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Chapter 85 T-Cell Lymphomas 1347

PTCL. While it shares morphologic and immunophenotypic features classification, EATL types I and II, recent studies have suggested
with ALCL, ALK+, including CD30 expression, it characteristically distinct differences between these entities and proposed to designate
lacks ALK translocations, occurs in older individuals, and has a poorer EATL type II as “monomorphic epitheliotropic intestinal T-cell
prognosis. Additionally, a subset of PTCL-NOS can express CD30 lymphoma” (MEITL). EATL type I, now simply referred to as EATL,
and distinguishing ALCL, ALK− from these lesions can be challeng- occurs in individuals with celiac disease and is associated with the
ing. Refined, supervised gene expression analysis could reliably dif- HLA DQ2 or DQ8 haplotypes. Homozygosity for HLA-DQ2 has
ferentiate ALCL, ALK− from PTCL-NOS and metaanalysis of the been shown to increase the risk of developing EATL. Refractory celiac
transcriptional profiles of a large series of PTCLs revealed a three-gene disease (RCD), especially RCD type II, is considered a precursor of
model, comprising TNFRSF8, BATF3, and TMOD1, that could at least a subset of EATL. Cytogenetic analysis of RCD II has shown
accurately separate ALCL, ALK− from PTCL-NOS. Recently, an recurrent gains of chromosome 1q22–q44, a feature shared with
enrichment of MYC, IRF4 targets, mTOR and PI3K pathway gene EATL, indicating early acquisition of chromosome 1q abnormalities
signatures were described in ALCL, ALK−, while hypoxia-inducible in the pathogenesis of EATL.
factor 1-α targets, interleukin (IL)-10-induced genes and H/K-ras– Genomic analyses of EATL have revealed additional recurrent
induced genes appear enriched in ALCL, ALK+. chromosome abnormalities. Gains or amplifications of chromosome
Array comparative genomic hybridization (CGH) analysis of 9q34 are the most frequent (40%–58%), but recurrent gains at 5q
ALCL, ALK+ and ALCL, ALK− has highlighted differences in sec- and 7q and losses of 8p, 9p, and 13q have also been reported. The
ondary genetic aberrations between the two subtypes, and differential pattern of aberrations suggests at least two subtypes of EATL. Seg-
expression of microRNAs. Genome-wide single-nucleotide polymor- mental amplifications of the chromosome 9q31.3-qter region,
phism profiling has shown recurrent losses of 17p13.3–p12 (TP53) encompassing known protooncogenes (e.g. NOTCH1, ABL1, VAV),
and 6q21 (PRDM1) at a significantly higher frequency in ALCL, or, alternatively, deletions at 16q12.1 have been reported in greater
ALK− compared with ALCL, ALK+. In addition to loss, PRDM1 than 80% of EATLs, while a small subset exhibit allelic imbalances
mutations were also detected in a subset of ALCL, ALK− cases, and at 3q27.
loss of either PRDM1 and/or TP53 conferred a worse prognosis. MEITL has a wider geographic distribution than EATL and it
Next-generation sequencing analysis has identified a recurrent appears to be more common in Asians and Hispanics. Serologic
balanced translocation t(6;7)(p25.3;q32.3) in 10% of ALCL, ALK−, evidence of celiac disease is lacking in the vast majority of cases and
leading to juxtaposition of the DUSP22 phosphatase gene (6p25.3) the morphology is distinct from EATL. Recent studies from Asia have
with the fragile site FRA7H (7q32.3) locus, resulting in the down- reported 23%–78% of MEITLs to manifest the TCRγδ phenotype,
regulation of DUSP22 and upregulation of MIR29 microRNAs on and a lack of TCR expression has been described in up to a third of
7q32.3. Mutually exclusive and recurrent rearrangements of DUSP22 cases. On comparing genomic profiles of EATL and MEITL, mutu-
and TP63 have been identified in 30% and 8% of ALCL, ALK−, ally exclusive segmental amplifications of 9q31.3-qter and deletions
respectively, and differences in morphology and phenotype have been of 16q12.1 have been detected in both disease types, with gains of
reported for the different subsets. Cases with DUSP22 rearrange- 1q and 5q occurring more frequently in EATL and gains of the MYC
ments have a significantly better prognosis compared with those with locus (8q24) more often observed in MEITL. These data suggest the
TP63 rearrangements. Recent whole-exome sequencing analysis of possibility of common as well as distinct genetic alterations associated
ALCL, ALK− identified recurrent and concurrent mutations in JAK1 with the pathogenesis of the two subtypes of intestinal T-cell
and STAT3. Interestingly, a subset of cases lacking mutations in either lymphomas.
JAK1 or STAT3 harbored chimeric fusion proteins involving NF-κB2
and tyrosine kinases ROS1 and TYK2, which result in constitutive
STAT3 activation. Hence, activation of the STAT3 pathway may Hepatosplenic T-Cell Lymphoma
represent a common and critical event in the pathogenesis of ALCL,
ALK− and possibly a therapeutic target. HSTL is a rare subtype of PTCL that has been associated with
underlying immune dysfunction (Fig. 85.5). It is most commonly of
γδ T-cell lineage; however, lymphomas bearing the αβ TCR have
Enteropathy-Associated T-Cell Lymphoma been described, as have occasional cases lacking surface TCR. Iso-
chromosome 7q [i(7)(q10)] is reported to be a frequent recurrent
EATL is a rare subtype of PTCL, accounting for 5%–10% of PTCLs, chromosomal aberration, but specific abnormalities of particular
that is derived from small intestinal intraepithelial lymphocytes. genes have not been defined. Of interest, i(7)(q10) has been detected
Although two types of EATL were recognized in the 2008 WHO in hepatosplenic T-cell lymphoma irrespective of the phenotype (γδ

7

A B C D

Fig. 85.5 HEPATOSPLENIC T-CELL LYMPHOMA. Hepatosplenic γδ T-cell lymphoma is commonly
diagnosed from a bone marrow biopsy specimen in a patient being evaluated for hepatosplenomegaly. The
bone marrow typically shows a subtle lymphoid infiltrate (A), which becomes more evident with a T-cell stain
such as CD3 (B). This highlights the classic sinusoidal distribution of the lymphoma. Lymphoma cells may
be seen in the circulation or in the marrow aspirate and can resemble monocytes or blasts (C). The lymphoma
is typically associated with isochromosome 7q, as illustrated in the partial karyotype (D).