Lymphoma and plasma cell neoplasms
T/NK cell disorders
Adult T cell leukemia / lymphoma (HTLV-1 positive)

Author: Dragos Luca, M.D. (see Authors page)

Revised: 3 April 2017, last major update January 2012

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PubMed Search: adult T cell leukemia / lymphoma (HTLV-1 positive)

Cite this page: Adult T cell leukemia / lymphoma (HTLV-1 positive). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomanonBatlv.html. Accessed November 18th, 2017.
Definition / general

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
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

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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

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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
Negative stains
Flow cytometry Images

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CD3+, CD4+, CD25+, CD7-, CD8-

Electron microscopy images

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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