Chapter 104: Mature T-Cell and Natural Killer Cell Lymphomas

The peripheral T-cell lymphomas (PTCLs) represent approximately 10 to 15 percent of non-Hodgkin lymphomas and are made up of 23 heterogeneous diseases (Table 104–1).¹ The most common entities, peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), and ALK-negative ALCL, account for approximately 60 percent of cases. This overview primarily pertains to these most common subtypes of PTCL and more detailed discussion of other subsets of PTCL follows this discussion.

As a result of the rarity of these disorders, there are no randomized controlled clinical trials to drive treatment decisions in PTCL. Our most comprehensive knowledge of the expected outcomes for patients with PTCL is mainly based upon three large retrospective series: the International Peripheral T-Cell Lymphoma Project (IPTCLP), the British Columbia Cancer Agency (BCCA) series, and a Swedish series which reported outcomes on 1314 cases, 199 cases, and 755 cases, respectively.^2,3,4 The prospective Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study is an ongoing registry of patients from the United States that has reported data on 253 subjects to date.⁵ These registries underscore the geographical variations in the incidence of these disorders (Table 104–2).

DIAGNOSIS OF PERIPHERAL T-CELL LYMPHOMA

The diagnosis of PTCL is based on histologic features, immunophenotype, molecular studies, and clinical presentation. While B-cell lymphomas are often characterized by a specific immunophenotypic profile, T-cell lymphomas are often characterized by antigen aberrancy that may vary within a subtype or even during the course of the disease.^6,7 In the IPTCLP, a consensus diagnosis (three of four expert pathologists arriving at the same diagnosis) was reached only 74 to 81 percent of the time for ALK-negative ALCL, PTCL-NOS, and AITL. Diagnoses were significantly refined in 154 out of 1314 cases when clinical information was available.³ In establishing the diagnosis of T-cell non-Hodgkin lymphoma, it is important to exclude a reactive process, particularly when the clinical picture is not congruent with the pathologic features, when the diagnostic biopsy is small, or when a clonal T-cell receptor (TCR) rearrangement is the primary or only reason for the diagnosis because reactive nonmalignant conditions often mimic PTCL.^8,9,10

INITIAL WORKUP

In addition to routine physical examination, initial evaluation should include systemic imaging (computed tomography [CT] of the chest, abdomen, and pelvis with contrast or positron emission tomography [PET]-CT), marrow aspirate/biopsy, and laboratory evaluation (including complete blood count, lactate dehydrogenase or lactate dehydrogenase [LDH], comprehensive metabolic panel). Serologic testing for human T-cell lymphotrophic virus (HTLV)-1 is particularly important in establishing a new diagnosis of PTCL in a person from an endemic area as adult T-cell leukemia/lymphoma (ATL) represents approximately 9 percent of PTCL, is associated with a different prognosis, and usually requires alternative therapy.³

Evaluating Prognosis in Peripheral T-Cell Lymphoma

The International Prognostic Index (IPI) established for evaluating aggressive lymphomas has been effective in risk stratifying patients with PTCL, although the utility in AITL is less clear (Table 104–3).¹¹ The “prognostic index for T-cell lymphoma (PIT),” is an improved index developed specifically for PTCL that includes age, performance status, LDH level, and marrow involvement.^7,12 Other prognostic indices, such as the IPTCLP score, have been suggested for PTCL. Each has some value, although none provides a significant improvement over IPI in terms of impacting clinical management.¹³ It is important to note that even patients identified as low risk by these indices often experience disappointing outcomes. For example, in the IPTCLP, the 5-year failure-free survival (FFS) for patients with 0 or 1 IPI risk factors were only 33 percent for PTCL-NOS and 34 percent for AITL. For this reason, the approach to management of PTCL patients usually does not differ significantly based on IPI alone. Nevertheless, in patients with ALK-positive ALCL, which tends to be more responsive to chemotherapy, the progression-free survivals for patients with zero/one, two, three, and four/five IPI risk factors are 80 percent, 60 percent, 40 percent and 25 percent, respectively.¹⁴ Consequently, patients with higher risk ALK-positive ALCL may be treated similarly to those with the less-favorable PTCL histologies.

APPROACH TO INITIAL THERAPY

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy remains the most commonly employed backbone for upfront therapy of PTCL, based on extrapolation from studies done in aggressive B-cell lymphomas. In the IPTCLP, more than 85 percent of patients received CHOP-based therapy, and in contrast to ALK-positive ALCL where the 5-year FFS was 60 percent, the 5-year FFS for PTCL-NOS, AITL, and ALK-negative ALCL, were only 20 percent, 18 percent, and 36 percent, respectively (see Table 104-3). Similar outcomes were observed in the BCCA series with 5-year progression-free survival (PFS) of 29 percent, 13 percent, and 28 percent for PTCL-NOS, AITL, and ALCL, respectively.² In the Swedish Registry study where 84 percent of patients were treated with CHOP-like therapy, 5-year PFSs were 21 percent, 20 percent, and 31 percent for PTCL-NOS, AITL, and ALK-negative ALCL, respectively, compared to 63 percent for ALK-positive ALCL.⁴

Several prospective clinical trials in PTCL are available to inform us on the expected response rate to CHOP. In a phase II study evaluating CHOP induction therapy followed by autologous stem cell transplantation (ASCT) for untreated PTCL, the overall response rate (ORR) to CHOP was 79 percent with a complete response (CR) rate of 39 percent.¹⁵ Similarly, a small phase III study of CHOP versus VIP-rABVD (etoposide, ifosfamide, cisplatin alternating with Adriamycin, bleomycin, vinblastine and dacarbazine) showed no significant difference in outcomes with an ORR of 70 percent and a CR rate of 35 percent.¹⁶

Although the majority of patients receive CHOP, there is currently no standard frontline treatment approach for PTCL, as there are no randomized data guiding a preferred approach. Many have sought to augment the efficacy of CHOP by adding agents to the CHOP backbone. Several phase II studies adding the anti-CD52 antibody, alemtuzumab, to CHOP demonstrated impressive CR rates of 65 to 71 percent. However, the addition of alemtuzumab conferred significant toxicity including Jacob-Creutzfeldt virus encephalitis, invasive aspergillosis, Pneumocystis carinii pneumonia, sepsis, Epstein-Barr virus (EBV)-related lymphoma and cytomegalovirus reactivation.^17,18,19 Similarly, in a phase II study of denileukin diftitox plus CHOP, the ORR and CR rates were 65 percent and 55 percent, respectively; however three deaths occurred following one cycle of therapy and four other patients were taken off study because of toxicity.²⁰

The German High-Grade non-Hodgkin Lymphoma Study Group (DSHNHL) evaluated the addition of etoposide to the CHOP regimen. They analyzed patients with PTCL treated on seven different prospective phase II or phase III protocols with either CHOP or CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone).²¹ Younger patients (<60 years old) with a normal LDH exhibited better outcomes if treated with CHOEP than with CHOP, with 3-year event-free survival (EFS) of 75.4 and 51 percent, respectively, although no difference in overall survival (OS) was observed. The benefits were greatest in the more favorable ALK-positive ALCL subtype but there was a trend toward improved EFS in favor of CHOEP in other subsets as well (p = 0.057). However, the addition of etoposide led to excessive toxicity in elderly patients. The Nordic group adopted CHOEP induction for subjects younger than age 60 years in a prospective study evaluating upfront stem cell transplantation for PTCL.²² In this phase II study, patients received biweekly CHOEP followed by ASCT for the responders. The ORR to CHOEP was 82 percent with a CR rate of 51 percent. Although one must be cautious when comparing results from different study populations, these results appear superior to those reported by Reimer and colleagues for patients treated with CHOP followed by ASCT, who achieved CR in only 39 percent of cases.¹⁵

There are no randomized trials assessing the controversial approach of performing ASCT in first remission for PTCL, although several prospective studies suggest the benefit of this strategy. The aforementioned Nordic study enrolled 160 patients with PTCL, including 39 percent with PTCL-NOS, 19 percent with ALK-negative ALCL, and 19 percent with AITL, while excluding ALK-positive ALCL.²² Patients were treated with CHOEP for six cycles (etoposide was omitted for patients >60 years of age) and those in CR or partial response (PR) proceeded to high-dose therapy with carmustine, etoposide, cytarabine, and melphalan (or cyclophosphamide) and ASCT. By intent-to-treat analysis, 71 percent of patients underwent ASCT and the 5-year OS and PFS were 51 percent and 44 percent. Reimer and colleagues conducted the second largest prospective study evaluating ASCT in first remission following CHOP, enrolling 83 patients.¹⁵ A 3-year OS rate of 48 percent was observed by intent-to-treat analysis. For those who were transplanted (66 percent of patients enrolled) outcomes were considerably more favorable with a 3-year OS of 71 percent. In a retrospective analysis performed at Memorial Sloan Kettering Cancer Center to evaluate patients treated with the intent to transplant in first remission, interim PET imaging was found to be the most powerful predictor of outcome. Of the 53 percent of patients who had a negative interim PET scan after four cycles, 59 percent were progression free after 5 years, including 53 percent of those with IPI of 3 or greater.²³

APPROACH TO RELAPSED OR REFRACTORY THERAPY

There are no randomized data or standard of care to guide treatment of patients with relapsed or refractory PTCL.²⁴ In the largest series of patients with PTCL-NOS, AITL, and ALCL treated from 1976 to 2010, those with relapsed or refractory disease who did not proceed to hematopoietic stem cell transplant demonstrated a median OS of 5.5 months.²⁶ However, the outlook for this patient population may improve as several new agents have been approved for this setting, including romidepsin, belinostat, and pralatrexate.^28,29 In addition, brentuximab vedotin is listed in the National Comprehensive Cancer Network (NCCN) compendium of appropriate therapeutic agents for CD30-positive T-cell lymphomas (Table 104–4).^30,31,32,33

For patients who are transplantation-eligible, allogeneic transplantation should be considered in the relapsed/refractory setting. Once a donor is identified, intensive salvage chemotherapy options should be considered, including ICE (ifosfamide, carboplatin, etoposide) or DHAP (dexamethasone, cytarabine, cisplatinum), as they have a high potential to induce major remissions that will optimize outcomes after transplantation.³⁰ However, these regimens are generally only tolerated for three to four cycles and should be followed promptly by consolidation with transplantation. Both myeloablative and reduced intensity allogeneic stem cell transplantation have demonstrated up to 60 percent 3-year PFS.^37,38,39 The role of ASCT in relapsed/refractory PTCL is controversial. Several series suggest that ASCT rarely results in long-term disease control of PTCL, with the exception of patients with ALCL.^34,35 Other series, however, including registry data from the Center for International Blood and Marrow Transplant Research, report more salutary results for ASCT after relapse.³⁶

For patients who are not transplantation-eligible, the goals of treatment are palliative, and therapy should be geared toward maintaining quantity and quality of life. Options for treatment include romidepsin, belinostat, pralatrexate, gemcitabine, bendamustine, and alemtuzumab.^{26,27,28,29,40,41,42} In addition, brentuximab vedotin should be considered as the first choice for relapsed CD30-expressing ALCL patients, who have not previously received this agent.^21–33

In view of the heterogeneity of PTCL, there is an increasing interest in individualizing therapy based on histology and other factors. For example, brentuximab vedotin, a CD30 antibody–drug conjugate, induced responses in patient with relapsed or refractory ALCL as well as those with CD30-positive AITL and PTCL-NOS.^32,33 Similarly, crizotinib, an ALK inhibitor, demonstrated significant activity in a small number of patients with relapsed ALK-positive ALCL and is being further investigated.^43,44,45 The histone deacetylase (HDAC) inhibitors, such as belinostat and romidepsin, appear to have preferential activity and duration of response in patients with AITL (see Table 104–4).^27,29

Gene-expression profiling has identified molecular classifiers that improve classification and prognostication in ALK-negative ALCL, AITL, and PTCL-NOS.^46,47,48,49 Furthermore, additional translocations and recurrent mutations have been identified that may help better classify PTCLs and identify potential treatment targets. Next-generation sequencing has identified a novel translocation within ALK-negative ALCL, t(6;7),⁵⁰ which potentially identifies a unique entity within ALK-negative ALCL associated with a better prognosis.⁵¹ This mutation typically leads to reduced expression of the DUSP22 gene, which likely functions as a tumor suppressor. A translocation producing an ITK-SYK fusion gene, t(5;9), was initially found in a subset of PTCL-NOS cases.⁵² SYK expression was subsequently evaluated in 141 PTCL cases by immunohistochemistry and found to be overexpressed in 94 percent, although the translocation was only detected in 39 percent.⁵³ These findings suggest a potential role for SYK inhibitors in these cases.⁵⁴ Mutations involving the TET2 gene appear to be common in AITL as well as PTCL-NOS expressing T-follicular helper (T_FH) cell markers; they are less frequent among the other PTCL-NOS cases (24 percent) and absent in ALCL.⁵⁵ TET2 is involved in epigenetic control of transcription through DNA methylation and inactivating mutations of this gene were first identified in myeloid malignancies. These mutations signify a biologic connection between AITL and PTCL-NOS with AITL features (T_FH-like PTCL-NOS) and suggest a role for hypomethylating agents.

DEFINITION

PTCLs that do not fit into any of the currently recognized histopathologic categories are designated PTCL, not otherwise specified (PTCL-NOS; Chap. 96.)

EPIDEMIOLOGY

PTCL-NOS is the most common of the mature T-cell neoplasms, representing approximately 25 to 30 percent of the total cases of T-cell lymphoma in Western countries.^56,57,58 In the United States, there are approximately 0.4 cases per 100,000 adults.⁶² In Asia, PTCL-NOS accounts for 20 to 25 percent of cases mature T-cell neoplasms (see Table 104–2).^3,57 The median age of diagnosis is 60 years with a male predominance (2:1).^3,7

CLINICAL FINDINGS

In general, patients with PTCL-NOS have aggressive, rapidly growing disease. Diffuse lymphadenopathy, constitutional symptoms, extranodal involvement, an elevated LDH level, and advanced stage disease are common.^56,57 Hepatomegaly and splenomegaly occur in 17 percent and 24 percent of patients, respectively. Stages I, II, III, and IV disease are observed in approximately 14 percent, 17 percent, 26 percent, and 43 percent of cases, respectively. The marrow is involved in approximately 20 percent of cases.^2,4 Pruritus, peripheral eosinophilia, hypercalcemia, and hemophagocytic syndrome may accompany PTCL.^60,61

LABORATORY FINDINGS

Histopathology

The majority of cases arise in lymph nodes, which exhibit mixtures of small and large atypical lymphoid cells, typically admixed with an inflammatory background (Chap. 96).⁶² The immunophenotype is typically that of a mature T-cell expressing either a CD4 or CD8 phenotype, most commonly CD4, although CD4/CD8 double-positive and double-negative cases have been reported.^6,63 Malignant cells are often characterized by antigen aberrancy that may vary from one patient to another or even vary during the course of the disease within a single patient.^6,7 Deletion of one or more pan–T-cell antigens is frequently observed,⁶⁴ along with rearrangements of the TCR.

TREATMENT AND PROGNOSIS

As discussed previously, patients with PTCL-NOS are most commonly treated with CHOP-based regimens, although there is no uniform standard of care for first-line treatment. Little prospective data exists for CHOP alone in PTCL, but based on clinical trials employing CHOP as a component of therapy, it appears that CHOP produces an ORR as high as 79 percent and a CR rate as high as 39 percent.¹⁵ However, with CHOP alone long-term remissions are uncommon, with PFS rates of 20 to 30 percent seen in the larger retrospective series.^2,3,4 Efforts to improve the efficacy of first-line therapy by adding new agents to CHOP, such as alemtuzumab, bortezomib, or denileukin diftitox, have not clearly resulted in significant benefit.^20,12,19 The addition of etoposide to CHOP appears to provide some benefit over CHOP in more favorable young patients, according to a retrospective analysis of seven prospective studies conducted by the DSHNHL.²¹ Moreover, in a prospective study of CHOEP followed by ASCT, the ORR to CHOEP was 82 percent, with 51 percent achieving a CR.²² Newer agents approved in the relapsed setting, such as romidepsin and brentuximab vedotin, are currently being combined with CHOP-based regimens and compared to standard CHOP in ongoing phase III clinical trials.

Another strategy for improving frontline therapy for PTCL-NOS has been through consolidation with ASCT in first remission, as discussed in “Approach to Initial Therapy” above. Even though there are no randomized trials of ASCT in first remission, three prospective phase II trials support this approach.^15,22,23 The largest of these studies demonstrated 5-year OS and PFS of 47 percent and 38 percent, respectively in patients with PTCL-NOS.²²

Allogeneic transplantation provides long-term disease control for a select group of patients with relapsed PTCL-NOS. Although transplant-related mortality is significant, retrospective studies have demonstrated up to 61 percent OS at 2 years in some trials. Consequently, allogeneic transplantation is often considered for fit patients who fail frontline therapy.^23,39,66

Several promising new agents, including belinostat, bendamustine, gemcitabine, and alemtuzumab, have become available for the treatment of PTCL-NOS in the relapsed setting.^28,40,41,42 Pralatrexate, romidepsin, and belinostat are approved broadly for PTCL, with an approximately 20 to 30 percent ORR in large phase II studies (see Table 104–4).^27,71,72

Overall, the 5-year FFS for PTCL-NOS is 20 percent with a 5-year OS of 32 percent in patients treated with CHOP-based therapy.⁶⁰ The IPI and PIT have been used to risk stratify patients with PTCL-NOS and estimate prognosis. For patients with PIT scores of 0, 1, 2, or 3 or greater, the 5-year FFSs are 34 percent, 22 percent, 13 percent, and 8 percent, respectively. For patients with IPI scores of 1 or less, 2, 3, or 4 or greater, 5-year FFSs are 36 percent, 18 percent, 15 percent, and 9 percent, respectively.⁷ PIT scores have not been used to direct treatment decisions, however (see Table 104–3).^13,12

DEFINITION

AITL was initially described as angioimmunoblastic lymphadenopathy with dysproteinemia in 1974. It is now known that these entities are identical.^1,68

EPIDEMIOLOGY

AITL represents approximately 1 percent of all cases of lymphoma and approximately 20 percent of all T-cell lymphomas.⁵⁷ International series show that AITL represents a higher portion of T-cell lymphomas in Europe than North America or Asia.³ The male-to-female ratio is approximately 1:1 and the median age at diagnosis is approximately 65 to 70 years.^3,4,7

CLINICAL FINDINGS

Common features at presentation include B symptoms (fever, drenching sweats, and weight loss), generalized lymphadenopathy, rash, polyclonal hypergammaglobulinemia, blood eosinophilia, and autoimmune hemolytic anemia (direct Coombs positive). Some patients experience waxing and waning of symptoms over several years before a diagnosis is made. Patients with AITL can develop diffuse large B-cell lymphoma, which evolves from EBV-positive B cells, which usually are present in the lymphoid infiltrate. Emergence of diffuse large B-cell lymphoma can occur concomitantly with AITL at the time of diagnosis or may be the primary histology at relapse; therefore, repeat biopsies are strongly encouraged whenever relapse is suspected in order to guide therapy.^69,70

LABORATORY FINDINGS

Histopathology

AITL is characterized histologically by effacement of the normal lymphoid architecture with a pleomorphic cellular infiltrate and proliferation of small arborizing blood vessels. Small lymphocytes, plasma cells, immunoblasts, histiocytes, and eosinophils infiltrate involved lymph nodes. As a result, the normal lymphoid architecture may be obliterated, with loss of germinal centers and extensive intranodal neovascularization and expansion of the follicular dendritic cell meshwork (CD21). Scattered EBV+ B cells are almost always present and reflect the accompanying immunodeficient state. The malignant cells are CD4+ αβ T cells with TCR-β and -γ rearrangements^70,71,72 and express CD10, a marker typical for AITL, approximately 90 percent of the time.⁷³ Abnormal karyotypes involving the X chromosome and chromosomes 1, 3, and 5 are frequently found in AITL. A complex karyotype is a negative prognostic factor for AITL.⁷⁷ The normal counterpart of AITL is suspected to be the follicular T-helper cell based on genomic profiling, which reveals overexpression of specific markers, including CXCL13 and PD1.^74,75 A subset of PTCL-NOS exhibits a similar gene-expression profile, suggesting it may behave similarly.⁷⁶

TREATMENT AND PROGNOSIS

Most patients with AITL are treated with CHOP-based regimens as discussed in the section Approach to Initial Therapy. The CR rate is similar to the rate observed with PTCL-NOS (approximately 50 to 60 percent). Nonrandomized data support upfront ASCT in patients who achieve a CR to first-line therapy.²² Rare patients may be managed with glucocorticoid monotherapy, which can induce remissions, although responses are rarely sustained.⁷⁸ Responses to low-dose methotrexate and cyclosporine have also been reported.^79,80,81 Finally, response rates as high as 50 percent have been reported in CD30-positive relapsed/refractory AITL treated with brentuximab vedotin.³²

Both the IPI and the PIT have been used to risk stratify patients but have not been used to direct therapy (see Table 104–3).^13,12,82 One group has reported that immunoglobulin A levels, age older than 60 years, more than one extranodal site of involvement, anemia, and thrombocytopenia may also be of prognostic value in this disease.⁸²

DEFINITION

ALCL is defined as a CD30+ peripheral T-cell neoplasm. The disease has been provisionally subdivided into those that are ALK-positive (60 to 70 percent) or negative (30 to 40 percent).^1,83,84 In addition to the systemic form, there are primary cutaneous forms (Chap. 103), which generally behave in an indolent fashion, as well as a recently identified entity called breast implant–associated ALCL.^85,86

EPIDEMIOLOGY

ALCL accounts for 6 to 24 percent of all T-cell lymphomas.^2,3,4 However, the prevalence of ALCL varies by geographic region (see Table 104–2). ALK-positive ALCL accounts for 16 percent, 6 percent, and 3 percent of PTCL in North America, Europe, and Asia, respectively.³ The median age of ALK-positive ALCL is 30 to 40 years old. Ninety percent of children with ALCL are ALK-positive.^83,87 In the United States and Asia, the ALK-positive phenotype is more common (ratio being 2:1 and 3:2, respectively), whereas in Europe the ALK-negative phenotype is more common (3:2).³ Both diseases exhibit a slight male predominance. ALK-negative ALCL accounts for 8 percent, 9 percent, and 3 percent of PTCL in North America, Europe, and Asia, respectively.³ The median age of presentation is 55 to 60 for ALK-negative ALCL.^3,14,67

CLINICAL FEATURES

ALCL has an aggressive clinical course, frequently presenting with systemic symptoms, advanced disease, and extranodal localization. Patients with ALK-positive ALCL tend to be younger and have better performance statuses and lower serum LDH levels. Approximately 8 to 12 percent of patients with ALK-positive ALCL have morphologic evidence of marrow involvement.^2,3,4 The rate of detection of marrow involvement doubles when immunohistochemical staining techniques with anti-CD30 and anti-ALK antibodies are used.⁸⁸

Patients with ALK-negative ALCL tend to be older, with higher LDH values, and worse performance status than ALK-positive cases. Extranodal presentations are more common in the ALK-negative population,¹⁴ and include sites such as the marrow, liver, lung, and skin, but rarely the central nervous system. Marrow involvement occurs in 12 to 22 percent of cases of ALK-negative ALCL.^2,3,4

A new clinical variant of ALK-negative ALCL associated with textured saline and silicone breast implants has been reported. Although the natural history and treatment course of this variant needs further elucidation, the clinical course seems to be less aggressive and patients with localized disease may be adequately treated merely by surgical removal of the implant and capsule.^85,89,90,91 In the largest series to date (60 patients), most presented with disease limited to the breast (83 percent), whereas 10 percent and 7 percent, respectively, presented with stage II and stage IV disease. Patients most commonly presented with an effusion within the breast and less frequently with a distinct breast mass.⁸⁵

LABORATORY FEATURES

ALCL cells tend to grow cohesively and are found preferentially invading lymph node sinuses.⁹² There are three morphologic variants based on the size of the neoplastic and admixed reactive cells⁹³: the “common type,” representing most cases, is characterized by large pleomorphic tumor cells; the “small cell variant,” representing 5 to 10 percent of cases, has a dominant population of small- to medium-size tumor cells mixed with large anaplastic cells that stain for CD30 and ALK; and the “lymphohistiocytic variant,” representing 5 to 10 percent of cases, that is closely related to the small cell variant and contains small neoplastic cells mixed with large anaplastic cells and a large number of histiocytes (Chap. 96).⁹⁴

ALK-positive ALCL is characterized by a nonrandom t(2;5) (p23;q35) translocation resulting in fusion of the NPM and ALK genes.⁹⁵ The resultant NPM-ALK fusion gene encodes an 80-kDa chimeric protein NPM-ALK (p80) that functions as an oncogene in ALK-positive ALCL. Of note, other translocations resulting in ALK expression in ALK-positive ALCL have also been identified but are rarer.^{50,96,97,98,99,100,101,102} Thus, ALK immunoreactivity is a highly specific marker for this disease.^83,84,96 Either T or null immunophenotypes may be observed in ALCL. The T-cell variant expresses pan-T antigens CD2, CD2, CD4, CD5, and CD7, whereas the null variant lacks both T-cell and B-cell antigens, but usually expresses cytotoxic molecules such as granzyme B and perforin, and has rearranged TCR genes, suggesting a T-cell origin.^102,103

Genomic and proteomic cluster analyses strongly suggest that ALK-positive and ALK-negative ALCL are two distinct disease entities. CEBPB, PTPN12, SERPINA1, and BCL6 genes are typically overexpressed in ALK-positive ALCL, and CCR7, CNTFR, interleukin (IL)-21, and IL-22 are overexpressed in ALK-negative ALCL.¹⁰⁴ Based on comparative genomic hybridization and fluorescence in situ hybridization for TP53 and ATM loci, gains of 17p and 17q24, and losses of 4q13–q21 and 11q14 are more common in ALK-positive tumors, whereas gains of 1q and 6p21 are preferentially observed in ALK-negative tumors.¹¹² These differences are underscored by the different responses of these two entities to therapy.⁸⁷ Interestingly, cases of ALK-negative ALCL that express DUSP22 appear to have a similar prognosis to ALK-positive ALCL, while those with TP63 expression are associated with especially poor prognosis.⁵¹

TREATMENT AND PROGNOSIS

ALK-positive ALCL is the most chemosensitive of the T-cell lymphomas, with rates of survival and response similar to diffuse large B-cell lymphomas. ALCL is commonly seen in the pediatric age group, where intensive anthracycline-based chemotherapy regimens have been studied.^106,107 Approximately 90 percent of patients with ALK-positive ALCL treated with anthracycline-based chemotherapy achieve a tumor response, with 65 to 75 percent of pediatric patients remaining relapse-free after 5 years.^76,108 Among adults, treatment with CHOP-based therapy has remained the most commonly used approach as more intensive regimens, such as high-dose methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin (MACOP-B) and doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone have not shown superiority to CHOP-based therapy.^67,109

The IPI appears to be particularly helpful in risk-stratification of ALK-positive ALCL, with some authorities suggesting that patients with high risk ALK-positive ALCL should be treated similarly to those with other forms of PTCL (see Table 104–3).^2,3,110 The DSHNHL concluded in a retrospectively assessment of seven phase II and phase III trials that patients with ALK-positive ALCL who were 60 years of age or younger and had a normal LDH, had an improved EFS but not OS if treated with CHOP plus etoposide, rather than CHOP alone.²¹ The Groupe d’Étude des Lymphomes de l’Adulte (GELA) group has suggested that the prognostic significance of ALK expression is limited to those older than age 40 years.⁶⁷ After relapse, it appears that patients can be cured with intensive salvage therapy (including ASCT) at a higher rate compared to other T-cell lymphomas.

Brentuximab vedotin, which combines an anti-CD30 antibody with monomethylauristatin E (MMAE) has demonstrated objective responses in more than 80 percent of patients with relapsed/refractory ALCL treated on a single-agent phase II trial.³² The FDA approved brentuximab vedotin for the treatment of relapsed ALCL in 2011.¹¹¹ Brentuximab vedotin in combination with chemotherapy is being explored as a first-line therapy in ALCL. Crizotinib, an inhibitor of ALK tyrosine kinase that is FDA-approved for the treatment of ALK-positive non–small cell lung cancer, has demonstrated encouraging responses in small series of ALK-positive ALCL, leading to ongoing trials in relapsed/refractory ALCL.^44,45,112

ALK-negative ALCL typically presents with unfavorable features, including stages III and IV disease, B-symptoms, high IPI scores, high LDH serum levels, and expression of TP63.^51,114,115 The disease typically pursues an aggressive clinical course and is less responsive to chemotherapy than ALK-positive ALCL. It has been common practice to treat patients with CHOP-like therapy, as with other forms of PTCL, as discussed in the previous section Approach to Initial Therapy. Similar to PTCL-NOS, consolidation with ASCT in first remission is often considered for ALK-negative ALCL based upon large prospective studies suggesting improved remission durations.^22,15 The IPTCLP reported 5-year FFS and OS rates of 36 percent and 49 percent, respectively, for patients with ALK-negative ALCL (see Table 104–3).³ CD56 expression has been shown to be an independent favorable prognostic factor for ALK-negative ALCL, as has expression of DUSP22.^51,113

DEFINITION

Enteropathy-associated intestinal T-cell lymphoma (EATL) is a mature T-cell lymphoma that presents within the gastrointestinal tract. The World Health Organization divided EATL into two variants—type I and type II—which are differentiated based on their histopathology.¹¹⁶

EPIDEMIOLOGY

EATL constitutes approximately 2 to 10 percent of all PTCL and incidence varies by geographic distribution.^2,3,4 The median patient age at diagnosis is 55 to 65 years with a slight male predisposition.^116,117 Type I EATL comprises 60 to 80 percent of cases,¹¹⁶ is most common in patients who have underlying celiac disease, and is strongly associated with the human leukocyte antigen (HLA)-DQ2 haplotype. Among European patients with EATL, 80 percent have type I EATL.^116,118 Patients who have refractory celiac disease, which does not improve with a gluten-free diet, have a significantly higher risk of EATL. In particular, those with refractory celiac disease who demonstrate a clonal expansion of abnormal intraepithelial lymphocytes lacking CD3, CD8, and TCR markers, but expressing intracellular CD3, have a significantly higher risk of developing EATL.¹¹⁷ In contrast, type II EATL, present in 20 to 40 percent of cases, is less frequently associated with celiac sprue and the HLA-DQ2 haplotype.^116,119

CLINICAL FINDINGS

The majority of patients with EATL present with acute abdominal symptoms that often require urgent or emergent surgical procedures, resulting in diagnosis of the disease.¹²⁰ EATL typically presents with ulcerative lesions of the jejunum or ileum which may perforate, though other regions of the gastrointestinal tract may also be affected. As a result of the malabsorption that accompanies the disease, frequent presenting signs and symptoms include weight loss, diarrhea, nausea, and vomiting, accompanied by abdominal pain and bowel obstruction.¹²¹ The course can be fulminant; death may occur during treatment secondary to the consequences of intestinal perforation. Extraintestinal presentation of EATL is rare, and there is little data on the manifestations of cutaneous, neuromeningeal, or pulmonary presentations. Systemic symptoms should be considered signs of clinical progression, although they occur in less than 30 percent of patients with EATL.^124,129

LABORATORY FINDINGS

Histopathology

The two types of EATL are recognized on the basis of the specific immunophenotype: EATL type 1 is characterized by CD56 negativity and EATL type 2 exhibits CD56 expression.¹¹⁹ The histology of EATL type I demonstrates mostly medium to large tumor cells with round or angulated vesicular nuclei, prominent nucleoli, and pale-staining cytoplasm. There is often a moderate to abundant infiltrate of eosinophils, histiocytes, and small lymphocytes.¹²³ EATL type 1 characteristically demonstrates the following immunophenotype: positive for CD3, CD7, CD103, and usually CD30, but negative for CD4, CD5, CD8, and CD56. The cells also exhibit a cytotoxic phenotype and are positive for perforin, granzyme B, and TIA-1.^124,125 EATL type 2 is characterized by a monomorphic infiltrate of small- to medium-size lymphocytes positive for CD3, CD8, CD56, and TCR-β, and negative for CD4. CD30 is often negative in EATL type 2.¹¹⁹

TREATMENT AND PROGNOSIS

CHOP chemotherapy has been used most widely for both type I and type II EATL, with a 5-year relapse FFS of 4 to 22 percent and a 5-year OS of approximately 20 percent.^2,3,4,116 The addition of etoposide to CHOP does not appear to confer additional benefit.¹³³ Even patients who initially respond to CHOP therapy usually relapse after a median interval of 6 months, with a median survival after relapse of approximately 6 months to 1 year.^{116,121,126,12} In patients who are transplantation-eligible, high-dose chemotherapy followed by ASCT may improve outcomes.^15,127,128 The Scotland and Newcastle Group demonstrated that high-intensity therapy with CHOP alternating with IVE (ifosfamide, epirubicin, etoposide) and intermediate-dose methotrexate, followed by consolidation with ASCT resulted in a 5-year OS of 60 percent and PFS of 52 percent in the 50 percent of patients who were able to complete ASCT.¹²⁰ Many patients could not complete the course of chemotherapy, however, and there were a large number of complications, including gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae. Twelve patients required either enteral or parental feeding.

Adverse prognostic factors include a history of celiac sprue, a large tumor mass (≥5 cm) at diagnosis, an elevated LDH, and a nonambulatory performance status.¹¹⁶ The PIT score predicts both OS and FFS in EATL better than the IPI.¹¹⁶

DEFINITION

ATL is an uncommon lymphoproliferative neoplasm of mature CD4+CD25+ T-cells caused by infection with the retrovirus, HTLV-1, that was initially characterized in 1977.^130,131 These cells classically have a leukemic “flower-cell” appearance.¹³² At least 5 percent of circulating abnormal T lymphocytes are required to diagnose ATL in patients without histologically proven tumor lesions.¹³³

EPIDEMIOLOGY

The incidence of ATL in the United States is approximately 0.05 cases per 100,000 people.¹³⁴ The disease prevalence parallels the geographic distribution of the HTLV-1 virus, with the highest incidences occurring in southern Japan, the Caribbean, Central and South America, intertropical Africa, Romania, and northern Iran (see Table 104–2).^{135,136,137,138,139} Among approximately 10 to 20 million HTLV-1 carriers, the lifetime risk of developing ATL is approximately 2.5 to 4 percent, with a mean latency of greater than 50 years.^{134,137,139,140} HTLV-1 is transmitted through breastfeeding, blood products, and unprotected sexual intercourse. The overwhelming majority of ATL cases occur in patients infected during the early years of life,¹⁴¹ In addition, the prolonged infection may increase chances of accruing subsequent mutations, and ultimately malignant transformation. The mean age of patients with adult T-cell leukemia/lymphoma is 62 years, without a gender predominance.^142,143

CLINICAL FEATURES

Several clinical variants of ATL have been described: acute, lymphoma, chronic, and smoldering; these appear to have differing genomic alterations and different clinical courses.^133,143,144

The acute variant of ATL represents 60 percent of cases and is characterized by patients who present with a leukemic presentation. An additional 20 percent of cases present with the lymphoma variant characterized by lymphadenopathy and less than 1 percent of leukemic cells in the blood. These subtypes exhibit an aggressive clinical course with a median survival of less than 1 year. The majority of patients present with hepatosplenomegaly (50 percent of cases), lymphadenopathy, elevated LDH, hypercalcemia (50 percent of cases), and visceral and cutaneous lesions. The marrow is involved in approximately 35 percent of cases.¹⁴³ Most patients have generalized lymphadenopathy, particularly in the retroperitoneal and hilar regions, though the nodes are often relatively small and mediastinal masses are rare. Extranodal sites of disease include the lung, liver, skin, gastrointestinal tract, and central nervous system, including cord myelopathy and spastic paraparesis.

In contrast to the acute and lymphoma forms, the smoldering form of adult T-cell leukemia/lymphoma typically presents with a predominance of skin lesions or lung infiltration without visceral or marrow disease, and minimal blood involvement (<5 percent of lymphocytes). Patients with chronic ATL present with leukocytosis with lymphadenopathy and organomegaly without an elevated LDH, or visceral involvement. Although smoldering and chronic ATL are characterized initially by indolent courses, the prognosis remains poor with a survival of 4.1 years and 49 percent progressing to acute ATL after a median of 18.8 months.¹⁴⁵

Opportunistic infections are common in patients with adult T-cell leukemia/lymphoma, even indolent forms,¹⁴⁶ including P. carinii, strongyloides, and cryptococcal meningitis, as well as bacterial and other fungal infections.

LABORATORY FEATURES

Histopathology

The neoplastic cells are pleomorphic, have highly lobulated nuclei (“clover leaf” or “flower cell” appearances) with condensed nuclear chromatin, inconspicuous nucleoli, and a mature helper T-lymphocyte immunophenotype.¹³² At least 5 percent of circulating abnormal T-lymphocytes are required to diagnose ATL in patients without histologically proven tumor lesions.¹³³ In approximately 20 percent of cases, nuclear lobulation is less pronounced, and the cells may be difficult to distinguish from Sézary cells. These cells express the surface T-cell lymphocytic markers CD2, CD4 and CD5, CD45RO, CD29, and TCR-αβ, and are usually negative for CD7, CD8, and CD26, and show reduced CD3 expression. The lymphocytic activation markers HLA-DP, -DQ, and -DR, and IL-2Rα (CD25) are always present, whereas terminal deoxynucleotidyl transferase is typically absent.¹⁴⁷ Rare immunophenotypic variants (CD4-negative, CD8-positive, double-positive or double-negative variants) have also been reported.^148,149,150 Although there are no specific chromosomal abnormalities diagnostic of ATL, the karyotype of ATL cells is usually complex in the aggressive variants of the disorder.¹³¹ Clonal rearrangements of the TCR genes are typically present.^151,152,153

Laboratory Analysis

Patients with aggressive forms of ATL commonly present with an elevated LDH and hypercalcemia.

TREATMENT AND PROGNOSIS

Overall, prognosis in ATL remains poor with a median survival of less than 1 year for patients with aggressive subtypes. A multivariate analysis of 126 patients with acute (13 percent) and lymphoma (87 percent) subtypes of ATL performed by the IPTCLP indicated that the IPI was the only independent predictor of OS.¹⁴² Although smoldering and chronic ATL are characterized initially by indolent courses, the prognosis remains guarded with 5-year survivals of 40 percent and 50 percent, respectively; 49 percent of patients with the more indolent forms of ATL progress to acute ATL after a median time of 18.8 months.¹⁴⁵

Despite its limited efficacy, cytotoxic chemotherapy remains the mainstay of therapy for this disease. A Japanese cooperative group developed a multidrug regimen called LSG15, which consists of seven cycles of VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone), AMP (doxorubicin, ranimustine, and prednisone), and VECP (vindesine, etoposide, carboplatin, and prednisone). LSG15 was evaluated in a phase II study that enrolled 96 patients with treatment-naïve acute type (n = 58), lymphoma type (n = 28) or unfavorable chronic type (n = 10) ATL. The ORR was 81 percent, with 35 percent CRs and 45 percent PRs.¹⁵⁴ In view of these results, a phase III trial of LSG15 versus biweekly CHOP was performed in a similar patient population and demonstrated a superior CR rate (40 percent vs. 25 percent) and 3-year OS (24 percent vs. 13 percent), favoring the intensive arm; however the median survival was only 13 months in the LSG15 arm.¹⁵⁵ These results highlight the inadequacy of CHOP in this disease, but the results seen with LSG15 leave significant room for improvement as well.

The role of antiviral therapy remains controversial. A recent meta-analysis of 254 patients with ATL demonstrated that there appears to be a benefit to first-line antiviral therapy, including interferon for patients with acute, chronic, and smoldering ATL, whereas patients with the lymphoma variant did not benefit. In patients with chronic and smoldering ATL treated with first-line antiviral therapy in combination with either chemotherapy or interferon, a 100 percent 5-year survival has been reported. In patients with leukemic ATL who were treated upfront with combined antiviral therapy and chemotherapy a 5-year OS of 28 percent was observed, compared to 10 percent in patients treated with first-line chemotherapy alone. Maintenance antiviral therapy also was reported to confer an improved OS in patients treated with first-line chemotherapy. 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 adult T-cell leukemia-lymphoma. In a multicenter phase II study of 28 patients with relapsed/refractory ATL, the ORR with mogamulizumab was 50 percent, with a median OS of 13.7 months.¹⁵⁷ A randomized phase II study of modified LSG15 with or without mogamulizumab confirmed that the combination was well tolerated and had a CR rate of 52 percent compared to 33 percent with LGS15 alone.¹⁵⁸

A large nationwide Japanese retrospective report of 386 patients with ATL assessed the role of allogeneic hematopoietic stem cell transplantation in ATL and demonstrated a 3-year OS for entire cohort of 33 percent. Among patients who underwent related donor transplantation, donor HTLV-1 seropositivity adversely affected disease-associated mortality.¹⁵⁹ In patients who are transplantation-eligible, allogeneic transplantation is therefore an attractive option, but ASCT has been found to be ineffective in ATL.^160,161

DEFINITION

Hepatosplenic T-cell lymphoma (HSTCL) is a rare lymphoma that infiltrates 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

EPIDEMIOLOGY

HSTCL is a rare lymphoma representing 3 percent of all T-cell lymphomas.¹⁶² This disease typically occurs in young males at a median age of 35 years.^7,163 Immunosuppression following solid-organ transplantation or from use of anti–tumor necrosis factor-α or thiopurine agents (as are used for Crohn disease and other autoimmune diseases) has been implicated as a risk factor for this disease.^164,165

CLINICAL FINDINGS

Patients commonly present with isolated hepatosplenomegaly without lymphadenopathy, frequently accompanied by cytopenias, B symptoms, and an elevated serum LDH.^57,163

LABORATORY FINDINGS

Histopathology

Neoplastic cells localize to sinusoids in the spleen, liver, and marrow. The malignant lymphocytes typically express CD3, CD56, and TCR-δ, but are negative for CD4 and usually CD8.¹⁶⁶ Clonal rearrangement of the TCR-γ gene usually present, and in most cases the lymphoma cells have an isochromosome 7q [I⁷(q10)] along with trisomy 8, which also may be seen in the αβ variant of this disease.^167,168,169

TREATMENT AND PROGNOSIS

HSTCL is characterized by an aggressive course, with a median survival of 16 months.¹⁷⁰ The optimal therapy for HSTCL is not known. Small patient series and anecdotal reports describe limited responsiveness and poor survival with CHOP and suggest better outcomes with other non–cross-resistant regimens such as ICE, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, methotrexate, cytarabine), or IVAC (ifosfamide, etoposide, cytarabine).^{162,163,170,171,172} Successful treatment with pentostatin has been reported as well.¹⁸⁰ Consolidation with either allogeneic stem cell transplantation or ASCT is likely necessary to achieve long-term remission.¹⁷¹

DEFINITION

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type previously known as lethal midline granuloma, malignant granuloma, or angiocentric lymphoma, is an uncommon subtype of T-cell lymphoma.

EPIDEMIOLOGY

ENKTL represents approximately 2 to 9 percent of T-cell lymphomas.^{2,3,4,174,175} The disease typically afflicts middle-aged men, with a median age of 50 years at diagnosis, but may also affect children.^134,135 ENKTL occurs worldwide, with a strong geographic predilection for Asian populations from China, Japan, Korea, and Southeast Asia¹⁷⁷ and for Central and South American populations from Mexico,¹⁷⁸ Peru,¹⁷⁹ Argentina, and Brazil,¹⁸⁰ constituting 5 percent to 15 percent of lymphomas in these countries. Occasional case series have also been reported from Europe and North America (see Table 104–2).¹⁸¹

CLINICAL FEATURES

ENKTLs are almost exclusively extranodal.¹⁷⁷ Initial sites involved are often the nose and nasopharynx and occasionally the paranasal sinuses, tonsil, Waldeyer ring, and oropharynx. When nasal lymphomas destroy the floor of the nasal cavity, a characteristic hard-palate perforation is found.¹⁸² Although they are usually localized, ENKTLs may disseminate to the skin, salivary glands, testis, and gastrointestinal tract. Interestingly, the lymphoma occasionally presents primarily in these sites without an apparent nasal primary. These “nonnasal” ENKTLs were thought to be more aggressive.¹⁸³ Modern imaging technology, such as PET/CT, shows that most, if not all, nonnasal lymphomas are associated with occult nasal primaries, and imply that they are disseminated nasal lymphomas.^184,185 With improved treatment strategies, primary sites of presentation are no longer an independent prognostic indicator.¹⁸⁶ Rarely, the lymphoma can evolve into NK-cell leukemia, which is characterized by widespread systemic dissemination and involvement of the marrow and blood.

LABORATORY FINDINGS

Histopathology

The histopathology shows angiocentric plesiomorphic small- or medium-size atypical lymphoid cells with vascular invasion and ischemic tissue necrosis. Marrow hemophagocytosis may be present. As NK and T cells share a common ontogeny, the malignant cells express CD2 and CD7 but are negative for surface CD3. They also express CD16, CD56, cytoplasmic CD3ε, and CD57, and often demonstrate clonal rearrangements in the TCR genes.^1,175,182 Neoplastic cells are invariably infected by EBV which is detected most reliably by in situ hybridization for EBV-encoded RNA (EBER), a diagnostic requisite.¹⁷⁷ Rare cases may not express CD56.¹

Laboratory Assessments

EBV DNA polymerase chain reaction (PCR) measured in plasma has been found to correlate with tumor burden and serial EBV PCR monitoring is useful for assessing responses and disease recurrence.^187,188

TREATMENT AND PROGNOSIS

Outcomes of localized NK/T-cell lymphoma are best with combined chemotherapy and radiation therapy. In studies of radiation therapy alone, 75 to 100 percent of patients respond; however, systemic relapse rates are as high as 25 to 40 percent.^189,190 Previously, patients were treated with CHOP-based therapy in combination with radiation with a CR rate of 59 percent and 3-year disease-free survival of 25 percent.^191,192,193 l-Asparaginase has a major single-agent activity in NK/T-cell lymphomas, and is incorporated into most modern regimens for this disease.¹⁹⁴ l-Asparaginase combined with gemcitabine, oxaliplatin, and radiation therapy exhibits an ORR of 96 percent and a local and systemic relapse rate of 10 to 15 percent in a phase I study.¹⁹⁵ Vincristine and prednisolone in combination with l-asparaginase produce an ORR of 89 percent when combined with radiation therapy. SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) in combination with radiation therapy demonstrates an 82 percent response rate with a CR rate of 78 percent.¹⁸⁶ l-Asparaginase has also been studied in combination with methotrexate and dexamethasone with an ORR of 78 percent.¹⁹⁷ In patients with localized ENKTL, it is standard to consolidate asparaginase-based chemotherapy with radiation therapy. In the setting of patients with advanced stage or relapsed/refractory disease, combination chemotherapy remains the standard treatment.¹⁸² Studies of SMILE demonstrate an ORR of 25 to 80 percent in disseminated disease.^186,196 NK-cell leukemia is characterized by widespread systemic dissemination and involvement of the marrow and blood and is associated with an extremely poor survival measured only in weeks.

EBV DNA PCR measured in the plasma has been found to correlate with tumor burden and serial EBV PCR monitoring is useful for assessing responses and disease recurrence.^187,188 In view of the improved efficacy of l-asparaginase–based regimens, the role of ASCT remains unclear.

Even though the IPI has been found to be effective in risk stratification of ENKTL, Lee and colleagues have developed an NK/T-cell lymphoma-specific prognostic index that also predicts prognosis (see Table 104–3).^2,3,186 This model includes B-symptoms, elevated LDH, stage, and presence of regional lymph nodes. Those with no risk factors, one risk factor, two risk factors, and three or more risk factors had a 5-year OS of 81 percent, 64 percent, 34 percent, and 4 percent, respectively.¹⁹⁸

SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA

Definition

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a primary cutaneous T-cell lymphoma presenting with painful subcutaneous nodules.^{199,200,201,202} The lesions consist of atypical lymphoid cells, and reactive histiocytes with admixed adipose tissue often associated with coagulation necrosis. Histologically, the cells express an α/β phenotype. The γ/δ phenotype of this disease is now classified as cutaneous γ/δ T-cell lymphoma.^1,202

Epidemiology

As discussed in a worldwide retrospective analysis, SPTL is a rare disorder accounting for 0.9 percent all T-cell lymphomas.^7,203 SPTL is primarily a disorder of adults with an average age at diagnosis in the mid to late 30s, although cases have also been reported in children.²⁰⁴ SPTL has a female predominance with a male to female ratio of 0.5.²⁰⁴

Clinical Features

Patients present with subcutaneous nodules that typically begin in the extremities and may spontaneously regress for a number of years, but eventually progress.²⁰⁵ They may ulcerate, and patients may have systemic symptoms.

Laboratory Features

The lesions consist of atypical lymphoid cells, and reactive histiocytes with admixed adipose tissue often associated with coagulation necrosis. In most cases, the tumor is composed of mature CD8+ αβ cytotoxic T cells that express TIA-1, granzymes, and perforin genes.^202,204,205

Treatment and Prognosis

Responses to combination chemotherapy have been reported but are usually of short duration.^{204,205,206,207} Responses to glucocorticoids, interferon-α, zidovudine, and cyclosporine also have been reported.^206,208,209 Therapy for this disease remains controversial. Although standard chemotherapy may be effective, CRs are rare. Single patient cases of successful allogeneic stem cell transplantation have been reported, but the rarity of this disease hampers further investigation of this modality.^210,211 The use of denileukin diftitox in two patients has been reported with evidence of activity, and bexarotene restored a clinical response in one of the patients after disease progression.²¹² Single-agent bexarotene has also been shown to have significant clinical activity with an ORR of 82 percent.²¹³