PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.

Autonomic Dysfunction is Associated with Increased Cardiometabolic Risk in Patients with Childhood-Onset Craniopharyngioma.

Patients with craniopharyngioma are susceptible to autonomic dysfunction as a result of hypothalamic damage. We evaluated indices of heart rate variability (HRV) in patients with childhood-onset craniopharyngioma to investigate autonomic function and its relationship with components of the metabolic syndrome (MetS). This cross-sectional, case-only study included 53 patients (10-30 years of age). We measured the standard deviation of all normal R-R intervals (SDNN) and total power indicating overall HRV, the root-mean square of the difference of successive R-R intervals (RMSSD) and high frequency indicating parasympathetic modulation, and low frequency. These indices were compared according to the presence of the MetS. During the mean 10.8 years of follow-up, 25% of patients were diagnosed with the MetS. Patients with the MetS showed significantly lower levels of SDNN (29.0 vs. 40.6 ms), total power (416.1 vs. 1129.6 ms2), RMSSD (20.1 vs. 34.5 ms), high frequency (94.7 vs. 338.5 ms2), and low frequency (94.5 vs. 289.4 ms2) than those without (p <0.05, for all). Individual components of the MetS including insulin resistance, serum triglycerides levels, and systolic blood pressure were inversely associated with SDNN, total power, RMSSD and high frequency. Higher overall variability and parasympathetic modulation were related to decreased odds ratios for having the MetS (OR 0.91, p=0.029 for SDNN; OR 0.91, p=0.032 for total power). In conclusion, autonomic dysfunction, as evidenced by reduced HRV indices, is associated with increased cardiometabolic risk in patients with childhood-onset craniopharyngioma.

CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model.

CTLA4 is an inhibitory regulator of immune responses. Therapeutic CTLA4 blockade enhances T cell responses against cancer and provides striking clinical results against advanced melanoma. However, this therapy is associated with immune-related adverse events. Paraneoplastic neurologic disorders are immune-mediated neurological diseases that develop in the setting of malignancy. The target onconeural antigens are expressed physiologically by neurons, and aberrantly by certain tumour cells. These tumour-associated antigens can be presented to T cells, generating an antigen-specific immune response that leads to autoimmunity within the nervous system. To investigate the risk to develop paraneoplastic neurologic disorder after CTLA4 blockade, we generated a mouse model of paraneoplastic neurologic disorder that expresses a neo -self antigen both in Purkinje neurons and in implanted breast tumour cells. Immune checkpoint therapy with anti-CTLA4 monoclonal antibody in this mouse model elicited antigen-specific T cell migration into the cerebellum, and significant neuroinflammation and paraneoplastic neurologic disorder developed only after anti-CTLA4 monoclonal antibody treatment. Moreover, our data strongly suggest that CD8 + T cells play a final effector role by killing the Purkinje neurons. Taken together, we recommend heightened caution when using CTLA4 blockade in patients with gynaecological cancers, or malignancies of neuroectodermal origin, such as small cell lung cancer, as such treatment may promote paraneoplastic neurologic disorders.

Diagnostics of paraneoplastic neurological syndromes.

This document presents the guidelines for onconeural antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on paraneoplastic neurological syndromes, indications and limits of onconeural antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Autoimmune channelopathies in paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes and autoimmune encephalitides are immune neurological disorders occurring or not in association with a cancer. They are thought to be due to an autoimmune reaction against neuronal antigens ectopically expressed by the underlying tumour or by cross-reaction with an unknown infectious agent. In some instances, paraneoplastic neurological syndromes and autoimmune encephalitides are related to an antibody-induced dysfunction of ion channels, a situation that can be labelled as autoimmune channelopathies. Such functional alterations of ion channels are caused by the specific fixation of an autoantibody upon its target, implying that autoimmune channelopathies are usually highly responsive to immuno-modulatory treatments. Over the recent years, numerous autoantibodies corresponding to various neurological syndromes have been discovered and their mechanisms of action partially deciphered. Autoantibodies in neurological autoimmune channelopathies may target either directly ion channels or proteins associated to ion channels and induce channel dysfunction by various mechanisms generally leading to the reduction of synaptic expression of the considered channel. The discovery of those mechanisms of action has provided insights on the regulation of the synaptic expression of the altered channels as well as the putative roles of some of their functional subdomains. Interestingly, patients' autoantibodies themselves can be used as specific tools in order to study the functions of ion channels. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Cell-mediated immune responses in paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes (PNS) are disorders of the nervous system that are associated with remote effects of malignancy. PNS are considered to have an autoimmune pathology. It has been suggested that immune antitumor responses are the origin of improved outcome in PNS. We describe cell-mediated immune responses in PNS and their potential contributions to antitumor reactions. Experimental and neuropathological studies have revealed infiltrates in nervous tissue and disturbances in lymphocyte populations in both cerebrospinal fluid and peripheral blood. A predominance of cytotoxic T lymphocytes (CTLs) over T helper cells has been observed. CTLs can be specifically aggressive against antigens shared by tumors and nervous tissue. Based on genetic studies, a common clonal origin of lymphocytes from blood, tumor, and nervous tissue is suggested. Suppressive regulatory T (Treg) lymphocytes are dysfunctional. Simultaneously, in tumor tissue, more intense cell-mediated immune responses are observed, which often coincide with a less aggressive course of neoplastic disease. An increased titer of onconeural antibodies is also related to better prognoses in patients without PNS. The evaluation of onconeural and neuronal surface antibodies was recommended in current guidelines. The link between PNS emergence and antitumor responses may result from more active CTLs and less functional Treg lymphocytes.

Study on the pro-inflammatory mechanism of the HuD antibody in promoting M1 polarization and paraneoplastic neurological syndrome occurrence.

Paraneoplastic neurological syndrome (PNS) is a nonmetastatic complication of malignant tumors that may lead to immune-mediated neuronal dysfunction or death. The occurrence of PNS results from the binding of anti-neuronal antibodies to neuronal cell surface antigens or intracellular antigens, which hinders the function of target proteins and promotes cell death. The aim of this study is to research the effect and immune mechanism of the neuronal ELAV-like protein (HuD antibody) on PNS-related syndrome. Neuronal cells were co-cultured with monocyte macrophages with or without HuD antibody. Next, we detected the apoptosis of neuronal cells by flow cytometry. Meantime, macrophage M1/M2 polarization factors and the secretion of inflammatory factors in the co-culture system were also detected by quantitative polymerase chain reaction (qPCR), Western blots and ELISA technologies. The results showed that after adding the HuD antibody in the co-culture system, the apoptosis level of the neuroma cells were significantly increased, and the apoptosis level were not significant changed when co-culture with monocytes without HuD antibody. In addition, the level of factors of M1 macrophages TNF-α, IL-12, TGF-ß and IFN-γ increased, while the level of factors of M2 macrophages IL-10, IL-4, and Arg-1 decreased. The outcomes demonstrated that absorption of the HuD antibody by cerebellar neuronal cells could promote the proliferation of M1 macrophages and stimulates macrophages to secrete inflammatory factors, further damage the neuronal cells, eventually resulting in the occurrence of PNS. This finding provided a theoretical basis for the subsequent treatment and prevention of PNS.

Paraneoplastic encephalomyelopathies: pathology and mechanisms.

The last three decades have seen major advances in the understanding of paraneoplastic and idiopathic autoimmune disorders affecting the central nervous system (CNS). Neural-specific autoantibodies and their target antigens have been discovered, immunopathology and neuroimaging patterns recognized and pathogenic mechanisms elucidated. Disorders accompanied by autoantibody markers of neural peptide-specific cytotoxic effector T cells [such as anti-neuronal nuclear antibody type 1 (ANNA-1, aka anti-Hu), Purkinje cell antibody type 1 (PCA-1, aka anti-Yo) and CRMP-5 IgG] are generally poorly responsive to immunotherapy. Disorders accompanied by neural plasma membrane-reactive autoantibodies [the effectors of synaptic disorders, which include antibodies targeting voltage-gated potassium channel (VGKC) complex proteins, NMDA and GABA-B receptors] generally respond well to early immunotherapy. Here we describe in detail the neuropathological findings and pathophysiology of paraneoplastic CNS disorders with reference to antigen-specific serology and neurological and oncological contexts.

Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2.

OBJECTIVE: To report the presence of a new neuronal surface antibody against the metabotropic glutamate receptor 2 antibody (mGluR2-Ab) in 2 patients with paraneoplastic cerebellar ataxia. METHODS: mGluR2-Abs were initially characterized by immunohistochemistry on the rat brain and confirmed by immunofluorescence on HEK293 cells transfected with mGluR2. Additional studies included analysis of potential cross-reactivity with other mGluRs, expression of mGluR2 in patients' tumors, and the effects of mGluR2-Abs on cultures of rat hippocampal neurons. RESULTS: Patient 1 was a 78-year-old woman with progressive cerebellar ataxia with an initial relapsing-remitting course who developed a small-cell tumor of unknown origin. Patient 2 was a 3-year-old girl who presented a steroid-responsive acute cerebellitis preceding the diagnosis of an alveolar rhabdomyosarcoma. Patients' serum and CSF showed a characteristic immunostaining of the hippocampus and cerebellum in rat brain sections and immunolabeled the cell surface of live rat hippocampal neurons. HEK293 cells transfected with mGluR1, 2, 3, and 5 confirmed that patients' antibodies only recognized mGluR2. mGluR2-Abs were not detected in 160 controls, 120 with paraneoplastic, autoimmune, or degenerative ataxias, and 40 with autoimmune encephalitis and antibodies against mGluR5 or unknown antigens. Expression of mGluR2 in tumors was confirmed by immunohistochemistry using a commercial mGluR2-Ab. Incubation of live rat hippocampal neurons with CSF of patient 2 did not modify the density of surface mGluR2 clusters. CONCLUSIONS: mGluR2-Abs are a novel biomarker of paraneoplastic cerebellar ataxia. The potential pathogenic effect of the antibodies is not mediated by downregulation or internalization of neuronal surface mGluR2.

18 F-Fluorodeoxyglucose positron-emission tomography for the investigation of malignancy in patients with suspected paraneoplastic neurologic syndromes and negative or indeterminate conventional imaging: a retrospective analysis of the Ontario PET Access Program, with systematic review and meta-analysis.

Objective: Paraneoplastic neurologic syndrome (pns) is a rare condition indirectly caused by an underlying malignancy. In many cases, the malignancy is occult at the time of the pns diagnosis, and the optimal diagnostic modality to detect the underlying tumour is unclear. In the present study, we aimed to assess the utility of 18F-fluorodeoxyglucose positron-emission tomography (fdg-pet) or pet integrated with computed tomography (pet/ct) in the investigation of these patients. Methods: We retrospectively analyzed data from the PET Access Program (pap) database in the province of Ontario to identify patients who underwent fdg-pet/ct imaging as part of a workup for pns. In all patients, prior conventional imaging was negative or indeterminate. To determine the diagnostic accuracy of fdg-pet/ct, data about demographics, presenting symptoms, and biochemical and radiologic workup, including fdg-pet/ct imaging results, were compared with data collected by the Ontario Cancer Registry (ocr). A systematic review of the literature and meta-analysis using our study inclusion criteria were performed for studies of fdg-pet accuracy. Results: Of 29 patients identified in the pap database, 9 had fdg-pet/ct results suspicious for malignancy. When correlated with data from the ocr, 5 fdg-pet/ct results were informative, resulting in a detection rate of 17%. Local sensitivity and specificity were 0.83 and 0.83 respectively. Two studies meeting our criteria were identified in the literature. The pooled sensitivity and specificity from the literature and local data were 0.88 and 0.90 respectively. Conclusions: When investigating for underlying malignancy in patients with suspected pns and negative conventional imaging, pet has high sensitivity and specificity.

Utilization Review of Paraneoplastic Neurological Syndrome Antibody Screening Panels: Experience at a Tertiary Academic Health Center.

BACKGROUND: Pathology departments play a pivotal role in managing laboratory test utilization in healthcare, and inappropriate resource deployment can contribute to unnecessary healthcare costs. Here we share our experience reviewing a send-out test and implementing a utilization strategy. Antibody testing is often considered in the workup for patients with unexplained paraneoplastic syndrome-like neurological presentations. It has been unclear how helpful these antibody tests are. The goal of study is to evaluate diagnostic utility of antibody screening panel results in patients suspicious for paraneoplastic neurological syndrome and possibly underlying occult malignancy. METHODS: We retrospectively reviewed the paraneoplastic neurological syndrome antibody test results. The positive predictive value and negative predictive value were calculated. The proportion of the antibody screening results were compared between groups with and without tumor with 2-sided χ2 test statistics. RESULTS: In total 348 panels were sent to 2 reference laboratories. From ARUP (Associated Regional and University Pathologists; Salt Lake City, Utah), 2 out of 232 screening panels yielded positive results (0.86%) and from the Mayo Clinic (Rochester, Minnesota), 26 out of 116 screening panels yielded positive results (22.4%). The overall positive predictive value was 3.57% (1/28) and the overall negative predictive value was 91.2% (292/320). There were no statistically significant differences between the antibody screening test results between the 2 groups with and without tumor. CONCLUSION: We found the diagnostic utility and yield for the paraneoplastic antibody panel to be low. Following a multidisciplinary team review of the study results, the pathology department has implemented several new utilization strategies.

Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions.

RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing, transport, and stability. Disruption of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.

Paraneoplastic syndromes of the CNS.

Major advances in the management of paraneoplastic neurologic disorders (PND) include the detection of new antineuronal antibodies, the improved characterisation of known syndromes, the discovery of new syndromes, and the use of CT and PET to reveal the associated tumours at an early stage. In addition, the definition of useful clinical criteria has facilitated the early recognition and treatment of these disorders. In this article, we review some classic concepts about PND and recent clinical and immunological developments, focusing on paraneoplastic cerebellar degeneration, opsoclonus-myoclonus, and encephalitides affecting the limbic system.

Anti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are indirect remote effects of cancer on the nervous system, often associated with the presence of specific serum antibodies. The most recently described PNS defining reactivity is anti-Ma/anti-Ta. Here we present 22 newly diagnosed patients with anti-Ma or anti-Ta reactivity, refine the associated clinical picture and review all published patients to date. PATIENTS AND METHODS: Patients were identified by testing for PNMA1 and PNMA2 antibodies by western blotting and indirect immunofluorescence. Clinical data were obtained either by referral of the patient or from the referring physicians. RESULTS: Analysis of 22 new patients (14 anti-Ma, eight anti-Ta) confirmed that anti-Ta are usually found in young men with limbic encephalitis and testicular germ cell tumours who stabilise neurologically with long term survival after tumour treatment. Patients with anti-Ma were of either sex, middle-aged, presented with a range of tumours and neurological symptoms and had a limited response to treatment. Furthermore, we expanded the range of associated clinical features: (1) the peripheral nervous system may be involved; (2) an overlap with anti-Hu is possible; and (3) testicular tumour manifestation can be extragonadal or detectable only at orchiectomy. CONCLUSION: Refining and expanding the range of anti-Ma/anti-Ta associated neurological presentations and tumours clearly demonstrated that the distinction between anti-Ma and anti-Ta associated PNS is of high clinical relevance.

PNMA family: Protein interaction network and cell signalling pathways implicated in cancer and apoptosis.

Paraneoplastic Ma Family (PNMA) comprises a growing number of family members which share relatively conserved protein sequences encoded by the human genome and is localized to several human chromosomes, including the X-chromosome. Based on sequence analysis, PNMA family members share sequence homology to the Gag protein of LTR retrotransposon, and several family members with aberrant protein expressions have been reported to be closely associated with the human Paraneoplastic Disorder (PND). In addition, gene mutations of specific members of PNMA family are known to be associated with human mental retardation or 3-M syndrome consisting of restrictive post-natal growth or dwarfism, and development of skeletal abnormalities. Other than sequence homology, the physiological function of many members in this family remains unclear. However, several members of this family have been characterized, including cell signalling events mediated by these proteins that are associated with apoptosis, and cancer in different cell types. Furthermore, while certain PNMA family members show restricted gene expression in the human brain and testis, other PNMA family members exhibit broader gene expression or preferential and selective protein interaction profiles, suggesting functional divergence within the family. Functional analysis of some members of this family have identified protein domains that are required for subcellular localization, protein-protein interactions, and cell signalling events which are the focus of this review paper.

Neuronal autoantibodies: differentiating clinically relevant and clinically irrelevant results.

The aim of this study is to compare the rates of clinically relevant and clinically irrelevant neuronal autoantibodies among patients presenting with new neurological symptoms. We reviewed 401 neurological patients who were tested for the Mayo-Clinic paraneoplastic panel from January 2014 to December 2014 at the Johns Hopkins Hospital. We divided antibody-positive patients into two groups: clinically relevant (CR), in which a recognizable autoimmune or paraneoplastic syndrome was confirmed, and clinically irrelevant (CI), in which an autoimmune/paraneoplastic etiology was initially suspected but an alternative diagnosis was eventually found. We used Fisher's exact test for categorical variables and Mann-Whitney U test for continuous variables to identify differences between the two groups. Fifty-three patients tested positive for one or more neuronal autoantibodies. There were 17 CR (65% females, mean age 56 years), 33 CI, and 3 indeterminate patients. Compared to CI patients, CR patients were more likely to present with movement disorders or stiff person syndrome, have inflammatory CSF markers, cancer or smoking history, concomitant hyponatremia, and classical onconeuronal antibodies. CI patients were more likely to have a neuromuscular presentation, a chronic course, and antibodies against synaptic antigens. By combining the most robust differentiating factors, we developed a simple scale that predicted clinical relevance with an odds ratio of 50.3 (CI 8.2-309.9, P < 0.0001) if the score was ≥ 2. Up to 62% of neuronal autoantibody-positive patients are ultimately found to have an alternative diagnosis. Several clinical and laboratory factors can differentiate CR from CI patients to aid in interpretation of positive results.

Paraneoplastic Limbic Encephalitis in a Human Epidermal Growth Factor Receptor-2-positive Gastric Cancer Patient Treated with Trastuzumab-combined Chemotherapy: A Case Report and Literature Review.

Paraneoplastic neurological syndromes (PNSs) are rare nervous system dysfunctions in cancer patients, which are primarily observed with small-cell lung cancer, gynecological cancer, and thymoma. We herein present an uncommon case of PNS in an anti-Hu antibody-positive patient with human epidermal growth factor receptor (HER)-2-positive gastric cancer (GC), who developed limbic encephalitis and a worsening cognitive function. Trastuzumab-combined chemotherapy was initiated and appeared to be partially effective for controlling the neurological symptoms and tumor volume. Chemotherapy failure eventually led to uncontrollable neurological symptoms. This is the first case demonstrating that trastuzumab-combined chemotherapy may be effective for controlling neurological symptoms of PNS in HER2-positive GC patients.

Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies.

IMPORTANCE: Little is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment. OBJECTIVE: To report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series study and immunological investigations conducted in February 2014 in a center for autoimmune neurological disorders. Fifteen cases with GAD65-abs evaluated between 1995 and 2013 who fulfilled criteria of definite or possible PNS without concomitant onconeural antibodies were included in this study. MAIN OUTCOMES AND MEASURES: Analysis of the clinical records of 15 patients and review of 19 previously reported cases. Indirect immunofluorescence with rat hippocampal neuronal cultures and cell-based assays with known neuronal cell-surface antigens were used. One hundred six patients with GAD65-abs and no cancer served as control individuals. RESULTS: Eight of the 15 patients with cancer presented as classic paraneoplastic syndromes (5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus-myoclonus syndrome). When compared with the 106 non-PNS cases, those with PNS were older (median age, 60 years vs 48 years; P = .03), more frequently male (60% vs 13%; P < .001), and had more often coexisting neuronal cell-surface antibodies, mainly against γ-aminobutyric acid receptors (53% vs 11%; P < .001). The tumors more frequently involved were lung (n = 6) and thymic neoplasms (n = 4). The risk for an underlying tumor was higher if the presentation was a classic PNS, if it was different from stiff-person syndrome or cerebellar ataxia (odds ratio, 10.5; 95% CI, 3.2-34.5), or if the patient had coexisting neuronal cell-surface antibodies (odds ratio, 6.8; 95% CI, 1.1-40.5). Compared with the current series, the 19 previously reported cases had more frequent stiff-person syndrome (74% vs 13%; P = .001) and better responses to treatment (79% vs 27%; P = .005). Predictors of improvement in the 34 patients (current and previously reported) included presentation with stiff-person syndrome and the presence of a thymic tumor. CONCLUSIONS AND RELEVANCE: Patients with GAD-abs must be screened for an underlying cancer if they have clinical presentations different from those typically associated with this autoimmunity or develop classic PNS. The risk for cancer increases with age, male sex, and the presence of coexisting neuronal cell-surface antibodies.

Molecular cloning and characterization of human PTB-like protein: a possible retinal autoantigen of cancer-associated retinopathy.

Human homologue of polypyrimidine tract binding protein (PTB), a possible autoantigen for cancer-associated retinopathy (CAR), was isolated from a human retinal cDNA library. This homologue, named PTB-like protein (PTBLP), encodes a 532 amino acid residue and has a 75% homology to the human PTB. The human PTBLP had four RNA recognition motifs (RRMs) and had a RNA binding ability. There are four splicing variants in PTBLP. The CAR serum recognized the full length form of PTBLP and the antigenic determinant was localized within 12 amino acids of the C-terminal region. The sequence was included in the fourth RRM sequence.

Neuroblastic tumors associated with opsoclonus-myoclonus syndrome: histological, immunohistochemical and molecular features of 15 Italian cases.

The aim of this study was to investigate the histological, immunohistochemical and molecular features of a series of children with neuroblastic tumors (NTs) and opsoclonus-myoclonus syndrome (OMS). Of 1187 children (age 0-15 years) with previously untreated NTs registered between 1979 and 1995, 15 (1.3%) had OMS at presentation. The majority of patients showed favorable biological characteristics, such as lack of amplification of the neuroblastoma-associated avian myelocytomatosis homolog MYCN oncogene and aneuploid nuclear DNA content. Tumor histology was reviewed according to the International Neuroblastoma Pathology Classification. Histology of the 15 cases of NTs with OMS was ganglioneuroblastoma, intermixed, in 10 patients; ganglioneuroma, maturing, in 1; and neuroblastoma in 4. Of 15 tumors, 12 (10 ganglioneuroblastomas, 2 neuroblastomas) showed abundant interstitial or perivascular lymphoid infiltrates, the latter often organized in secondary lymphoid follicles. The three remaining cases had only minimal infiltrates. A review of 91 cases of age- and stage-matched neuroblastic tumors not associated with OMS tested as controls showed that the degree of lymphoid infiltration was significantly lower than that detected in OMS-related tumors. Furthermore, lymphoid follicles were always present in the latter tumors, whereas they were detected only in a few ganglioneuroma, intermixed tumors from the control group. In conclusion, ganglioneuroblastoma, intermixed subtype, lack of MYCN amplification, aneuploid DNA content and presence of lymphoid infiltrates may contribute to favorable prognosis in NTs associated with OMS.