0.01), and between rCBF max and rADC min (p < 0.01). Significant differences between histologically classified low- and high-grade DMG, independently of H3K27M-mutation, were found among all imaging techniques (p ≤ 0.02). Significant differences in terms of rCBF max, rADC min, Cho/NAA and 18F-DOPA uptake were also found between molecularly classified mutant and wild-type DMG (p ≤ 0.02), even though wild-type DMG included low-grade astrocytomas, not present among mutant DMG. When comparing only histologically defined high-grade mutant and wild-type DMG, only the 18F-DOPA PET data T/S demonstrated statistically significant differences independently of histology (p < 0.003). ROC analysis demonstrated that T/S ratio was the best parameter for differentiating mutant from wild-type DMG (AUC 0.94, p < 0.001).

Advanced MRI and 18F-DOPA PET characteristics of DMG depend on histological features; however, 18F-DOPA PET-T/S was the only parameter able to discriminate H3K27M-mutant from wild-type DMG independently of histology 2).

Baseline diffusion or apparent diffusion coefficient (ADC) characteristics have been shown to predict outcome related to DIPG, but the predictive value of post-radiation ADC is less well understood. ADC parametric mapping (FDM) was used to measure radiation-related changes in ADC and compared these metrics to baseline ADC in predicting progression-free survival and overall survival using a large multi-center cohort of DIPG patients (Pediatric Brain Tumor Consortium-PBTC).

MR studies at baseline and post-RT in 95 DIPG patients were obtained and serial quantitative ADC parametric maps were generated from diffusion-weighted imaging based on T2/FLAIR and enhancement regions of interest (ROIs). Metrics assessed included total voxels with: increase in ADC (iADC); decrease in ADC (dADC), no change in ADC (nADC), fraction of voxels with increased ADC (fiADC), fraction of voxels with decreased ADC (fdADC), and the ratio of fiADC and fdADC (fDM Ratio).

A total of 72 patients were included in the final analysis. Tumors with higher fiADC between baseline and the first RT time point showed a trend toward shorter PFS with a hazard ratio of 6.44 (CI 0.79, 52.79, p = 0.083). In contrast, tumors with higher log mean ADC at baseline had longer PFS, with a hazard ratio of 0.27 (CI 0.09, 0.82, p = 0.022). There was no significant association between fDM derived metrics and overall survival.

Baseline ADC values are a stronger predictor of outcome compared to radiation related ADC changes in pediatric DIPG. We show the feasibility of employing parametric mapping techniques in multi-center studies to quantitate spatially heterogeneous treatment response in pediatric tumors, including DIPG 3).

2017

Meyronet et al., from Lyon analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type).

The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3).

In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis 4).

2015

130 cases of DIPG biopsies and previous published data, these procedures appear to have a diagnostic yield and morbidity rates similar to those reported for other brain locations (3.9 % of transient morbidity in our series). In addition, the quality and the quantity of the material obtained allow to (1) confirm the diagnosis, (2) reveal that WHO grading was useless to predict outcome, and (3) perform an extended molecular screen, including biomarkers study and the development of preclinical models. Recent studies reveal that DIPG may comprise more than one biological entity and a unique oncogenesis involving mutations never described in other types of cancers, i.e., histones H3 K27M and activin receptor ACVR1.

Stereotactic biopsies of DIPG can be considered as a safe procedure in well-trained neurosurgical teams and could be incorporated in protocols. It is a unique opportunity to integrate DIPG biopsies in clinical practice and use the biology at diagnosis to drive the introduction of innovative targeted therapies, in combination with radiotherapy 5).

2007

A suboccipital, transcerebellar approach was used to obtain biopsy samples in 24 children.

Two patients suffered deficits. Both had a transient (< 2 months) new cranial nerve palsy; one of these patients also experienced an exacerbation of a preoperative hemiparesis. No patient died during the perioperative period. A histological diagnosis was made in all 24 patients as follows: 22 had a malignant infiltrative astrocytoma, one had a low-grade astrocytoma, and one had a pilocytic astrocytoma. The diagnosis of the latter two patients affected the initial treatment after the biopsy.

The findings of this study imply that stereotactic biopsy sampling of a diffuse pontine tumor is a safe procedure, is associated with minimal morbidity, and has a high diagnostic yield. A nonmalignant tumor was identified in two of the 24 patients in whom the imaging findings were characteristic of a malignant infiltrative astrocytoma. With the advent of new treatment protocols, stereotactic biopsy sampling, which would allow specific tumor characterization of diffuse pontine lesions, may become standard 6).

1)

Li J, Ma YY, Feng J, Zhao D, Ding F, Tian L, Chen R, Zhao R. [Diffuse midline gliomas with H3K27 alteration in children: a clinicopathological analysis of forty-one cases]. Zhonghua Bing Li Xue Za Zhi. 2022 Apr 8;51(4):319-325. Chinese. doi: 10.3760/cma.j.cn112151-20210830-00625. PMID: 35359043.
2)

Piccardo A, Tortora D, Mascelli S, Severino M, Piatelli G, Consales A, Pescetto M, Biassoni V, Schiavello E, Massollo M, Verrico A, Milanaccio C, Garrè ML, Rossi A, Morana G. Advanced MR imaging and (18)F-DOPA PET characteristics of H3K27M-mutant and wild-type pediatric diffuse midline gliomas. Eur J Nucl Med Mol Imaging. 2019 Apr 27. doi: 10.1007/s00259-019-04333-4. [Epub ahead of print] PubMed PMID: 31030232.
3)

Ceschin R, Kocak M, Vajapeyam S, Pollack IF, Onar-Thomas A, Dunkel IJ, Poussaint TY, Panigrahy A. Quantifying radiation therapy response using apparent diffusion coefficient (ADC) parametric mapping of pediatric diffuse intrinsic pontine glioma: a report from the pediatric brain tumor consortium. J Neurooncol. 2019 Feb 27. doi: 10.1007/s11060-019-03133-y. [Epub ahead of print] PubMed PMID: 30810873.
4)

Meyronet D, Esteban-Mader M, Bonnet C, Joly MO, Uro-Coste E, Amiel-Benouaich A, Forest F, Rousselot-Denis C, Burel-Vandenbos F, Bourg V, Guyotat J, Fenouil T, Jouvet A, Honnorat J, Ducray F. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017 Aug 1;19(8):1127-1134. doi: 10.1093/neuonc/now274. PubMed PMID: 28201752; PubMed Central PMCID: PMC5570304.
5)

Puget S, Beccaria K, Blauwblomme T, Roujeau T, James S, Grill J, Zerah M, Varlet P, Sainte-Rose C. Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas. Childs Nerv Syst. 2015 Oct;31(10):1773-80. doi: 10.1007/s00381-015-2832-1. Epub 2015 Sep 9. PubMed PMID: 26351229.
6)

Roujeau T, Machado G, Garnett MR, Miquel C, Puget S, Geoerger B, Grill J, Boddaert N, Di Rocco F, Zerah M, Sainte-Rose C. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg. 2007 Jul;107(1 Suppl):1-4. PubMed PMID: 17647306.

Diffuse midline glioma H3 K27-altered treatment

Diffuse midline glioma H3 K27-altered treatment

Stereotactic biopsy is being performed in some centers, and may become routine when therapies specifically targeted to these mutations become available.

Diffuse midline glioma H3 K27-altered have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease.

Until recently biopsies were considered not informative enough and therefore not recommended.

GD2-CAR T cell therapy

see GD2-CAR T cell therapy

Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation 1).

Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma 2).

Findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of Diffuse intrinsic pontine glioma (DIPG) that warrants further investigation 3).

1)

Himes BT, Zhang L, Daniels DJ. Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges. Front Oncol. 2019 Feb 8;9:31. doi: 10.3389/fonc.2019.00031. PMID: 30800634; PMCID: PMC6375835.
2)

Gojo J, Pavelka Z, Zapletalova D, Schmook MT, Mayr L, Madlener S, Kyr M, Vejmelkova K, Smrcka M, Czech T, Dorfer C, Skotakova J, Azizi AA, Chocholous M, Reisinger D, Lastovicka D, Valik D, Haberler C, Peyrl A, Noskova H, Pál K, Jezova M, Veselska R, Kozakova S, Slaby O, Slavc I, Sterba J. Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities. Front Oncol. 2020 Jan 10;9:1436. doi: 10.3389/fonc.2019.01436. PMID: 31998633; PMCID: PMC6965319.
3)

Amani V, Prince EW, Alimova I, Balakrishnan I, Birks D, Donson AM, Harris P, Levy JM, Handler M, Foreman NK, Venkataraman S, Vibhakar R. Polo-like Kinase 1 as a potential therapeutic target in Diffuse Intrinsic Pontine Glioma. BMC Cancer. 2016 Aug 18;16:647. doi: 10.1186/s12885-016-2690-6. PubMed PMID: 27538997.

Adult-type diffuse gliomas

Adult-type diffuse gliomas

TERT promoter mutations are one of the most common genetic alterations in adult-type diffuse gliomas and show specific patterns compared with other genetic alterations according to glioma subtypes. This mutation has variable impacts on patient outcomes in association with other genetic alterations, including IDH1/2 mutations or histological types. Arita et al. reviewed the knowledge on the values of TERT promoter mutations in the diagnosis and prognostication of adult-type diffuse gliomas. Although its impact on prognosis is somewhat complicated and enigmatic, the mutational status of the TERT promoter provides highly useful information for predicting patients’ outcomes in the conventional classification of gliomas defined by IDH1/2 and 1p/19q status 1).

Astrocytoma IDH-mutant

Oligodendroglioma IDH-mutant and 1p/19q-codeleted

Glioblastoma IDH-wildtype

1)

Arita H, Ichimura K. Prognostic significance of TERT promoter mutations in adult-type diffuse gliomas. Brain Tumor Pathol. 2022 Jan 31. doi: 10.1007/s10014-021-00424-z. Epub ahead of print. PMID: 35098369.

Diffuse midline glioma H3 K27M-mutant treatment

Diffuse midline glioma H3 K27M-mutant treatment

Stereotactic biopsy is being performed in some centers, and may become routine when therapies specifically targeted to these mutations become available.

Diffuse midline glioma H3 K27M-mutant have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease.

Until recently biopsies were considered not informative enough and therefore not recommended.

Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation 1).

Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma 2).

Although GD2–CAR T-cells demonstrated significant anti-tumor activity against Diffuse midline glioma H3 K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. de Billy et al. investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.

Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.

GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual Insulin-like growth factor 1 receptor( IGF1R/IR) antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo and in vivo.

The study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for Diffuse midline glioma H3 K27M-mutant treatment and, potentially, by pHGG 3).

Findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of Diffuse intrinsic pontine glioma (DIPG) that warrants further investigation 4).

1)

Himes BT, Zhang L, Daniels DJ. Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges. Front Oncol. 2019 Feb 8;9:31. doi: 10.3389/fonc.2019.00031. PMID: 30800634; PMCID: PMC6375835.
2)

Gojo J, Pavelka Z, Zapletalova D, Schmook MT, Mayr L, Madlener S, Kyr M, Vejmelkova K, Smrcka M, Czech T, Dorfer C, Skotakova J, Azizi AA, Chocholous M, Reisinger D, Lastovicka D, Valik D, Haberler C, Peyrl A, Noskova H, Pál K, Jezova M, Veselska R, Kozakova S, Slaby O, Slavc I, Sterba J. Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities. Front Oncol. 2020 Jan 10;9:1436. doi: 10.3389/fonc.2019.01436. PMID: 31998633; PMCID: PMC6965319.
3)

de Billy E, Pellegrino M, Orlando D, Pericoli G, Ferretti R, Businaro P, Ajmone-Cat MA, Rossi S, Petrilli LL, Maestro N, Diomedi-Camassei F, Pezzullo M, De Stefanis C, Bencivenga P, Palma A, Rota R, Del Bufalo F, Massimi L, Weber G, Jones C, Carai A, Caruso S, De Angelis B, Caruana I, Quintarelli C, Mastronuzzi A, Locatelli F, Vinci M. Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant. Neuro Oncol. 2021 Dec 29:noab300. doi: 10.1093/neuonc/noab300. Epub ahead of print. PMID: 34964902.
4)

Amani V, Prince EW, Alimova I, Balakrishnan I, Birks D, Donson AM, Harris P, Levy JM, Handler M, Foreman NK, Venkataraman S, Vibhakar R. Polo-like Kinase 1 as a potential therapeutic target in Diffuse Intrinsic Pontine Glioma. BMC Cancer. 2016 Aug 18;16:647. doi: 10.1186/s12885-016-2690-6. PubMed PMID: 27538997.

Diffuse midline glioma H3 K27M-mutant MRI

Diffuse midline glioma H3 K27M-mutant MRI

T1: decreased intensity

T2: heterogeneously increased

T1 C+ (Gd): usually minimal (can enhance post-radiotherapy)

DWI/ADC: usually normal, occasionally mildly restricted

Extensive spread is relatively frequent, both craniocaudally to involve the cerebral hemispheres and spinal cord, as well as leptomeningeal spread 1)

A study included 66 cases (40 in men, 26 in women) of H3 K27M-mutant glioma in adult patients. Tumors were found in the following sites: thalamus (n = 38), brainstem (n = 6), brainstem with cerebellar or thalamic involvement (n = 4), whole-brain (n = 8), corpus callosum (n = 3), hypothalamus (n = 1), hemispheres (n = 2), and spinal cord (n = 4). All pure brainstem lesions were located posteriorly, and all corpus callosal lesions were in the genu. Most spinal tumors were long-segment lesions. Hemispheric lesions mimicked gliomatosis cerebri in presentation, with the addition of traditional midline structure involvement. Most tumors were solid with relatively uniform signals on plain MRI. Of the 61 cases with contrast-enhanced MR images, 36 (59%) showed partial to no enhancement, whereas 25 (41%) showed diffuse or irregular peripheral enhancement. Hemorrhage and edema were rare. Most lesions were solid and showed mild diffusion restriction on diffusion-weighted imaging. Tumor dissemination to the leptomeninges (n = 8) and subependymal layer (n = 3) was observed.

Qiu et al. described the MRI features of diffuse midline glioma with H3 K27M mutation in the largest study done to date in adult patients. Tumors were found in both midline and nonmidline structures, with the thalamus being the most common site. Although adult H3 K27M-mutant gliomas demonstrated highly variable presentations in this cohort of patients, the authors were able to observe shared characteristics within each location 2).

The radiographic features of diffuse midline gliomas with histone H3 K27M mutation were highly variable, ranging from expansile masses without enhancement or necrosis with large areas of surrounding infiltrative growth to peripherally enhancing masses with central necrosis with the significant mass effect but little surrounding T2/FLAIR hyperintensity. When we compared diffuse midline gliomas on the basis of the presence or absence of histone H3 K27M mutation, there was no significant correlation between enhancement or border characteristics, infiltrative appearance, or presence of edema 3)

Zhuo et al. from the Beijing Tiantan Hospital aimed to predict H3K27M mutation status by Amide proton transfer imaging (APTw) and radiomic features.

Methods: Eighty-one BSG patients with APTw imaging at 3T MR and known H3K27M status were retrospectively studied. APTw values (mean, median, and max) and radiomic features within manually delineated 3D tumor masks were extracted. Comparison of APTw measures between H3K27M-mutant and wildtype groups was conducted by two-sample Student’s T/Mann-Whitney U test and receiver operating characteristic curve (ROC) analysis. H3K27M-mutant prediction using APTw-derived radiomics was conducted using a machine learning algorithm (support vector machine) in randomly selected train (n = 64) and test (n = 17) sets. Sensitivity analysis with additional random splits of train and test sets, 2D tumor masks, and other classifiers were conducted. Finally, a prospective cohort including 29 BSG patients was acquired for validation of the radiomics algorithm.

Results: BSG patients with H3K27M-mutant were younger and had higher max APTw values than those with wildtype. APTw-derived radiomic measures reflecting tumor heterogeneity could predict H3K27M mutation status with an accuracy of 0.88, the sensitivity of 0.92, and specificity of 0.80 in the test set. Sensitivity analysis confirmed the predictive ability (accuracy range: 0.71-0.94). In the independent prospective validation cohort, the algorithm reached an accuracy of 0.86, the sensitivity of 0.88, and specificity of 0.85 for predicting H3K27M-mutation status.

Conclusion: BSG patients with H3K27M-mutant had higher max APTw values than those with wildtype. APTw-derived radiomics could accurately predict an H3K27M-mutant status in BSG patients 4).

Piccardo et al., from Genoa, retrospectively analyzed 22 pediatric patients with DMG histologically proved and molecularly classified as H3K27M-mutant (12 subjects) and wild-type (10 subjects) who underwent DWI, Proton magnetic resonance spectroscopic imaging, and ASL performed within 2 weeks of 18F-FDOPA PET. DWI-derived relative minimum apparent diffusion coefficient (rADC min), 1H-MRS data choline/N-acetylaspartate (Cho/NAA), choline/creatine (Cho/Cr), and presence of lactate and relative ASL-derived cerebral blood flow max (rCBF max) were compared with 18F-DOPA uptake Tumor/Normal tissue (T/N) and Tumor/Striatum (T/S) ratios, and correlated with histological and molecular features of DMG. Statistics included Pearson’s chi-squared test and Mann-Whitney U tests, Spearman’s rank correlation and receiver operating characteristic (ROC) analysis.

The highest degrees of correlation among different techniques were found between T/S, rADC min and Cho/NAA ratio (p < 0.01), and between rCBF max and rADC min (p < 0.01). Significant differences between histologically classified low- and high-grade DMG, independently of H3K27M-mutation, were found among all imaging techniques (p ≤ 0.02). Significant differences in terms of rCBF max, rADC min, Cho/NAA and 18F-DOPA uptake were also found between molecularly classified mutant and wild-type DMG (p ≤ 0.02), even though wild-type DMG included low-grade astrocytomas, not present among mutant DMG. When comparing only histologically defined high-grade mutant and wild-type DMG, only the 18F-DOPA PET data T/S demonstrated statistically significant differences independently of histology (p < 0.003). ROC analysis demonstrated that T/S ratio was the best parameter for differentiating mutant from wild-type DMG (AUC 0.94, p < 0.001).

Advanced MRI and 18F-DOPA PET characteristics of DMG depend on histological features; however, 18F-DOPA PET-T/S was the only parameter able to discriminate H3K27M-mutant from wild-type DMG independently of histology 5).

References

1)

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97-109. doi: 10.1007/s00401-007-0243-4. Epub 2007 Jul 6. Erratum in: Acta Neuropathol. 2007 Nov;114(5):547. PMID: 17618441; PMCID: PMC1929165.
2)

Qiu T, Chanchotisatien A, Qin Z, Wu J, Du Z, Zhang X, Gong F, Yao Z, Chu S. Imaging characteristics of adult H3 K27M-mutant gliomas. J Neurosurg. 2019 Nov 15:1-9. doi: 10.3171/2019.9.JNS191920. Epub ahead of print. PMID: 31731269.
3)

Aboian MS, Solomon DA, Felton E, Mabray MC, Villanueva-Meyer JE, Mueller S, Cha S. Imaging Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3 K27M Mutation. AJNR Am J Neuroradiol. 2017 Apr;38(4):795-800. doi: 10.3174/ajnr.A5076. Epub 2017 Feb 9. PMID: 28183840; PMCID: PMC5394943.
4)

Zhuo Z, Qu L, Zhang P, Duan Y, Cheng D, Xu X, Sun T, Ding J, Xie C, Liu X, Haller S, Barkhof F, Zhang L, Liu Y. Prediction of H3K27M-mutant brainstem glioma by amide proton transfer-weighted imaging and its derived radiomics. Eur J Nucl Med Mol Imaging. 2021 Jun 16. doi: 10.1007/s00259-021-05455-4. Epub ahead of print. PMID: 34131804.
5)

Piccardo A, Tortora D, Mascelli S, Severino M, Piatelli G, Consales A, Pescetto M, Biassoni V, Schiavello E, Massollo M, Verrico A, Milanaccio C, Garrè ML, Rossi A, Morana G. Advanced MR imaging and (18)F-DOPA PET characteristics of H3K27M-mutant and wild-type pediatric diffuse midline gliomas. Eur J Nucl Med Mol Imaging. 2019 Apr 27. doi: 10.1007/s00259-019-04333-4. [Epub ahead of print] PubMed PMID: 31030232.

Diffuse leptomeningeal melanocytosis

Diffuse leptomeningeal melanocytosis

Primary melanocytic tumors of the central nervous system (CNS) are rare lesions arising from melanocytes of the leptomeninges. They include diffuse leptomeningeal melanocytosis or melanomatosis, melanocytoma and primary malignant melanoma 1).

Diffuse leptomeningeal melanocytosis is a rare tumor of meninges arising from leptomeningeal melanocytes, characterized by diffuse infiltration of the leptomeninges (pia mater and arachnoidea) anywhere in the central nervous system.

Leptomeningeal melanocytes, are derived from neural crest and include diffuse melanocytosis, melanocytomas, and malignant melanomas. Meningeal melanocytomas are extremely rare benign lesions.

Pathology

The aim of a study was to analyze melanocytic proliferation in 2 rare and severe cases of isolated Diffuse leptomeningeal melanocytosis (DLM) and neurocutaneous melanocytosis (NCM) of prenatal onset by neuropathologic and molecular analysis. Uguen et al. performed neuropathologic examination, comparative genomic hybridization arrays, fluorescence in situ hybridization, BRAF and NRAS pyrosequencing in the 2 cases, and next-generation sequencing in the case of isolated DLM. The neuropathologic examination showed diffuse meningeal melanocytic proliferation involving the whole central nervous system with multiple areas of intraneural invasion, associated with large nevi in 1 case. They did not find any chromosomal imbalances. A NRAS(Q61K) mutation was found in the cutaneous and meningeal lesions from the NCM. No mutation was found within a panel of oncogenes including BRAF, NRAS, HRAS, KIT, GNAQ, and GNA11 concerning the isolated DLM. They reported 2 exceptional cases of hydrocephalus of prenatal onset related to DLM and NCM. The molecular mechanisms underlying the case of DLM remain unsolved despite the panel of analysis applied 2).

Clinical features

May include stillbirth, intracranial hypertension and hydrocephalus, seizure, ataxia, syringomyelia, cranial nerve palsy, intracranial hemorrhage, sphincter dysfunction and neuropsychiatric symptoms. Transformation into malignant melanoma of the central nervous system was reported. It may be associated with congenital nevi, as a part of neurocutaneous melanosis.

Diagnosis

Brain MRI showing diffuse thickening of the leptomeninges with T1 shortening is useful in diagnosing Neurocutaneous melanocytosis. Heterocellular melanin may be of great value for early diagnosis of NCM in challenging cases 3).

Over a 5-year period (1989-1994) Byrd et al. evaluated with MR imaging the central nervous system of five children with a confirmed histologic diagnosis of neurocutaneous melanosis. The children ranged in age from 7 to 10 years and consisted of two girls and three boys. They all had multiple pigmented skin lesions (cutaneous nevi) and presented with seizures, signs of raised intracranial pressure, cranial nerve palsies and/or myelopathy. The MR studies were performed with T1-weighted, T2-weighted and T1-weighted post-gadolinium images of the brain in addition to T1-weighted post-gadolinium images of the entire spine. The MR findings in all the children consisted of marked, diffuse enhancement of thickened leptomeninges surrounding the brain and spinal cord which was only demonstrated on the post-gadolinium T1-weighted images and mild to moderate hydrocephalus. We present our MR findings and compare these findings with other imaging findings in the literature. The findings represent part of a spectrum of imaging abnormalities seen in patients with neurocutaneous melanosis 4).

Differential diagnosis

Pigmented lesions of the central nervous system (CNS) are a diverse group of entities that run the gamut from benign to malignant. These lesions may be well circumscribed or diffuse, and their imaging appearances are influenced by the degree of melanin content as well as the presence or absence of hemorrhage. Pigmented lesions include primary melanocytic lesions of the CNS and metastatic melanoma, as well as other CNS neoplasms that may undergo melanization, including schwannoma, medulloblastoma, and some gliomas. Primary melanocytic lesions of the CNS arise from melanocytes located within the leptomeninges, and this group includes diffuse melanocytosis and meningeal melanomatosis (seen in neurocutaneous melanosis), melanocytoma, and malignant melanoma. Primary melanin-containing lesions of the CNS must be differentiated from metastatic melanoma because these lesions require different patient workup and therapy. Absence of a known primary malignant melanoma helps in the differential diagnosis, but an occult primary lesion outside the CNS must be sought and excluded. Pigmented lesions of the CNS are uncommon, and knowledge of their imaging characteristics and pathologic features is essential for their identification 5).

Melanocytoma and meningeal melanocytosis, are similar but different lesions.

Meningeal melanomatosis is an extra-axial well-encapsulated malignant tumour with diffuse meningeal growth and dark coloration (due to high melanin contents), while meningeal melanocytoma is the focalized benign variant. Melanocytic tumors may be secondary to melanoma or be histologically benign, however, their diffuse nature makes them impossible to cure. Melanocytosis is a diffuse tumour that can form solitary extra-axial tumours, which invades the parenchyma and presents signs of malignancy with increased mitosis and Ki67, observed in 1 to 6% of immunopathological exams. Melanoma of the leptomeninges, presents signs of malignancy with anaplastic cells, which cluster in fascicles of melanin in the cytoplasm, with more than 3 atypical mitoses per field and Ki67 presenting in more than 6% of the immunopathological fields analysed 6).

Treatment

The usual treatment of intradural extramedullary melanocytomas involves surgical removal through a posterior approach using a laminectomy or laminotomy.

Outcome

Diffuse leptomeningeal melanocytosis (DLM) is a rare nevomelanocytic proliferation arising in the meninges. Despite their lack of morphological features of malignancy, these clonal nevomelanocytic cells are capable of extensive invasion and of malignant behavior. When associated with congenital melanocytic nevi, the disorder is named neurocutaneous melanocytosis (NCM). When symptomatic, DLM is usually revealed during childhood, but some cases remain clinically silent 7).

Leptomeningeal melanocytosis: a fatal course of a benign tumor 8).

Case reports

A 30-year-old female harboring a C6-T1 ventrally located intradural extramedullary lesion compressing the cord anteriorly. The lesion was totally resected via an anterior approach with oblique corpectomy even if the usual treatment involves surgical removal through a posterior approach using a laminectomy or laminotomy.

There is no evidence of recurrence at 4-year follow-up records of the patient 9).

A 38 years old male with primary diffuse leptomeningeal melanomatosis with presence of a NRASQ61K mutation without features of neurocutaneous melanosis 10).

Two cases of primary leptomeningeal melanomatosis presenting as subacute meningitis. Both cases have pleocytosis and high protein on cerebrospinal fluid analysis, and demonstrated atypical cells on cytology. On magnetic resonance imaging, there is diffuse leptomeningal thickening and avid enhancement of intracranial and intraspinal leptomeninges. One of them demonstrates T1 shortening due to magnetic effects of melanin, the other case is amelanotic and shows hypointensity on precontrast T1-weighted images. Both cases can be diagnosed with biopsy. In conclusion, these cases highlight the importance of the correct interpretation of cytological and magnetic resonance imaging findings in patients with atypical findings 11).

Padilla-Vázquez et al. presented the case of a patient with long-term meningeal melanomatosis, with progressive neurologic deficit and characteristic radiologic features, and another case of meningeal melanocytoma.

Benign melanocytic neoplasms of the central nervous system must be treated aggressively in the early phases with strict follow-up to avoid progression to advanced phases that do not respond to any treatment method. Unfortunately, the prognosis for malignant melanocytic lesions is very poor irrespective of the method of treatment given 12).

Uguen et al. reported 2 exceptional cases of hydrocephalus of prenatal onset related to DLM and NCM. The molecular mechanisms underlying our case of DLM remain unsolved despite the panel of analysis applied 13).

A 30-year-old woman with a giant congenital melanocytic nevus covering nearly the entire right thoracodorsal region and multiple disseminated melanocytic nevi presented with neurological symptoms. Cerebral magnetic resonance imaging revealed a large expansive lesion in the left frontal region. Postsurgically pathological diagnosis revealed characteristics of melanoma. Immunohistochemical examination showed S100(+), HMB45(+), MelanA(+), and MiTF(+). She received radiotherapy with temozolomide followed by two more chemotherapy cycles with temozolomide. She followed a rapidly progressive course, reflecting widespread leptomeningeal infiltration, and she died of multiorgan failure seven months after diagnosis of cerebral melanoma. Discussion. This patient was diagnosed as having a neurocutaneous melanosis with malignant widespread leptomeningeal infiltration. Diffuse spinal involvement is unusual and is described in only another patient 14).

An autopsy case of leptomeningeal melanomatosis associated with neurocutaneous melanosis (NCM) involving a 44-year-old male is reported. The autopsy showed that the leptomeningeal surface of the brain and the spinal cord were covered with a diffuse black lesion. A histological examination detected diffusely distributed, proliferating, melanin-containing cells and demonstrated that the lesion consisted of three different components; i.e. regions of melanomatosis, melanocytosis, and melanocyte hyperplasia. In the leptomeningeal melanomatosis component, tumor cells with pleomorphic nuclei and prominent nucleoli had infiltrated into the cerebral parenchyma via Virchow-Robin spaces. The Ki-67 labeling index and the nuclear accumulation of p53 and p16 protein were immunohistochemically examined in each component. The Ki-67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were 8.7%, 0.8%, and 0%, respectively. Immunostaining of nuclear p16 produced a negative result in the melanomatosis component, but positive results in the melanocytosis and melanocyte hyperplasia components, whereas nuclear p53 expression was not detected in any of the components. This case suggests that p16(INK4) /CDKN2 may play a significant role in progression of leptomeningeal melanocytic neoplasms. We also reviewed previously reported cases of leptomeningeal neoplasms associated with NCM and discussed the relationship between the biological behavior and proliferative activity of such lesions 15).

A 43-year-old woman presented with a 1-week history of neck pain and dizziness. Computed tomography of brain showed communicating hydrocephalus and subarachnoid hyperintensity suspicious of previous subarachnoid haemorrhage. Investigations revealed no underlying vascular lesion and leptomeningeal biopsy showed diffuse melanocytosis 16).

Dechaphunkul A, Kayasut K, Oearsakul T, Koonlaboon K, Sunpaweravong P. Common presentation in an uncommon disease: case report of a patient with primary diffuse leptomeningeal melanocytosis. J Clin Oncol. 2011 Nov 20;29(33):e816-8. doi: 10.1200/JCO.2011.37.3175. Epub 2011 Oct 24. PMID: 22025160.

A rare and atypical case of a 31-year-old adult male with no evident congenital melanocytic lesions who presented with neurologic symptoms and was found to have leptomeningeal melanocytosis. The brain biopsy demonstrated a conspicuous but benign-appearing melanocytic infiltrate that was discordant with the severity of the patient’s symptoms. Ultimately, the patient was suspected to represent a case of former fruste neurocutaneous melanosis. Herein the relevant clinical and histopathologic features are discussed along with a brief review of the literature 17).

A 75-year-old man, undergoing treatment for metastatic prostate cancer with a novel cancer cell vaccine, presented with a 4 week history of poor balance, gait disturbance and cognitive decline. Blood tests including HIV and onconeuronal and voltage gated potassium channel antibodies were normal. Computed tomography and two magnetic resonance images of the brain showed possible non-specific meningeal or vascular enhancement. Two cerebrospinal fluid analyses, including cytology, were negative, other than six lymphocytes in the former. Despite intravenous aciclovir and dexamethasone the patient deteriorated over 16 days, with worsening confusion and involuntary movements, and died. Postmortem examination showed that the leptomeninges overlying the brain and spinal cord were diffusely infiltrated by a melanocytosis with a focal area of melanomatosis. Moreover, there were two sites of metastases of a highly malignant clone present in the pulmonary parenchyma 18).

A rapidly fatal case in an 18-year-old man presenting with symptoms and imaging features suggestive for subarachnoid hemorrhage or meningitis. The laboratory findings and imaging examination were still confusing and the diagnosis remained unclear during the patient’s life. Autopsy was the cornerstone in disclosing the lesion, confirming its usefulness in the assessment of such unusual cases. The complete profile of the tumor was obtained only by histology and immunohistochemistry. Clinicians and pathologists must be aware of diagnosis difficulties in this rare disease which can represent a serious challenge in clinical practice 19).

1-year-old boy with congenital melanocytic nevi had met normal developmental milestones until the age of 11 months, when he began regressing in ambulation and language function. Intractable vomiting had developed 1 week later. Magnetic resonance (MR) imaging of the brain revealed DWC with hydrocephalus, and spinal MR images demonstrated a proliferative process within the meninges, consistent with NM. The patient underwent right frontal VP shunt placement resulting in immediate symptom relief, but 3 weeks later became irritable, increasingly lethargic, unable to pull to stand, and unable to tolerate solid food without choking. Due to these symptoms and intractable vomiting, the patient presented to the authors’ institution. Brain MR imaging revealed a new-onset diffuse cystic process with anterior and posterior brainstem compression, marked kinking of the cervicomedullary junction, melanocyte pigmentation of the left temporal lobe, diffuse leptomeningeal enhancement, and no evidence of hydrocephalus. Consistent with these imaging findings, the degree of brainstem involvement upon gross visualization predictably deterred resection attempts beyond those necessary for biopsy. Pathological examination revealed diffuse melanocytosis, and the family decided not to pursue aggressive measures postoperatively. This report indicates the potential for rapid intracranial manifestation of diffuse melanocytosis in NM patients. Although the prognosis is poor, early neurosurgical involvement in these patients may provide tissue diagnosis and the potential for decompression if the process is caught early in its course 20).

A 26-year-old man had had a large patch of pigmented nevus over his back and left arm since birth. He had begun to have seizures as well as symptoms and signs of increased intracranial pressure about six months before admission. Serial computed tomography of brain showed hydrocephalus, diffuse leptomeningeal enhancement and multiple well-enhanced, rapid-growing nodules on the surface of the cerebellum and left parietal lobe. Magnetic resonance imaging (MRI) revealed T1 shortening of leptomeninges on precontrast T1 weighted imaging. Skin biopsy was done twice and showed intradermal nevus. Biopsy on one of the intracranial nodules revealed malignant melanoma arising in the melanocytosis. He died one year after the onset of neurologic symptoms. For early diagnosis of neurocutaneous melanocytosis, we suggest 1) MRI, and 2) leptomeningeal biopsy in patients with suspected leptomeningeal malignant melanoma 21).

References

1)

Liubinas SV, Maartens N, Drummond KJ. Primary melanocytic neoplasms of the central nervous system. J Clin Neurosci. 2010 Oct;17(10):1227-32. doi: 10.1016/j.jocn.2010.01.017. Epub 2010 Jun 16. PMID: 20558070.
2) , 7) , 13)

Uguen A, Laurent C, Samaison L, Boisselier B, Talagas M, Costa S, Aziza J, Mokhtari K, Le Maréchal C, Marcorelles P. Severe hydrocephalus caused by diffuse leptomeningeal and neurocutaneous melanocytosis of antenatal onset: a clinical, pathologic, and molecular study of 2 cases. Hum Pathol. 2015 Aug;46(8):1189-96. doi: 10.1016/j.humpath.2015.04.013. Epub 2015 May 13. PMID: 26037215.
3)

Qian M, Ren H, Qu T, Lu Z, Zou Y, He J, Zhao Y, Chen L, Guan H. Spectrum of Clinical, Neuroimaging, and Cerebrospinal Fluid Features of Adult Neurocutaneous Melanocytosis. Eur Neurol. 2018;80(1-2):1-6. doi: 10.1159/000488687. Epub 2018 Jul 13. PMID: 30007971.
4)

Byrd SE, Darling CF, Tomita T, Chou P, de Leon GA, Radkowski MA. MR imaging of symptomatic neurocutaneous melanosis in children. Pediatr Radiol. 1997 Jan;27(1):39-44. doi: 10.1007/s002470050060. PMID: 8995166.
5)

Smith AB, Rushing EJ, Smirniotopoulos JG. Pigmented lesions of the central nervous system: radiologic-pathologic correlation. Radiographics. 2009 Sep-Oct;29(5):1503-24. doi: 10.1148/rg.295095109. PMID: 19755608.
6) , 12)

Padilla-Vázquez F, Escobar-de la Garma VH, Ayala-Arcipreste A, Mendizábal-Guerra R, Cuesta-Mejía T. Melanocitoma y melanomatosis meníngea, lesiones similares pero diferentes [Melanocytoma and meningeal melanocytosis, similar but different lesions]. Cir Cir. 2017 May-Jun;85(3):273-278. Spanish. doi: 10.1016/j.circir.2016.11.006. Epub 2017 Jan 23. PMID: 28126183.
8)

Grini-Mazouzi M, Thouvenot E, Sabaah M, Rigau V, Charif M. Mélanocytose leptoméningée diffuse : évolution fatale d’une tumeur bénigne [Leptomeningeal melanocytosis: a fatal course of a benign tumor]. Rev Neurol (Paris). 2012 May;168(5):461-3. French. doi: 10.1016/j.neurol.2011.08.021. Epub 2012 Mar 7. PMID: 22405462.
9)

Akgun MY, Isler C, Ulu MO. C6-T1 Intradural Extramedullary Ventral Meningeal Melanocytoma Resected Via Anterior Corpectomy with Reconstruction. World Neurosurg. 2020 Jun;138:457-460. doi: 10.1016/j.wneu.2020.03.122. Epub 2020 Apr 3. PMID: 32251820.
10)

Girolami I, Cima L, Ghimenton C, Zannoni M, Mombello A, Riva G, Cirielli V, Corradi G, Vogrig A, Di Stefano G, Novelli L, Gessi M, Eccher A. NRASQ61K mutated diffuse leptomeningeal melanomatosis in an adult patient with a brief review of the so-called “forme fruste” of neurocutaneous melanosis. Brain Tumor Pathol. 2018 Oct;35(4):217-223. doi: 10.1007/s10014-018-0328-x. Epub 2018 Aug 25. PMID: 30145692.
11)

Aslan S, Gocmen R, Acar NP, Khasiyev F, Gumeler E, Soylemezoglu F, Tuncer A, Arsava EM, Topçuoglu MA, Unal Cevik I. Two cases of primary leptomeningeal melanomatosis mimicking subacute meningitis. Neuroradiol J. 2018 Feb;31(1):42-46. doi: 10.1177/1971400917708581. Epub 2017 Jun 19. PMID: 28627959; PMCID: PMC5789992.
14)

Araújo C, Resende C, Pardal F, Brito C. Giant congenital melanocytic nevi and neurocutaneous melanosis. Case Rep Med. 2015;2015:545603. doi: 10.1155/2015/545603. Epub 2015 Feb 4. PMID: 25722729; PMCID: PMC4334432.
15)

Matsumura M, Okudela K, Tateishi Y, Umeda S, Mitsui H, Suzuki T, Nakayama T, Inayama Y, Ohashi K. Leptomeningeal melanomatosis associated with neurocutaneous melanosis: an autopsy case report. Pathol Int. 2015 Feb;65(2):100-5. doi: 10.1111/pin.12238. Epub 2014 Dec 17. PMID: 25521302.
16)

Ng RY, Siu DY, Wong GK, Ng HK, Poon WS. An uncommon mimic of spontaneous subarachnoid haemorrhage. Hong Kong Med J. 2013 Feb;19(1):80-1. PMID: 23378361.
17)

Sutton BJ, Tatter SB, Stanton CA, Mott RT. Leptomeningeal melanocytosis in an adult male without large congenital nevi: a rare and atypical case of neurocutaneous melanosis. Clin Neuropathol. 2011 Jul-Aug;30(4):178-82. doi: 10.5414/np300363. PMID: 21726502.
18)

Michael BD, Syndikus I, Clark A, Baborie A. Diffuse primary leptomeningeal melanocytosis in a patient receiving a novel cancer cell vaccine for prostate cancer. BMJ Case Rep. 2010 May 4;2010:bcr11.2009.2495. doi: 10.1136/bcr.11.2009.2495. PMID: 22736604; PMCID: PMC3047541.
19)

Arsene D, Ardeleanu C, Balescu C, Nistorescu A. Meningeal melanocytosis in a young patient–an autopsy diagnosis. Clin Neuropathol. 2007 Nov-Dec;26(6):294-8. doi: 10.5414/npp26294. PMID: 18232596.
20)

McClelland S 3rd, Charnas LR, SantaCruz KS, Garner HP, Lam CH. Progressive brainstem compression in an infant with neurocutaneous melanosis and Dandy-Walker complex following ventriculoperitoneal shunt placement for hydrocephalus. Case report. J Neurosurg. 2007 Dec;107(6 Suppl):500-3. doi: 10.3171/PED-07/12/500. PMID: 18154021.
21)

Chang CS, Hsieh PF, Chia LG, Chen CC, Chen CC, Pan ST, Wang YC. Leptomeningeal malignant melanoma arising in neurocutaneous melanocytosis: a case report. Zhonghua Yi Xue Za Zhi (Taipei). 1997 Dec;60(6):316-20. PMID: 9531740.

Diffuse idiopathic skeletal hyperostosis

Diffuse idiopathic skeletal hyperostosis

Diffuse idiopathic skeletal hyperostosis (DISH), also referred to as Forestier’s disease, was first described by Jacques Forestier and his student Jaume Rotes-Querol in 1950.

It is a non-inflammatory skeletal disease characterized by calcification and ossification of soft tissues, primarily ligaments and entheses. DISH is also known as senile ankylosing hyperostosis 1).

However, it is now known that this disease is neither limited to the spine nor to older subjects. In 1976, Resnick and Niwayama coined the term “diffuse idiopathic skeletal hyperostosis” (DISH), which is currently widely utilized. Independently of how this condition is named, it consists in a systemic noninflammatory disease characterized by ossification of the entheses – the bony attachment of tendons, ligaments, and joint capsules 2).

This common disorder of unknown etiology is characterized by back pain and spinal stiffness. There may be mild pain if ankylosis has occurred. The condition is recognized radiographically by the presence of “flowing” ossification along the anterolateral margins of at least four contiguous vertebrae and the absence of changes of spondyloarthropathy or degenerative spondylosis. Even in patients who present with either lumbar or cervical complaints, radiographic findings are almost universally seen on the right side of the thoracic spine. Thus, radiographic examination of this area is critical when attempting to establish a diagnosis of DISH. The potential sequelae of hyperostosis in the cervical and lumbar spine include lumbar stenosis, dysphagia, cervical myelopathy, and dense spinal cord injury resulting from even minor trauma. There may be a delay in diagnosis of spinal fractures in a patient with DISH because the patient often has a baseline level of spinal pain and because the injury may be relatively trivial. The incidence of delayed neurologic injury due to such fractures is high as a result of unrecognized instability and subsequent deterioration. Extraspinal manifestations are also numerous and include an increased risk of heterotopic ossification after total hip arthroplasty. Prophylaxis to prevent heterotopic ossification may be indicated for these patients 3).

Epidemiology

The disease has about the same frequency in men (65%) and women (35%); it is most common in the thoracic spine and occurs less frequently in the lumbar and cervical spine. The disease most commonly presents in the sixth and seventh decades of life and its estimated frequency in the elderly is 5-15%.

DISH most commonly affects the elderly, especially 6th to 7th decades 4).

The cervical and thoracic (particularly T7-11) 5). spines, in particular, are affected. Additionally, enthesopathy may be identified in the pelvis and extremities.

Etiology

The aetiology of DISH is still unknown.

Although many external and genetic factors have been reported as being contributors of the pathogenesis of DISH, most of the current theories focus on the pathologic calcification of the anterior longitudinal ligament of the spine. The majority of these theories postulate that this process is due to the abnormal growth and function of the osteoblasts in the osteoligamentary binding 6).

However, it is important to clarify that not all authors accept the association between pathologic calcification and increased bone mineral density 7).

Pathology

Histopathological features of spinal DISH include :

focal and diffuse calcification and ossification of the anterior longitudinal ligament

paraspinal connective tissue and annulus fibrosis

degeneration in the peripheral annulus fibrosus fibres

anterolateral extensions of fibrous tissue

hypervascularity

chronic inflammatory cellular infiltration

periosteal new bone formation on the anterior surface of the vertebral bodies 8).

Clinical features

The condition is commonly identified as an incidental finding when imaging for other reasons.

Spinal hyperostosis can predispose the affected to chronic myelopathic symptoms and acute spinal cord injury.

The involvement of vertebral and extravertebral sites including the pelvis, calcaneum, ulnar olecranon, and patella is frequently found in the literature. The lesions described are the anterior and lateral ossification of the spine, hyperostosis at sites of tendon and ligament insertion, ligamentous ossification, and periarticular osteophytes.

Signs and symptoms include stiffness and pain in the back, dysphagia due to direct esophageal compression/distorsion, pain related to associated tendinitis, myelopathy related to core compression associated to the ossification of the posterior longitudinal ligament, and pain related to vertebral complications–e.g. fracture/subluxation 9).

Neurological complications occur in DISH when the pathological process of ossification extends to other vertebral ligaments, causing ossification of the posterior longitudinal ligaments (OPLL) and/or ossification of the ligamentum flavum (OLF) 10).

Recognised associations include:

Hyperglycaemia 11). approximately one-third of patients tests positive for HLA-B27

Diagnosis

The criteria for the diagnosis of diffuse idiopathic skeletal hyperostosis involving the spine are: flowing ossification along the anterior and anterolateral aspects of at least four contiguous vertebrae, preserved intervertebral disc height, no bony ankylosis of the posterior spinal facet joints, and finally no erosion, sclerosis or bony ankylosis of the sacroiliac joints 12) 13).

On imaging, it is typically characterised by the flowing ossification of the anterior longitudinal ligament involving the thoracic spine and enthesopathy (e.g. at the iliac crest, ischial tuberosities, and greater trochanters). There is no involvement of the sacroiliac synovial joints.

While conventional radiography clearly confirms the diagnosis of diffuse idiopathic skeletal hyperostosis, CT and MRI better detect associated findings (e.g. ossification of the posterior longitudinal ligament) and complications (e.g. spinal cord compressive myelomalacia) 14).

Radiographic features

DISH involving the spine is identified radiologically by flowing ligamentous ossification and calcification of the anterolateral aspect of the vertebral body with relatively well-preserved disc space of at least four contiguous vertebrae, so-called flowing ossifications 15).

The radiographic criteria, as defined by Utsinger et al., includes:

(1) bridging osteophytes extending over four contiguous vertebral bodies

(2) relatively normal intervening disk space height in relation to height in relation to age

(3) absence of apophyseal joints, bony ankyloses, and absence of erosion, sclerosis, or osseous fusion of the sacroiliac joints 16).

Extraspinal features

enthesopathy of the iliac crest, ischial tuberosities, and greater trochanters and spur formation in the appendicular skeleton (olecranon, calcaneum, patellar ligament) are frequently present ‘whiskering’ enthesophytes 17).

Differential diagnosis

Diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) share involvement of the axial skeleton and peripheral entheses. Both diseases produce bone proliferations in the later phases of their course. Although the aspect of these bone proliferations is dissimilar, confusion of radiologic differential diagnosis between the two diseases exists mostly as a consequence of a lack of awareness of their characteristic clinical and radiographic features. The confusion may extend to the clinical field because both advanced DISH and advanced AS may cause the same limitations of spinal mobility and postural abnormalities. However, the radiologic spinal findings are so different that changes due to each disease can be recognized even in patients in whom both diseases occur. This article reviews the clinical and radiologic characteristics that should help clinicians differentiate between the two diseases without much difficulty 18).

ankylosing spondylitis

syndesmophytes: thinner, form over the annulus, and are vertically oriented (“bamboo spine”)

sacroiliac joint involvement early on and is in the synovial portion (inferior two-thirds)

osteoporosis is prominent

degenerative spine disease

usually has prominent facet and apophyseal joints degenerative changes as well

disc degenerative changes

retinoid arthropathy

patients using retinoid acid for skin diseases

skeletal hyperostosis

predominantly involves the cervical spine

fluorosis

fluorite intoxication due to long-term ingestion

can cause paraspinal ligament calcification

if seen in a child, consider juvenile idiopathic arthritis (JIA).

Complications

Dysphagia Provoked by Diffuse Idiopathic Skeletal Hyperostosis in the Cervical Spine.

A study aimed to predict the surgical outcomes of diffuse idiopathic skeletal hyperostosis (DISH)-related dysphagia (DISH-phagia) and to evaluate the importance of prevertebral soft tissue thickness (PVST).

In total, 21 surgeries (anterior osteophytectomy or anterior cervical decompression and fixation) were included in this study for DISH-phagia from 2003 to 2019. Clinical outcomes were assessed using the Dysphagia Outcome and Severity Scale (DOSS) preoperatively, at 1 month postoperatively, and last follow up (mean 29.5 months). PVST was measured using lateral plain radiographs. Paired t-test and Spearman’s correlation test was used to identify relationships between various PVST indices and DOSS.

Comparisons were made from 17 patients out of 21, in which the record had all of three measurements. The narrowest PVST preoperatively was 2.55±0.90 mm, with a DOSS score of 4.47±1.61, and that at 1 month after surgery was 5.02±2.33 mm, with a DOSS score of 6.12±1.32. At last follow up, PVST and DOSS values were 3.78±0.92 mm and 5.82±1.34, and three patients experienced symptom relapse. Significant relationships were found between PVST and DOSS at all time points: before surgery (R=0.702, p<0.001), 1 month after surgery (R=0.539, p=0.012), and last follow up (R=0.566, p=0.020).

Surgical removal of anterior osteophytes is an effective treatment option for DISH-phagia, and PVST is a useful parameter in DISH-phagia. The goal of DISH surgery should be to remove DISH as much as possible to ensure sufficient PVST postoperatively 19).

Treatment

DISH is generally managed clinically with analgesics and non-steroidal anti-inflammatory drugs when pain and stiffness are related. Possible complications may require specific treatment:

acute spinal fractures

chalk stick fracture

rarely dysphagia caused by mechanical compression due to anterior cervical bone production 20).

Outcome

DISH rarely causes neurological complications, as evidenced by isolated case reports on the subject; however, if neurological complications do occur, they are often severe enough to warrant major neurosurgical intervention 21) 22) 23) 24).

Case series

Diffuse idiopathic skeletal hyperostosis case series

Case reports

Diffuse idiopathic skeletal hyperostosis case reports.

References

1)

FORESTIER J, ROTES-QUEROL J. Senile ankylosing hyperostosis of the spine. Ann Rheum Dis. 1950 Dec;9(4):321-30. PubMed PMID: 14800245; PubMed Central PMCID: PMC1011670.
2) , 15)

Resnick D, Niwayama G. Radiographic and pathologic features of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). Radiology. 1976 Jun;119(3):559-68. PubMed PMID: 935390.
3)

Belanger TA, Rowe DE. Diffuse idiopathic skeletal hyperostosis: musculoskeletal manifestations. J Am Acad Orthop Surg. 2001 Jul-Aug;9(4):258-67. Review. PubMed PMID: 11476536.
4) , 9) , 14)

Cammisa M, De Serio A, Guglielmi G. Diffuse idiopathic skeletal hyperostosis. Eur J Radiol. 1998 May;27 Suppl 1:S7-11. Review. PubMed PMID: 9652495.
5) , 8)

Taljanovic MS, Hunter TB, Wisneski RJ, Seeger JF, Friend CJ, Schwartz SA, Rogers LF. Imaging characteristics of diffuse idiopathic skeletal hyperostosis with an emphasis on acute spinal fractures: review. AJR Am J Roentgenol. 2009 Sep;193(3 Suppl):S10-9, Quiz S20-4. doi: 10.2214/AJR.07.7102. Review. PubMed PMID: 19696239.
6)

Atzeni F, Sarzi-Puttini P, Bevilacqua M. Calcium deposition and associated chronic diseases (atherosclerosis, diffuse idiopathic skeletal hyperostosis, and others). Rheum Dis Clin North Am. 2006 May;32(2):413-26, viii. Review. PubMed PMID: 16716887.
7)

Eser P, Bonel H, Seitz M, Villiger PM, Aeberli D. Patients with diffuse idiopathic skeletal hyperostosis do not have increased peripheral bone mineral density and geometry. Rheumatology (Oxford). 2010 May;49(5):977-81. doi: 10.1093/rheumatology/keq014. Epub 2010 Feb 15. PubMed PMID: 20156975.
10)

Sharma RR, Mahapatra A, Pawar SJ, Sousa J, Lad SD, Athale SD. Spinal cord and cauda equina compression in ‘DISH’. Neurol India. 2001 Jun;49(2):148-52. PubMed PMID: 11447434.
11) , 17)

https://radiopaedia.org/articles/diffuse-idiopathic-skeletal-hyperostosis
12)

Nascimento FA, Gatto LA, Lages RO, Neto HM, Demartini Z, Koppe GL. Diffuse idiopathic skeletal hyperostosis: A review. Surg Neurol Int. 2014 Apr 16;5(Suppl 3):S122-5. doi: 10.4103/2152-7806.130675. eCollection 2014. PubMed PMID: 24843807; PubMed Central PMCID: PMC4023007.
13) , 18)

Olivieri I, D’Angelo S, Palazzi C, Padula A, Mader R, Khan MA. Diffuse idiopathic skeletal hyperostosis: differentiation from ankylosing spondylitis. Curr Rheumatol Rep. 2009 Oct;11(5):321-8. Review. PubMed PMID: 19772826.
16)

Utsinger PD, Resnick D, Sapiro R. Diffuse skeletal abnormalities in Forestier’s disease. Arch Int Med. 1976;136:163–8. doi: 10.1001/archinte.1976.03630070011006.
19)

Chung YS, Zhang HY, Ha Y, Park JY. Surgical Outcomes of Dysphagia Provoked by Diffuse Idiopathic Skeletal Hyperostosis in the Cervical Spine. Yonsei Med J. 2020 Apr;61(4):341-348. doi: 10.3349/ymj.2020.61.4.341. PubMed PMID: 32233177.
20)

Krishnarasa B, Vivekanandarajah A, Ripoll L, Chang E, Wetz R. Diffuse Idiopathic Skeletal Hyperostosis (DISH)-A Rare Etiology of Dysphagia. Clin Med Insights Arthritis Musculoskelet Disord. 2011;4:71-5. doi: 10.4137/CMAMD.S6949. Epub 2011 Sep 20. PubMed PMID: 22084604; PubMed Central PMCID: PMC3201108.
21)

Reisner A, Stiles RG, Tindall SC. Diffuse idiopathic skeletal hyperostosis causing acute thoracic myelopathy: a case report and discussion. Neurosurgery. 1990 Mar;26(3):507-11. Review. PubMed PMID: 2181336.
22)

Alenghat JP, Hallett M, Kido DK. Spinal cord compression in diffuse idiopathic skeletal hyperostosis. Radiology. 1982 Jan;142(1):119-20. PubMed PMID: 7053520.
23)

Johnsson KE, Petersson H, Wollheim FA, Säveland H. Diffuse idiopathic skeletal hyperostosis (DISH) causing spinal stenosis and sudden paraplegia. J Rheumatol. 1983 Oct;10(5):784-9. PubMed PMID: 6644701.
24)

Stechison MT, Tator CH. Cervical myelopathy in diffuse idiopathic skeletal hyperostosis. Case report. J Neurosurg. 1990 Aug;73(2):279-82. PubMed PMID: 2366085.

Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the World Health Organization Classification of Tumors of the Central Nervous System 2016 grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histone H3 tail.

In the past, pediatric diffuse gliomas were grouped with their adult counterparts, despite known differences in behavior between pediatric and adult gliomas with similar histological appearances. Information on the distinct underlying genetic abnormalities in pediatric diffuse gliomas is beginning to allow the separation of some entities from histologically similar adult counterparts.

One narrowly defined group of tumors primarily occurring in children (but sometimes in adults too) is characterized by K27M mutations in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene, a diffuse growth pattern, and a midline location (e.g., thalamus, brain stem, and spinal cord). This newly defined entity is termed diffuse midline glioma, H3 K27M–mutant and includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG). The identification of this phenotypically and molecularly defined set of tumors provides a rationale for therapies directed against the effects of these mutations.

Epidemiology

Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults.

Diagnosis

see Diffuse midline glioma H3 K27M-mutant diagnosis.

Differential diagnosis

After the start of the era of biopsy, Diffuse intrinsic pontine gliomas (DIPG)s bearing Histone H3K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group 1).

Treatment

see Diffuse midline glioma H3 K27M-mutant treatment.

Outcome

Prognosis remains poor, with a 2-year survival of less than 10%

Research

Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study 2).

Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain.These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease 3).

Case series

Diffuse midline glioma H3 K27M-mutant case series.

Case reports

A 36-year-old man presented with subacute progressive cognitive and visual deterioration, and hydrocephalus requiring ventricular shunting. MRI revealed a diffusely infiltrating lesion with a gliomatosis cerebri growth pattern, multiple foci of contrast enhancement, and diffuse leptomeningeal involvement. Suboccipital craniotomy with exploration of the posterior fossa revealed a subtle capsular lesion infiltrating into the choroid plexus. Although histologically low-grade, the tumor was found to have an H3K27 M mutation establishing the diagnosis.

In spite of diverse clinicopathologic characteristics, H3K27M-mutant diffuse midline gliomas are incurable, WHO grade IV lesions with poor prognosis. Yekula et al. discussed the case in the context of a review of published reports of H3K27-mutant diffuse midline gliomas in adults. Findings late in the disease course may mimic inflammatory or infectious pathologies radiographically, and low-grade infiltrative neoplasms histologically.

The diverse clinical, radiographic and molecular features of H3K27M-mutant diffuse midline gliomas in adults remain to be completely characterized. A high index of suspicion is required to avoid missing the diagnosis. Early biopsy and detailed molecular characterization are critical for accurate diagnosis and patient counseling 4).

References

1)

Porkholm M, Raunio A, Vainionpää R, Salonen T, Hernesniemi J, Valanne L, Satopää J, Karppinen A, Oinas M, Tynninen O, Pentikäinen V, Kivivuori SM. Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer. 2017 Aug 9. doi: 10.1002/pbc.26751. [Epub ahead of print] PubMed PMID: 28792659.
2)

Cooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary SES, Foreman NK, Packer RJ, Broniscer A, Minturn JE, Shih CS, Chintagumpala M, Hassall T, Gottardo NG, Dholaria H, Hoffman L, Chaney B, Baugh J, Doughman R, Leach JL, Jones BV, Fouladi M, Warren KE, Monje M. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 2017 Sep 1;19(9):1279-1280. doi: 10.1093/neuonc/nox107. PubMed PMID: 28821206.
3)

Plessier A, Dret LL, Varlet P, Beccaria K, Lacombe J, Mériaux S, Geffroy F, Fiette L, Flamant P, Chrétien F, Blauwblomme T, Puget S, Grill J, Debily MA, Castel D. New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15002. [Epub ahead of print] PubMed PMID: 28178670.
4)

Yekula A, Gupta M, Coley N, U HS. Adult H3K27M-mutant diffuse midline glioma with gliomatosis cerebri growth pattern: Case report and review of the literature. Int J Surg Case Rep. 2020 Feb 28;68:124-128. doi: 10.1016/j.ijscr.2020.02.046. [Epub ahead of print] PubMed PMID: 32145563.

Diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma

see also Diffuse midline glioma H3 K27M-mutant.

Diffuse midline glioma H3 K27M-mutant includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG). The identification of this phenotypically and molecularly defined set of tumors provides a rationale for therapies directed against the effects of these mutations.

Epidemiology

Approximately 300 children are diagnosed with diffuse intrinsic pontine gliomas (DIPG) each year, usually between the ages of 5 and 9.

They account for 10% to 25% of pediatric brain tumors.

The majority of DIPGs are astrocytic, infiltrative, and localized to the pons.

Etiology

The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). The results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors 1).

Results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation 2).

Clinical Features

The symptoms of DIPG usually develop very rapidly prior to diagnosis, reflecting the fast growth of these tumors. Most patients start experiencing symptoms less than three months—and often less than three weeks—before diagnosis. The most common symptoms include:

Rapidly developing problems controlling eye movements, facial expressions, speech, chewing, and swallowing (due to problems in the cranial nerves) Weakness in the arms and legs

Problems with walking and coordination.

Diagnosis

Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis 3).

After the start of the era of biopsy, DIPGs bearing Histone H3K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group 4).

Platelet-derived growth factor receptor A is altered by amplification and/or mutation in diffuse intrinsic pontine glioma (DIPG).

A retrospective review of magnetic resonance imaging (MRI) scanning in a pure population of DIPG was undertaken. Baseline diagnostic MRI findings included; local tumour extension in upper medulla (74%) or midbrain (62%), metastatic disease (3%), basilar artery encasement (82%), necrosis (33%), intratumoural haemorrhage (26%), hydrocephalus (23%) and dorsal exophytic component (18%). Post-treatment MRI scans demonstrated increases in; leptomeningeal metastatic disease (16%), cystic change/necrosis (48%), enhancement (72%) and intratumoural haemorrhage (32%). Response rates were calculated according to both RECIST (4%) and WHO (24%) criteria. No MRI parameter in either the diagnostic or response scans had prognostic significance 5).

Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important.

Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post-radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin’s concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement.

The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods highlighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interobserver agreement and produced tumor volumes with delineated borders 6).

Biopsy

The place of stereotactic biopsy in the management of Diffuses Intrinsic Pontine Gliomas (DIPG) in children has changed over the years.

Due to the improvement of neurosurgical technics, it regained credit. Moreover, the era of targeted therapy with molecular and genomic discoveries paved the way to research protocol that requires a biopsy to include the patient. Nonetheless, stereotactic biopsy remains a surgical procedure with its risks. A complication has never been reported in case of a biopsy of a DIPG : metastatic seeding along the tract of the biopsy. Beuriat et al report the first two cases in the literature 7).

Nevertheless, most neurosurgical teams are reluctant to perform biopsy in pediatric patients, citing potential risks and lack of direct benefit. Yet, in reviewing 90 patients with and the published data on brainstem biopsy, these procedures have a diagnostic yield and morbidity and mortality rates similar to those reported for other brain locations. In addition, the quality and quantity of the material obtained confirm the diagnosis and inform an extended molecular screen, including biomarker study-information important to designing next-generation trials with targeted agents. Stereotactic biopsies can be considered a safe procedure in well-trained neurosurgical teams and could be incorporated in well-defined protocols for patients with DIPG 8).

Treatment

see Diffuse intrinsic pontine glioma treatment.

Outcome

see Diffuse intrinsic pontine glioma outcome.

Complications

see Diffuse intrinsic pontine glioma complications.

Case series

As part of a trial using CED for diffuse intrinsic pontine glioma (DIPG), Bander et al. measured treatment-related volumetric alterations in the brainstem and ventricles.

Enrolled patients underwent a single infusion of radioimmunotherapy. Between 2012 and 2019, 23 patients with volumetric pre- and postoperative day 1 (POD1) and day 30 (POD30) MRI scans were analyzed using iPlan® Flow software for semiautomated volumetric measurements of the ventricles and pontine segment of the brainstem.

Children in the study had a mean age of 7.7 years (range 2-18 years). The mean infusion volume was 3.9 ± 1.7 ml (range 0.8-8.8 ml). Paired t-tests demonstrated a significant increase in pontine volume immediately following infusion (p < 0.0001), which trended back toward baseline by POD30 (p = 0.046; preoperative 27.6 ± 8.4 ml, POD1 30.2 ± 9.0 ml, POD30 29.5 ± 9.4 ml). Lateral ventricle volume increased (p = 0.02) and remained elevated on POD30 (p = 0.04; preoperative 23.5 ± 15.4 ml, POD1 26.3 ± 16.0, POD30 28.6 ± 21.2). Infusion volume had a weak, positive correlation with pontine and lateral ventricle volume change (r2 = 0.22 and 0.27, respectively). Four of the 23 patients had an increase in preoperative neurological deficits at POD30. No patients required shunt placement within 90 days.

CED infusion into the brainstem correlates with immediate but self-limited deformation changes in the pons. The persistence of increased ventricular volume and no need for CSF diversion post-CED are inconsistent with obstructive hydrocephalus. Defining the degree and time course of these deformational changes can assist in the interpretation of neuroimaging along the DIPG disease continuum when CED is incorporated into the treatment algorithm 9).

1)

Ballester LY, Wang Z, Shandilya S, Miettinen M, Burger PC, Eberhart CG, Rodriguez FJ, Raabe E, Nazarian J, Warren K, Quezado MM. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol. 2013 Sep;37(9):1357-64. doi: 10.1097/PAS.0b013e318294e817. PubMed PMID: 24076776; PubMed Central PMCID: PMC3787318.
2)

Taylor IC, Hütt-Cabezas M, Brandt WD, Kambhampati M, Nazarian J, Chang HT, Warren KE, Eberhart CG, Raabe EH. Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition. J Neuropathol Exp Neurol. 2015 Jun 25. [Epub ahead of print] PubMed PMID: 26115193.
3)

Coca HA, Cebula H, Benmekhbi M, Chenard MP, Entz-Werle N, Proust F. Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note. Neurochirurgie. 2016 Dec;62(6):327-331. doi: 10.1016/j.neuchi.2016.07.005. PubMed PMID: 28120771.
4)

Porkholm M, Raunio A, Vainionpää R, Salonen T, Hernesniemi J, Valanne L, Satopää J, Karppinen A, Oinas M, Tynninen O, Pentikäinen V, Kivivuori SM. Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer. 2017 Aug 9. doi: 10.1002/pbc.26751. [Epub ahead of print] PubMed PMID: 28792659.
5)

Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol. 2008 Feb;86(3):313-9. Epub 2007 Oct 2. PubMed PMID: 17909941.
6)

Singh R, Zhou Z, Tisnado J, Haque S, Peck KK, Young RJ, Tsiouris AJ, Thakur SB, Souweidane MM. A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume. J Neurosurg Pediatr. 2016 Jul 8:1-8. [Epub ahead of print] PubMed PMID: 27391980.
7)

Beuriat PA, Szathmari A, Di Rocco F, Kanold J, Mottolese C, Frappaz D. Diffuse Intrinsic Pontine Glioma in children : document or treat ? World Neurosurg. 2016 Jul 12. pii: S1878-8750(16)30533-2. doi: 10.1016/j.wneu.2016.07.011. [Epub ahead of print] PubMed PMID: 27422681.
8)

Puget S, Blauwblomme T, Grill J. Is biopsy safe in children with newly diagnosed diffuse intrinsic pontine glioma? Am Soc Clin Oncol Educ Book. 2012:629-33. doi: 10.14694/EdBook_AM.2012.32.629. PubMed PMID: 24451809.
9)

Bander ED, Tizi K, Wembacher-Schroeder E, Thomson R, Donzelli M, Vasconcellos E, Souweidane MM. Deformational changes after convection-enhanced delivery in the pediatric brainstem. Neurosurg Focus. 2020 Jan 1;48(1):E3. doi: 10.3171/2019.10.FOCUS19679. PubMed PMID: 31896089.

Diffuse astrocytoma

Diffuse astrocytoma

Types

Diffuse astrocytoma IDH Mutant 9400/3

Gemistocytic astrocytoma 9411/3

Diffuse astrocytoma IDH wild type 9400/3

Diffuse astrocytoma NOS 9400/3

WHO grade determinations are still made on the basis of histologic criteria. Another reason why phenotype remains essential is that, there are individual tumors that do not meet the more narrowly defined phenotype and genotype criteria, e.g., the rare phenotypically classical diffuse astrocytoma that lacks the signature genetic characteristics of IDH and ATRX mutations. Nevertheless, it remains possible that future WHO classifications of the diffuse gliomas, in the setting of deeper and broader genomic capabilities, will require less histological evaluation—perhaps only a diagnosis of “diffuse glioma.” For now, the World Health Organization Classification of Tumors of the Central Nervous System 2016 is predicated on the basis of combined phenotypic and genotypic classification, and on the generation of “integrated” diagnoses.

Diffuse astrocytoma and oligodendrogliomas are in this classification now nosologically more similar than are diffuse astrocytoma and pilocytic astrocytoma; the family trees have been redrawn.

In the setting of a diffuse astrocytoma or anaplastic astrocytoma, if IDH testing is not available or cannot be fully performed (e.g., negative immunohistochemistry without available sequencing), the resulting diagnosis would be diffuse astroctyoma, NOS, or anaplastic astrocytoma, NOS, respectively.

Historically, the prognostic differences between WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas were highly significant.

Some studies, however, have suggested that the prognostic differences between IDH-mutant WHO grade II diffuse astrocytomas and IDH-mutant WHO grade III anaplastic astrocytomas are not as marked.

Nonetheless, this has not been noted in all studies. At this time, it is recommended that WHO grading is retained for both IDH-mutant and IDH-wildtype astrocytomas, although the prognosis of the IDH-mutant cases appears more favorable in both grades. Cautionary notes have been added to the 2016 classification in this regard.

Of note, two diffuse astrocytoma variants have been deleted from the WHO classification: protoplasmic astrocytoma, a diagnosis that was previously defined in only vague terms and is almost never made any longer given that tumors with this histological appearance are typically characterized as other more narrowly defined lesions; and fibrillary astrocytoma, since this diagnosis overlaps nearly entirely with the standard diffuse astrocytoma. As a result, only gemistocytic astrocytoma remains as a distinct variant of diffuse astrocytoma IDH-mutant.

Outcome

For the diffuse astrocytomas, there have been many such studies over the past century and these have proven useful in estimating prognosis for patients. With the advent of molecular diagnostics and the recent World Health Organization (WHO) Classification of Tumors of the Central Nervous System it is necessary testing for isocitrate dehydrogenase (IDH) gene status in the classification of diffuse astrocytic gliomas. Novel approaches to diffuse astrocytic tumor grading are required in the era of IDH testing 1).

Alattar et al. determined the influence of age and tumor location on survival benefit from GTR in diffuse astrocytoma (DA).

They used The Surveillance, Epidemiology and End Results (SEER) database (1999-2010). They used Kaplan-Meier curves and Cox survival models to determine the survival benefit from GTR in populations stratified by age and tumor location. They determined the prevalence of the IDH mutation (mIDH) using The Cancer Genome Atlas (TCGA).

They identified 1980 patients with DA. For frontal DAs, GTR resulted in improved survival relative to subtotal resection in all ages (age ≤50 years hazard ratio [HR], 0.56; P = 0.002; age >50 years HR, 0.41; P < 0.001). For nonfrontal DAs, only patients ≤50 years experienced improved survival with GTR (age ≤50 years HR, 0.55; P = 0.002; age >50 years HR, 0.78; P = 0.114). For patients ≤50 years with frontal tumors, survival was comparable between DA and AA after GTR (75% survival DA: 80 months, AA: 89 months, P = 0.973). In TCGA, these tumors were nearly uniformly mIDH (DA: 98%; AA: 90%, P = 0.11). However, for patients ≤50 years with nonfrontal tumors, there was a survival difference after GTR (75% survival DA: 80 months, AA: 30 months, P = 0.001) despite comparable mIDH prevalence (DA: 82%, AA: 75%, P = 0.49).

Age and tumor location modify the survival benefit derived from GTR in DA. Survival patterns in SEER imperfectly correlated with mIDH prevalence in TCGA, suggesting that tumor grade and mIDH status convey nonredundant prognostic information in select clinical contexts 2).

References

1)

von Deimling A, Ono T, Shirahata M, Louis DN. Grading of Diffuse Astrocytic Gliomas: A Review of Studies Before and After the Advent of IDH Testing. Semin Neurol. 2018 Feb;38(1):19-23. doi: 10.1055/s-0038-1636430. Epub 2018 Mar 16. PubMed PMID: 29548048.
2)

Alattar AA, Carroll KT, Bryant AK, Hirshman B, Joshi R, Carter BS, Harismendy O, Chen CC. Prognostic Importance of Age, Tumor Location, and Tumor Grade in Grade II Astrocytomas: An Integrated Analysis of the Cancer Genome Atlas and the Surveillance, Epidemiology, and End Results Database. World Neurosurg. 2019 Jan;121:e411-e418. doi: 10.1016/j.wneu.2018.09.124. Epub 2018 Sep 26. PubMed PMID: 30266697.