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Background
HTLV-1 stands for Human T-cell Lymphotropic Virus. It is a retrovirus, in the same class of virus as the AIDS virus, HIV-1. HTLV-I is associated with a rare form of blood dsycrasia known as Adult T-cell Leukemia/lymphoma (ATLL) and a myelopathy, tropical spastic paresis. However, even with infection, fewer than 4% of seropositive persons will experience overt associated disease.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE Science 1988;240:643-6.
American Red Cross has reported 0.025% HTLV-I seropositivity among blood donors in the United States
J Infect Dis 1983;147:406-16.
Japan, the Caribbean basin, South and Central America, West Africa, and the southeastern United States.
- The World Health Organization classification of malignant lymphoma: incidence and clinical prognosis in HTLV-1-endemic area of Fukuoka.
Ohshima K, Suzumiya J, Kikuchi M.
Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan.
Pathol Int. 2002 Jan;52(1):1-12. Abstract quote
New insights into the pathogenesis of lymphoid malignancies have been gained through novel genetic, molecular and immunological techniques. A new classification system for lymphoid malignancies, known as the new World Health Organization (WHO) classification, has been proposed recently based on these findings. The relative incidence of the subtypes of malignant lymphoma is known to differ according to geographic location. Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with human T-cell leukemia virus type 1 (HTLV-1), and the Kyushu islands are an HTLV-1 endemic area.
To clarify the relationship between the histological classification and prognosis of lymphoid malignancies, we reclassified previous cases in our department and summarized our previous reports using the WHO classification. Of 933 cases of lymphoid malignancies, 471 (50%) were B-cell lymphoma, 396 (42%) T/natural killer (NK)-cell lymphoma and 41 (4%) Hodgkin lymphoma (HL). Analysis of clinical outcome showed favorable prognosis for HL, intermediate for B-cell lymphoma and poor prognosis for T-cell lymphoma. Among B-cell lymphomas, the commonest type was diffuse large B-cell lymphoma (n = 281; 60%). Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) was diagnosed in 82 cases (17%), follicular lymphoma in 52 (11%) and mantle cell lymphoma in 24 (5%). Other less common lymphomas were Burkitt lymphoma (n = 9; 2%) and lymphoblastic lymphoma (n = 5; 1%).
Using overall survival rates, the various B-cell lymphoma types could be divided into three broad groups for prognostic purposes: (i) low-risk group comprising follicular lymphoma and MALT; (ii) intermediate-risk group comprising diffuse large B-cell lymphoma and Burkitt lymphoma; and (iii) high-risk group comprising mantle cell lymphoma and lymphoblastic lymphoma. Among the T/NK-cell lymphomas, the commonest type was ATLL (n = 191; 48%), followed by peripheral T-cell lymphoma, unspecified (n = 83; 21%), angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) (n = 38; 10%), anaplastic large cell lymphoma (ALCL) (n = 22; 6%). Less common types were lymphoblastic lymphoma (n = 17; 4%), nasal and nasal-type NK/T-cell lymphoma (n = 17; 4%), mycosis fungoides (MF) (n = 9; 2%) and other rare types.
With respect to clinical prognosis, T/NK-cell lymphomas fell into three groups: (i) relative low-risk group comprising ALCL, AILD, MF and lymphoblastic lymphoma; (ii) relative intermediate-risk group comprising NK/T-cell lymphoma and unspecified lymphoma; and (iii) extremely high-risk group comprising ATLL. Among the lymphoblastic lymphomas, B-cell type and T-cell type lymphomas exhibited different clinical outcomes.
We conclude that the histological, phenotypic and genotypic classification of the new WHO system should be beneficial for the clinical approach to these tumors.
Human T-cell lymphotropic virus type I and adult T-cell leukemia/lymphoma outside Japan and the Caribbean Basin.Levine PH, Jaffe ES, Manns A, Murphy EL, Clark J, Blattner WA.
Environmental Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20892.
Yale J Biol Med 1988 May-Jun;61(3):215-22 Abstract quote Ninety-six patients with the diagnosis of adult T-cell leukemia/lymphoma (ATLL) were identified in countries outside Japan and the Caribbean Basin. Seventy-four of these patients were initially diagnosed in the United States; 25 of 52 patients whose places of birth were known had been born in the United States.
The detection of 14 patients born in the southeastern United States, all black, indicates a group deserving particular attention for studies of human T-cell lymphotropic virus type I (HTLV-I), a suspected etiologic agent in most cases of ATLL. Although geographic clustering of ATLL in areas endemic for HTLV-I, particularly southwest Japan and the Caribbean Basin, is a dramatic feature of this disease, a review of the literature indicates that HTLV-I-associated ATLL probably occurs sporadically in a much wider distribution, the disease being diagnosed in native-born African, Chinese, European, and Latin American patients.
A registry for ATLL cases is suggested, to assist in the identification of risk factors for this disease and, at the same time, improve case definitions and early diagnosis.
PATHOGENESIS CHARACTERIZATION HTLV-I
Identification of human T-lymphotropic virus type I (HTLV-I) subtypes using restricted fragment length polymorphism in a cohort of asymptomatic carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis from Sao Paulo, Brazil.Segurado AA, Biasutti C, Zeigler R, Rodrigues C, Damas CD, Jorge ML, Marchiori PE.
Laboratorio de Virologia (LIM-52), Departamento de Doencas Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, 05403-000, Brasil.
Mem Inst Oswaldo Cruz 2002 Apr;97(3):329-33 Abstract quote Although human T-lymphotropic virus type I (HTLV-I) exhibits high genetic stability, as compared to other RNA viruses and particularly to human immunodeficiency virus (HIV), genotypic subtypes of this human retrovirus have been characterized in isolates from diverse geographical areas.
These are currently believed not to be associated with different pathogenetic outcomes of infection. The present study aimed at characterizing genotypic subtypes of viral isolates from 70 HTLV-I-infected individuals from Sao Paulo, Brazil, including 42 asymptomatic carriers and 28 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), using restricted fragment length polymorphism (RFLP) analysis of long terminal repeat (LTR) HTLV-I proviral DNA sequences. Peripheral blood mononuclear cell lysates were amplified by nested polymerase chain reaction (PCR) and amplicons submitted to enzymatic digestion using a panel of endonucleases. Among HTLV-I asymptomatic carriers, viral cosmopolitan subtypes A, B, C and E were identified in 73.8%, 7.1%, 7.1% and 12% of tested samples, respectively, whereas among HAM/TSP patients, cosmopolitan A (89.3%), cosmopolitan C (7.1%) and cosmopolitan E (3.6%) subtypes were detected. HTLV-I subtypes were not statistically significant associated with patients' clinical status.
We also conclude that RFLP analysis is a suitable tool for descriptive studies on the molecular epidemiology of HTLV-I infections in our environment.
High frequencies of Th1-type CD4(+) T cells specific to HTLV-1 Env and Tax proteins in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.Goon PK, Hanon E, Igakura T, Tanaka Y, Weber JN, Taylor GP, Bangham CR.
Department of Immunology and Genito-Urinary Medicine and Communicable Diseases, Imperial College Faculty of Medicine, St Mary's Campus, London, United Kingdom.
Blood 2002 May 1;99(9):3335-41 Abstract quote CD4(+) T cells are critical for inducing and maintaining efficient humoral and cellular immune responses to pathogens. The CD4(+) T-cell response in human T-lymphotropic virus 1 (HTLV-1) infection has not been studied in detail. However, CD4(+) T cells have been shown to predominate in early lesions in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
We present direct estimates of HTLV-1 Env- and Tax-specific CD4(+) T-cell frequencies in patients infected with HTLV-1. We first showed that there was a strong bias toward the Th1 phenotype in these HTLV-1-specific CD4(+) T cells in patients with HAM/TSP. We then demonstrated significantly higher frequencies of HTLV-1-specific Th1-type CD4(+) T cells in HAM/TSP patients than in asymptomatic HTLV-1 carriers. The majority of these HTLV-1-specific CD4(+) T cells did not express HTLV-1 Tax and were therefore unlikely to be infected by HTLV-1.
High frequencies of activated HTLV-1-specific CD4(+) T cells of the Th1 phenotype might contribute to the initiation or pathogenesis of HAM/TSP and other HTLV-1-associated inflammatory diseases.
IFN regulatory factor 4 participates in the human T cell lymphotropic virus type I-mediated activation of the IL-15 receptor alpha promoter.Mariner JM, Mamane Y, Hiscott J, Waldmann TA, Azimi N.
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol 2002 Jun 1;168(11):5667-74 Abstract quote IL-15Ralpha mRNA and protein levels are increased in human T cell lymphotropic virus type-I (HTLV-I)-associated adult T cell leukemia. Previously, we demonstrated that IL-15Ralpha expression was activated by HTLV-I Tax, in part, through the action of NF-kappaB. However, there appeared to be additional motifs within the IL-15Ralpha promoter that were responsive to HTLV-I Tax.
In this study, we demonstrated that IL-15Ralpha mRNA expression was activated in human monocytes by IFN treatment, suggesting a role for IFN regulatory factors (IRFs) in IL-15Ralpha transcription. In addition, an IRF element within the Tax-responsive element of the IL-15Ralpha promoter was necessary for maximal Tax-induced activation of this promoter. Furthermore, we demonstrated that IRF-4, a transcription factor known to be elevated in HTLV-I-infected cells, activated the IL-15Ralpha promoter. Inhibition of IRF-4 action lead to reduced Tax-induced activation of the IL-15Ralpha promoter, while inhibition of both IRF-4 and NF-kappaB severely inhibited the Tax-induced activation of this promoter. These findings suggest a role for both NF-kappaB and IRF-4 in the transcriptional regulation of IL-15Ralpha by HTLV-I Tax.
It is possible that the HTLV-I Tax-mediated induction of IL-15Ralpha and IL-15 may lead to an autocrine cytokine-mediated stimulatory loop leading to the proliferation of HTLV-I infected cells. This loop of proliferation may facilitate viral propagation and play a role in HTLV-I-mediated disease progression.
CHROMOSOMAL ALTERATIONS
- Cytogenetic analysis and clinical significance in adult T-cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki.
Itoyama T, Chaganti RS, Yamada Y, Tsukasaki K, Atogami S, Nakamura H, Tomonaga M, Ohshima K, Kikuchi M, Sadamori N.
Laboratory of Cancer Genetics, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA.
Blood. 2001 Jun 1;97(11):3612-20. Abstract quote
Identification of cytogenetic abnormalities is an important clue for the elucidation of carcinogenesis. However, the cytogenetic and clinical significance of adult T-cell leukemia/lymphoma (ATLL) is still unclear.
To address this point, cytogenetic findings in 50 cases of ATLL were correlated with clinical characteristics. Karyotypes showed a high degree of diversity and complexity. Aneuploidy and multiple breaks (at least 6) were observed frequently in acute and lymphoma subtypes of ATLL. Breakpoints tended to cluster at specific chromosomal regions, although characteristic cytogenetic subgroups of abnormalities were not found.
Of these, aberrations of chromosomes 1p, 1q, 1q10-21, 10p, 10p13, 12q, 14q, and 14q32 correlated with one or more of the following clinical features: hepatosplenomegaly, elevated lactate dehydrogenase, hypercalcemia, and unusual immunophenotype, all indicators of clinical severity of ATLL. Multiple breaks (at least 6); abnormalities of chromosomes 1p, 1p22, 1q, 1q10-21, 2q, 3q, 3q10-12, 3q21, 14q, 14q32, and 17q; and partial loss of chromosomes 2q, 9p, 14p, 14q, and 17q regions correlated with shorter survival. These cytogenetic findings are relevant in predicting clinical outcome and provide useful information to identify chromosomal regions responsible for leukemogenesis.
This study also indicates that one model of an oncogenic mechanism, activation of a proto-oncogene by translocation of a T-cell-receptor gene, may not be applicable to the main pathway of development of ATLL and that a multistep process of leukemogenesis is required for the development of ATLL.
LABORATORY/
RADIOLOGICCHARACTERIZATION FLOW CYTOMETRY
- Flow cytometric immunophenotyping of adult T-cell leukemia/lymphoma using CD3 gating.
Yokote T, Akioka T, Oka S, Hara S, Kobayashi K, Nakajima H, Yamano T, Ikemoto T, Shimizu A, Tsuji M, Hanafusa T.
First Department of Internal Medicine, Osaka Medical College, Osaka, Japan.
Am J Clin Pathol. 2005 Aug;124(2):199-204. Abstract quote
Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative neoplasm of helper T lymphocytes caused by human T-cell leukemia virus type-1 (HTLV-1). The disease was first described in Kyushu, in southwestern Japan, and most frequently occurs in endemic areas, such as Japan, the Caribbean basin, West Africa, Brazil, and northern Iran. ATLL is essentially a disease of adults, characterized clinically by generalized lymphadenopathy, hepatosplenomegaly, skin lesions, and hypercalcemia. The prognosis of most patients is quite poor, with a median survival time of only 13 months, even if multiagent combination chemotherapy is given.
In the present study, flow cytometric immunophenotyping with CD3 gating was performed on 30 samples from 26 patients who had been given a diagnosis of ATLL. The records of these patients also were reviewed retrospectively. In 14 of the 30 samples, an abnormal CD3(low) T-cell population was distinguishable from the normal T-cell populations by flow cytometric analysis.
Herein we report a novel strategy for flow cytometric immunophenotyping of ATLL facilitated by CD3(low) gating.
- Adult T-cell leukemia/lymphoma: a cytopathologic, immunocytochemical, and flow cytometric study.
Dahmoush L, Hijazi Y, Barnes E, Stetler-Stevenson M, Abati A.
National Institutes of Health/National Cancer Institute, Section of Cytopathology, Bethesda, Maryland 20892, USA.
Cancer. 2002 Apr 25;96(2):110-6. Abstract quote
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.
HISTOLOGICAL TYPES CHARACTERIZATION General Br J Dermatol 1993;128:483-92.
Br J Dermatol 1989;121:603-12Histologic features may mimic mycosis fungoides, with epidermotropism including Pautrier's microabscesses
Mixed dermal infiltrate composed of morphologically atypical lymphoid cells, small lymphocytes, and variable numbers of eosinophils and plasma cells are seen
Prominent histiocytic component has occasionally been reported
The atypical mononuclear cells vary from small to medium-sized cells with hyperchromatic convoluted nuclei to large pleomorphic cells with scant cytoplasm.
VARIANTS ANGIOCENTRIC
A case of adult T-cell leukemia/lymphoma (ATLL) with angiocentric and angiodestructive features.Ohtake N, Setoyama M, Fukumaru S, Kanzaki T.
Department of Dermatology, Kagoshima University Faculty of Medicine, Japan.
J Dermatol 1997 Mar;24(3):165-9 Abstract quote This report describes a case of adult T-cell leukemia/lymphoma (ATLL) with angiocentric and angiodestructive features. The patient was a 66-year-old Japanese woman who began developing widespread skin lesions ten months prior to admission.
The diagnosis of ATLL was made on the basis of her having an antibody to human T-cell lymphotropic virus type-1 (HTLV-1) and typical flower cells (ATLL cells) in peripheral blood smears. Once hospitalized, the course of her disease was very acute and severe, as is seen with angiocentric lymphoma. Based on histological features, this case was judged not to be angiocentric lymphoma; however, it may lie within the spectrum of angiocentric immunoproliferative lesions (AIL).
The findings in this case strongly suggest that HTLV-1 can be a pathogenic factor in the expression of angiocentric and angiodestructive features in ATLL, as is Epstein-Barr virus (EBV) (1-4). To our knowledge the present case is the sixth reported in the literature of lymphoma in which these features are associated with HTLV-1 infection (5-7).
ANGIOIMMUNOBLASTIC FEATURES
- Karube K,
- Suzumiya J,
- Okamoto M,
- Takeshita M,
- Maeda K,
- Sakaguchi M,
- Inada T,
- Tsushima H,
- Kikuchi M,
- Ohshima K.
*Department of Pathology, School of Medicine, Kurume University, Kurume daggerJapan Society for the Promotion of Science (JSPS), Japan Departments of paragraph signPathology double daggerInternal Medicine, School of Medicine, Fukuoka University, Fukuoka section signDepartment of Internal Medicine, Fujita Health University School of Medicine, Toyoake parallelNational hospital organization Miyakonojo Hospital, Miyakonojo musical sharpSocial Insurance Yatsushiro General Hospital, Yatsushiro perpendicularHealth Insurance Amakusa Chuo General Hospital, Hondo **Department of Hematology, Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
In adult T-cell lymphoma/leukemia (ATLL), the neoplastic lymphoid cells are usually medium-sized to large, often with pronounced nuclear pleomorphism compatible with the diagnosis of diffuse pleomorphic peripheral T-cell lymphoma.
We describe here 11 patients with the rare morphologic variant of ATLL, angioimmunoblastic T-cell lymphoma (AILT)-like type. The examined lymph nodes showed proliferation of high endothelial venules and presence of various infiltrating inflammatory cells including plasma cells and eosinophils. The lymphoma cells were medium-to-large size with clear cytoplasm. These findings were suggestive of AILT. However, immunohistochemical features of AILT, namely, CD10 and CXCL13 expression in lymphoma cells and proliferation of CD21-positive follicular dendritic cells, were not detected. Two cases were CXCR3-positive, whereas 9 expressed CCR4, which are usually positive in ATLL. All patients were positive for antiadult T-cell leukemia/lymphoma-associated antigen, which is a specific antibody for human T-cell lymphotropic virus type-I.
Southern blot analysis revealed proviral DNA integration in lymphoma cells in 9 patients. The latter was not evident in the first biopsy of 2 patients but in the second biopsy obtained within several months after the first biopsy revealed definite proviral integration.
Almost all patients showed aggressive clinical course and poor survival (median survival: 5 mo). This is the first report of ATLL with AILT-like morphologic features.GRANULOMATOUS HTLV-I-associated granulomatous T-cell lymphoma in a child J Am Acad Dermatol 2001;44:525-9
A case of a 13-year-old boy with an 8-year history of skin eruptions. After complete evaluation, a diagnosis of HTLV-I-associated lymphoma/leukemia was made. The T-cell lymphoma exhibited a granulomatous histomorphology.
Conclusion:
ATLL may rarely present as a chronic granulomatous eruption in a child
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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