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1700 Part XI: Malignant Lymphoid Diseases Chapter 104: Mature T-Cell and Natural Killer Cell Lymphomas 1701

perforin, granzyme B, and TIA-1. 124,125 EATL type 2 is characterized by a The acute variant of ATL represents 60 percent of cases and is
monomorphic infiltrate of small- to medium-size lymphocytes positive characterized by patients who present with a leukemic presentation. An
for CD3, CD8, CD56, and TCR-β, and negative for CD4. CD30 is often additional 20 percent of cases present with the lymphoma variant char-
negative in EATL type 2. 119 acterized by lymphadenopathy and less than 1 percent of leukemic cells
in the blood. These subtypes exhibit an aggressive clinical course with
TREATMENT AND PROGNOSIS a median survival of less than 1 year. The majority of patients present
CHOP chemotherapy has been used most widely for both type I and with hepatosplenomegaly (50 percent of cases), lymphadenopathy, ele-
vated LDH, hypercalcemia (50 percent of cases), and visceral and cuta-
type II EATL, with a 5-year relapse FFS of 4 to 22 percent and a 5-year neous lesions. The marrow is involved in approximately 35 percent of
OS of approximately 20 percent. 2–4,116 The addition of etoposide to cases. Most patients have generalized lymphadenopathy, particularly
143
CHOP does not appear to confer additional benefit. Even patients in the retroperitoneal and hilar regions, though the nodes are often rela-
133
who initially respond to CHOP therapy usually relapse after a median tively small and mediastinal masses are rare. Extranodal sites of disease
interval of 6 months, with a median survival after relapse of approx- include the lung, liver, skin, gastrointestinal tract, and central nervous
imately 6 months to 1 year. 116,121,126,12 In patients who are transplantation- system, including cord myelopathy and spastic paraparesis.
eligible, high-dose chemotherapy followed by ASCT may improve out- In contrast to the acute and lymphoma forms, the smoldering form
comes. 15,127,128 The Scotland and Newcastle Group demonstrated that of adult T-cell leukemia/lymphoma typically presents with a predom-
high-intensity therapy with CHOP alternating with IVE (ifosfamide, inance of skin lesions or lung infiltration without visceral or marrow
epirubicin, etoposide) and intermediate-dose methotrexate, followed by disease, and minimal blood involvement (<5 percent of lymphocytes).
consolidation with ASCT resulted in a 5-year OS of 60 percent and PFS Patients with chronic ATL present with leukocytosis with lymphade-
of 52 percent in the 50 percent of patients who were able to complete nopathy and organomegaly without an elevated LDH, or visceral
ASCT. Many patients could not complete the course of chemother- involvement. Although smoldering and chronic ATL are characterized
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apy, however, and there were a large number of complications, including initially by indolent courses, the prognosis remains poor with a survival
gastrointestinal bleeding, small bowel perforation, and enterocolic fistu- of 4.1 years and 49 percent progressing to acute ATL after a median of
lae. Twelve patients required either enteral or parental feeding. 18.8 months. 145
Adverse prognostic factors include a history of celiac sprue, a large Opportunistic infections are common in patients with adult
tumor mass (≥5 cm) at diagnosis, an elevated LDH, and a nonambula- T-cell leukemia/lymphoma, even indolent forms, including P. carinii,
146
tory performance status. The PIT score predicts both OS and FFS in strongyloides, and cryptococcal meningitis, as well as bacterial and
116
EATL better than the IPI. 116 other fungal infections.

ADULT T-CELL LEUKEMIA/LYMPHOMA LABORATORY FEATURES
Histopathology
DEFINITION The neoplastic cells are pleomorphic, have highly lobulated nuclei
ATL is an uncommon lymphoproliferative neoplasm of mature (“clover leaf” or “flower cell” appearances) with condensed nuclear
CD4+CD25+ T-cells caused by infection with the retrovirus, HTLV-1, chromatin, inconspicuous nucleoli, and a mature helper T-lymphocyte
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that was initially characterized in 1977. 130,131 These cells classically have immunophenotype. At least 5 percent of circulating abnormal T-lym-
a leukemic “flower-cell” appearance. At least 5 percent of circulating phocytes are required to diagnose ATL in patients without histologically
132
133
abnormal T lymphocytes are required to diagnose ATL in patients with- proven tumor lesions. In approximately 20 percent of cases, nuclear
out histologically proven tumor lesions. 133 lobulation is less pronounced, and the cells may be difficult to distin-
guish from Sézary cells. These cells express the surface T-cell lympho-
cytic markers CD2, CD4 and CD5, CD45RO, CD29, and TCR-αβ, and
EPIDEMIOLOGY are usually negative for CD7, CD8, and CD26, and show reduced CD3
The incidence of ATL in the United States is approximately 0.05 cases expression. The lymphocytic activation markers HLA-DP, -DQ, and
-DR, and IL-2Rα (CD25) are always present, whereas terminal deoxy-
per 100,000 people. The disease prevalence parallels the geographic nucleotidyl transferase is typically absent. Rare immunophenotypic
134
147
distribution of the HTLV-1 virus, with the highest incidences occurring variants (CD4 negative, CD8-positive, double-positive or double-
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in southern Japan, the Caribbean, Central and South America, intertro- negative variants) have also been reported. 148–150 Although there are no
pical Africa, Romania, and northern Iran (see Table 104–2). 135–139 Among specific chromosomal abnormalities diagnostic of ATL, the karyotype of
approximately 10 to 20 million HTLV-1 carriers, the lifetime risk of ATL cells is usually complex in the aggressive variants of the disorder.
131
developing ATL is approximately 2.5 to 4 percent, with a mean latency Clonal rearrangements of the TCR genes are typically present. 151–153
of greater than 50 years. 134,137,139,140 HTLV-1 is transmitted through
breastfeeding, blood products, and unprotected sexual intercourse. The Laboratory Analysis
overwhelming majority of ATL cases occur in patients infected dur- Patients with aggressive forms of ATL commonly present with an elevated
ing the early years of life, In addition, the prolonged infection may LDH and hypercalcemia.
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increase chances of accruing subsequent mutations, and ultimately
malignant transformation. The mean age of patients with adult T-cell
leukemia/lymphoma is 62 years, without a gender predominance. 142,143 TREATMENT AND PROGNOSIS
Overall, prognosis in ATL remains poor with a median survival of less
than 1 year for patients with aggressive subtypes. A multivariate analysis
CLINICAL FEATURES of 126 patients with acute (13 percent) and lymphoma (87 percent) sub-
Several clinical variants of ATL have been described: acute, lymphoma, types of ATL performed by the IPTCLP indicated that the IPI was the
142
chronic, and smoldering; these appear to have differing genomic altera- only independent predictor of OS. Although smoldering and chronic
tions and different clinical courses. 133,143,144 ATL are characterized initially by indolent courses, the prognosis

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