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 April 27th, 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
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
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
Positive stains
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