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Chapter 83 Virus-Associated Lymphoma 1323

HTLV-1 infection

Apoptosis

Tax

Viral control Tax activates AKT and NF-κB,
by cytotoxic CTL inactivates p53
T lymphocytes

Tax Tax induces
Tax aneuploidy
and DNA damage
Proliferation Cellular
transformation
Tax to ATL
30-40 years

Fig. 83.4 HUMAN T-LYMPHOTROPIC VIRUS-1 (HTLV-1) AND THE EVOLUTION OF ADULT
T-CELL LEUKEMIA/LYMPHOMA. Following HTLV-1 infection, many cells undergo apoptosis, but some
+
infected CD4 T cells are driven to proliferate by the effects of Tax on the nuclear factor-κB (NFκB) pathway
and on the AKT pathway. Tax is also suggested to result in inactivation of p53, aneuploidy, and deoxyribo-
nucleic acid (DNA) damage. Over many decades, malignancy evolves.

57
transformed T cells to elude immune surveillance. Tax interferes with
various DNA repair pathways and induces reactive oxygen species, Adult T-Cell Leukemia/Lymphoma
facilitating the development of aneuploidy. 56,58 Tax leads to functional Diagnostic Considerations
inactivation of p53 and may interfere with the spindle assembly
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checkpoint that normally operates in mitosis to preserve euploidy. There is a spectrum of ATL. In the acute leukemic subtype of ATL,
comprising around 60% of cases, leukocytosis, diffuse lymphoade-
Epidemiology of Viral Infection and Adult T-Cell nopathy, and hypercalcemia are common. The classic findings on a
peripheral blood smear are lymphocytes with flower-shaped nuclei
Leukemia/Lymphoma (Fig. 83.3C). Twenty percent of patients with ATL present with a
lymphomatous subtype dominated by lymphadenopathy and hepa-
HTLV-1 is endemic in particular regions of Japan, Africa, South tosplenomegaly. Cutaneous infiltration, lytic bone lesions, malignant
America, and some Caribbean islands. 58,59 As assessed by seropreva- effusions, and involvement of the CNS and other extranodal sites are
57
lence, rates up to 37% are found on the southwestern Japanese islands not uncommon. There are also chronic and smoldering subtypes
of Shikoku, Kyushu, and Okinawa, whereas most other areas of Japan that behave much more indolently and may in some cases not require
have an intermediate prevalence of 1%–5%. In the United States, the treatment upon diagnosis. Across all subtypes, presentations reflect-
incidence in blood donors is 0.025%. It has been estimated that ing immune dysfunction such as strongyloidiasis with dissemination,
about 20 million individuals are infected worldwide. The major Pneumocystis jiroveci pneumonia (PJP), mycobacterium, or crypto-
mode of transmission in endemic areas is from mother to child in coccal infection are common. The immune dysfunction seen in
breast milk, although infection is also transmitted through sexual patients with ATL may be due to the fact that the leukemic cells have
intercourse, transfusion of cellular blood products, and the sharing a regulatory T-cell phenotype that fosters an immunosuppressive
of needles and syringes. Evidence has been presented that HTLV-1 environment.
infection persists in association with certain human leukocyte antigen Histologically ATL shows lymph node effacement by large, atypi-
+
+
+
(HLA) types and may be more readily transmitted from mother to cal T cells usually expressing CD4 , CD25 , and CD52 , with vari-
child when these HLA types are shared. able CD30 and CD15 expression. Aneuploidy is consistent, although
ATL is more common in men than in women and typically pre- characteristic cytogenetic abnormalities have not been identified.
sents in the fourth or fifth decade of life. Perhaps as a function of the Serologic analysis confirms the presence of HTLV-1 infection. 61
long latency period, cases of ATL following blood transfusion or
needle sharing are vanishingly rare. The lifetime risk for ATL has been
estimated to be in excess of 6% in men who are HTLV-1 carriers in Therapies Specific to HTLV-1 ATL
an endemic region of Japan, although in other settings the risk may
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be much lower. As with EBV, the subset of the infected population The leukemic and lymphomatous forms of ATL are aggressive and
that develops lymphoma is quite small. are associated with poor responses to chemotherapy, high relapse