Clinicopathological Features Of

ATL was the name given by Japanese investigators to the first human malignancy known to be induced by a retrovirus. ATL patients usually have antibodies against HTLV-1 as well as clon-ally rearranged T-antigen receptor V-P and V-y genes and mon-oclonally integrated proviral HTLV-1 DNA in their mature malignant T lymphocytes. ATL patients have increased numbers of either circulating or tissue-associated lymphocytes with convoluted or "flowered" nuclei, or both. The surface pheno-type of the malignant cell is usually CD3+, CD4+, CD7-, CD8-, CD30+, CD25+, and TdT-. Occasional tumors will be CD4+, CD8+, (double positive) or will lack CD4 and CD8 altogether (double negative). Fresh peripheral blood ATL cells secrete high levels of transforming growth factor P1 (TGF-P1) but low levels of IL-2, IL-4, IL-5, and y-interferon, suggesting that they function (either before or after HTLV-1 infection) as immunological suppressors of normal T- and B-lymphocyte proliferation and function.118

Clinically ATL is characterized by 1. adult age of onset; 2. ATL cells with typical morphology; 3. cutaneous involvement (25 to 50 percent); 4. high propensity for parenchymal organ and central nervous system (CNS) involvement (with some patients pre senting with primary CNS lymphoma); 5. hypercalcemia usually with concomitant lytic bone disease; 6. impaired immunoglobulin and T-cell immune responses with over 50 percent of patients presenting with or developing opportunistic infections; and 7. geographic or familial associations. Lymphomas are usually deemed to be of the diffuse intermediate or high grade of mixed, lymphoblastic, or immunoblastic morphology.12 Many patients present with eosinophilia and, in the past, ATL cases were often misdiagnosed as Hodgkin's disease or Wegener's granulomatosis because of the marked proliferation of other hematopoietic cells in biopsy specimens due to release of cytokines by the virally infected cells and the formation of virally induced multinucleated syncytial cells that look like Reed-Stern-berg cells or a common midline nasopharyngeal location.21,119 Most experienced hematopathologists and clinicians can now make a clear distinction among these various entities. The term ATL is actually a misnomer, because ATL has been diagnosed in children as young as 14 months. Also, the disease clinically overlaps with other mature T-cell neoplasms (e.g., cutaneous T-cell lymphomas and peripheral T-cell lymphomas) that are HTLV-1 negative. We consider that a more appropriate term might be HTLV-1-associated T-cell lymphoma/leukemia (HATL) and that the disease be virologically defined, preferably by molecular techniques and certainly in therapeutic clinical trials.

Only a small fraction (estimates range from 0.1 to 3 percent) of HTLV-1-infected patients progress from polyclonal to oligo-clonal to monoclonal leukemia proliferation over their lifetime. This figure approaches 10 percent in patients infected perina-tally, and no transfusion-acquired cases of HATL have been reported. The disease usually takes three to four decades to manifest after infection. Four clinical presentations of HATL have been described.120 Acute or prototypic HATL patients present with the common abnormalities listed above. Elevated lactate dehydrogenase (LDH), serum calcium, and bilirubin and high leukemic cell counts are associated with a poor prognosis, and most patients do not survive beyond 1 to 2 years. Smoldering HATL is characterized by a waxing and waning of symptoms over many years. Patients have a low percentage (0.5 to 3 percent) of leukemic cells in their peripheral blood and minimal lymphadenopathy, liver, spleen, and bone marrow involvement. Chronic HATL patients have increased numbers of circulating HTLV-1-infected lymphocytes and slight parenchymal organ involvement. Survival time is midway between the acute and smoldering forms. Eventually, most chronic and smoldering forms evolve into the acute form, which carries a poor prognosis. Lymphoma-type HATL is characterized by a lack of obvious leukemia, marked lymphadenopathy with an intermediate- or high-grade histology, elevated LDH and calcium, and poor survival.12 It would seem probable that more scientific or molecu-larly defined grading and staging systems will emerge for HATL as the use of novel clinical treatment increases.

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