Primary leptomeningeal lymphoma: report of 9 cases, diagnosis with immunocytochemical analysis, and review of the literature

We describe 9 patients who presented with a neoplastic meningitis of lymphomatous origin. No evidence of parenchymal central nervous system or systemic tumor was identified either at the time of presentation or throughout the course of their disease. We have chosen to call this entity "primary leptomeningeal lymphoma" (PLML). This unusual form of neurologic lymphoma must be differentiated from the more common clinical situations of primary parenchymal lymphoma with meningeal involvement and systemic lymphoma complicated by lymphomatous meningitis.     

Craniocerebral involvement in lymphoma

Nine-hundred-eighty-nine patients with lymphoma were studied. Fifty-three cases (5.3%) had lymphomatous craniocerebral infiltration. The principal factors of risk for this complication were: advanced stage of the lymphoma (III or IV), diffuse histiocytic, diffuse poorly differentiated lymphocytic, or mixed cellularity lymphoma histological type, bone marrow involvement, and previous systemic chemotherapy. Thirty-two per cent of the cases of meningeal lymphomatous infiltration were asymptomatic and represented autopsy findings. CT-scan was an useful test to detect brain focal parenchymatous infiltration, as opposed to meningeal infiltration. Mean survival time in patients with lymphomatous meningeal infiltration was 4.3 months, following the combined use of systemic chemotherapy, radiation therapy and intrathecal methotrexate. Two cases had primary cerebral lymphoma, although without associated immunodeficiency. Twenty patients (2%) had intracranial hemorrhage, in clear relationship with platelet alterations. Fifteen patients (1.5%) had CNS infection, caused by common bacteria or opportunistic agents. In 7 cases, the diagnosis was made at autopsy. Thirty-six autopsies were performed. In 8 cases (22%), pathologic findings such as, demyelination, microcalcifications, coagulative necrosis, or gliosis, suggested complications from treatment.     

Meningeal involvement in leukemias and malignant lymphomas of adults: Incidence, course of disease, and treatment for prevention

As prognosis has improved over the last several years, an increasing incidence of meningeal involvement has been recognized in adult patients with acute leukemias and malignant lymphomas. In 210 patients evaluated retrospectively, the incidence of meningeal disease was 33% for patients with acute lymphocytic leukemia (ALL), 20% for patients with acute myelogenous leukemia (AML), 22% for patients with non-Hodgkin's lymphomas with an unfavorable histology (NHL), 3% for patients with chronic myelogenous leukemia (CML), and 1% for patients with chronic lymphocytic leukemia (CLL). In most patients, meningeal involvement appeared several months after diagnosis of acute leukemia, often preceding systemic relapse if bone marrow remission had been achieved before. Prophylactic treatment of the CNS was begun in eight patients with ALL or AML after bone marrow remission was achieved. Of these patients, three with ALL and one with AML were free of disease up to 2 years after diagnosis. Methods, benefits, and risks of prophylactic treatment of the CNS for adult patients are discussed in detail.     

Hematological neoplasms with first presentation as spinal cord compression syndromes: a 10-year retrospective series and review of the literature

CONTEXT: The epidural space is a well-known, albeit uncommon, location for lymphomatous involvement, estimated to occur in less than 3% of all systemic lymphomas. Initial presentation of the patient with disease in this site (i.e. primary spinal epidural lymphoma) has been considered to be "rare". When it has been reported, many studies have emphasized the occurrence of aggressive lymphomas with a poor prognosis. DESIGN: A 10-year retrospective search of our files generated 7 patients who presented initially with back pain, incontinence and/or lower extremity weakness, and by neuroimaging studies were found to have masses causing spinal cord compression syndromes necessitating neurosurgical intervention. RESULTS: The 7 patients included 4 males and 3 females with thoracic and lumbar epidural masses. Tumor types included high-grade non-Hodgkin lymphoma, B cell type (n = 4), indolent B cell lymphoma (n = 1), nodular sclerosing Hodgkin lymphoma (n = 1) and plasmacytoma (n = 1). Advanced disease (stage 4) was subsequently identified in all 7 patients. Despite this, survival varied greatly with therapy, from 3 weeks to almost 6 years, underscoring the need for correct classification of the lymphoma in order to optimize chemotherapeutic choices. The epidural space was the site of presentation of disease in 4% of all lymphomas diagnosed at our institution. CONCLUSIONS: Combining all reports in the literature, epidural presentation of lymphoma is not rare. Epidural lymphomas are distinct from both primary central nervous system lymphomas and from primary dural lymphomas. A broad range of systemic hematological tumor types can present as epidural masses. A full work-up for lymphoma classification may only be possible from the tissues received at the time of the neurosurgical decompression or biopsy procedure.     

Clinical aspects and pathogenesis of neurological complications due to malignant lymphomas]

Malignant lymphomas cause various neurological complications by several ways. They include 1) infiltration and compression due to lymphoma itself, 2) ischemia due to intravascular proliferation of lymphoma cells, 3) paraneoplastic syndrome, 4) immunodeficiency due to lymphomas, 5) organ dysfunction due to lymphomatous infiltration, and 6) complication related to therapies against lymphomas. We presented 4 patients with neurological complications caused by B cell lymphomas as follows. Our first patient was a 67-year-old woman with primary intracranial lymphoma whose onset simulated that of a cerebral infarct. The second patient was a 52-year-old man with lymphoma, who developed myelopathy caused by an intradural extramedullary spinal cord tumor. He received chemotherapy and radiation therapy, followed by complete remission. The third was a 80-year-old man with left cavernous sinus syndrome, which did not respond to therapies against lymphoma. The fourth was a 55-year-old man who presented with numb chin syndrome on both sides, followed by multifocal lymphomatous involvement of the cranial nerves, spinal roots and leptomeninges. Malignant lymphomas may affect any regions of the central and peripheral nervous systems by various ways. Early diagnosis and treatment are essential for the better outcome of neurological complications due to lymphomas.     

T-cell lymphoma in the CNS: clinical and pathologic features

T-cell lymphoma may involve the CNS as either a primary or secondary neoplasm. This report describes 8 patients with either primary or secondary T-cell malignancies in the CNS. Five patients presented with symptoms and signs of CNS disease that included seizures, visual impairment, cranial nerve palsies, sensory and motor deficits, gait ataxia, and paraparesis. Three of them had primary parenchymal CNS lymphoma, and 2 had epidural lymphoma that originated in adjacent bone marrow. Three patients were neurologically asymptomatic, but had leptomeningeal tumor and focal parenchymal infiltration at postmortem examination. Histologically, 4 lymphomas were large cell, 3 were mixed large and small cell, and 1 could not be classified by the working formulation for non-Hodgkin's lymphomas. The clinical and pathologic manifestations of T-cell lymphoma in the CNS may be diverse. This report demonstrates that neurologic abnormalities may be the presenting signs of either primary CNS or systemic T-cell lymphoma.     

Anterior panhypopituitarism in diffuse large B-cell stage IV lymphoma

The most common presentation of metastases to the pituitary gland in systemic lymphoma is diabetes insipidus resulting from infiltration of the infundibulum/posterior lobe. We describe a 69-year-old man with diffuse large B-cell stage IV lymphoma who presented with anterior pituitary hypofunction, without features of posterior pituitary involvement. He presented with a few months of postural dizziness and hypotension, weight loss, fever, strabismus of right eye and a superficial abdominal wall mass. At this time he had no history of malignancy. Biochemically he had hypovolemic hyponatremia, secondary hypothyroidism and adrenal insufficiency. Further hormonal work-up revealed panhypopituitarism but no diabetes insipidus. Imaging of the brain, thorax and abdomen demonstrated diffuse intracranial pachymeningeal thickening and enhancement, multiple lymphadenopathies, a bulky right adrenal gland and a large left suprarenal mass, which were indicative of an infiltrative disease. Imaging of the pituitary showed heterogeneous enhancement of the anterior lobe with an unremarkable pituitary stalk and posterior lobe. Biopsy of the superficial abdominal wall mass revealed diffuse large B-cell lymphoma confirmed by bone marrow aspiration biopsy. Positron emission tomography (PET) scan confirmed diffuse systemic disease involving the right orbital apex, bilateral adrenal glands, bone and bone marrow, retroperitoneum and subcutaneous tissues; however, the pituitary gland, infundibulum and hypothalamus did not show any lesions on the PET scan. The patient was commenced on two cycles of chemotherapy but unfortunately died, thus recovery of pituitary function was not tested. Pure anterior pituitary hypofunction can uncommonly present in individuals with metastases to the pituitary gland, in contrast to the more common posterior pituitary/infundibulum involvement.     

Successful long-term control of lymphomatous meningitis with intraventricular rituximab

Most primary central nervous system lymphomas (PCNSL) are highly malignant B-cell non-Hodgkin lymphomas. First-line therapy consists of high-dose methotrexate-based chemotherapy with or without whole brain radiotherapy. However, no standard of care is defined for refractory or recurrent PCNSL. We report a patient with lymphomatous meningitis, which was refractory to standard treatment but was successfully controlled for more than 6 years with intraventricular rituximab. Apart from two infections of the Ommaya reservoir, no severe side effects of intraventricular long-term treatment could be detected. This report indicates that intraventricular administration of rituximab might be beneficial in select patients with refractory or recurrent lymphomatous meningitis.     

Pituitary tumour as a presenting symptom of a systemic lymphoma

Pituitary non Hodgkin malignant lymphomas are rare. We report a case of large cell systemic lymphoma with pituitary and meningeal localizations in a 40-year-old patient. The clinical picture was panhypopituitarism with MRI appearance of pituitary adenoma and VII and VIII cranial nerves involvement. Diagnosis was made by identification of lymphomatous cells in CSF. The patient deceased in less than one year despite chemotherapy.     

Clinicopathological and molecular biological studies in a patient with neurolymphomatosis

We describe a patient with a clinical disorder that resembled vasculitic neuropathy in which peripheral nerves were successively affected over several months, but without systemic involvement. An initial muscle biopsy near the involved nerves showed signs of nonspecific inflammation around the muscle and nerve fibers. Immunosuppressive treatment resulted in a dramatic reduction in pain, but relapses of the disease eventually occurred, and the patient died 22 months after onset of the first symptoms. Pathologically, a malignant non-Hodgkin's B-cell lymphoma, restricted to the intra- and extradural peripheral nervous system, was found. The demonstration by Southern blotting of immunoglobulin heavy chain gene rearrangement confirmed the monoclonal nature of the lymphomatous cells. In situ hybridization tests for Epstein-Barr and herpes virus subtypes were negative. Our case underlines i) how difficult diagnosis can be despite extensive investigations, ii) the usefulness of immunosuppressive treatment in the early stage of the disease, iii) the importance of immunostaining and genome analysis for distinguishing between different types of human neurolymphomatosis, and iv) the fact that the initial inflammatory process in the muscle biopsy may be interpreted either as a paraneoplastic effect of the lymphoma or as a viral inflammatory neuromyopathy that triggers the development of the malignant lymphoma.     

Low‐grade follicular lymphoma in the dura: Rare mimic of meningioma

Lymphomas rarely present as a localized mass within the dura. We report a case of a 72‐year‐old woman, normally fit and well, who presented with a sudden episode of grand mal seizure. Imaging studies showed an extra‐axial mass arising from the dura, with radiologic features characteristic of a meningioma. The mass was surgically excised, and the histologic features were of a grade 1 follicular lymphoma. Analysis using fluorescent in situ hybridization (FISH) demonstrated t(14:18) translocation. A bone marrow aspirate showed focal infiltration of lumbar vertebra by low‐grade follicular lymphoma. Intracranial meningeal involvement by non‐Hodgkin lymphoma usually occurs in the form of diffuse leptomeningeal spread. It is seen in high‐grade lymphomas, often in association with widespread systemic disease. The majority of cases of dural lymphomas reported in the literature have been primary mucosa‐associated lymphoid tissue (MALT)‐type lymphomas. Most of these presented as localized dural masses mimicking meningiomas. Low‐grade follicular lymphoma, either primary or secondarily involving the dura, appears to be an exceedingly rare occurrence.     

Lymphomatous polyneuropathy. Biopsy of clinically involved nerve and successful treatment

We present a patient with large-cell lymphoma in remission who, over several weeks, developed widespread multifocal polyneuropathy. There was involvement of all four limbs, most severely the left upper extremity that had become useless. Biopsy of the left saphenous nerve within an area of sensory loss showed lymphoma in the endoneurium. There was no other evidence of recurrent lymphoma despite extensive investigation, including bone marrow, lumbar puncture, magnetic resonance imaging of the spine, and computed tomography of the abdomen and pelvis. Intensive systemic chemotherapy was accompanied by nearly complete recovery. Biopsy of a symptomatic nerve is preferable to routine sural nerve biopsy in this condition because of its patchy distribution. Treatment with systematic chemotherapy can be effective.     

Epstein-Barr virus DNA load in cerebrospinal fluid and plasma of patients with AIDS-related lymphoma

Detection of Epstein-Barr virus (EBV) DNA in the cerebrospinal fluid (CSF) is associated with acquired immunodeficiency syndrome (AIDS)-related brain lymphoma. Real-time polymerase chain reaction (PCR) was performed to quantify EBV DNA in CSF and plasma from 42 patients with AIDS-related non-Hodgkin's lymphoma (NHL). Twenty patients had primary central nervous system lymphoma (PCNSL) and 22 systemic NHL, including 12 with central nervous system involvement (CNS-NHL). As controls, 16 HIV-infected patients with other CNS disorders were examined. EBV DNA was detected in the CSF from 16/20 (80%) patients with PCNSL, 7/22 (32%) with systemic NHL, 8/12 (67%) with CNS-NHL, and 2/16 (13%) of the controls. The viral EBV DNA levels were significantly higher in the CSF from patients with PCNSL or CNS-NHL compared to patients with systemic NHL or controls. EBV DNA was detected in plasma from 5/16 (31%) patients with PCNSL, 9/16 (56%) with systemic NHL, 4/9 (44%) with CNS-NHL, and 4/15 (27%) controls. No difference in plasma viral load was found between patient groups. From the patients with CNS-NHL, plasma samples drawn prior to CNS involvement contained significantly higher EBV DNA levels than those from systemic NHL patients without subsequent CNS involvement. EBV DNA levels in the CSF, but not in plasma, from patients treated with antiherpes drugs were significantly lower than in untreated patients. High CSF EBV DNA levels were found in HIV-associated brain lymphomas and the viral load can be clinically useful. High plasma EBV DNA levels might predict CNS involvement in systemic NHL.     

Peripheral neuropathy associated with acquired immunodeficiency syndrome (AIDS)-related Burkitt's lymphoma

Peripheral neuropathy associated with acquired immunodeficiency syndrome (AIDS)-related Burkitt's lymphoma usually occurs as a toxic effect of chemotherapeutic agents. Whereas primary peripheral nerve involvement is an unusual complication, we report on a human immunodeficiency virus (HIV)-positive patient with Burkitt's lymphoma and sciatic neuropathy due to compression by a lymphomatous mass. Therapy with radiation and chemotherapy was followed by clinical and radiological improvement, but recurrent neurological deficits in a similar distribution occurred later from lymphomatous meningitis.     

Neurologic complications in high-grade non-Hodgkin's lymphomas. Clinico-neuropathological correlations]

The neurological and electroneurographic assessment was carried out in 56 patients with high-grade non-Hodgkin lymphomas. In 37 patients the neuropathological examination was also done. Polyneuropathy was the most frequent sign of nervous system involvement, observed in 40% of patients before chemotherapy and markedly enhanced by cytostatics. The signs of the central nervous system involvement were usually caused by lymphomatous infiltrations within leptomeninges, especially in lymphoblastic and immunoblastic lymphomas. The authors stress that cerebro-spinal fluid should be investigated several times for avoiding of false negative results. Signs of lymphomatous infiltrations disappeared after treatment, while signs of polyneuropathy due to chemotherapy increased during cytostatic treatment.     

脑膜淋巴瘤的临床脑脊液细胞学研究

目的探讨脑脊液细胞学、免疫细胞化学和流式细胞分析在脑膜淋巴瘤诊断中的灵敏性和特异性。方法13例诊断为脑膜淋巴瘤的患者，其中原发性中枢神经系统淋巴瘤5例，均为非霍奇金淋巴瘤B细胞型（NHL-B）；继发性8例，包括NHL-B6例，非霍奇金淋巴瘤T细胞型（NHL-T）1例，mantle型1例。神经系统表现为头痛、视乳头水肿、脑脊膜刺激征、脊髓腰骶神经根受累和多脑神经麻痹等。腰穿脑脊液压力升高，细胞计数、蛋白均升高，糖减低。所有患者均采用沉淀池法，免疫细胞化学单克隆抗体CD19、CD20、CD79a、CD34和免疫球蛋白轻链等；其中3例脑脊液进行淋巴细胞亚群流式细胞分析。以4例病毒性脑炎和5例炎性脱髓鞘病患者的脑脊液为对照。结果脑脊液细胞学发现每例患者均有淋巴瘤细胞或异型淋巴细胞。免疫细胞化学发现5例患者多数细胞B细胞标记物阳性；例6多数细胞CD34阳性；例8CD20阳性细胞比例升高；例7CD19、CD20阴性。除例8外，其余脑脊液中细胞呈CD4和CD8阴性或极少数阳性。对照组CD4阳性细胞为主，伴有少量CD8阳性细胞，CD19和CD20阴性或极少数阳性。脑脊液流式细胞分析发现例9和例11的B淋巴细胞占85．9％～97．4％，提示异常的B细胞克隆。对照组以CD4、CD8阳性细胞为主，CD19阳性细胞低于4．0％。结论脑脊液细胞学和免疫细胞化学是诊断脑膜淋巴瘤的重要方法，脑脊液淋巴细胞亚群的流式分析能够对诊断脑膜淋巴瘤有所帮助。     

Myopathy in primary systemic amyloidosis.

OBJECTIVE--To define the natural history of primary systemic amyloidosis when muscle involvement is prominent at presentation. METHODS--A retrospective review was carried out of all patients seen at the tertiary referral practice of the Mayo Clinic between 1 January 1960 and 31 December 1994. All patients with primary systemic amyloidosis and proof of amyloid deposits by muscle biopsy were included for analysis. No patients were lost to follow up. RESULTS--Twelve patients were identified with amyloidosis in muscle. Muscle involvement was the most prominent symptom in patients who had widespread visceral involvement, which included the heart, peripheral nerve, and tongue. Of the 12, three had skeletal muscle pseudohypertrophy. All patients had a demonstrable dysproteinaemia by the finding of free light chain in the serum or urine, a discrete monoclonal peak on serum or urine protein electrophoresis, or a monoclonal population of plasma cells in the bone marrow. Measurement of creatine kinase was not a useful test. Of eight patients treated with chemotherapy based on alkylating agents, three responded. The median survival for the entire group was 12 months. CONCLUSIONS--The finding of a monoclonal protein in a patient with muscle weakness is an important clue to the diagnosis of primary systemic amyloidosis. Most patients have visceral involvement outside the musculoskeletal system. A subset of patients seems to respond to systemic chemotherapy. The overall survival, however, remains poor, with most patients dying of cardiac failure. Immunoelectrophoresis of serum and urine should be a routine diagnostic test during the evaluation of myopathy of unknown cause.     

Lymphoma and peripheral neuropathy: a clinical review

Lymphoma occasionally affects the peripheral nervous system. When it does, the diagnosis can be elusive since many patients present without known lymphoma. Most peripheral nerve complications are due to non-Hodgkin's lymphoma (NHL), which infiltrates nerves causing axonal damage. This disorder can affect nerve roots and cranial nerves, often associated with lymphomatous meningitis. NHL may also infiltrate peripheral nerves and cause plexopathy, mononeuropathy, or generalized neuropathy. These neuropathies may resemble an asymmetric mononeuropathy multiplex or a generalized disorder such as chronic inflammatory demyelinating polyradiculoneuropathy. When NHL infiltrates diffusely, the term neurolymphomatosis is used. Hodgkin's lymphoma (HL), by contrast, rarely infiltrates nerves. More often, HL causes immunological disorders of the peripheral nervous system such as inflammatory plexopathy or Guillain-Barré syndrome. Other rare lymphomas such as intravascular lymphoma and Waldenstrom's macroglobulinemia can also affect peripheral nerves in specific ways. In addition, other malignant and nonmalignant lymphoproliferative disorders enter into the differential diagnosis of lymphomatous neuropathy. This review discusses the multiple peripheral nerve presentations of lymphoma from the clinician's point of view and provides a guide to the evaluation and diagnosis of these uncommon, challenging disorders.     

Lymphoma of the central nervous system in AIDS

Central nervous system (CNS) lymphoma is a common complication of patients with HIV infection occurring in as many as 20% of patients with AIDS. This article reviews current observations on primary CNS lymphoma and systemic AIDS-related lymphoma with CNS involvement. Clinical features, diagnosis, differential diagnosis, clinical course, and therapeutic options are herein reviewed.     

Neurolymphomatosis associated with muscle and cerebral involvement caused by natural killer cell lymphoma: a case report and review of literature

We report a biopsy-proven case of neurolymphomatosis (NL) presenting with sensory motor axonal polyneuropathy, polymyositis, and cerebral involvement. Ours is the second reported case of NL caused by natural killer-cell lymphoma defined by morphology and immunophenotyping. For 3 months, the patient developed stocking-glove distribution of hypesthesia, subacute progressive weakness and mental deterioration. EMG showed severe sensorimotor mixed axonal-demyelinating polyradiculoneuropathy. Lumbar puncture revealed mildly high protein level with normal glucose and cell count. Sural nerve biopsy demonstrated lymphomatous axonal neuropathy and muscle biopsy was indicative of lymphomatous polymyositis. Brain MRI revealed multiple white matter lesions, consistent either with progressive multifocal leukoencephalopathy or cerebral lymphoma. Bone marrow biopsy showed neoplastic infiltrates. The patient died of multiple organ failure prior to initiation of chemotherapy.