Page 1521 - Hematology_ Basic Principles and Practice ( PDFDrive )

1348 Part VII Hematologic Malignancies

or αβ). Moreover, an increase in the number of 7q signals, often receptor signaling and NF-κB pathway genes, as well as defects in
accompanied by trisomy 8, has been associated with disease progres- immunosurveillance mechanisms.
sion. The gene expression profile of HSTL appears distinct from
other types of PTCL and is characterized by overexpression of NK
cell-associated molecules such as killer cell immunoglobulin (Ig)-like Clinical Manifestations
receptor (KIR) genes and killer lectin-like receptors. Mutually exclu-
sive STAT5B and STAT3 mutations have been reported in a subset PTCLs, with the exclusion of CTCL, recapitulate the general presen-
of HSTL cases. tation of aggressive NHL, which can vary depending on histologic
features, patient age, and immune status. PTCL generally presents
with lymphadenopathy, and patients can range from being asymp-
Extranodal Natural Killer/T-Cell Lymphoma tomatic to presenting in extremis with diverse symptoms and signifi-
cant end-organ compromise. PTCL can present as discrete nodal,
Extranodal NK/T-cell lymphoma (ENKTCL) is an aggressive PTCL extranodal, leukemic, or cutaneous disease, or with any combination
associated with clonal episomal EBV infection of NK or T cells. It is of these involved sites. An extranodal presentation is common in
less common in the western hemisphere but it has a significantly PTCL and often contributes to a delay in the diagnosis. When
higher incidence in Asia, excluding Japan. It occurs most commonly compared with aggressive B-cell lymphomas, patients with PTCL
in the nasopharynx (nasal type) and less frequently at other anatomic tend to present with more advanced disease, a poorer performance
sites (extranasal). Cooperating genetic and environmental factors are status, and frequently B symptoms. Patients may have constitutional
likely to play roles in disease pathogenesis. Gene expression profiling manifestations because of the production of inflammatory cytokines
of ENKTCL has revealed overexpression of cytotoxic proteins (gran- and chemokines produced by the lymphoma cells and host tissues.
zyme H) and PDGFRA. Early studies showed recurrent deletions of Paraneoplastic syndromes, including eosinophilia, hemophagocytic
chromosome 6q21–25 in ENKTCL and array CGH analysis detected syndrome, and autoimmune phenomena, have been well described
recurrent gains of 2q, and losses of 6q16.1–q27 and 11q22.3–q23.3, in different PTCL subtypes. For example, AITL is often characterized
with loss of potential tumor supressor genes PRDM1, ATG5, and by systemic symptoms, skin rash, organomegaly, hypergammaglobu-
AIM1 located on 6q12–25. Oligonucleotide array CGH and func- linemia, and hemolytic anemia. It affects older adults, and patients
tional studies have identified FOXO3 in addition to PRDM1 frequently present with peripheral lymphadenopathy, hepatospleno-
(BLIMP1) as candidate tumor suppressor genes located at 6q21. megaly, skin rash, and constitutional symptoms. In contrast, hepato-
Analysis of a small cohort of ENKTCL cases described recurrent loss splenic T-cell lymphoma, which often occurs in young adults, is
of 8p11.23 in 46% cases, which was associated with an adverse characterized by marked hepatosplenomegaly and bone marrow
prognosis. Genetic analysis of this locus showed recurrent mutations involvement.
in ADAM3A, a metalloproteinase family member. Recent studies
have shown JAK3 and STAT3 mutations resulting in the constitutive
activation of these transcription factors as well as loss of PTPRK on Laboratory Manifestations
6q22, which can also lead to STAT3 activation. These findings
suggest a role for JAK-STAT signaling in the pathogenesis of Laboratory tests should include a complete blood count, serum
ENKTCL. Similar to other types of PTCLs, mutations in epigenetic chemistry determination (including lactate dehydrogenase [LDH]),
modifier genes are also frequent in this disease. titers, and viral studies, including HTLV-1 status and EBV in appro-
priate cases. The level of β 2 -microglobulin is usually normal compared
Human T-Lymphotropic Virus-1–Associated Adult with that found with the B-cell lymphomas. Peripheral blood flow
cytometry and bone marrow biopsy can be helpful in understanding
T-Cell Leukemia/Lymphoma the extent of disease.
HTLV-1 is a retrovirus endemic in Japan, central Africa, Iran and the
Caribbean basin. HTLV-1 infection is transmitted via infected T cells Differential Diagnosis
present in body fluids, especially breast milk and semen, and blood of
carriers of the HTLV-1 provirus. HTLV-1 infection leads to the clonal Accuracy in the diagnosis of PTCLs more often than not requires the
+
expansion and immortalization of CD4 T cells. Disease pathogenesis consensus of hematopathologists with a specific expertise in this field.
involves viral and host factors. A variety of viral proteins cooperate in Diagnosis is based on examination of peripheral blood or tissue
cellular transformation, including Tax and HBZ, which modulate biopsy specimens for histologic features supplemented by detailed
multiple signal transduction pathways (CREB/ATF, NF-κB, JAK- immunohistochemistry, flow cytometry, cytogenetics, and molecular
STAT, mTOR-AKT). This leads to deregulated cytokine production genetics. Expert hematopathologic review is essential for the correct
and impairment of host immunity, which allows survival of HTLV-1– classification of the different subtypes, given the often poor concor-
infected lymphocytes. Clinicopathologic subsets of ATLL include dance among hematopathologists in matching the diagnosis. Detailed
leukemic, lymphomatous, smoldering, and chronic. Array CGH clinical information is essential for the hematopathologist to make
studies have identified differences in chromosome alterations between the correct diagnosis. For example, in patients from Japan, informa-
acute and lymphomatous subtypes, and have suggested distinct tion regarding HTLV-1 status is essential to aiding the pathologist in
oncogenic pathways in disease pathogenesis. Single-nucleotide poly- distinguishing between lymph node involvement due to PTCL-NOS
morphism array and genomic PCR analysis have revealed rearrange- and ATL. Because this disease also occurs in the West, HTLV-1 status
ments at 10p11.2 involving the EPC1 gene locus and ASXL2 as a should be evaluated in patients at high risk for the disease or from
partner fusion gene. Gene expression profiling has uncovered dysregu- endemic areas. Other diagnoses such as AITL and EATL are often
lation of MYC, REL-1, and NOTCH-1 genes, all known to be upregu- clarified by the clinical information. For cases in which it is difficult
lated by the Tax protein. Cases exhibiting C-REL and IRF4 to distinguish between different entities, gene expression profiling
overexpression have been associated with resistance to antiviral agents. may become helpful in the future for confirming the correct
Somatic gain-of-function CCR4 mutations have been reported in 26% diagnosis.
of ATLL, leading to enhanced activation of the PI3K/AKT pathway.
Hyperactivity of PI3K secondary to inhibition of protein phosphatases
is known to play an important role in ATLL pathogenesis and has been Prognostic Factors
linked to the formation of the characteristic multilobated “flower-like”
nuclei in tumor cells. Recent comprehensive genomic analysis of a large The majority of PTCLs are associated with a very poor prognosis
series of ATLL samples identified mutations or alterations in T-cell compared with their B-cell counterparts (Fig. 85.6). Treatment