Adult T-cell Leukemia/Lymphoma, HTLV-1+



Adult T-cell Leukemia/Lymphoma, HTLV-1+


Carlos E. Bueso-Ramos, MD, PhD

Roberto N. Miranda, MD





Key Facts


Terminology



  • Peripheral T-cell leukemia/lymphoma caused by human T-cell lymphotropic virus type 1 (HTLV-1)


  • 4 clinical variants are recognized



    • Acute, lymphomatous, chronic, smoldering


Clinical Issues



  • Lymphadenopathy that spares the mediastinum


  • Hepatosplenomegaly, skin lesions


  • Leukemic involvement, hypercalcemia, lytic lesions


  • Seropositivity for HTLV-1 can be used as surrogate for HTLV-1 integration into tumor



    • Useful in areas with low prevalence of HTLV-1 infection


Microscopic Pathology



  • Diffuse effacement of lymph node architecture


  • Variable cytologic composition in tissues


  • “Flower cells” in peripheral blood


Ancillary Tests



  • Immunophenotype



    • CD2(+), CD3(+), CD5(+), TCR-α/β(+)


    • CD25(+), CCR4(+), FOXP3(+), CD62 (L-selectin)(+)


    • CD45RO(+); most cases CD4(+), CD8(−)


  • Complex cytogenetic abnormalities


  • Monoclonal integration of HTLV-1 into host genome


  • Monoclonal TCR gene rearrangements


Top Differential Diagnoses



  • Peripheral T-cell lymphoma, NOS


  • Angioimmunoblastic T-cell lymphoma


  • Anaplastic large cell lymphoma


  • Mycosis fungoides/Sézary syndrome







Adult T-cell leukemia/lymphoma (ATLL) diffusely involving lymph node. In this case a “starry sky” pattern can be appreciated, indicating a high cell turnover.






Peripheral blood smear of a patient with adult T-cell leukemia/lymphoma (ATLL). Note the markedly irregular, multilobulated nuclei (“flower cells”) that are seen most frequently in the acute variant.


TERMINOLOGY


Abbreviations



  • Adult T-cell leukemia/lymphoma (ATLL)


Synonyms



  • HTLV-1-associated T-cell lymphoma


  • T-cell lymphoma small cell type or pleomorphic medium and large cell type (HTLV-1[+])


  • T-cell immunoblastic sarcoma


Definitions



  • Peripheral T-cell leukemia/lymphoma caused by human T-cell lymphotropic virus type 1 (HTLV-1) infection


  • 4 clinical variants are recognized



    • Acute, lymphomatous, chronic, smoldering


  • 5th clinical variant has been proposed: Cutaneous


ETIOLOGY/PATHOGENESIS


Infectious Agents



  • HTLV-1 is a type C retrovirus, delta retrovirus genus


  • Single strand of RNA that, during infection is



    • Converted into double strand of DNA in host


    • Monoclonally integrated into host cell genome



      • All cells have same site of proviral integration


Pathogenesis



  • HTLV-1 is spread in 4 general ways



    • Vertical transmission from mother to child via breast-feeding


    • Sexual intercourse with infected person


    • Transfusion of contaminated blood products


    • Sharing of contaminated needles and syringes among drug users


  • HTLV-1 can infect immature thymocytes and mature CD4(+) T cells


  • HTLV-1 infection occurs and spreads via cell-to-cell contact


  • Genome of HTLV-1 is composed of



    • Long terminal repeat (LTR) regions at each end


    • Structural genes: gag, pol, and env


    • pX region that encodes for tax, rex, p12, p13, p21, and p30 proteins


  • P40 tax viral protein is needed for HTLV-1 to transform cells in early stages of disease



    • Many cellular genes are transcriptionally activated by tax



      • Growth factor interleukin (IL)-2


      • Its high-affinity receptor α subunit (IL-2Rα; CD25) promotes autocrine stimulation


      • JAK/STAT pathway is constitutively activated in HTLV-1-infected cells


    • Tax can repress transcription of genes that



      • Negatively control cell cycle


      • Inhibit proteins involved in tumor suppression and DNA repair


  • Host immunity is involved in control of HTLV-1 infection



    • Insults to host immune system in viral carrier can result in onset of ATLL


  • Marked immunodeficiency that results from HTLV-1-infection can lead to opportunistic infections


Molecular Aberrations



  • HTLV-1 infection alone is insufficient to cause ATLL


  • Numerous cytogenetic and molecular abnormalities are present


  • Molecular models suggest 6 or 7 “hits” involved in pathogenesis of full-blown ATLL


CLINICAL ISSUES


Epidemiology



  • Incidence



    • HTLV-1 is endemic in




      • Southwestern Japan, sub-Saharan Africa


      • Caribbean basin: Jamaica and Martinique


      • South America: Northern Brazil, Colombia, and French Guyana


    • Cumulative incidence of ATLL is estimated to be 2.5% among HTLV-1 carriers in Japan



      • Over 1.2 million persons in Japan are infected with HTLV-1


    • Prevalence of HTLV-1 infection is very low in North America and Europe


    • Variable frequency of seroprevalence in various countries probably related to



      • Genetic predisposition, cultural, and geographical factors


    • ˜ 10% of patients have positive family history


  • Age



    • Range: 20-80 years; mean: 58 years


    • Median age of onset of ATLL is younger in Central and South America, between 40-50 years of age


  • Gender



    • M:F ≈ 1.5:1


Site



  • Lymph nodes


  • Extranodal sites: Main sites are skin and peripheral blood



    • Other sites: Spleen, lungs, liver, gastrointestinal (GI) tract, and central nervous system


Presentation



  • Common widespread lymphadenopathy and peripheral blood involvement


  • 4 clinical variants: Acute, lymphomatous, chronic, and smoldering


  • Acute variant



    • ˜ 50% of cases in Japan


    • Leukocytosis, skin rash, and lymphadenopathy


    • Common peripheral blood involvement and hypercalcemia


  • Lymphomatous variant



    • ˜ 20% of cases in Japan


    • Lymphadenopathy and skin lesions


  • Chronic variant



    • ˜ 20% of cases in Japan


    • Lymphocytosis and mild organ involvement


  • Smoldering variant



    • ˜ 5% of cases in Japan


    • Skin or lung lesions


    • Up to 5% of atypical lymphocytes in absence of leukocytosis


  • Skin lesions



    • Scaly and erythematous rash, cutaneous plaques, or nodules


    • Acute and lymphomatous variants more frequently associated with skin lesions


  • T-cell immunodeficiency is common



    • Associated with Pneumocystis jirovecii pneumonia and strongyloidiasis


Endoscopic Findings



  • Stomach, colon, and small intestine can be affected



    • Edema, erosions, or polypoid lesions can be identified


  • Upper GI tract endoscopy with biopsy is recommended for staging



    • GI tract involvement is frequent in patients with aggressive ATLL


Laboratory Tests



  • Seropositivity for HTLV-1 can be used as surrogate for monoclonal integration of virus



    • Only useful in areas with low prevalence of HTLV-1 infection


  • Complete blood count: Elevated leukocyte count and circulating neoplastic lymphocytes (leukemic phase)


  • Elevated serum lactate dehydrogenase level reflects disease burden/activity


  • Hypercalcemia is more common in patients with acute variant



    • With or without associated lytic bone lesions


  • Eosinophilia and neutrophilia are common


  • Elevated soluble interleukin-2 receptor α-chain levels in patients with aggressive ATLL



Natural History



  • Patients with chronic or smoldering variant can progress to acute or lymphomatous picture


Treatment



  • Options, risks, complications



    • Chronic and smoldering variants



      • Watchful waiting


    • Acute and lymphomatous variants



      • Antiviral agents; chemotherapy


      • Allogeneic hematopoietic stem-cell transplant


      • Novel targeted therapies


  • Drugs



    • Zidovudine (AZT)/interferon (IFN) α therapy can achieve long-term response



      • Patients with wild-type p53 and low interferon regulatory factor 4 expression


    • No standard chemotherapy regimen



      • Usually transient response or no response


Prognosis



  • Acute and lymphomatous variants



    • Median survival time is 13 months


  • Chronic and smoldering variants have protracted clinical course


IMAGE FINDINGS


Radiographic Findings



  • Extensive lytic lesions are present in some patients



    • Skull, pelvis, spine, and long bones can be affected


  • “Punched-out” lesions similar to multiple myeloma can be found


CT Findings



  • Computed tomography (CT) scans of body detect sites of nodal and extranodal disease


MICROSCOPIC PATHOLOGY


Cytologic Features



  • ATLL cells show variable appearances



    • Irregular/polylobulated nuclei, homogeneous, condensed chromatin, small nucleoli


    • Agranular basophilic cytoplasm


Lymph Nodes



  • ATLL initially involves paracortical T-cell zones, leaving B-cell regions unaffected


  • Subsequently ATLL diffusely replaces lymph node


  • Lymph nodes involved by ATLL have been subdivided according to cell type and pattern into



    • Pleomorphic small-cell (usually monotonous)


    • Pleomorphic medium- and large cell type/pattern; this is most common


    • Anaplastic large-cell (resembling anaplastic large cell lymphoma)



      • CD30(+), anaplastic lymphoma kinase(−)


    • Angioimmunoblastic T-cell lymphoma-like



      • Medium to large neoplastic cells with abundant clear cytoplasm


      • Inflammatory cells and proliferation of high endothelial venules


      • Neoplastic cells are CD3(+), CD10(−), PD-1(−), CXCL13(−)


      • No proliferation of follicular dendritic cells


    • Hodgkin lymphoma-like; contains multinucleated HRS-like cells



      • Epstein-Barr virus positive B cells are interspersed within lesion


      • Smaller lymphocytes show marked atypia; distinguishing feature from Hodgkin lymphoma


  • Mitotic and apoptotic rates are variable



    • Often very high in acute and lymphomatous variants


  • Inflammatory background including eosinophils is sparse


Peripheral Blood and Bone Marrow



  • ATLL cells are of intermediate or large size, up to 3x size of normal lymphocytes



    • Convoluted or multilobulated nuclei, coarse chromatin, and prominent nucleoli


    • Distinctive appearance of these cells has led to their designation as “flower cells”


    • Basophilic cytoplasm, with or without vacuoles


  • In some ATLL patients, neoplastic cells are more uniform in size and shape



    • Nuclei are smaller and less pleomorphic


  • Bone marrow involvement may be difficult to identify



    • Infiltrates of ATLL are usually patchy and interstitial


    • Diffuse replacement of the medullary space is rare


    • Increased bone resorption can be seen



      • Osteoclasts can be increased


    • Independent poor prognostic factor


Skin



  • Skin lesions are common in ATLL patients: ˜ 40-70%


  • Erythematous rash, papules, or tumor nodules


  • Erythematous lesions tend to be composed of smaller cells in perivascular pattern in dermis


  • Papules and nodules tend to be composed of larger cells that replace dermis


  • Epidermotropism, including well-formed Pautrier-like microabscesses, can occur


ANCILLARY TESTS


Immunohistochemistry



  • Pan-T-cell antigens(+)



    • CD2, CD3, CD5, and T-cell receptor (TCR)-α/β


  • CD25(+), CCR4(+), HLA-DR(+), CD62 (L-selectin)(+)


  • FOXP3(+), which is a marker of regulatory T cells


  • CD45RO(+); most cases CD4(+), CD8(−)


  • IRF-4/MUM1(+/−), CD15(−/+), CD30(−/+), CD56(−/+)


  • Ki-67/MIB-1 shows high proliferation index


  • TdT(−), ALK1(−), TCL1(−), cytotoxic molecules(−)


  • B-cell antigens(−), myeloid-associated antigens(−)

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Adult T-cell Leukemia/Lymphoma, HTLV-1+

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