Early sequential development of infective dermatitis, human T cell lymphotropic virus type 1-associated myelopathy, and adult T cell leukemia/lymphoma.

We describe a patient with human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis who developed HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia/lymphoma at 16 years of age. Long inverse polymerase chain reaction was used to demonstrate monoclonal integration of proviral DNA in the lymphomatous skin lesion.

Identification of human T cell leukemia virus type 1 tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein.

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a number of pathologic abnormalities, including adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The viral oncoprotein Tax has been implicated in the pathogenesis of these diseases. Recently, cell-free Tax was detected in the cerebrospinal fluid of HAM/TSP patients, implying that extracellular Tax may be relevant to neurologic disease. Additionally, the presence of a nuclear export signal within Tax and its active secretion has been demonstrated in vitro. However, the mechanism of Tax secretion remains to be established. Studies reported herein elucidate the process of Tax secretion and identify domains of Tax critical to its subcellular localization and secretion. Tax was shown to interact with a number of cellular secretory pathway proteins in both the model cell line BHK (baby hamster kidney)-21 and an HTLV-1-infected T cell line, C8166, physiologically relevant to HTLV-1-induced disease. Silencing of selected components of the secretory pathway affected Tax secretion, further confirming regulated secretion of Tax. Additionally, mutations in two putative secretory signals within Tax DHE and YTNI resulted in aberrant subcellular localization of Tax and significantly altered protein secretion. Together, these studies demonstrate that Tax secretion is a regulated event facilitated by its interactions with proteins of the cellular secretory pathway and the presence of secretory signals within the carboxyl-terminal domain of the protein.

The clinical value of follow-up examinations in childhood T-cell acute lymphoblastic leukemia and T-cell non-Hodgkin's lymphoma.

BACKGROUND: The aim of this study was to evaluate the value of follow-up investigations of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell non-Hodgkin's lymphoma (T-NHL), including cerebrospinal fluid (CSF) examination, bone marrow (BM) aspiration, peripheral blood (PB) count, serum lactate dehydrogenase (LDH) and chest X-rays in patients with an initial mediastinal enlargement. PROCEDURE: We reviewed clinical records of all T-ALL patients from 1987 to 2002 and all T-NHL patients from 1977 to 2002, seen at a single institution. RESULTS: Of 48 T-ALL patients, 15 suffered from a relapse, 6 (40%) were asymptomatic at the time of relapse. T-ALL (13/30) with mediastinal enlargement at first diagnosis relapsed versus 2/16 of those without mediastinal enlargement. However, at relapse, only one patient had a mediastinal mass, which in addition was symptomatic. Of 39 T-NHL patients, 6 patients relapsed. Forty percent of relapsed T-ALL and 17% of relapsed T-NHL were asymptomatic. The seven asymptomatic relapses were detected by CSF (n = 4), BM (n = 2) or blood count (n = 1) examinations. All T-ALL and T-NHL patients with a mediastinal relapse were symptomatic. CONCLUSIONS: This study suggests that routine CSF examinations during treatment can detect relapses of T-ALL and T-NHL before onset of symptoms, which might be of clinical value. Relapses are rarely detected by BM or blood examinations and whether this translates in a clinical benefit is unlikely. Routine chest X-rays are not useful.

Adult T-cell leukemia/lymphoma: a cytopathologic, immunocytochemical, and flow cytometric study.

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is a postthymic lymphoproliferative neoplasm of T cells caused by human T-cell lymphotropic virus (HTLV-1). Most cases are found in Japan, the Caribbean basin, and West Africa. DESIGN: To identify diagnostic parameters for cytology in this neoplasm, the authors undertook a retrospective review of all ATLL samples from 1990 to 2000. RESULTS: One hundred fourteen samples from 34 patients with the diagnosis of ATLL were reviewed: 80 cerebrospinal fluids, 7 pleural effusions, 4 bronchoalveolar lavages, 2 peritoneal effusions as well as fine-needle aspirations of 15 lymph nodes, 4 subcutaneous lesions, and 2 breast nodules. Twenty-one patients were women and 13 were men, with an age range of 30 to 71 years. Morphologically, all specimens were characterized by the presence of a polymorphous population of lymphocytes ranging from small bland-appearing lymphocytes to large atypical ones with bizarre, multilobulated nuclei (flower-like or clover leaf cells) with coarse chromatin and prominent nucleoli. The cytoplasm was deeply basophilic with occasional vacuoles. Immunocytochemistry was performed on 17 specimens from 14 patients. In all cases tested, tumor cells were immunoreactive for CD3, CD4, CD5, and CD25 and were nonimmunoreactive for CD7 and CD8. Flow cytometry was performed on 12 specimens from 9 patients. The tumor cells in all cases tested were positive for CD2, CD3, CD4, CD5, and CD25 and were negative for CD7. CONCLUSIONS: Despite the polymorphous nature of ATLL, diagnosis can be established by close attention to nuclear cytologic features in conjunction with ancillary studies such as immunocytochemistry and/or flow cytometry.

[Syndrome of inappropriate antidiuretic hormone secretion associated with meningeal infiltration of tumor cells and elevated interleukin-1 beta and interleukin-6 in cerebrospinal fluid of a patient with adult T-cell leukemia].

A 73-year-old man with acute adult T-cell leukemia (ATL) in remission was re-admitted to our hospital due to drowsiness, headache, and bilateral knee joint pain on May 17, 1998. On admission, examinations revealed decreased serum sodium concentration (112 mEq/l), low plasma osmotic pressure (259 mOsm/l), and elevated antidiuretic hormone(5.6 pg/ml). Cerebrospinal fluid examination showed an increased number of abnormal flower-like lymphocyte (951/microliter). Brain computed tomography and magnetic resonance imaging found no abnormality in the hypothalamus or pituitary gland. These findings yielded a diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Though ATL patients typically exhibit a variety of clinical symptoms, SIADH is rarely one of the complications. Further investigation showed that IL-1 beta and IL-6 concentrations were increased in spinal fluid but not in serum. Recently, it has been reported that exogeneous IL-6 is an inducer of ADH secretion, and that primary ATL cells and HTLV-I infected cell lines can produce IL-6. In this case, we speculated that IL-6 produced by ATL cells that infiltrated a cerebral lesion may have played an important role in the development of SIADH.

Cerebrospinal fluid atypical lymphocytes in Japanese encephalitis.

Among atypical lymphocytes (AL) examined morphologically and immunohistochemically in the cerebrospinal fluid (CSF) of adult patients with encephalitis, we distinguished a CD4+ 'type I' AL, with a multilobulated nucleus resembling those of the abnormal cells in adult T-cell leukemia (ATL), from a CD8+ 'type II' AL, a large lymphocyte with basophilic cytoplasm and a nucleus containing coarse chromatin. Type I AL were detected in 7 of 8 patients with Japanese encephalitis (JE), but in none of 11 patients with herpes simplex encephalitis (HSE) and none of 19 patients with unspecified acute viral encephalitis. Type II AL were seen frequently in all three groups. The observation of type I AL in CSF strongly suggests JE, which warrants careful follow-up without antiherpetic drugs. In identifying type I AL, which presumably are virally transformed lymphocytes, care must be taken to distinguish them from leukemic involvement by ATL cells, which frequently includes the meninges. Both type I and type II AL also must be differentiated from lymphoma cells.

Myasthenia gravis, acute transverse myelitis, and HTLV-I.

We present the unusual case of a 49-year-old female carrier of HTLV-I with myasthenia gravis who presented with acute transverse myelitis. Laboratory data suggested a recent infection with varicella zoster virus and demyelination by an autoimmune process in the central nervous system. Adult T-cell leukemia-like cells were observed in the cerebrospinal fluid. T-cell-mediated immune responses modulated by HTLV-I infection may be involved in the pathogenesis of myasthenia gravis and acute transverse myelitis in this case.

[Meningoradiculitis disclosing T-lymphocyte leukemia in HTLV-1 infection]. / Méningo-radiculite révélatrice d'une leucémie à lymphocytes T au cours d'une infection à HTLV1.

A case of HILV1-associated adult T cell leukaemia/lymphoma (ATLL) in à 21-year olf African woman is reported. The patient presented with lymphomatous meningoradiculopathy. The usual clinical features of ATLL were absent. Lumbar MRI showed a pial enhancement by DTPA-gadolinium of the conus medullaris which extended to the proximal cauda equina. Under systemic chemotherapy coupled with intrathecal chemotherapy the patient progressively improved, and at the second MRI examination complete disappearance of the lumbar enhancement was observed. MRI of the brain using axial and coronal T2-weighted sequences detected multifocal lesions of high-intensity signal in the subcortical white matter. ATLL is unusual in people of African origin. The ATLL-strongyloïdes infestation association has previously been reported, suggesting that parasitic infestation may be an important co-factor leading to the development of ATLL.

Central nervous system involvement in adult T-cell leukemia/lymphoma.

Central nervous system (CNS) involvement was reviewed in 99 patients with adult T-cell leukemia/lymphoma (ATLL). Fifteen episodes of CNS involvement developed in ten of 99 patients (10.1%); nine had leptomeningeal involvement, whereas two developed intracerebral invasion, one developed cord involvement, and one developed both. CNS involvement was more frequent in the lymphoma type than in the other types of ATLL. Nuchal rigidity was not common (33%) and a syndrome of inappropriate secretion of antidiuretic hormone (ADH) occurred in association with CNS involvement (40%). Three episodes of marked hypoglycorrhachia also were noticed. The systemic progression of ATLL was the most common setting of CNS involvement (80%) and the major cause of death (80%). As for the acute and lymphoma types of ATLL, no significant difference was observed in survival between patients with and those without CNS involvement. These results indicate that CNS involvement is not an essential prognostic factor of ATLL and that it should be treated with systemic chemotherapy coupled with intrathecal chemotherapy. The control of systemic ATLL is important for the prophylaxis of CNS involvement.

[Use of an immunoenzyme method with monoclonal antibodies in cytologic studies for the optimal diagnosis of non-Hodgkin's lymphoma in children]. / Zastosowanie metody immunoenzymatycznej z uzyciem MoP w badaniach cytologicznych do optymalizacji diagnostyki non-Hodgkin-lymphoma u dzieci.

From January 1987 to April 1988 six children we studied cytologically with the use of alkaline phosphatase-anti-alkaline phosphatase (APAAP) method and monoclonal antibodies (MoP) in order to establish the diagnosis of Non-Hodgkin Lymphoma. (NHL). Cytologic studies concerned pleural fluid (3 patients) imprints of the lymph node (3 patients), bone marrow smears (2 patients) and cerebrospinal fluid (1 patient). We performed simultaneously routine cytologic and histopathologic studies of the lymph nodes. Antigen T6 (thymocytes) was present in blasts of all patients, which permitted us to classify the blasts as common stage II group according to Reinherz. In all cases we found at least two positive antigen detected by MoP pan T (CD2, CD3, CD5, CD7) in one case--no expression of antigen T3 (CD3) and in two cases no antigen detected by an antibody CD2. Antigen Ia was found in one patient, and weak expression of antigen CALLA (CD10) in one patients. In three patients we showed a simultaneous expression of antigens T4, T8, whereas in two patients they were not observed. One child possessed mature phenotype T4, T6. By using APAAP method with MoP in cytologic studies it was possible to diagnose T-lymphoblastic lymphoma in six children before the results of histopathologic examination of the lymph nodes.