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

remains guarded with 5-year survivals of 40 percent and 50 percent, or from use of anti–tumor necrosis factor-α or thiopurine agents (as
respectively; 49 percent of patients with the more indolent forms of ATL are used for Crohn disease and other autoimmune diseases) has been
progress to acute ATL after a median time of 18.8 months. 145 implicated as a risk factor for this disease. 164,165
Despite its limited efficacy, cytotoxic chemotherapy remains the
mainstay of therapy for this disease. A Japanese cooperative group CLINICAL FINDINGS
developed a multidrug regimen called LSG15, which consists of seven
cycles of VCAP (vincristine, cyclophosphamide, doxorubicin, and pred- Patients commonly present with isolated hepatosplenomegaly without
nisone), AMP (doxorubicin, ranimustine, and prednisone), and VECP lymphadenopathy, frequently accompanied by cytopenias, B symptoms,
(vindesine, etoposide, carboplatin, and prednisone). LSG15 was evalu- and an elevated serum LDH. 57,163
ated in a phase II study that enrolled 96 patients with treatment-naïve
acute type (n = 58), lymphoma type (n = 28) or unfavorable chronic LABORATORY FINDINGS
type (n = 10) ATL. The ORR was 81 percent, with 35 percent CRs and
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45 percent PRs. In view of these results, a phase III trial of LSG15 ver- Histopathology
sus biweekly CHOP was performed in a similar patient population and Neoplastic cells localize to sinusoids in the spleen, liver, and marrow.
demonstrated a superior CR rate (40 percent vs. 25 percent) and 3-year The malignant lymphocytes typically express CD3, CD56, and TCR-δ,
166
OS (24 percent vs. 13 percent), favoring the intensive arm; however the but are negative for CD4 and usually CD8. Clonal rearrangement of
median survival was only 13 months in the LSG15 arm. These results the TCR-γ gene usually present, and in most cases the lymphoma cells
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7
highlight the inadequacy of CHOP in this disease, but the results seen have an isochromosome 7q [I (q10)] along with trisomy 8, which also
167–169
with LSG15 leave significant room for improvement as well. may be seen in the αβ variant of this disease.
The role of antiviral therapy remains controversial. A recent
meta-analysis of 254 patients with ATL demonstrated that there appears TREATMENT AND PROGNOSIS
to be a benefit to first-line antiviral therapy, including interferon for HSTCL is characterized by an aggressive course, with a median survival
patients with acute, chronic, and smoldering ATL, whereas patients with of 16 months. The optimal therapy for HSTCL is not known. Small
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the lymphoma variant did not benefit. In patients with chronic and smol- patient series and anecdotal reports describe limited responsiveness
dering ATL treated with first-line antiviral therapy in combination with and poor survival with CHOP and suggest better outcomes with other
either chemotherapy or interferon, a 100 percent 5-year survival has been non–cross-resistant regimens such as ICE, hyper-CVAD (cyclophos-
reported. In patients with leukemic ATL who were treated upfront with phamide, vincristine, doxorubicin, methotrexate, cytarabine), or IVAC
combined antiviral therapy and chemotherapy a 5-year OS of 28 percent (ifosfamide, etoposide, cytarabine). 162,163,170–172 Successful treatment with
was observed, compared to 10 percent in patients treated with first-line pentostatin has been reported as well. Consolidation with either allo-
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chemotherapy alone. Maintenance antiviral therapy also was reported to geneic stem cell transplantation or ASCT is likely necessary to achieve
confer an improved OS in patients treated with first-line chemotherapy. long-term remission. 171
These findings have not yet been prospectively validated, however. 156
Additionally, mogamulizumab (anti-CCR4 monoclonal antibody)
has been approved in Japan for the treatment of relapsed or refractory EXTRANODAL NATURAL KILLER/T-CELL
adult T-cell leukemia-lymphoma. In a multicenter phase II study of
28 patients with relapsed/refractory ATL, the ORR with mogamuli- LYMPHOMA
zumab was 50 percent, with a median OS of 13.7 months. A random-
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ized phase II study of modified LSG15 with or without mogamulizumab DEFINITION
confirmed that the combination was well tolerated and had a CR rate of Extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type
52 percent compared to 33 percent with LGS15 alone. 158 previously known as lethal midline granuloma, malignant granu-
A large nationwide Japanese retrospective report of 386 patients loma, or angiocentric lymphoma, is an uncommon subtype of T-cell
with ATL assessed the role of allogeneic hematopoietic stem cell trans- lymphoma.
plantation in ATL and demonstrated a 3-year OS for entire cohort of
33 percent. Among patients who underwent related donor transplan- EPIDEMIOLOGY
tation, donor HTLV-1 seropositivity adversely affected disease-associ-
159
ated mortality. In patients who are transplantation-eligible, allogeneic ENKTL represents approximately 2 to 9 percent of T-cell lympho-
2–4,174–175
transplantation is therefore an attractive option, but ASCT has been mas. The disease typically afflicts middle-aged men, with a
134,135
found to be ineffective in ATL. 160,161 median age of 50 years at diagnosis, but may also affect children.
ENKTL occurs worldwide, with a strong geographic predilection for
Asian populations from China, Japan, Korea, and Southeast Asia and
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179
178
HEPATOSPLENIC T-CELL LYMPHOMA for Central and South American populations from Mexico, Peru,
Argentina, and Brazil, constituting 5 percent to 15 percent of lympho-
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DEFINITION mas in these countries. Occasional case series have also been reported
from Europe and North America (see Table 104–2).
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Hepatosplenic T-cell lymphoma (HSTCL) is a rare lymphoma that infil-
trates the spleen, liver, and marrow. In the majority of cases, cells consist
of mature γ/δ T-cells, however, α/β HSTCL has also been reported. 1 CLINICAL FEATURES
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ENKTLs are almost exclusively extranodal. Initial sites involved are
often the nose and nasopharynx and occasionally the paranasal sinuses,
EPIDEMIOLOGY tonsil, Waldeyer ring, and oropharynx. When nasal lymphomas destroy
HSTCL is a rare lymphoma representing 3 percent of all T-cell lympho- the floor of the nasal cavity, a characteristic hard-palate perforation is
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mas. This disease typically occurs in young males at a median age of found. Although they are usually localized, ENKTLs may disseminate
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35 years. 7,163 Immunosuppression following solid-organ transplantation to the skin, salivary glands, testis, and gastrointestinal tract. Interestingly,

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