Anti-Tr/DNER antibody paraneoplastic cerebellar degeneration preceding a very late relapse of Hodgkin Lymphoma after 12 years

Paraneoplastic neurological syndromes in lymphoid neoplasms: a clinical and laboratorial challenge.

Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962

Paraneoplastic neurological syndromes in patients with Hodgkin's disease are rare findings. Subacute, paraneoplastic cerebellar degeneration or autonomic dysfunctions were described before. In some of these cases, autoantibodies against central or peripheral nervous system structures were found in serum and CSF. We present a 30-year-old white male who developed a progredient, clinical and electrophysiological distal sensomotoric neuropathy. Six months after the beginning of the neurological disturbances, Hodgkin's disease (Stadium III BE) was diagnosed. Other reasons for neuropathy, such as direct impairment of the peripheral nervous system by tumor masses or drug-induced neuropathy, were excluded. Cerebrospinal fluid (CSF) analysis showed a mild pleocytosis, elevated total protein (9.8 g/l) and identical oligoclonal bands in serum and CSF. Blood-CSF barrier damage was detected by Reiber formula. Indirect immunofluorescence and western blot analysis demonstrated an autoantibody against peripheral and central nervous system structures in serum and CSF. Although the autoantibody responded to a 38-40 kDa-protein in western blot and showed nuclear staining of myenteric plexus and Purkinje cell nuclei in the immunofluorescence test, this antibody was shown to be not identical to anti-Hu. An intrathecal synthesis of the antineuronal antibody was detected by antibody specificity index. Tumor therapy, plasmapheresis and treatment with intravenous immunoglobulins did not improve the neuropathy. According to our knowledge this is the first case of antineuronal antibody-associated sensomotoric neuropathy in Hodgkin's disease.

The international, randomized phase 3 HD15 trial established 6xeBEACOPP as standard therapy for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) within the German Hodgkin Study Group (GHSG). We performed a follow-up analysis to assess long-term efficacy and safety of this approach. Between 2003 and 2008, 2182 patients aged 18 to 60 years were recruited and randomized in a 1:1:1 ratio between 8 or 6 cycles of eBEACOPP or 8 cycles of the dose-dense BEACOPP-14 regimen, each followed by 30 Gy radiotherapy in case of positron emission tomography (PET)-positive residual lesions ≥2.5 cm. The study aimed at demonstrating non-inferiority regarding efficacy of the 2 experimental arms on a significance level of 2.5% each. The intention-to-treat analysis comprised 2126 patients with a median follow-up of 102 months. Ten-year progression-free survival was 81% (97.5% CI 77–85) with 8xeBEACOPP, 84% (80–87) with 6xeBEACOPP, and 84% (80–87) with 8xBEACOPP-14; the non-inferiority margin of 1.51 for the hazard ratio (HR) could be excluded for both comparisons (6xeBEACOPP, HR = 0.7, 97.5% CI 0.5–1.0; 8xBEACOPP-14, HR = 0.9, 97.5% CI 0.7–1.2). Overall survival at 10 years was 88% (85–91), 90% (88–93), and 92% (89–94), respectively. A total of 142 second malignancies corresponding to 10-year cumulative incidences of 10%, 7%, and 7% and standardized incidence ratios of 4.3, 2.5, and 2.8 were reported for 8xeBEACOPP, 6xeBEACOPP, and 8xBEACOPP-14, respectively. This updated analysis of the HD15 trial thus confirms the efficacy and reports on the long-term safety of a shortened first-line chemotherapy consisting of 6xeBEACOPP followed by PET-guided radiotherapy in advanced-stage HL.

To define the frequency and clinical and immunologic characteristics of patients affected by paraneoplastic neurologic syndromes (PNS) and lymphoma. Patients fulfilling the criteria for PNS associated with lymphoma collected from the European Commission-funded PNS Euronetwork group database were analyzed. Fifty-three patients with Hodgkin lymphoma (HL) (24 patients, mean age 51, range 16-84) or non-Hodgkin lymphoma (NHL) (29 patients, mean age 64, range 31-82) and PNS were analyzed. The most commonly associated PNS was paraneoplastic cerebellar degeneration, present in 21 cases, with a higher prevalence in HL (16/24 cases). Peripheral nervous system (mainly demyelinating polyradiculopathies) and motor neuron involvement were more common in NHL. Onconeural antibodies were more frequent in patients with paraneoplastic cerebellar degeneration, most commonly against the Tr antigen. Fifty percent of the patients with PNS and HL responded to chemotherapy, whereas neurologic improvement was less frequent (24%) in patients with PNS and NHL. In both groups, the survival rate was good. Overall, 10 out of 53 patients eventually died, with only 2 patients (1 with HL, 1 with NHL) dying from PNS. PNS in patients with lymphoma are relatively rare. Paraneoplastic cerebellar degeneration, mainly associated with anti-Tr antibodies, is more prevalent in HL and NHL, followed in our study by motor neuron disease in patients with NHL. Involvement of the peripheral nervous system is heterogeneous, with a prevalence of polyradiculoneuritis in patients with NHL.

Long-Term Responders after Brentuximab Vedotin: Experience on 57 Patients with Relapsed and Refractory Hodgkin and Anaplastic Large Cell Lymphoma

Comparison of Outcomes of HLA-Matched Related, Unrelated, or HLA-Haploidentical Related Hematopoietic Cell Transplantation following Nonmyeloablative Conditioning for Relapsed or Refractory Hodgkin Lymphoma

Primary refractory Hodgkin lymphoma: Limited options and poor survival—but not always

BackgroundParaneoplastic neurological syndromes are a rare presentation of malignant lymphomas at diagnosis or relapse. The most frequent form is the cerebellar degeneration associated with Hodgkin’s lymphoma (HL), but several other syndromes, such as limbic encephalitis, sensorimotor neuropathies and dermatomyositis, have also been described in association with both HL and non‐Hodgkin’s lymphomas.Case presentationHere, we describe a unique case of a 64‐year‐old man with HL presenting at diagnosis with two distinct well‐defined paraneoplastic neurological syndromes – autoimmune limbic encephalitis with memory loss and opsoclonus‐myoclonus syndrome. Intriguingly, the patient tested positive for anti‐paraneoplastic antigen Ma2/Ta antibody, which is almost exclusively detected in solid cancers, such as testicular germ cell tumors and small cell lung cancer. The patient had early‐stage HL, and showed rapid improvement of neurological symptoms after initiation of corticosteroid treatment and specific lymphoma therapy with the adriamycin, bleomycin, vinblastine and dacarbazine regimen.ConclusionsThis case supports the general view of the complex immune system deregulation in HL, which can trigger various autoimmune phenomena, even in early‐stage disease.

IntroductionParaneoplastic neuropathies are rare. They are often difficult to diagnose, especially when they precede the diagnosis of cancer. Hodgkin's lymphoma is associated with multiple paraneoplastic neurological syndromes, of which demyelinating polyneuropathies are very unusual. Association with chronic inflammatory demyelinating polyneuropathy is even more uncommon.Case presentationWe report the rare case of a 74-year-old Caucasian man who presented with a complex neurological syndrome and was eventually diagnosed with the nodular sclerosing variant of Hodgkin's lymphoma. With timely diagnosis and early institution of treatment of the underlying malignancy, our patient began to show gradual improvement of his symptoms.ConclusionHodgkin's lymphoma is associated with several paraneoplastic neurological syndromes. Sometimes it can be the only presenting feature of an underlying Hodgkin's lymphoma, posing a diagnostic challenge. Prompt oncologic treatment and immunotherapy can be beneficial if instituted early in the course of the disease.

Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas

The case of a 17-year-old man with Hodgkin's lymphoma who presented with paraneoplastic sensory neuropathy is presented. The patient visited our hospital because of acute progression of dysesthesiae in the bilateral face and extremities. He also developed an ataxic gait due to decreased deep sensation. Post-contrast T1-weighted MRI showed enhancement of both trigeminal nerves and the cauda equina. Cerebrospinal fluid examination was unremarkable. Intravenous immunoglobulin therapy and subsequent steroid pulse therapy did not improve his symptoms. Laboratory data showed an elevated serum soluble interleukin-2 receptor level. His chest X-ray and CT showed enlarged lymph nodes in the mediastinum, and the histopathologic examination of a lymph node biopsy specimen showed classical Hodgkin's lymphoma. He was treated with chemotherapy. His symptoms of neuropathy improved promptly while the lymphoma was being successfully treated, and he was able to walk with a cane. The present case was characterized by paraneoplastic sensory neuropathy as the initial clinical feature in association with Hodgkin's lymphoma. It is necessary to consider a paraneoplastic neurological syndrome even in a young patient with acute/subacute sensory neuropathy. Paraneoplastic sensory neuropathy associated with Hodgkin's lymphoma could be expected to improve with oncotherapy, and examination of the malignancy and early treatment are important.

Patients with relapsing or primary refractory Hodgkin lymphoma, still have unsatisfactory outcomes after high dose chemotherapy followed by autologous stem cell transplantation (ASCT). Brentuximab Vedotin (BV) is the only approved agent for maintenance therapy for up to one year in these patients, however, this agent is often not available or affordable for many patients, especially in the developing countries. In this study, we used Everolimus as maintenance therapy after ASCT among patients with relapsing/refractory Hodgkin lymphoma. We collected the data of 20 patients with primary refractory or relapsing Hodgkin lymphoma who had undergone ASCT between June 2016 and June 2021. Everolimus was started at 10 mg daily on day +90 after ASCT for at least two years in patients with stable disease status, confirmed by imaging modalities. Patients were followed for disease status and drug side effects every 3 months. In our single-arm case-series study, the median duration of treatment was 22.95 months. Except for three patients, who had progression, others had no progression and are still receiving Everolimus (85%). No serious side effect was seen. We had no mortality due to disease recurrence. Until now, results showed promising effects of Everolimus in patients with relapsing or primary refractory Hodgkin lymphoma as maintenance therapy after ASCT.

Objective To explore the clinical features of paraneoplastic neurological syndrome (PNS). Methods Sixty PNS patients in Peking Union Medical College Hospital from January 2008 to December 2012 according to the international diagnostic criteria for PNS recommended by Graus were diagnosed and their clinical features were retrospectively analyzed. Results Sixty PNS patients had 11 different clinical syndromes, including 29/60 (48.3%) classical syndromes and 27/60 (45.0%) non-classical syndromes. The most common classical syndromes were limbic encephalitis (11/60, 18.3%) and subacute cerebellar degeneration (10/60, 16.7%), while the most common non-classical syndrome was subacute/chronic sensorimotor neuropathies. Thirty-three of sixty (55.0%) PNS patients were found with underlying tumors, the most common of which was lung cancer (13/33, 39.4%), and 46.2% (6/13) of lung cancer was small cell lung cancer. And 19/60 (31.7%) PNS patients had well characterized onconeuronal antibodies in their serum/cerebral spinal fluid, and anti-Hu and anti-Yo antibodies were most commonly seen (16/19). No partially characterized onconeuronal antibody was found. Eight of sixty (13.3%) patients were found with neuronal cell-surface antibodies, all of which were anti-N-methyl-D-aspartate receptor antibodies. Eleven of thirty-one followed-up patients died, including 7 (7/15) definite PNS and 4 (4/16) possible PNS, without significant difference between groups (χ2=0.782 P=0.380). The 1-, 3- and 5-year survival rates were 84.0%, 61.0% and 54.0% respectively. Conclusions PNS patients with either classical or non-classical syndromes should be screened for onconeural antibodies and underlying tumors. Those patients without underlying tumor should be closely followed up. Key words: Paraneoplastic syndromes, nervous system; Antibodies, neoplasm; Retrospective studies

We report the case of a 23-year-old female with severe neurologic dysfunction without a clear cause at the time of initial presentation. The search for an underlying malignancy revealed a slightly enlarged cervical lymph node with Hodgkin's disease (HD). There was no evidence of a brain tumor despite nonspecific bright changes in proton density in the basal ganglia of the right hemisphere of the cerebellum, right cerebellar tonsil, posterior limb of the internal capsule, and the right side of the medulla spinae as shown by magnetic resonance imaging (MRI) as well as reactive lymphocytosis with slightly elevated protein levels in the cerebrospinal fluid (CSF). The findings suggested a cerebellar disorder, with main differential diagnosis between neurologic paraneoplastic syndrome (NPS) and HD involving the CNS. Based on limited experience with NPS and HD in the CNS, possible diagnostic and therapeutic options are discussed.