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Table of Contents
Definition / general | Terminology | Epidemiology | Sites | Etiology / Pathogenesis | Diagrams / tables | Postulated Normal Counterpart | Clinical features | Case reports | Treatment and Prognosis | Clinical images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Flow cytometry Images | Electron microscopy images | Molecular / cytogenetics description | Differential diagnosis | Additional referencesCite this page: Adult T cell leukemia / lymphoma (HTLV-1 positive). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomanonBatlv.html. Accessed October 16th, 2018.
Definition / general
- A peripheral T cell neoplasm usually composed of highly pleomorphic lymphoid cells
- Disease is usually widely disseminated and is caused by the human retrovirus known as human T cell leukemia virus type I (HTLV-I) (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th ed, 2008)
Clinical and morphological spectrum of HTLV-I related diseases:
Neoplastic disorders:
- Peripheral blood (leukemia)
- Smoldering type
- Chronic type
- Acute type
- Lymph node (lymphoma)
- Hodgkin-like type
- Pleomorphic small cell type
- Pleomorphic (medium and large cell) type
- Anaplastic large cell type
- Skin
- Erythema
- Papule
- Nodule
- Gastrointestinal tract
- Erosion
- Ulceration
- Tumor
- Liver
- Portal or sinus infiltration
- Bone marrow
- Infiltration with or without fibrosis
Reactive disorders:
- Confirmed
- HTLV-I associated myelopathy (HAM)
- HTLV-I associated uveitis
- HTLV-I associated lymphadenitis
- Not confirmed
- HTLV-I associated bronchopneumopathy (HAB)
- HTLV-I associated arthropathy (HAAP)
- HTLV-I associated nephropathy
Terminology
- Also called HTLV-I associated T cell lymphoma; T cell lymphoma small cell type or pleomorphic medium and large cell type HTLV-I+; T cell immunoblastic sarcoma
Epidemiology
- Most common where HTLV-I is endemic (southwestern Japan, Caribbean Basin, parts of Central and West Africa, South America)
- Sporadic cases also described but patients often lived in an endemic region
- Acquired vertically from mother at birth (most common), human milk, blood products or sexually transmitted; usually several decades before clinical features appear
- Almost only adults, age 20 to 80s, average 58 years; very rarely in children (Brazil)
- M:F ratio 1.5:1
- Patients have defects of cell mediated immunity, are at risk for multiple opportunistic infections (Arch Pathol Lab Med 2000;124:1241)
- Occurs in 1 - 5% of HTLV-I+ patients
- Cumulative incidence among HTLV-I carriers in Japan is 2.5%
- Long latency, virus exposure usually occurs very early in life
Sites
- Most patients present with widespread lymph node and peripheral blood involvement
- Degree of peripheral blood involvement does not correspond with degree of bone marrow involvement (circulating cells probably recruited from other organs like skin)
- Most common extralymphatic site is skin (> 50%)
- Usually systemic, affecting skin, spleen, lung, liver, GI tract and CNS; usually spares the mediastinum
- Epidemiological differences exist: peripheral blood involvement is much more common in Japan than in the Caribbean Basin
Etiology / Pathogenesis
- HTLV-I identified in a cell line from a patient with T cell lymphoma involving the skin (1979) - first oncogenic human virus discovered
- Type C virus belongs to retrovirus family and delta retrovirus genus
- Infection occurs and is transmitted via cell to cell contact
- HTLV-I is causally linked to adult T cell leukemia / lymphoma (ATLL) but is insufficient for neoplastic transformation (molecular models suggest 6 or 7 "hits" required)
- HTLV-I p40 tax viral protein: nonstructural protein that causes transcriptional activation of many genes in infected lymphocytes; has central role in leukemogenesis
- Enhancement of c-AMP response element binding transcription factor (CREB) phosphorylation by HTLV-I - also important in leukemogenesis
- HTLV-I basic leucine zipper factor (HBZ): causes T cell proliferation and oncogenesis
- JAK / STAT pathway constitutively activated in HTLV-I infected cells
- HTLV-I can also infect immature thymocytes
Diagrams / tables
Images hosted on PathOut server:
Diagnostic criteria for clinical subtypes of ATLL
Postulated Normal Counterpart
- Peripheral CD4+ cells, probably the CD4+ CD25+ FOXP3+ regulatory T cells (also correlates with the immunodeficiency characteristic of the disease)
Clinical features
- Hypercalcemia in 50% during course of disease (28% at diagnosis); associated with increased osteoclastic activity (J Clin Oncol 2009;27:453)
- Note: HTLV-I also causes HTLV-I associated myelopathy / tropical spastic paraparesis
Acute subtype:
- Most common; has leukemic phase, constitutional symptoms, elevated LDH; also hepatosplenomegaly, generalized lymphadenopathy, bone marrow infiltration, skin lesions, high WBC count and lymphocytosis / eosinophilia, hypercalcemia, variable lytic bone lesions
- Associated T cell immunodeficiency with frequent opportunistic infections (P. jirovecii pneumonia and Strongyloidiasis)
- Median survival of less than 1 year despite aggressive chemotherapy
Lymphomatous subtype:
- Prominent lymphadenopathy without significant peripheral blood involvement
- Most patients present with advanced stage similar to the acute form
- Hypercalcemia less common, cutaneous lesions as common
Chronic subtype:
- Increased WBC count, slight lymphadenopathy or hepatosplenomegaly
- Frequently associated with an exfoliative skin rash
- May have lymphocytosis but only a few atypical lymphocytes
- No hypercalcemia
Smoldering subtype:
- Few malignant cells in peripheral blood, may have slight lymphadenopathy, hepatosplenomegaly or marrow infiltrates
- WBC usually normal with < 5% circulating neoplastic cells
- Frequent skin or lung lesions but no hypercalcemia
- Note: chronic and smoldering subtypes may evolve into acute form in 25% of cases but usually after a long duration
- A fifth variant has been proposed: cutaneous ATLL (no leukemic phase, no lymphadenopathy, no hepatosplenomegaly or hypercalcemia)
Case reports
- 15 year old boy from Brazil (Rev Inst Med Trop Sao Paulo 2001;43:283)
- 32 year old man from West Africa (Arch Pathol Lab Med 2003;127:636)
- 43 year old Caribbean man with CD4+ / CD8+ disease (Case Rep Oncol 2010;3:489)
- 47 year old woman with CLL-like morphology (Korean J Hematol 2011;46:9)
- 48 year old woman presenting with intracranial mass (Neurol Med Chir (Tokyo) 2010;50:492)
- 66 year old man with GI lymphomatous polyposis (World J Gastroenterol 2008;14:6584)
Treatment and Prognosis
- Major prognostic factors: clinical subtype, age, performance status, serum calcium and LDH levels
- Acute and lymphomatous variants: survival ranges from 2 weeks to > 1 year
- Chronic and smoldering forms: more protracted clinical course and better survival but can progress
- Death usually from infectious complications (P. jirovecii pneumonia, Cryptococcus meningitis, disseminated herpes zoster) and hypercalcemia
Clinical images
Images hosted on other servers:
Nodules
Microscopic (histologic) description
- Diffuse infiltrate of medium to large cells with agranular basophilic cytoplasm, multilobated nuclei (cloverleaf / flower cells), thick nuclear membranes and coarse chromatin, distinct / prominent nucleoli
- Reed-Sternberg like cells (in Hodgkin lymphoma like cases with expansion of EBV+ B cells), blast-like cells, giant cells may also be present
- Cutaneous infiltrates are dermal (mainly perivascular but larger nodules extending into the subcutaneous fat also possible) or epidermotropic with Pautrier microabscesses (resembling mycosis fungoides)
- Rare cases have predominantly small lymphocytes with irregular nuclei (cell size not correlated with clinical course except chronic and smoldering forms where lymphocytes appear more normal)
- Bone marrow: usually patchy infiltrates; may have increased osteoclastic activity without marrow involvement by lymphoma; broad morphologic spectrum of pleomorphic small, medium and large cell types, anaplastic, and rarely angioimmunoblastic T cell lymphoma-like
- Lymph node: Paracortical T cell zones initially, may have leukemic pattern of infiltration with preservation or dilation of sinuses containing malignant cells and sparse inflammatory background, variable eosinophilia
Microscopic (histologic) images
Images hosted on other servers:
Left: cloverleaf-type cell; right: flower cells
Lymph node
Skin
47 year old woman with CLL-like morphology
66 year old man with GI lymphomatous polyposis
Positive stains
Flow cytometry Images
Images hosted on other servers:
CD3+, CD4+, CD25+, CD7-, CD8-
Electron microscopy images
Images hosted on other servers:
Adult T cell leukaemia / lymphoma cell
Molecular / cytogenetics description
- HTLV-I provirus present in tumor cells; clonal T cell receptor gene rearrangement
- Monoclonal integration of HTLV-I in neoplastic cells (no clonal integration in healthy carriers)
- Clonal chromosome abnormalities but none is specific
Differential diagnosis
- Peripheral T cell lymphoma, NOS
- Angioimmunoblastic T cell lymphoma
- Anaplastic large cell lymphoma
- Mycosis fungoides / Sézary syndrome
- HTLV-I positive reactive lymphadenitis
Additional references
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