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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1255-1264. Prepublished online as a Blood First Edition Paper on October 6, 2005; DOI 10.1182/blood-2005-03-1306.
REVIEW ARTICLES T-cell non-Hodgkin lymphomaFrom the Division of Hematology/Oncology, Department of Medicine, and the Division of Hematopathology, Department of Pathology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.
T-cell non-Hodgkin lymphomas (NHLs) are uncommon malignancies. The current WHO/EORTC classification recognizes 9 distinct clinicopathologic peripheral T-cell NHLs. These disorders have unique characteristics and require individualized diagnostic and therapeutic strategies. Tremendous progress has been made in recent years in the understanding of the pathogenesis of these disorders. Specific chromosomal translocations and viral infections are now known to be associated with certain lymphomas. In this review, we describe their clinical and pathologic features. We also discuss the use of molecular studies in the diagnostic work-up of T-cell lymphomas. Because of the rarity of these disorders and the lack of well-designed clinical trials, the treatment of peripheral T-cell NHLs is often challenging. Additional studies are required to learn more about the biology of these diseases, which may lead to more optimal and possibly targeted therapies.
T-cell non-Hodgkin lymphomas (NHLs) are uncommon malignancies that represent approximately 12% of all lymphomas.1 Various geographic frequencies of T-cell NHL have been documented, ranging from 18.3% of NHLs diagnosed in Hong Kong to 1.5% in Vancouver, British Columbia, Canada. This may in part reflect increased exposure to pathogenic factors such as human T-cell leukemia virus-1 (HTLV-1) and Epstein-Barr virus (EBV) in Asian nations.2 T-cell NHL commonly presents with extranodal disease and often contains varying amounts of necrosis/apoptosis on biopsy specimens, making differentiation between a reactive process and lymphoma challenging. Immunophenotypic, cytogenetic, and molecular analyses have enhanced diagnostic capabilities and improved classification and prognostication for T-cell NHL. The current World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification recognizes 9 distinct clinicopathologic peripheral T-cell NHLs.3,4 The broad spectrum of pathologic subtypes with varied clinical behavior poses a challenge to the systematic study of these diseases. Furthermore, these distinct T-cell NHL subtypes have unique characteristics and often warrant individualized diagnostic and therapeutic treatment strategies. The primary cutaneous T-cell lymphomas were reviewed recently.4 We review herein the etiology, pathology, diagnosis, and treatment strategies for patients with peripheral T-cell lymphomas (Table 1).
The retrovirus HTLV-1 is critical to the development of adult T-cell leukemia/lymphoma (ATL).5 In endemic areas in Japan, approximately 6% to 37% of the population is infected with HTLV-1.6 The United States and Europe are considered low-risk areas; less than 1% of each population is seropositive.7 ATL develops in only 2% to 4% of patients who are carriers of the HTLV-1 virus.7 HTLV-1 is transmitted through sexual intercourse, blood products containing white blood cells, shared needles, breast milk, and vertically (ie, via childbirth).6 Transfusion of HTLV-1-contaminated blood products results in seroconversion in approximately 30% to 50% of patients at a median of 51 days.8 The median age at presentation is 55 years. Patients present with lymphadenopathy (72%), skin lesions (53%), hepatomegaly (47%), splenomegaly (25%), and hypercalcemia (28%).6 Cellular immunosuppression is common, and a significant minority of patients may have concurrent strongyloides infection.9 Subtypes ATL is classified into 4 subtypes based on clinicopathologic features and prognosis: acute, lymphoma, chronic, and smoldering.10 In 1991, Shimoyama10 reported on the characteristics of 818 patients with ATL. Patients with the acute type had hypercalcemia, leukemia manifestations, tumor lesions, and the worst prognosis, with a median survival time of approximately 6 months. Patients with lymphoma had low levels of circulating abnormal lymphocytes (less than 1%) and nodal, liver, splenic, central nervous system, bone, and gastrointestinal disease and had a median survival time of 10 months. Patients with the chronic type had more than 5% abnormal circulating lymphocytes and a median survival time of 24 months, whereas the median survival time of patients with the smoldering type had not yet been reached. Pathology
Abnormal T-lymphocytes are often seen in the peripheral-blood smear. The cells have indented or lobulated nuclei suggesting the term flower cells (Figure 1). HTLV-1 is a single-stranded, diploid RNA virus that integrates into the host DNA.11 HTLV-1 encodes 3 structural genes (pol, gag, and tax) and 2 regulatory genes (tax and rex). Tax, a potent HTLV-1 transcription activator, plays an important role in HTLV-1-induced transformation and resistance to apoptosis, in part through the activation of the NF- Molecular genetics Itoyama et al13 examined the cytogenetic abnormalities in 50 patients with newly diagnosed ATL.13 All 50 patients had abnormal karyotypes, and almost all chromosomes were affected. Multiple chromosomal breaks (more than 6) and aneuploidy were significantly more frequent in patients with the combined acute and lymphoma subtypes than in those with chronic ATL. Moreover, multiple chromosomal breaks (more than 6) and abnormalities of 1p, 1p22, 2q, 3q, 14q, and 14q32 were associated with worse overall survival (OS). Gains in 1q and 4q were significantly more common in patients with aggressive ATL, whereas a gain of 7q was associated with good prognosis within the group of patients with aggressive disease.14 The T-cell receptor genes are clonally rearranged, and there is evidence of clonal integration of HTLV-1.15,16 Treatment
ATL is a difficult malignancy to treat. Patients may initially respond to combination chemotherapy, but OS is poor (median, 8 months).6 Response rates of 70% to 90% to combination IFN-
PTCL-u is predominantly a nodal lymphoma that represents the most common T-cell lymphoma subtype in Western countries. Rudiger et al2 noted that it comprises approximately 60% to 70% of T-cell lymphomas and 5% to 7% of all NHLs. PTCL-u usually affects adults (male-female ratio, 1.5) at a median age of 61 years (range, 17-90 years). In that study,2 27% of patients presented with stage I or IIE disease, 12% had stage III disease, and 61% had stage IV disease. Patients with PTCL-u commonly have unfavorable characteristics, including B symptoms, elevated LDH levels, bulky tumor measuring 10 cm or greater, nonambulatory performance status, and extranodal disease leading to most (53%) patients falling into the unfavorable International Prognostic Index (IPI) category (score of 3-5). In a recent report, multivariate analysis showed that the IPI was a better predictor of survival than the histologic subtype of mature T-cell lymphoma.25 Pathology Earlier studies of peripheral T-cell NHL recognized a variety of morphologic subtypes based on cell size: diffuse small cleaved, mixed cell, large cell, and immunoblastic. In addition, lymphoepithelioid (Lennert) lymphoma is considered a cytopathologic variant rich in epithelioid cells. However, reliable histologic definitions based on these morphologic subtypes have not been defined. Moreover, no clinical differences have been demonstrated based on these varied histologic subgroups.2 T-cell-associated antigens such as CD3, CD5, and CD7 are variably expressed on immunophenotypic analysis, although one of the mature T-cell antigens (CD5 or CD7) is usually lost. Furthermore, CD4 is more commonly expressed than CD8. Molecular genetics
Ninety percent of patients with PTCL-u have clonally rearranged TCR genes.26 The gamma locus is more frequently rearranged whatever the TCR expression; therefore, analysis of
A Japanese study30 documented p53 gene mutations in 5 of 5 patients with peripheral T-cell lymphoma after renal transplant. This study also demonstrated that 25% of patients had k-ras mutations and that 33.3% of patients had mutations of c-kit and
Treatment Randomized trials comparing cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone (CHOP) with other combination regimens confirm CHOP as a standard regimen for intermediate-grade B-cell NHL, although these trials do not allow for subset analysis of T-cell patients.34,35 Rituximab should not be included in the treatment for PTCL-u unless other conditions, such as immune thrombocytopenic purpura, exist. Nucleoside analogs, such as 2'-deoxycoformin (dCF; pentostatin), fludarabine, and 2-chlorodeoxyadenosine (2-CdA), have been evaluated, mainly in patients with cutaneous NHL, though several anecdotal reports have reported activity in other T-cell NHL subytpes.36,37 The response rate to pentostatin is variable, ranging from 15% to 100% in patients with PTCL-u.37-39 Gemcitabine has activity in patients with relapsed/refractory T-cell NHL as a single agent, with response rates of 60% in small, single-institution studies.40,41 Denileukin diftitox (Ontak), a recombinant fusion protein consisting of peptide sequences of diphtheria toxin and recombinant interleukin-2 receptor (CD25), has been studied mostly in cutaneous T-cell NHL, though clinical benefit has also been reported in patients with other types of T-cell NHL.42,43 Preliminary data from a phase 2 trial with single-agent denileukin diftitox showed a 40% overall response rate in patients with relapsed/refractory PTCL-u.44 A recent European pilot study showed a 36% response rate with alemtuzumab in heavily pretreated PTCL-u patients. Three of 14 patients had a complete remission (CR) that lasted up to 12 months. However, significant hematologic and infectious complications occurred.45
Angioimmunoblastic T-cell lymphoma (AITL), also known as angioimmunoblastic lymphadenopathy with dysproteinemia, is one of the more common T-cell lymphomas, accounting for 15% to 20% of cases and 4% to 6% of all lymphomas.2 Median age at presentation is 64 years, with a slight male predominance; most patients present with stage III or IV disease.46 AITL is commonly a systemic disease with nodal involvement and various associated disease features such as organomegaly, B symptoms (50%-70%), skin rash, pruritus, pleural effusions, arthritis, eosinophilia, and a spectrum of immunologic abnormalities.46 Pathology AITL is characterized by a polymorphous infiltrate of lymph nodes with the normal nodal architecture commonly effaced with opened and dilated peripheral sinuses. There is often significant proliferation of high endothelial venules and follicular dendritic cells (Figure 2). The lymphoid cells commonly consist of a mixture of small and medium-sized lymphocytes with plasma cells and B-immunoblasts, while clusters of epithelioid histiocytes and many eosinophils may be present. T-cell-associated antigens are usually expressed, with CD4 expression more common than CD8 expression.
Molecular genetics
Histologic diagnosis of AITL may be difficult; therefore, demonstration of TCR clonality is often important for diagnosis. Feller et al47 documented that specific patterns of clonal gene rearrangement correlate with prognosis inAITL. In their study, 47 patients with concomitant TCR Conventional cytogenetics (metaphase analysis) will detect chromosomal abnormalities in approximately 70% to 80% of patients with AITL.28,29 One study incorporating interphase cytogenetic (fluorescence in situ hybridization [FISH]) analysis increased the number of aberrant chromosomes identified to 90% of patients, and more than 40% of patients were noted to have varied T-cell populations.49 Trisomy 3 and 5 and an additional X chromosome are the most frequent cytogenetic abnormalities detected in patients with AITL.49 The presence of a complex karyotype was associated with inferior survival.50 B-cell EBV genomes are detected by polymerase chain reaction (PCR) or FISH analysis in up to 100% of AITL-involved lymph nodes.51 The exact role of EBV in the pathogenesis ofAITL is unknown, though recent research demonstrates significant interplay between AITL and the survival and clonal expansion of EBV.51,52 Treatment AITL typically follows an aggressive clinical course; spontaneous regression occurs on rare occasions. Treatment with anthracycline-based combination chemotherapy results in complete remission (CR) rates of 50% to 70%, but only 10% to 30% of patients are long-term survivors.53,54 In one prospective, nonrandomized, multicenter study of patients with newly diagnosed stable AITL, patients were treated with single-agent prednisone, whereas patients presenting with life-threatening disease or relapsed/refractory disease received combination chemotherapy.55 The CR rate was 29% with single-agent prednisone, whereas CR rates for relapsed/refractory patients or patients treated initially with combination chemotherapy were 56% and 64%, respectively. With a median follow-up of 28 months, the OS and disease-free survival (DFS) rates were 40.5% and 32.3%, respectively, though median OS was 15 months.55 There are anecdotal reports of patients with relapsed AITL who have responded to immunosuppressive therapy, such as low-dose methotrexate/prednisone and cyclosporine, purine analogs, and denileukin diftitox.44,56,57
Anaplastic large-cell lymphoma (ALCL), primary systemic type, accounts for approximately 2% to 3% of all NHLs.58 This disease mainly affects lymph nodes, although extranodal sites may be involved. ALCL may be divided in part based on the expression of the tyrosine kinase anaplastic lymphoma kinase (ALK). When heterogeneous patient populations are analyzed, the prevalence of ALK positivity in patients with primary systemic ALCL is 50% to 60%.59,60 ALK-positive ALCL is typically diagnosed in men before age 35 (male-female ratio, 3.0) with frequent systemic symptoms, extranodal disease, and advanced-stage disease.60 ALK-negative patients are usually older (median age, 61 years), with a male-female ratio of 0.9, and are less likely to present with extranodal disease.60 The determination of ALK positivity is important because it denotes a significant favorable prognosis, with reported 5-year OS rates of 79% in contrast to 46% for patients with ALK-negative ALCL.59 Moreover, the prognosis for ALK-positive and ALK-negative ALCL may be further divided based on CD56 positivity (neural cell-adhesion molecule), which portends a significantly worse outcome when it is expressed in either ALCL subgroup.61 Pathology The morphology of ALCL, systemic type, consists of large lymphoid cells with pleomorphic or multiple prominent nuclei and abundant cytoplasm (Figure 3). Tumor cells grow in a cohesive pattern, and there is often sinusoidal spread in the lymph nodes. Tumor cells express CD30 and either T cell or no specific lineage antigens (null cell). Molecular genetics
PCR analysis for TCR rearrangements have demonstrated clonal rearrangements in most (70-90%) patients with T-cell and null-type ALCL, with clonal
Other mechanisms of oncogenesis in ALCL include increased bcl-2,75 hypermethylation,76 and c-myc expression.77 Furthermore, the NPM/ALK fusion protein constitutively activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, suggesting that this pathway may be involved in the molecular pathogenesis of ALCL.78 Treatment Therapy for pediatric ALCL is often based on prognostic risk factors, with treatment regimens modeled after high-grade B-cell NHL protocols. After a brief cytoreductive prephase, short, intensified polyagent chemotherapy is administered, with the number of cycles depending on the stage of disease.79 Therapy for adult ALCL, systemic type, has commonly included anthracycline-based regimens.80 Autologous hematopoietic stem cell transplantation (HSCT) in first complete remission has been advocated by some groups, though this approach warrants prospective validation.
Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) is a rare T-cell lymphoma that primarily infiltrates the subcutaneous fat without dermal or epidermal involvement, causing erythematous to violaceous nodules, plaques, or both. It is often associated with a systemic hemophagocytic syndrome and is characterized by high fever, skin lesions, lung infiltrates, jaundice, hepatosplenomegaly, liver dysfunction, coagulation abnormalities, pancytopenia, and a benign prominent histiocytic proliferation with hemophagocytosis. The hemophagocytic syndrome associated with T-cell neoplasms can occur before, during, or while the disease is in remission.81,82 Moreover, a controversial entity known as cytophagic histiocytic panniculitis (CHP) has been described as an inflammatory disease with a possible association to SCPTCL.83 CHP has been recognized to have diverse outcomes ranging from indolent to aggressive/fatal clinical courses.83 In the recent WHO/EORTC classification, only cases with an   phenotype are classified as SCPTCL. Cases previously classified as SCPTCL with a   phenotype, which comprised of 25% of all cases, are now classified as cutaneous T-cell lymphomas.4 SCPTCL has a more indolent course and is less likely to be associated with the hemophagocytic syndrome than cutaneous T-cell lymphomas.4,84 Pathology SCPTCL is a rare T-cell lymphoma localized to subcutaneous tissue consisting of a mixture of small, medium, and large atypical cells with prominent tumor necrosis and karyorrhexis. The neoplastic lymphocytes often rim individual adipocytes (Figure 4). Benign/reactive histiocytes may be present with associated phagocytosis of red cells or nuclear debris. Necrosis of fat and connective tissue is always seen, but not with angiodestruction. Molecular genetics PCR gene rearrangement studies have recently demonstrated that CHP is likely part of the same clinicopathologic spectrum as SCPTCL, with SCPTCL representing a neoplastic clonal process and CHP representing premalignant lymphoid disease.82,83,85 Most reports demonstrate a monoclonal TCR, and many patients are EBV positive. Retrospective case series with larger patient numbers have corroborated the clonality of TCR in most patients with SCPTCL but have not validated an association with EBV.82 Chromosome abnormalities and proto-oncogenes associated with SCPTCL are reported rarely in the literature. Treatment
The clinical course of SCPTCL is variable, ranging from indolent disease to rapidly fatal fulminant hemophagocytosis.82,86 When treatment is warranted, most patients respond to systemic combination chemotherapy or local radiation therapy, though median survival time is typically less than 2 years.86 Recent studies, with more accurate phenotypic analysis, show that the
Cutaneous T-cell lymphoma (CGD-TCL) includes lymphomas previously classified as SCPTCL with a phenotype.4 CGD-TCL has a more aggressive course than SCPTCL. Patients present with skin lesions similar to those of SCPTCL, but they may have epidermal and dermal involvement. Patients with subcutaneous disease do worse than those with only epidermotropic or dermal disease.87 Patients with CGD-TCL may also have mucosal involvement.88 It is still debated whether cutaneous lymphoma and mucosal lymphoma are 2 different diseases or are different presentations of the same disease. Hemophagocytic syndrome can occur with CGD-TCL, but generally patients do not have evidence of systemic disease on presentation.88,89 Pathology
Three histologic patterns are present in the skin: epidermotropic, dermal, and subcutaneous. A single biopsy specimen may contain more than one histologic type. The cells are medium to large and have features of angiocentrism, angioinvasion, epitheliotropism, and necrosis. There may be rimming of adipocytes as in SCPTCL. Arnulf et al88 showed that 5 of 11 patients with nonhepatosplenic Molecular genetics No specific chromosomal abnormalities are seen in patients with CGD-TCL. The TCR is clonally rearranged.
Treatment
Patients are usually treated with aggressive regimens.88,89 Toro et al89 treated patients with local therapies such as topical steroids, psoralen, and psoralen plus ultraviolet light of A wavelength (PUVA) radiation and with systemic therapies such as interferon-
Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon T-cell lymphoma that is seen mainly in young males (median age, 35 years). Patients have B symptoms, prominent hepatosplenomegaly, anemia, neutropenia, thrombocytopenia (commonly severe), peripheral-blood lymphocytosis, and lymphadenopathy. It is often associated with an aggressive clinical course (median survival, 16 months).90 Pathology HSTCL infiltrates the sinuses of the liver, bone marrow (two thirds of patients), and splenic red pulp. HSTCL tumor cells are usually homogeneous, medium-sized lymphoid cells with round nuclei, moderately condensed chromatin, and pale cytoplasm. Erythrophagocytosis may be present in the spleen and bone marrow, and circulating peripheral-blood tumor cells are seen in approximately 25% to 50% of patients (Figure 5). TIA-1 is almost always present, but commonly granzyme B and perforin are not present, indicating a nonactivated cytotoxic T-cell phenotype. Tumor cells are usually CD4-, CD5-, and CD8- and CD3+, CD7+, and CD56+. Molecular genetics
HSTCL likely arises from Treatment
The clinical course of HSTCL is usually aggressive despite multiagent chemotherapy.90 Anecdotal reports have described activity with the purine analog pentostatin in relapsed disease.94 In a recent case report, a patient with
Extranodal NK/T-cell lymphoma, nasal and nasal-type, formerly known as angiocentric lymphoma, is rare in Western countries and is more prevalent in Asia and in South and Central America.96 The disease commonly manifests in men at the median age of 43. It is associated with EBV and is typically characterized by extranodal presentation and localized stage I/II disease, but with angiodestructive proliferation and an aggressive clinical course.97-99 These tumors have a predilection for the nasal cavity and paranasal sinuses (nasal), although the nasal-type designation encompasses other extranodal sites of NK/T-cell lymphomatous disease (skin, gastrointestinal, testis, kidney, upper respiratory tract, and rarely orbit/eye). Pathology Extranodal NK/T-cell lymphoma is designated NK/T secondary to the uncertainty of its cellular origin. The characteristic histologic feature is an angiodestructive pattern with frequent necrosis. Tumor cells consist of a mixture of small, medium, and large cells, but most are large dysplastic cells. The cells often express NK antigens (CD16, CD56, CD57), cytoplasmic CD3, and cytotoxic granules (granzyme B and TIA-1). Molecular genetics
The rearrangement of TCR genes has been inconsistently identified in extranodal NK/T-cell lymphoma.100,101 When present, Identifying oncogenes related to extranodal NK/T-cell lymphoma has been difficult, in part related to the sufficient recovery of viable, nonnecrotic tissue for appropriate analyses. p53 has been shown to be overexpressed in many patients with extranodal NK/T-cell lymphoma, nasal type.99 Mutations of k-ras have been described in this lymphoma.30 Homozygous deletions of the p15, p16, and p14 genes have been documented in nasal NK lymphoma.103 EBV may play a role in the oncogenesis of extranodal NK/T-cell lymphoma, nasal type. EBER-1 RNA transcripts are detectable in most cells in nearly all patients.100,104 Moreover, EBV-latent membrane protein (LMP-1) is expressed in most patients.104 Treatment Combined modality therapy incorporating adriamycin-based chemotherapy, involved-field (IF) radiation,98 and intrathecal prophylaxis is recommended for patients with extranodal NK/T-cell lymphoma, nasal type. The benefit of adding chemotherapy to radiation has not been confirmed for limited-stage disease.97 Response rates for NK/T-cell lymphoma, nasal type, have been reported to be near 85% (66% CR) after radiation alone, although 50% of patients experience local relapse and 25% of patients experience systemic relapse with a predilection to extranodal sites such as testis, orbit, skin, gastrointestinal tract, and central nervous system.105 Kim et al105 showed that after a median follow-up of 56 months, the OS rate for patients with stage I and II disease was 40%. Systemic relapse was rapidly fatal.105 Li et al106 recently reported on 77 patients with NK/T-cell sinonasal lymphoma (56 locoregional, 21 systemic disease) with a 5-year OS rate of 36% (median follow-up, 89 months). Combined chemotherapy/radiation or radiation alone resulted in better survival than chemotherapy alone (5-year survival rates, 59%, 50%, and 15%, respectively; P = .01). Patients with systemic disease have poor long-term survival (5-year survival rate, 25%).106 The traditional approach for stage III and IV extranodal NK/T-cell lymphoma, nasal type, is combined modality therapy with adriamycin-based chemotherapy followed by radiation therapy.107
Enteropathy-type intestinal T-cell lymphoma (EITCL), also known as intestinal T-cell lymphoma, is a rare T-cell lymphoma of intraepithelial lymphocytes that com | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract
Introduction
B pathway.
