Adult T-cell Leukemia/Lymphoma Flashcards
What is the definition of ATLL ?
- mature T cell neoplasm
- highly pleomorphic lymphocytes with usually wide dissemination and lymph node involvement
- caused by HTLV-1 infection
- peripheral blood is usually involved
What is the frequency of ATLL
in HTLV1 carriers?
- 2.5%
- usually occurs in adults around age 58 with a slight male predominance
- generally the prognosis is poor
What is the epidemiology of ATLL?
- ATLL is endemic to regions of Japan, Caribbean, and parts of central Africa
- distribution is highly associated with HTLV1
- long latency with virus exposure early in life
- virus spreads through breast milk, exposure to peripheral blood and blood products
What are the clinical spectrum of
neoplastic diseases associated with HTLV-1 infection?
- ATLL
- smouldering
- chronic
- acute
- lymphomatous
What are the non-neoplastic diseases
associated with HTLV-1 infection ?
- HTLV-1 associated myelopathy (tropical spastic paraparesis)
- HTLV-1 associated infective dermatitis
- Other HTLV-1 Inflammatory Disorders
- Uveitis
- Thyroiditis
- Pnemonitis
- Myositis
What is the etiology of ATLL ?
- HTLV-1 is associated with the disease but infection alone is not enough to cause neoplastic transformation
- HTLV-1 enters mainly through cell:cell contact
- Neuropilin 1 acts as the viral receptor
- additional genetic alterations after viral infection lead to disease
- hypermethylation is associated with disease progression
- HTLV-1 enters mainly through cell:cell contact
What is the localization of
ATLL ?
- most present with widespread lymph node and peripheral blood involvement
- number of circulating neoplastic lymphocytes does not correlate with bone marrow involvement
- this suggests lymphocytes come from other organs, particularly the skin which is involved in >50% of cases
- number of circulating neoplastic lymphocytes does not correlate with bone marrow involvement
- multiorgan involvement is also common:
- spleen, skin, lungs, liver, GI tract and CNS
What are the clinical features
of ATLL ?
- smouldering
- chronic
- acute
- lymphomatous
What is the presentation of the
acute form of ATLL ?
- this is the most common type
- characterized by:
- leukemic presentation
- markedly increased WBC
- skin rash, generalized lymphadenopathy
- hypercalcemia with or without lytic bone lesions is frequent
- systemic disease is frequent with increased LDH
- eosinophilia is common
- acquired T cell immunodeficiency with infections with:
- strongyloides
- Pneumocystis
What is the clinical presentation of
the lymphomatous variant ?
- prominent lymphadenopathy but no peripheral blood involvement
- still very sick with advanced disease
- less frequently see hypercalcemia
Note: cutaneous lesions are seen in both the acute and lymphomatous forms
What are the clinical features of
chronic variant of ATLL?
- frequently associated with an exfoliative skin rash
- absolute lymphocytosis can be seen
- but atypical lymphocytes are not numerous in the PB
- hypercalcemia is absent in this form
What are the clinical features in
the smouldering variant ?
- WBC count is normal with >5% circulating neoplastic cells
- cells are usually small with normal appearance
- usually have skin or pulmonary lesions
- no hypercalcemia is present
Note: progression from the chronic or smouldering variant occurs in 25% of cases –> usually after long duration
What are the microscopic features
of ATLL ?
- broad spectrum of morphologies
- pleomorphic, small, medium, large, anaplastic cells
- rare type resembling AITL - IMP always think of ATLL and do HTLV-1 serology
- Leukemic pattern with preservation of LN architecture
- dilation of sinuses with lymphocytes in them
- eosinophilia may be present
What is the morphology of the
neoplastic lymphocytes ?
- typically medium to large in size
- often have pronounced nuclear pleomorphism
- chromatin is clumped with distinct, sometimes prominent nucleoli
- blast like cells with fine chromatin can be present
- giant cells with convoluted or multilobed nuclear contours can be present
Note: cell size does not correlate with outcome….although chronic and smouldering ATLL have small, normal looking lymphocytes
What is the lymph node morphology
most often seen in ATLL ?
- lymph nodes in early ATLL may exhibit a Hodgkin like morphology
- paracortical expansion by small to medium sized lymphocytes with scattered B lymphoblasts that are EBV positive with Hodgkin-like morphology
- this expansion of EBV positive cells is thought to be secondary to the immunodeficiency that arises due to ATLL
- paracortical expansion by small to medium sized lymphocytes with scattered B lymphoblasts that are EBV positive with Hodgkin-like morphology
What is the morphology of
ATLL in the peripheral blood and marrow ?
- multilobed appearance with deep blue cytoplasm
- “flower cells”
- marrow infiltrates are patchy and may be sparse
- osteoclast like activity can be prominent even if there are only a few of the neoplastic cells within the bone marrow
What is the morphology of
ATLL in the skin?
- skin lesions are seen in >50% of cases
- epidermal infiltration with pautrier microabscesses is common
- dermal infiltration is mainly perivascular
- but large tumor nodules with subQ fat extension can be seen
What is the immunophenotype of ATLL ?
- Positive:
- T cell antigens: CD2, CD3, CD5
- CD4> CD8 or can be rarely double positive
- CD25 strongly positive
- **CD30 in large cell transformed
- CCR4 and FOXP3 (TREG molecule)
- these are positive in only a subset
- Negative:
- CD7
- ALK and cytotoxic molecules
What is the postulated normal
counterpart of ATLL?
- peripheral CD4+ T cell
- likely TREG due to positivity of CD25 and FOXP3
- makes sense since there is an immunodeficiency that arises
What is the genetic profile
of ATLL?
- T cell receptor genes are clonally rearranged
- neoplastic cells have clonal integration of HTLV-1
- Many genes are key to leukemiagenesis:
- HBZ (leucine zipper) only gene that is consistently expressed in leukemia cells
- modulates many pathways
- realted to cell growth, immune response, and T cell differentiation
- HBZ (leucine zipper) only gene that is consistently expressed in leukemia cells
- high genomic instability with high number of structural variations
- 50 genes were recurrently mutated
- high amounts of hypermethylation leading to gene silencing
What are the prognostic and predictive
factors of ATLL?
- Major prognostic factors:
- clinical subtype, patient age, performance status, serum calcium and LDH
- Survival time for acute and lymphomatous variants
- ranges from 2 weeks to > 1 year
- death is often caused by infection and or hypercalcemia
