Objective
To describe the neuropathological features of N‐methyl‐D‐aspartate receptor (NMDAR)‐encephalitis in an archival autopsy cohort.
Methods
We examined four autopsies from patients with ...NMDAR‐encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post‐transplant lymphoproliferative disease (PTLD), and overlapping demyelination.
Results
The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+/CD8− T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR‐immunoreactivity that correlated with disease severity. The patient with NMDAR‐encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR‐encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro‐inflammatory activation markers HLA‐DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR‐encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination.
Interpretation
The topographic distribution of inflammation in patients with NMDAR‐encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR‐immunoreactivity correlates with disease severity. Co‐occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients’ clinical presentation and outcome. ANN NEUROL 2021;90:725–737
Summary
Frequency, distribution and prognostic meaning of ALK‐partner genes other than NPM1 in ALK‐positive anaplastic large‐cell lymphoma (ALCL) are unknown. Forty‐nine of 316 ALCL diagnosed in the ...NHL‐BFM study group showed no nuclear ALK expression suggestive of a variant ALK‐partner; 41 were analysed by genomic capture high‐throughput sequencing or specific RT‐PCRs. NPM1::ALK was detected in 13 cases. Among the 28 patients with a non‐NPM1::ALK‐fusion partner, ATIC (n = 8; 29%) and TPM3 (n = 9; 32%) were the most common. Five of eight patients with ATIC::ALK‐positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK‐partners are rare and potentially associated with different prognoses.
Summary
Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation. We studied a patient with ...autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI. Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres. The autoimmune phenotype was associated with an increased CD21lowT‐bet+CD11c+ subset along with decreased regulatory T cells, impaired T‐cell proliferation and T‐cell exhaustion. The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency.
Background
18F‐FDG‐PET/MR carries a high diagnostic value in whole‐body oncologic imaging and allows simultaneous quantitative measurements of glucose metabolism (SUV) and cell density (ADC).
Purpose
...To determine the relationship between SUV and ADC values extracted from simultaneously acquired 18F‐FDG‐PET/MR data of patients with FDG‐avid lymphomas at staging.
Study Type
Prospective.
Population
Patients with histologically proven lymphoma referred for staging.
Field Strength/Sequences
Hybrid PET/MR device (3T); axial, two‐point Dixon, 3D, volume‐interpolated, T1‐weighted breath‐hold sequence; coronal T2‐weighted half‐Fourier acquisition single‐shot turbo spin‐echo. Single‐shot, echo‐planar imaging‐based, spectral adiabatic inversion recovery diffusion‐weighted imaging.
Assessment
Staging was performed according to the modified Ann Arbor system by a board‐certified radiologist and a board‐certified nuclear medicine physician, blinded to the clinical and histological information, in consensus. SUVs and ADCs values were collected, for each positive nodal and extranodal region, from the lesion demonstrating the largest diameter.
Statistical Tests
Descriptive data included absolute frequencies and percentages for categorical data, and arithmetic means and 95% confidence intervals for scale‐type data. The Pearson correlation coefficient was used to assess the relationship between SUVs and ADCs (P ≤ 0.05). Additional separate analyses were performed according to histological lymphoma subtype, for nodal and extranodal lesions and excluding bone lesions.
Results
Overall, 100 patients were examined (55 males, 45 females; age ± SD in years, 51.6 ± 19.5). Histology revealed Hodgkin‐lymphoma and non‐Hodgkin‐lymphoma in 26 and 74 patients, respectively. Twenty patients were stage I, 21 stage II, 24 stage III, and 31 stage IV on 18F‐FDG‐PET/MR (ie, four patients negative at imaging). Based on 391 lesions (ie, 367 excluding bone lesions) no significant correlations between SUVmax and ADCmin, or between SUVmean and ADCmean, emerged (respectively, r = 0.091, P = 0.073, 95% CI –0.01, 0.19 and r = –0.032, P = 0.527, 95% CI –0.13, 0.07 including bone lesions; r = 0.06, P = 0.21, 95% CI –0.04, 0.17 and r = –0.05, P = 0.32, 95% CI –0.15, 0.05 excluding bone lesions). A significant correlation was observed only between ADCmean and SUVmean for follicular lymphoma (r = −0.33, P = 0.001).
Data Conclusion
SUVs and ADCs were demonstrated to be independent biomarkers in lymphomas. A moderate correlation between SUVs and ADCs likely is present in follicular lymphoma.
Level of Evidence: 1
Technical Efficacy: Stage 3
J. Magn. Reson. Imaging 2018;47:1217–1226.
Given the lack of consistent data regarding the clinico‐pathological features and clonal lymphomagenesis of patients with mucosa‐associated lymphoid tissue (MALT) lymphoma and histological ...transformation (HT), we have systematically analysed 379 patients (32% gastric, 68% extra‐gastric; median follow‐up 52 months) diagnosed with HT at the Medical University Vienna 1999–2017, and reassessed tissues of identified patients by polymerase chain reaction (PCR)‐based clonality analysis. HT was documented in 12/379 patients (3·2%) and occurred at a median time of 22 months (range; 6–202 months) after diagnosis of MALT lymphoma. By PCR‐based clonality analysis, we detected a clear‐cut clonal relationship of MALT lymphoma and diffuse large B‐cell lymphoma (DLBCL) in 8 of 11 analysed cases proving that the large majority of DLBCL following MALT lymphoma are clonally‐related and constitute a real transformation. Interestingly, HT occurred within the first 2·5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally‐unrelated (most likely secondary) lymphoma (82–202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1·5–33 months after HT, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.
TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements ...activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.
Objectives
A treatment regimen consisting of bendamustine and brentuximab vedotin (BV) has been described as a highly potent salvage therapy and as an effective induction therapy leading to high ...response rates before autologous stem cell transplantation (ASCT) in patients with classical Hodgkin lymphoma (cHL). In this retrospective analysis, we aimed to assess this therapy's efficacy in unselected patients with cHL and CD30+ peripheral T‐cell lymphoma (PTCL).
Patients and methods
Data of 28 patients with cHL and five patients with PTCL treated with a combination of bendamustine and BV at three Austrian tertiary cancer centers were analyzed.
Results
In patients with cHL, the ORR was 100% (78.6% CR, 21.4% PR). After 17 months median follow‐up, median survival times were not reached; 1‐year PFS was 81.9%, and 1‐year OS was 95.7%. Thirteen eligible patients (46.4%) successfully underwent planned ASCT after salvage therapy with bendamustine and BV and subsequent high‐dose chemotherapy. Three of the five PTCL patients achieved CR, while two did not respond and died during or shortly after therapy.
Conclusion
A combination of bendamustine and BV is an effective salvage and induction therapy before ASCT in patients with relapsed/refractory cHL. Further research is warranted to evaluate the use in patients with PTCL.
The 2016 revised WHO criteria for the diagnosis of pre‐fibrotic/early primary myelofibrosis (pre‐PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, ...leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre‐PMF patients and compared them to 225 ET cases. More than 91% of pre‐PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre‐PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre‐PMF and ET. Molecular characterization showed differences in survival in pre‐PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre‐PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre‐PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
Non‐anaplasticperipheral T‐cell lymphomas (PTCL) are rare tumors in children, adolescents, and young adults (CAYA) with poor prognosis and scarce genetic data. We analyzed lymphoma tissue from 36 ...patients up to 18 years old with PTCL, not otherwise specified (PTCL‐NOS), hepatosplenic T‐cell lymphoma, Epstein–Barr virus (EBV)‐positive T‐lymphoproliferative diseases, subcutaneous panniculitis‐like T‐cell lymphoma, and other PTCL types. Twenty‐three patients (64%) had at least one genetic variant detectable, including TET2, KMT2C, PIK3D, and DMNT3A. TP53 and RHOA variants, commonly found in adults, were not identified. Eight of 20 (40%) CAYA PTCL‐NOS had no detectable mutations. The genetic findings suggest that CAYA PTCL differ from adult cases.
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