Immunopathology of Tumefactive Demyelinating Lesions-From Idiopathic to Drug-Related Cases.

Tumefactive demyelinating lesions (TDL) represent a diagnostic dilemma for clinicians, and in rare atypical cases a collaboration of a neuroradiologist, a neurologist, and a neuropathologist is warranted for accurate diagnosis. Recent advances in neuropathology have shown that TDL represent an umbrella under which many different diagnostic entities can be responsible. TDL can emerge not only as part of the spectrum of classic multiple sclerosis (MS) but also can represent an idiopathic monophasic disease, a relapsing disease with recurrent TDL, or could be part of the myelin oligodendrocyte glycoprotein (MOG)- and aquaporin-4 (AQP4)-associated disease. TDL can appear during the MS disease course, and increasingly cases arise showing an association with specific drug interventions. Although TDL share common features with classic MS lesions, they display some unique features, such as extensive and widespread demyelination, massive and intense parenchymal infiltration by macrophages along with lymphocytes (mainly T but also B cells), dystrophic changes in astrocytes, and the presence of Creutzfeldt cells. This article reviews the existent literature regarding the neuropathological findings of tumefactive demyelination in various disease processes to better facilitate the identification of disease signatures. Recent developments in immunopathology of central nervous system disease suggest that specific pathological immune features (type of demyelination, infiltrating cell type distribution, specific astrocyte pathology and complement deposition) can differentiate tumefactive lesions arising as part of MS, MOG-associated disease, and AQP4 antibody-positive neuromyelitis optica spectrum disorder. Lessons from immunopathology will help us not only stratify these lesions in disease entities but also to better organize treatment strategies. Improved advances in tissue biomarkers should pave the way for prompt and accurate diagnosis of TDL leading to better outcomes for patients.

Clinico-radiologic features and therapeutic strategies in tumefactive demyelination: a retrospective analysis of 50 consecutive cases.

AIMS: Our goal was to expand the spectrum of clinico-radiologic characteristics and the possible therapeutic choices in patients with tumefactive demyelinating lesions (TDLs). METHODS: A retrospective analysis of 50 patients with at least one TDL was performed at an academic neurology center (2008-2020). RESULTS: Our cohort comprised mostly women (33/50) with a mean age of 38 years at TDL onset. The mean follow-up time was 76 months. The mean Expanded Disability Status Scale score at TDL onset and at the latest neurological evaluation was 3.7 and 2.3, respectively. We subcategorized the patients into seven groups based mainly on the clinical/radiological findings and disease course. Group A included patients presenting with a Marburg-like TDL (n = 4). Groups B and C comprised patients presenting with monophasic (n = 7) and recurrent TDLs (n = 12), respectively. Multiple sclerosis (MS) patients who subsequently developed TDL (n = 16) during the disease course were categorized as Group D. Group E comprised patients who initially presented with TDL and subsequently developed a classical relapsing-remitting MS without further evidence of TDL (n = 5). Groups F (n = 2) and G (n = 4) involved MS patients who developed TDL during drug initiation (natalizumab, fingolimod) and cessation (interferon, fingolimod), respectively. Regarding long-term treatments applied after corticosteroid administration in the acute phase, B-cell-directed therapies were shown to be highly effective especially in cases with recurrent TDLs. Cyclophosphamide was spared for more aggressive disease indicated by a poor response to corticosteroids and plasma exchange failure. CONCLUSION: Tumefactive central nervous system demyelination is an heterogenous disease; its stratification into distinct groups according to different phenotypes can establish more efficient treatment strategies, thus improving clinical outcomes in the future.

Cold snare polypectomy vs. hot snare polypectomy vs. argon plasma coagulation for small (5-9mm) left-sided colorectal polyps: a prospective randomized trial.

OBJECTIVE: To compare recurrence rates among three endoscopic treatment modalities for 5-9 mm left-sided colorectal polyps. METHODS: Consecutive adults referred for elective colonoscopy (1/2015-1/2018) with at least one polyp of eligible size (5-9 mm) located distally to the splenic flexure were randomly assigned (1:1:1) to one of three treatment modalities: (1) cold snare polypectomy (CSP), (2) hot snare polypectomy (HSP) and (3) argon plasma coagulation (APC) ablation (50-60 W, flow: 2 l/min). The polyp site was marked with an endoscopic tattoo, and a follow-up colonoscopy with scar biopsies was performed >6 months after the index procedure. Outcomes were polyp recurrence rate and occurrence of complications. RESULTS: One hundred nineteen patients were enrolled, of whom 112 (62.5% males, mean age 61.1 ± 9.9 years) with 121 polyps (CSP, 39; HSP, 45; APC, 37) returned for follow-up colonoscopy. Mean polyp size was 6.7 ± 0.91 mm, 58% were located in the sigmoid, 33% in the rectum and 8% in the descending colon. The majority of polyps resected by CSP or HSP were neoplastic (tubular adenomas: 25.9%, tubulovillous adenomas: 11.1% and sessile serrate adenomas/polyps: 17.5%). No cases of delayed bleeding or perforation occurred. Scar biopsies at follow-up colonoscopy (performed after a mean interval of 13.4 ± 3.8 months) revealed 7 (5.8%) cases of polyp recurrence, showing no significant difference among the three treatment groups [CSP, 3/39 (7.7%); HSP, 1/45 (2.2%); APC, 2/37 (5.4%); P = 0.51). CONCLUSIONS: CSP, HSP and APC-ablation are effective and well-tolerated treatment modalities for 5-9 mm left-sided colorectal polyps. The present randomized study did not detect any difference in polyp recurrence rate among the three endoscopic techniques.

Recurrent Fulminant Tumefactive Demyelination With Marburg-Like Features and Atypical Presentation: Therapeutic Dilemmas and Review of Literature.

Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe a 50-year-old woman presenting with subacute onset of left hemiparesis, memory difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion with perilesional edema, mass effect and homogenous post-contrast enhancement, along with other small atypical lesions in the white-matter. Brain biopsy of cerebral lesion ruled out lymphoma or any other neoplastic process and patient placed on corticosteroids with complete clinical/radiological remission. Two years after disease initiation, there was disease exacerbation with reappearance of the tumor-like mass. The patient initially responded to high doses of corticosteroids but soon became resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance to therapeutic efforts led to a second biopsy that showed perivascular demyelination, predominantly consisting of macrophages, with a small number of T and B lymphocytes, and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient received high doses of cyclophosphamide with substantial clinical/radiological response but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with disease exacerbation and brainstem involvement. She eventually died with complicated pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions, with atypical tumor-like characteristics, with initial response to corticosteroids and cyclophosphamide, but subsequent development of drug-resistance and unexpected exacerbation upon rituximab administration. Our clinical case raises therapeutic dilemmas and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions with Marburg-like features.

Anaplastic lymphoma kinase expression and gene alterations in glioblastoma: correlations with clinical outcome.

AIMS: To study anaplastic lymphoma kinase (ALK) protein expression and possible underlying gene alterations in glioblastoma (GBM), correlating them with clinical outcome. METHODS: We studied ALK immunohistochemical expression and fluorescent in situ hybridisation (FISH)-detected ALK gene alterations in 51 GBMs (46 isocitrate dehydrogenase-1 (IDH1)R132H-negative and 5 IDH-mutant (IDH1R132H-positive)). We compared two anti-ALK antibodies and immunohistochemical detection systems (5Α4/Nichirei Biosciences, D5F3/Ventana). The results were correlated with tumour cell proliferation and clinical outcome. RESULTS: Intense granular cytoplasmic ALK immunostaining was observed in 10/51 (19.61%) GBM and correlated with high Ki67 proliferation index; only 1 in 10 ALK-positive cases displayed multiple alk gene signals by FISH. Moderate ALK immunostaining was observed in 21 (41.17%), weak immunostaining in 5 (9.80%) while 15 (29.42%) cases were negative. p53 was expressed in 26/51 GBM (50.9%) (10% cut-off). IDH1R132H-negative GBM showed higher ALK expression compared with IDH-mutant GBM (65.2% vs 20%). ALK overexpression was more common in older patients but did not correlate with other clinicopathological variables or patient overall survival. CONCLUSIONS: ALK overexpression can be identified in up to 70% of GBMs and does not correlate with underlying alk gene amplification. Despite being more common in rapidly growing, clinically aggressive GBM, ALK overexpression did not show correlation with prognosis in this study.

A Case of Distal Epithelioid Sarcoma of the Thumb Expressing Podoplanin, TLE1 and Ca 125.

Distal epithelioid sarcoma is a rare and slowly growing tumor that usually develops in the upper extremities of young adults. Neoplastic cells have both spindle and epithelioid appearance and are characterized by the loss of the nuclear protein SMARCB1/INI1. We present the case of a distal epithelioid sarcoma arising in the thumb of a 14-year-old girl, which immunohistochemically was characterized by the loss of SMARCB1/INI1 protein as well as the expression of podoplanin (D2-40), TLE1, Glut1, and Ca 125; plus, we highlight the differential diagnosis of epithelioid sarcoma from its histological mimics.

The Evangelismos hospital central nervous system tumor registry: Analysis of 1414 cases (1998-2009).

BACKGROUND: The Evangelismos Hospital central nervous system (CNS) Tumor Registry represents the current effort of the Departments of Neurosurgery and Pathology to collect data for primary and metastatic CNS tumor patients. In the present study, 12-year hospital data (1998-2009) were reviewed and analyzed. METHODS: Patients that underwent surgery for CNS tumors for the first time were identified. Histologically confirmed tumor rates by age and gender were compared. Time trends in annual rates for specific tumor types were investigated. In-hospital mortality rates and length of hospital stay were analyzed by age and gender and their putative variations across the study period investigated. RESULTS: A total of 1414 patients (age 15-89 years) were identified. The most frequently encountered histologies were gliomas and meningiomas, accounting for, respectively, 32.8% and 29.1% of the total sample. A greater proportion of meningiomas was found in women; the proportion of glioblastomas and metastatic tumors, as well as of mixed gliomas, were greater in men. Increased rates of glioblastoma and meningioma with advancing age at diagnosis were also apparent. There were no significant variations in time trends for specific tumor types. In-hospital mortality was significantly higher for older patients (≥70 years). An increase in the length of hospital stay was apparent between the first and middle third of the study period. CONCLUSIONS: Analysis of tumor rates in relation to age at diagnosis and gender showed significant bias in accordance with salient literature. Available data indicated no significant variations in time trends for specific tumor types across the study period, while an adverse effect of advanced age on in-hospital mortality was shown. The present findings can guide the formulation of future treatment programs and preventive strategies and provide the basis for further intra- and/or interdepartmental research.

Galectin-3 as a marker distinguishing functioning from silent corticotroph adenomas.

OBJECTIVE: Galectin-3 (Gal-3) belongs to the family of carbohydrate-binding proteins with high affinity for galactoside and is involved in many biological processes including cell growth and differentiation, cell adhesion, tumor progression, apoptosis and metastasis. The aim of this study was to disclose differences in the expression of Gal-3 in silent and functioning corticotroph pituitary adenomas. DESIGN: We examined 30 pituitary adenomas (19 functioning corticotroph, 11 silent corticotroph adenomas). Two prolactinomas and 2 functioning somatotroph adenomas served as positive controls. Antigen retrieval was done by three-minute incubation via pressure boiler in citrate buffer solution, pH 6.0. A polymer was used as a secondary link to DAB chromogen. The independent variables t-test was used for comparison of the mean expression of Gal-3 in the two different corticotroph adenoma subgroups. RESULTS: Eighteen of the functioning corticotroph adenomas (94.73%) were positive for Gal-3 with a cytoplasmic and focally membranous distribution; two cases also exhibited nuclear expression, whereas 9 of the silent corticotroph adenomas (81.81%) had zero or<1% expression of Gal-3 (p=0.001). CONCLUSIONS: Gal-3 is highly expressed in functioning corticotroph adenomas of the pituitary gland, while silent adenomas exhibit very focal to null expression of Gal-3. This observation can be used in the pathological diagnosis to separate functioning from silent corticotroph adenomas of the pituitary.

Blastic natural killer (NK)-cell lymphoma: report of an unusual CD4 negative case and review of the CD4 negative neoplasms with blastic features in the literature.

Blastic Natural Killer (NK)-cell lymphoma is a relatively new entity which has been recently included in the WHO classification. CD4 expression is observed in most cases of blastic NK-cell lymphomas and has been related with skin tropism. We report an unusual CD4 negative blastic NK-cell lymphoma with primary presentation in the skin, subsequent infiltration of the bone marrow and aggressive behavior. It is emphasized that extensive immunophenotyping and EBER RNA in situ hybridization are required in order to establish the diagnosis of blastic NK-cell lymphoma. We also present a review of the literature with respect to the CD4 negative NK-cell lymphomas with blastic morphological features.