Chapter 98: Diffuse Large B-Cell Lymphoma and Related Diseases

Diffuse large B-cell lymphomas (DLBCLs) comprise a heterogeneous group of aggressive malignancies of large, transformed B cells which cause diffuse effacement of the normal lymph node structure. DLBCL has masqueraded under a variety of colorful but misleading monikers in early lymphoma classification systems, including “reticulum cell sarcoma,” and “diffuse histiocytic lymphoma,” as described in an excellent recent review of the history of the lymphomas.¹ Distinct disease entities are distinguished based on morphologic, biologic, and clinical features as established by an international panel of experts on behalf of the World Health Organization (WHO, Table 98–1).² The disease can arise de novo or may transform from an indolent lymphoma, such as small lymphocytic lymphoma or follicular lymphoma.

DLBCL is the most common B-cell lymphoid neoplasm in the United States and Europe and accounts for approximately 28 percent of all mature B-cell lymphomas.^3,4 Incidence varies by ethnicity, with Americans of European descent being more likely to develop DLBCL than Americans of African descent. Like most other lymphomas, there is a male predominance. The disease most commonly presents in late middle-aged and older persons with a median age at diagnosis of approximately 65 years. Because lymphoma incidence rates increased dramatically from the 1940s to the 1990s, numerous exogenous factors have been examined to ascertain if one or more play a role in pathogenesis of the disease, including herbicides (e.g., phenoxyacids), pesticides (e.g., organochlorines), organic solvents (e.g., toluene, benzene), dark hair dyes, body mass index, tobacco use, alcohol use, and inflammatory states. At this time, no inhalant, exposure, or ingestant has been unequivocally proven to increase the relative risk of DLBCL.⁵

DLBCL is a molecularly heterogeneous disease with multiple complex chromosomal translocations and genetic abnormalities as identified by cytogenetics, gene expression profiling, and whole-genome sequencing. The disease is derived from B cells whose immunoglobulin (Ig) genes have undergone somatic mutation in the lymph node germinal center.⁶ Approximately 40 percent of cases in immunocompetent hosts and approximately 20 percent of HIV-related cases display BCL6 rearrangements.^7,8,9 Chromosomal translocations involving band 3q27 lead to a truncated BCL6 gene within its 5′ flanking region. Such truncations commonly occur within the first exon or first intron, leading to complete removal or truncation of the promoter sequences; the coding sequence is left intact.¹⁰ In a small number of cases, the breakpoint is not located in the immediate proximity of the BCL6 gene. Increased expression of BCL6 occurs from a process termed promoter substitution by which heterologous promoters are juxtaposed to the BCL6 coding domain. This process occurs through reciprocal translocations between 3q27 and chromosomal partner sites, including 14q32 (IgH), 2p11 (Igκ), and 22q11 (Igλ).^10,11 The BCL6 protein mediates the specific binding of several transcription factors to DNA. It also may be involved in induction of germinal-center-associated functions, as it is expressed in germinal center B cells but not in plasma cells. Therefore, downregulation of BCL6 may be necessary for terminal differentiation of B cells to memory B cells and plasma cells.¹²

Approximately 30 percent of DLBCLs possess a t(14;18) translocation involving the Ig heavy-chain gene and BCL2. Such BCL2 gene rearrangements occur in DLBCL in either of two circumstances: (1) in DLBCLs arising by histologic transformation of a previous follicular lymphoma or (2) in de novo DLBCLs with a germinal center gene-expression profile. The presence of a p53 mutation in combination with BCL2 denotes that the tumor is derived from a histologic transformation of a prior follicular lymphoma.¹³

Normally, mutations in the variable region of the Ig genes confer antibody diversity in germinal center B cells. However, aberrant somatic hypermutation occurs in more than 50 percent of cases of DLBCL. Such alterations target multiple loci, including the protooncogenes PIM1, MYC, RhoH/TTF (ARHH), and PAX5.¹¹ The c-MYC gene rearrangement occurs in 10 percent of patients with DLBCL.

Gene-expression profiling studies have distinguished three molecular subtypes of DLBCL known as (1) germinal center B-cell–like (GCB), (2) activated B-cell–like (ABC), and (3) primary mediastinal B-cell lymphoma (PMBCL).^14,15,16,17 GCB DLBCLs are believed to arise from normal germinal center B cells, whereas ABC DLBCLs appear to arise from postgerminal center B cells that are arrested during plasmacytic differentiation, and PMBCLs arise from thymic B cells. These DLBCL subtypes arise by distinct pathogenetic mechanisms, as judged by high-resolution, genome-wide copy-number analysis coupled with gene-expression profiling.¹⁸ Furthermore, genomic studies employing massively parallel sequencing (genome/exome/RNAseq) have demonstrated common recurrent mutations in histone modification and chromatin remodeling genes in the GCB-DLBCL subtype of DLBCL, whereas mutations affecting the B-cell signaling pathway and nuclear factor (NF)-κB family are typical of the ABC subtype of lymphoma, as summarized in Table 98–2.^{19,20,21,22,23} In addition, GCB DLBCLs often exhibit amplification of the oncogenic microRNA (miRNA)-17–92 cluster and deletion of the tumor-suppressor PTEN, whereas these events are rare in the ABC-type of DLBCL.

SIGNS AND SYMPTOMS

Patients with DLBCL typically present with rapidly enlarging, symptomatic, lymphatic masses, typically in the neck or abdomen. B symptoms (drenching night sweats, fever, weight loss) are observed in approximately 30 percent of patients. Extranodal disease occurs in approximately 40 percent of patients, most commonly involving the gastrointestinal tract or marrow.^24,25 Other sites that may be affected include the testis, bone, thyroid, salivary glands, skin, liver, breast, nasal cavity, paranasal sinuses, and CNS. DLBCL may cause local compression of vessels (e.g., superior vena cava syndrome) or airways (e.g., tracheobronchial compression) requiring urgent treatment.

Unusual symptoms and presentations occur with some subtypes of DLBCL, such as intravascular large B-cell lymphoma, which may present with unexplained fever, or primary effusion lymphoma, which may present in immunocompromised hosts with human herpesvirus-8 infection. Approximately 60 percent of patients present with disseminated DLBCL (stage III or IV). Marrow involvement occurs in approximately 15 percent of patients. Discordant disease in which the lymph nodes are involved with DLBCL but the marrow contains an indolent lymphoma may occur. This combination is not associated with a poorer prognosis but increases the risk of late relapse. CNS dissemination occurs more frequently in patients with multiple extranodal sites of disease, particular testicular, paranasal sinus or marrow involvement²⁶ and in patients with marked elevations of serum lactic dehydrogenase (LDH). Patients at high risk for CNS involvement should undergo an examination of spinal fluid by flow cytometry for clonal B cells, which is the most sensitive method for detection of CNS disease. Patients with involvement of Waldeyer ring have an increased risk of gastrointestinal lymphoma.

BLOOD AND MARROW

Lymphomatous involvement of the marrow occurs in approximately 10 to 20 percent of cases of DLBCL, with blood involvement noted on morphologic examination of blood films in approximately 3 to 8 percent of cases. These percentages are undoubtedly underestimates, and data using more sensitive tests, such as flow cytometry, are needed. Marrow involvement may lead to anemia, and in severe cases to leucopenia and thrombocytopenia, which may worsen when cytotoxic therapy is administered.

CELL IMMUNOPHENOTYPE

The malignant cells of DLBCL express monoclonal surface immunoglobulin with κ or λ light-chain restriction. IgM is the most commonly expressed isotype of surface immunoglobulin, although occasionally cells may be negative for surface immunoglobulin.²⁷ The lymphoma cells generally express the pan–B-cell antigens, CD19, CD20, CD22, PAX5, and CD79a, as well as the pan-hematopoietic antigen, CD45 and, less commonly, CD10 or CD5.^27,28 CD5-expressing DLBCLs appear to be more aggressive and have a worse prognosis.²⁹ CD10+ DLBCL may be difficult to distinguish from Burkitt lymphoma or from grade 3 follicular lymphoma.³⁰ When a mature CD10+ B-cell phenotype is identified by flow cytometry, distinction between these possibilities should be further evaluated by morphology and genetic studies. Adhesion molecules such as LFA-1 (leukocyte function-associated antigen-1; CD16/CD18) and CD44 are expressed in 50 to 75 percent of cases of DLBCL. CD44 is expressed in highly aggressive subsets of DLBCL and is associated with disseminated disease and a poor prognosis.³¹

HISTOPATHOLOGY

Lymph nodes affected by DLBCL are usually effaced by a diffuse infiltrate of large lymphocytes. Three cytologic patterns are commonly recognized, namely, centroblastic, immunoblastic, and anaplastic, which are distinguished based on the size of the cells, the number of nucleoli, the basophilia of the cytoplasm, and the presence of bizarre and pleomorphic nuclei. Other rare morphologic variants occur, for example, with myxoid or fibrillary appearances. Although the diffuse growth pattern of DLBCL can be distinguished on histologic sections from the nodular growth pattern of follicular lymphoma, this distinction is usually not possible in fine-needle aspirates, body fluids, blood, or marrow specimens. Furthermore, genotypic characteristics overlap between follicular lymphoma and DLBCL, with the t(14;18)(q32;q21) translocation identified in approximately 20 percent of DLBCL and approximately 85 percent of follicular lymphomas (Chap. 99). The cells in DLBCL undergo immunoglobulin variable-region gene rearrangement and are commonly somatically mutated. Furthermore, isotype switch variants may occur.³²

The differential diagnosis of DLBCL includes nonmalignant conditions characterized by immunoblastic infiltrates (infectious mononucleosis), nonlymphoid malignancies (carcinoma), and other lymphoma subtypes, including Hodgkin lymphoma (Chap. 97), lymphoblastic lymphoma, and Burkitt lymphoma (Chap. 102). Adequate tissue sampling is crucial at the time of initial diagnosis, and excisional biopsies are strongly preferred to small core needle biopsies. Fine-needle aspirates are inadequate for securing a definitive diagnosis of DLBCL and are strongly discouraged. The presence of a neoplastic clone should be confirmed with molecular or and immunophenotypic studies in most cases.

GENERAL CONSIDERATIONS

DLBCL is commonly curable with combination chemotherapy regimens containing an anthracycline. The best outcomes are obtained in patients who receive full doses of chemotherapy on schedule, without dose attenuations or treatment delays. Before therapy is instituted, several factors should be evaluated, including the patient’s clinical stage, symptoms, and the international prognostic index (IPI). In addition, response to therapy should be evaluated according to defined criteria.³³ Other considerations, such as the patient’s age and comorbid conditions, are important before a therapeutic intervention is selected. Future trials and therapies may be precisely tailored to subgroups of DLBCL based on biologic features of the tumor, but detailed staging, recognition of important variants, and IPI score calculation presently form the cornerstone of patient assessment.

LIMITED STAGE DIFFUSE LARGE B-CELL LYMPHOMA (STAGES I AND II)

Localized disease occurs in approximately 30 percent of patients, and historically was treated with radiation therapy alone.³⁴ However, the 5-year disease-free survival with radiation therapy in stage I disease was only 50 percent, and in stage II disease was approximately 20 percent. Combining chemotherapy with radiation therapy improved the control of local disease and resulted in a lower rate of delayed dissemination.^{35,36,37,38,39,40} The role of chemotherapy alone, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in particular, has been studied in several randomized trials (Table 98–3).

A Southwest Oncology Group study randomly assigned 401 patients with stage I and nonbulky stage II disease to receive either eight cycles of CHOP chemotherapy or three cycles of CHOP plus involved-field radiotherapy (IFRT).⁴¹ The 5-year overall and progression-free survival (PFS) rates of the patients treated with the short-course, combined modality approach were significantly better (82 percent and 72 percent, respectively, p = 0.02) than outcomes among patients treated with chemotherapy alone (77 percent and 64 percent, respectively, p = 0.03). Cardiac and hematologic toxicity was greater in patients treated with eight cycles of CHOP without radiation therapy. A subset analysis using modified IPI criteria showed that patients with poor risk factors had a worse overall survival. However, with longer followup, failure-free survival curves overlapped at 7 years and the overall survival (OS) curves overlapped at 9 years. The early treatment advantage of CHOP plus IFRT disappeared as a result of lymphoma recurrence between 5 and 10 years after therapy.⁴²

In an Eastern Cooperative Oncology Group (ECOG) trial involving 399 patients with bulky stage I (mediastinal or retroperitoneal mass, or a mass >10 cm), stage IE, stage II, or stage IIE disease, patients who achieved complete remission (CR) after CHOP chemotherapy were randomized to observation or 30 Gy involved-field radiation.⁴³ All patients with partial remission received 40 Gy to the involved field and radiation to the contiguous noninvolved regions. Among 172 CR patients, the 6-year disease-free survival (DFS) was 73 percent for low-dose involved-field radiation versus 56 percent for CHOP followed by observation only (p = 0.05) without a survival difference between the two arms. After 6 years failure-free survival was 63 percent in patients in partial remission (PR), and conversion to CR with radiation therapy did not influence outcome. For patients in CR after eight cycles of CHOP, low-dose involved-field radiation prolonged DFS and provided local control, but did not influence survival.

In a Group d’Etude des Lymphomes de l’Adulte (GELA) study, 576 patients older than age 60 years with stages I and II disease and an IPI score of 0 were randomized to four cycles of CHOP with or without involved-field radiation (40 Gy).⁴⁴ The 5-year event-free survival (EFS) was 61 percent for patients treated with CHOP compared to 64 percent for patients treated with CHOP plus involved-field radiation, and the OS was 72 and 68 percent, respectively. In another GELA study, 647 patients younger than age 61 years with low-risk localized aggressive lymphoma were randomized to three cycles of CHOP followed by 30 to 40 Gy of involved-field radiation or doxorubicin (Adriamycin), cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) chemotherapy followed by consolidation chemotherapy with methotrexate, ifosfamide, etoposide, and cytarabine.⁴⁵ The EFS (82 percent vs. 74 percent, p = 0.001) and OS (90 percent vs. 87 percent, p <0.001) were significantly better for patients given intensive chemotherapy alone compared to patients given CHOP chemotherapy plus radiation therapy. The ACVBP regimen cannot be given in the United States, however, because vindesine is not available.

These studies were conducted before the incorporation of rituximab into frontline regimens for DLBCL. Subsequently, in a phase II study, 60 patients older than age 60 years with at least one adverse risk factor as defined by the IPI (but excluding bulky stage II disease) received rituximab and CHOP (R-CHOP), followed by 40 to 46 Gy involved-field radiation.⁴⁶ PFS was 95 percent at 2 years and 88 percent at 4 years, and OS was 95 percent at 2 years and 92 percent at 4 years. PFS and OS for historical controls not treated with rituximab were 78 percent and 88 percent at 4 years, respectively. Additional, retrospective analyses suggest a role for radiotherapy in unselected DLBCL patients (including limited stage disease) treated with R-CHOP,⁴⁷ and in subsets age 61 to 80 years with bulky disease (7.5 cm or greater).⁴⁸

Although the data available are not clearcut, at this time either three cycles of R-CHOP followed by 40 to 46 Gy of involved-field radiation or six cycles of R-CHOP without radiotherapy represent standard therapeutic options.

ADVANCED STAGE DIFFUSE LARGE B-CELL LYMPHOMA

Combination chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone [MOPP]) proved so successful for treatment of Hodgkin lymphoma that similar regimens were soon explored for treatment of DLBCL, including cyclophosphamide, vincristine, procarbazine, and prednisone (C-MOPP; synonym: COPP)⁴⁹ and cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, vincristine 1.4 mg/m,² and prednisone 100 mg orally administered daily for days 1 through 5 of each cycle (CHOP). Between 1972 and 1975, reports of CRs with long-lasting PFS with these regimens heralded the advent of curative therapy for patients with DLBCL, with CHOP administered every 21 days for six to eight cycles emerging as the most popular regimen in the United States for treatment of DLBCL (Table 98–4).

In an effort to improve upon the efficacy of CHOP, a number of intensified, multidrug combinations were developed. Early single-institution, single-armed trials showed promising results, including CR rates up to 80 percent and prolonged DFS rates of 60 percent.^50,51 Phase II trials of m-BACOD (moderate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), ProMACE (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide)/CytaBOM (cytarabine, bleomycin, vincristine, methotrexate), and MACOP-B (high-dose methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) appeared to show superior response rates compared to previously published results achieved with CHOP.⁵² However, the benefits demonstrated in single-institution studies could not be replicated in multiinstitutional studies, or with extended followup. A prospective randomized study that compared m-BACOD with CHOP showed no difference in the CR rates, DFS, or OS.⁵³ Because of these conflicting data, a four-arm phase III study was conducted and enrolled patients in a randomized prospective trial comparing CHOP, m-BACOD, MACOP-B, and ProMACE/CytaBOM.⁵⁴ This landmark trial enrolled 897 patients with intermediate- or high-grade lymphoma, of whom 85 percent had diffuse or follicular large cell lymphoma. In the trial, each of these regimens produced equivalent results. The DFS was 35 to 40 percent with a 4-year survival of 36 percent in the patients who received CHOP, 34 percent in the m-BACOD group, 45 percent in those treated with ProMACE/CytaBOM, and 39 percent in the MACOP-B group (p = 0.14). CHOP chemotherapy was the safest regimen, with only 1 percent treatment-related mortality compared to 6 percent mortality with MACOP-B. In this randomized phase III trial, the more intensive regimens offered no improvement in the remission rate, DFS, or OS compared to the simpler and safer CHOP regimen. In retrospect, the improved complete response rates observed in the initial, single-institution phase II clinical trials of the augmented regimens appear to have been a result of enrollment of a disproportionate patients with favorable IPI scores.

In 2002, a major randomized clinical trial conducted by GELA demonstrated not only increased efficacy, but minimal added toxicity, with the addition of the monoclonal antibody rituximab to CHOP in older adults with DLBCL.^55,56 In this study, 399 patients 60 to 80 years of age with newly diagnosed DLBCL were randomized to receive either eight cycles of CHOP given every 21 days (CHOP-21) or the same chemotherapy with eight infusions of rituximab. The combination of CHOP and rituximab significantly improved the CR rate from 63 to 76 percent, EFS from 38 to 57 percent, and OS from 57 to 70 percent compared to CHOP-21 without rituximab. There were no differences in toxicity other than a higher risk of minor cardiac events, many of which were attributed to rituximab infusion reactions. These results were confirmed by an ECOG group trial, in which 632 older patients were treated with six to eight cycles of CHOP-21 and randomized to the same chemotherapy plus five infusions of rituximab.⁵⁷ In this study, 2-year failure-free survival was 53 percent after a median followup of 3.5 years in patients receiving R-CHOP compared to 46 percent for patients receiving CHOP alone. A second randomization in this trial suggested that patients who received R-CHOP did not benefit from maintenance rituximab therapy. In the RICOVER-60 study, 1222 elderly patients were randomized to six or eight cycles of CHOP given every 14 days with leukocyte growth factor support (CHOP-14) or six to eight cycles of R-CHOP-14.⁵⁸ Six cycles of R-CHOP-14 significantly improved EFS, PFS, and OS compared to six cycles of CHOP-14. No benefit was conferred by administering eight cycles of R-CHOP-14 rather than six cycles of R-CHOP-14.

The benefit of adding rituximab to CHOP-like chemotherapy in younger patients was subsequently confirmed by The Monoclonal Antibody Therapeutic International Trial (MInT) Group.⁵⁹ A total of 824 patients with a good prognosis and an age-adjusted IPI of 0 or 1, and stage II to IV disease or stage I with bulky adenopathy, were randomized to receive six cycles of a CHOP-like regimens or the same regimen plus rituximab. Patients with bulky (>5 cm) disease received additional radiotherapy to those areas. After a median observation time of 34 months, the addition of rituximab increased the EFS from 59 percent to 79 percent, and the OS from 84 percent to 93 percent, both statistically significant findings (p <0.05). These results suggest that six cycles of rituximab with a CHOP-like regimen is the best therapy for young patients with good-prognosis DLBCL. Subset analysis suggested that patients with an IPI of zero and no bulky disease represent a very favorable subgroup with a 3-year EFS of 89 percent whereas patients with an age-adjusted IPI of 1 and bulky disease represent a less-favorable subgroup with only a 74 percent 3-year EFS.

Investigators have attempted to improve the efficacy of R-CHOP by reducing the time between doses to every 14 days (R-CHOP-14), thereby increasing the “dose-density.” Unfortunately, three randomized trials have shown no improvement in EFS, PFS, or OS with R-CHOP-14 compared to R-CHOP-21, and the dose-dense regimen was associated with increased hematologic toxicity.^60,61 On the other hand, an intensified combination chemotherapy regimen developed for younger patients by GELA, known as R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone as induction, followed by consolidation, including methotrexate, etoposide, and cytarabine) was shown to have superior EFS (81 percent vs. 67 percent) and OS (92 percent vs. 84 percent) compared to R-CHOP-21 in a randomized trial of 379 DLBCL patients younger than the age of 60 years with an age-adjusted IPI of 1.⁶² However, patients experienced a substantially higher risk of hematologic toxicity and serious adverse events with R-ACVBP (42 percent vs. 15 percent with R-CHOP).

In a novel strategy to enhance chemotherapy efficacy, investigators at the United States National Cancer Institute developed an infusional chemotherapy regimen known as EPOCH (containing etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). In this regimen, vincristine, etoposide, and doxorubicin are administered by continuous infusion over 96 hours, and cyclophosphamide is administered as a bolus. The regimen is based on in vitro data that showed that lymphoma cells exhibited less chemotherapy resistance when exposed to prolonged low concentrations of vincristine, doxorubicin, and etoposide than when exposed to brief, higher concentrations of the same drugs.⁶³ EPOCH was initially evaluated in 131 patients with relapsed or refractory lymphoma and demonstrated a 74 percent overall response rate and tolerable toxicity.⁶⁴ Pharmacokinetics demonstrated considerable interpatient variability and suggested the need for dose adjustments to optimize outcomes for individual patients.⁶⁵ This observation led to incorporation of a dose-adjustment strategy based on the observed hematopoietic nadir with each cycle of treatment.⁶⁶ Fifty patients with previously untreated DLBCL were treated with dose-adjusted EPOCH and demonstrated a complete response rate of 92 percent with PFS and OS rates of 70 and 73 percent, respectively. In a subsequent trial, 72 patients with untreated DLBCL were treated with dose-adjusted EPOCH and rituximab with 5-year PFS and OS of 79 percent and 80 percent, respectively.⁶⁷ A randomized study comparing rituximab plus EPOCH (R-EPOCH) to R-CHOP in untreated DLBCL has recently been completed but the results have not yet been reported (Cancer and Leukemia Group B study 50303).⁶⁸

In summary, R-CHOP administered every 21 days has emerged as the modern standard of care for DLBCL, based on the demonstration of superior outcomes and acceptable toxicity compared to CHOP in randomized clinical trials. Neither intensifying therapy by adding chemotherapy agents, nor altering dose density, have substantially improved upon the therapeutic ratio of the standard R-CHOP regimen. As a novel approach, infusional chemotherapy with dose-adjusted R-EPOCH remains under investigation in a prospective randomized trial in the United States. An improved understanding of the heterogeneous biology of DLBCL, and identification of tumor-defined prognostic subgroups with therapy modified accordingly, may soon permit tailored treatment approaches to maximize cure rates for the ABC and GCB subtypes.

ROLE OF HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM CELL TRANSPLANTATION IN INITIAL THERAPY

High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been established as the standard of care for patients with relapsed, chemotherapy-sensitive aggressive lymphomas. However, the role of ASCT as part of initial treatment remains very contentious.^{69,70,71,72,73,74,75,76} A recent phase III U.S. cooperative group study evaluated this question by enrolling 397 patients with high-intermediate and high-risk aggressive non-Hodgkin lymphoma who were treated with CHOP or R-CHOP and then randomized responders (N = 253) to ASCT or further chemotherapy alone.⁷⁵ The ASCT group achieved superior PFS after 2 years (69 percent vs. 55 percent for further chemotherapy, p = 0.005) but no difference in OS was observed (74 percent vs. 71 percent, p = 0.3). In an unplanned subgroup analysis, patients with high-risk DLBCL based on the IPI achieved superior PFS and OS with ASCT.

A meta-analysis evaluated the role of high-dose chemotherapy with ASCT as part of initial treatment.⁷⁷ Fifteen randomized control trials including 3079 patients were eligible for this meta-analysis. Overall treatment-related mortality was 6 percent in the ASCT group, which was not significantly different than with conventional chemotherapy. Thirteen studies including 2018 patients showed significantly higher CR rates in the group receiving ASCT (p = 0.004). However, ASCT did not have an effect on OS, when compared to conventional chemotherapy. Subgroup analysis of prognostic groups according to IPI did not show any survival difference between ASCT and chemotherapy alone in 12 trials. EFS also showed no significant difference between ASCT and conventional chemotherapy.

High-dose chemotherapy and ASCT is not routinely recommended as part of frontline therapy of DLBCL. Some authorities believe that high-risk DLBCL patients who achieve at least a PR with firstline therapy may achieve superior outcomes if consolidated with ASCT, but available data supporting this approach are flawed, preventing uniform adoption. Because abbreviated courses of chemotherapy prior to transplantation impair outcomes, patients should receive a full course of standard chemotherapy even if subsequent ASCT is planned.

RECURRENT AND REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

Chemotherapy

Despite major advances in initial treatment of advanced DLBCL a substantial proportion of patients is either refractory to initial induction chemotherapy or relapses after chemotherapy. Relapse usually occurs within the first 2 years after diagnosis, and the probability of long-term survival among immunochemotherapy-treated patients who survive 2 years from DLBCL diagnosis without an event (relapse, retreatment, or death) is similar to age-matched controls.⁷⁸ Several second-line regimens have been evaluated in refractory and relapsed DLBCL with response rates of 50 to 70 percent, but none of these regimens has distinguished itself as the preferred regimen. The use of single agents, such as etoposide,⁷⁹ cytarabine,⁸⁰ mitoxantrone,⁸¹ lenalidomide,⁸² and paclitaxel,⁸³ result in response rates from 20 to 40 percent; however, responses to monotherapy are generally not long-lasting.

A prospective phase II study of EPOCH was examined in 131 patients with relapsed or resistant lymphoma.⁶⁴ In 125 assessable patients, 29 (23 percent) achieved complete responses and 60 (48 percent) achieved partial responses. Among 42 patients with resistant disease, 57 percent responded, and in 28 patients with relapsed lymphomas, 89 percent responded with 54 percent complete responses. With a median followup of 76 months, the overall and EFSs were 17.5 and 7 months, respectively. In 33 patients with chemotherapy-sensitive, aggressive disease who did not receive ASCT, EFS was 19 percent at 36 months.

The addition of rituximab to the ifosfamide-carboplatin-etoposide (ICE) chemotherapy regimen (R-ICE) increased the CR rate of patients with relapsed or primary refractory DLBCL under consideration for ASCT.⁸⁴ The CR rate was 53 percent, significantly better than the 27 percent CR rate (p = 0.01) achieved among 147 similar, consecutive historical control patients with DLBCL treated with ICE. PFS for patients who underwent transplantation after R-ICE was marginally better than those of 95 consecutive historical control patients who underwent transplantation after ICE (54 percent vs. 43 percent, P = 0.25).

A prospective study of 122 patients with relapsed and refractory DLBCL evaluated the role of etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP).⁸⁵ Forty-five patients (37 percent) attained a CR and 33 (27 percent) attained a PR, for a total response rate of 64 percent. The median duration of CR was 20 months, with 28 percent in CR at 3 years. The overall median survival duration was 14 months with an OS rate of 31 per cent after 3 years. Only 10 percent of all patients were alive and disease free after 40 months, however.

A randomized trial of second-line chemotherapy was published in 2010, comparing three cycles of either R-ICE or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) before planned ASCT.⁸⁶ This study of 396 patients demonstrated no difference in terms of efficacy (response rate 64 percent vs. 63 percent) or survival (3-year OS 47 percent vs. 51 percent) with R-ICE or DHAP, respectively. In the absence of high-level evidence supporting one salvage regimen over another, treatment for relapsed/refractory DLBCL requires individualized consideration of comorbidities and patient factors.

Autologous Stem Cell Transplantation

The role of ASCT in relapsed DLBCL was demonstrated in a randomized trial of 109 patients who responded to salvage chemotherapy with the DHAP chemotherapy regimen and were randomly assigned to receive four courses of chemotherapy plus radiotherapy (54 patients) or radiotherapy plus intensive chemotherapy and ASCT (55 patients).⁸⁷ After 5 years, the EFS was 46 percent in the transplantation group and 12 percent in the chemotherapy/radiotherapy group (p = 0.001), and the rate of OS was 53 and 32 percent, respectively (p = 0.038). Patients with relapsed or primary refractory DLBCL who achieved CR before ASCT, had better outcomes than those who achieved only PR. Disease sensitivity at the time of ASCT and time from initial diagnosis to relapse remain key prognostic variables for predicting treatment outcome after standard ASCT.^86,87 Patients who undergo ASCT when the disease is resistant to the initial induction therapy have less than a 20 percent probability of durable DFS.

Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has also been used in patients with DLBCL. The European Bone Marrow Transplant Group performed a case-controlled study by matching 101 allo-HSCT patients with 101 ASCT patients.⁸⁸ The PFS was similar in both types of transplants (49 percent for allo-HSCT vs. 46 percent for ASCT). The overall relapse and progression rate for the allo-HSCT patients was 23 percent compared with 38 percent for the ASCT patients. This difference was not statistically significant. Nine patients who had undergone ASCT died from early procedure-related toxicity and 17 patients who had undergone allo-HSCT died from early procedure-related toxicity. To reduce the treatment-related mortality associated with allo-HSCT, nonmyeloablative preparative regimens were developed to minimize the toxicity associated with standard high-dose chemotherapy, achieve sufficient engraftment to prevent graft rejection and exploit the graft-versus-tumor effect of allo-HSCT. In a prospective study, 31 patients with DLBCL and one patient with Burkitt lymphoma received allo-HSCT following 2 Gy total-body irradiation with or without fludarabine.⁸⁹ Twenty-four patients had undergone prior ASCT. With a median followup of 45 months, 3-year OS and PFS were 45 percent and 35 percent, respectively. Three-year cumulative incidences of relapse and nonrelapse mortality were 41 percent and 25 percent, respectively. Cumulative incidences of acute graft-versus-host disease (GVHD) grades II to IV, grades III and IV, and chronic GVHD were 53, 19, and 47 percent, respectively. In another study, 48 consecutive patients with relapsed or refractory DLBCL (30 patients with de novo disease and 18 patients with transformed follicular lymphoma) underwent transplantation with an alemtuzumab-containing regimen.⁹⁰ The PFS and OS rates after 4 years were 48 and 47 percent, respectively. Seventeen percent of patients developed grades II to IV acute GVHD, and 13 percent experienced extensive chronic GVHD. Four-year estimated nonrelapse mortality was 32 percent, and relapse risk was 33 percent. Although these results are promising, allo-HSCT cannot be recommended before ASCT except in the context of a clinical trial.

Radioimmunotherapy

Radioimmunotherapy as monotherapy is not recommended for DLBCL but its role as part of a conditioning regimen prior to ASCT has been encouraging. A phase II trial evaluated the safety and efficacy of combining ⁹⁰Y-ibritumomab tiuxetan with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and ASCT in patients with lymphoma who were considered ineligible for total-body irradiation because of older age or prior radiotherapy.⁹¹ The addition of ⁹⁰Y-ibritumomab tiuxetan to BEAM with ASCT was feasible and the toxicity and tolerability profile similar to that observed with BEAM alone. Similarly, ¹³¹I-tositumomab (up to 0.75 Gy) was combined with BEAM followed by ASCT for the treatment of chemotherapy-resistant relapsed or refractory lymphoma. Short-term and long-term toxicities were similar to that in patients previously treated with BEAM alone, with an OS rate of 55 percent and an EFS rate of 39 percent.⁹²

Summary of Approach to Patients with Relapsed Disease

Patients with relapsed disease should receive multidrug chemotherapy, such as R-ICE or R-DHAP. If chemosensitivity is demonstrated and no contraindications are present, ASCT should be performed. If patients are elderly or have comorbid conditions the goal should be palliation. Radiotherapy can be used to alleviate symptoms at particular sites of involvement in patients with relapsed DLBCL and single-agent therapy can be used but with low expected response rates and duration of responses.

INTERNATIONAL PROGNOSTIC INDEX

In 1993, a model was proposed to assign a prognosis to patients with aggressive lymphoma undergoing treatment with doxorubicin-containing chemotherapeutic regimens termed the international prognostic index (IPI).^93,94 The model used clinical data, including (1) tumor stage, (2) serum LDH level, (3) number of extranodal disease sites involved, (4) performance status, and (5) patient age. This model resulted in the IPI, which is used to forecast the behavior of aggressive lymphoma (Table 98–5 and Fig. 98-1). For patients younger than age 60 years, an age-adjusted IPI has been proposed in which all the factors of the IPI are used, except for age and presence of extranodal sites. The 5-year survival rates for patients age 60 years or younger with IPI scores of 0, 1, 2, and 3 were 83, 69, 46, and 32 percent, respectively (Table 98–6).⁹³ To better estimate prognosis among modern DLBCL patients, a revision of the IPI was recently developed by the National Comprehensive Cancer Network (the NCCN-IPI).⁹⁵ This model employs the same five risk factors but uses a different scoring algorithm, and improves discrimination of groups treated with rituximab-containing chemoimmunotherapy.

GENE-EXPRESSION PROFILING AND DETERMINATION OF DIFFUSE LARGE B-CELL LYMPHOMA SUBTYPES

Gene-expression profiling has also been used to delineate groups of patients with DLBCL who may differ in their response to therapy and prognosis (Fig. 98–2).^{14,15,16,17,96,97} Six genes identified by gene-expression analysis and detected by quantitative real-time polymerase chain reaction can identify three prognostic groups in patients with DLBCL.⁹⁸ The six genes that were used in this model occur in the germinal center B-cell signature (LMO2, BCL6), activated B-cell signature (BCL2, CCND2, SCYA3), and lymph node signature (FN1). In this study, expression of LMO2, BCL6, and FN1 correlated with prolonged survival, whereas expression of BCL2, CCND2, and SCYA3 correlated with short survival. Protein immunohistochemistry (IHC) has also been used to delineate DLBCL subtypes, but shows imperfect concordance with gene expression results.⁹⁶ Even though various algorithms have been developed for subtyping DLBCL by IHC, further refinement is needed prior to relying on IHC for management decisions and prognostication.

SERUM LACTIC DEHYDROGENASE AND β₂-MICROGLOBULIN

Patients with an elevated β₂-microglobulin level and high serum LDH have a poor prognosis, with a 26 percent survival compared to 81 percent survival in patients without elevation of either of these markers.^93,99

PRESENCE OF MYC GENE REARRANGEMENT OR ELEVATED PROTEIN EXPRESSION

Approximately 10 percent of DLBCL patients harbor a translocation involving the MYC gene. Patients with a MYC rearrangement detected by fluorescence in situ hybridization (FISH) have been shown to have an inferior 5-year survival of 33 percent when treated with standard R-CHOP therapy, compared to 72 percent survival for those without MYC rearrangements.¹⁰⁰ Concurrent translocation of BCL2 or BCL6 is seen in a subset of cases. These “double-hit” lymphomas are often classified morphologically as “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma” using the 2008 WHO classification of lymphomas and have a very bad prognosis.² MYC protein overexpression by IHC is also associated with an inferior prognosis, particularly when accompanied by BCL2 protein overexpression.^101,102

POSITRON EMISSION TOMOGRAPHY

Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) is used for initial staging and at the end of treatment (to assess remission status) in patients with DLBCL. FDG-PET is superior to computed tomography imaging in detecting nodal and extranodal sites of aggressive lymphoma, with the potential to alter stage, prognosis, and selection of therapy.¹⁰³ In addition, FDG-PET performed at the end of therapy is highly informative. A negative PET predicts a high probability of disease control, and is required to designate a CR by modern response criteria.^33,104 Other uses of PET in DLBCL are investigational or not routinely recommended.

PRIMARY TESTICULAR LYMPHOMA

Primary testicular lymphoma represents 1 to 2 percent of all lymphomas, with an estimated incidence of 0.26 per 100,000 males per year.¹⁰⁵ Even though lymphomas account for only 1 to 7 percent of all testicular malignancies, they represent the most common testicular tumor in men older than 50 years of age. Histologically, 80 to 90 percent of primary testicular lymphomas are DLBCL, with a mean age at diagnosis of 68 years (range: 21 to 98 years).^106,107 Most patients present with stage I or II disease with isolated involvement of the right or left testis equal in frequency, whereas 6 percent of cases have bilateral involvement. Primary testicular lymphoma shows a tendency to disseminate to several extranodal sites, including the contralateral testis, CNS, skin, Waldeyer ring, lung, pleura, and soft tissues. Treatment using radiation therapy alone provides suboptimal disease control, even for patients with stage I disease. Chemotherapy without anthracyclines was shown to produce inferior results compared with regimens containing anthracyclines. Thus, R-CHOP is the regimen recommended by most lymphoma specialists following orchiectomy for testicular DLBCL, with a median OS of 4.4 years. Radiation therapy to the contralateral testis should also be administered.^105,108,109 CNS prophylaxis with intrathecal chemotherapy or high-dose methotrexate should be strongly considered because of the observed propensity for CNS relapses.

LYMPHOMA DURING PREGNANCY

Lymphoma is the fourth most frequent malignancy diagnosed during pregnancy, occurring in approximately 1 in 6000 deliveries.¹¹⁰ Reports of therapeutic interventions in pregnant patients with lymphoma are limited, and management recommendations are largely based on small retrospective studies and case reports. Both radiation therapy and chemotherapy during pregnancy are potentially teratogenic. Fetal exposure to antineoplastic agents may result in impaired growth, diminished neurologic and/or intellectual function, decreased gonadal and reproductive function, mutagenesis of germline tissue, and carcinogenesis.¹¹¹ The risks of treatment to the fetus are greatest during the first trimester and therapeutic abortion is a consideration under these circumstances. CHOP during the second and third trimesters may be administered relatively safely with little risk of significant adverse fetal outcomes.^112,113 The prognosis of patients who receive optimal chemotherapy is similar to that of nonpregnant patients.¹¹⁴

Only a few cases of rituximab administration during pregnancy have been reported, most of them for the treatment of nonmalignant disorders such as autoimmune diseases. Patients with supradiaphragmatic stage I disease may be considered for localized radiotherapy as a temporary measure until the second trimester, when chemotherapy holds less risk for the fetus.¹¹⁵ Patients in the second or third trimester should be treated with full-dose chemotherapy.

PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA

Definition

Primary mediastinal large B-cell lymphoma arises in the mediastinal lymphatic structures, probably from a thymic B-cell precursor.

Epidemiology

This variant type of DLBCL accounts for approximately 3 percent of lymphomas, and is most commonly seen in young and middle-aged adults, with about two-thirds of cases occurring in females.

Clinical Features

The clinical presentation is typically with an anterior mediastinal mass that is locally invasive into neighboring tissues including the lungs and pericardium. Upper airway obstruction and superior vena cava syndrome occur in approximately 40 percent of patients.¹¹⁶ Regional lymph nodes, especially the cervical chain, are often involved, but distant nodal involvement at presentation is uncommon with this entity. Relapses tend to be extranodal, including sites such as the liver, gastrointestinal tract, kidneys, ovaries, and CNS. Marrow involvement is very unusual.

Laboratory Features

PMBCL and Hodgkin lymphoma exhibit similar gene-expression profiles, raising questions about biologic relationships.^16,117 Sometimes bizarre multinucleated cells mimicking Reed-Sternberg cells are seen in PMBCL along with other morphologic features suggestive of Hodgkin lymphoma. Fibrotic bands may be prominent in biopsies, leading to the appellation “primary B-cell mediastinal lymphoma with sclerosis.” IHC may be helpful in the differential diagnosis since primary mediastinal lymphoma expresses weak CD30, lacks CD15 antigen as seen in Hodgkin lymphoma, and expresses B-cell–associated antigens CD19, CD20, CD22, and CD79a.¹¹⁸ Other useful markers include the melanocytic marker, HMB-45, keratin, and placental leukocyte alkaline phosphatase which can help distinguish PMBCL from sarcoma, melanoma, thymoma, and seminoma.

Therapy

Several regimens have been evaluated in PMBCL. A retrospective study compared the outcomes of 426 patients who had fibrotic tumor reactions (sclerosis) and previously untreated disease using CHOP-like regimens, third-generation (MACOP-B, VACOP-B [etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin], ProMACE CytaBOM) regimens, or high-dose chemotherapy with autologous hematopoietic stem cell transplantation.¹¹⁹ With chemotherapy, the CR rates were 49, 51, and 53 percent with first-generation, third-generation, and high-dose chemotherapy treatments, respectively. All patients who achieved CR or PR had radiation therapy to the mediastinum. The final CR rates were 61 percent for CHOP-like regimens, 79 percent for MACOP-B and other regimens, and 75 percent for high-dose chemotherapy/autologous hematopoietic stem cell transplantation. Projected 10-year PFS rates were 35, 67, and 78 percent, respectively, and projected 10-year OS rates were 44, 71, and 77 percent, respectively.

In another retrospective study of 138 patients with PMBCL the effectiveness of two chemotherapy regimens (CHOP vs. MACOP-B/VACOP-B) and the role of mediastinal IFRT as consolidation were evaluated.¹²⁰ CR occurred in 51 percent of the CHOP group and 80 percent in MACOP-B/VACOP-B. EFS was 40 percent with CHOP and 76 percent in the MACOP-B/VACOP-B group. The addition of IFRT improved the outcome, regardless of the type of chemotherapy used. The incorporation of rituximab in the dose-adjusted EPOCH regimen, without radiotherapy consolidation, resulted in 97 percent OS and 93 percent EFS in a nonrandomized, phase II clinical trial.¹²¹ Based on this study, which included 5-year followup data, many authorities believe that the dose-adjusted R-EPOCH regimen should be the preferred firstline regimen for this entity, without routine incorporation of radiotherapy.

LYMPHOMATOID GRANULOMATOSIS

Definition

Lymphomatoid granulomatosis is a rare lymphoproliferative disorder characterized by angiocentric and angiodestructive Epstein-Barr virus (EBV)–driven B-cell proliferation associated with extensive reactive T-cell infiltration.²

Epidemiology

Approximately two-thirds of cases occur in males. The median age of presentation is in the fifth decade of life, although pediatric cases occur.

Clinical Features

The lung is the most common site of involvement (90 percent), followed by the skin (25 to 50 percent), kidney (30 to 40 percent), liver (29 percent), and CNS (26 percent). The spleen and the lymph nodes are uncommonly involved.¹²² Nearly all patients are symptomatic at presentation with cough, dyspnea, chest pain, fever, weight loss, and joint pain. Abdominal pain and diarrhea occur as a result of gastrointestinal involvement and various neurologic signs, including diplopia, ataxia, and mental status changes may occur as a result of CNS involvement. Skin manifestations are clinically diverse, and include ulcerations, plaques, and maculopapules, although subcutaneous nodules are most common.

Laboratory Features

Imaging Studies Pulmonary involvement typically involves bilateral, lower lobe nodules, which frequently cavitate. Nodules may also be found in the brain and kidney and other locations.

Histopathology The grading of lymphomatoid granulomatosis depends upon the proportion of EBV-positive B cells identified by in situ hybridization with an EBV-encoded RNA probe relative to the number of reactive lymphocytes in the background.² Grade 1 lesions contain a polymorphous lymphoid infiltrate without cytologic atypia. Large transformed lymphoid cells are absent or rare and EBV-positivity is detectable in only a few cells. Grade 2 lesions contain occasional large lymphoid cells or immunoblasts in a polymorphous background. In situ hybridization for EBV readily identifies EBV-positive cells, which are present at 5 to 20 per high-power field. Grade 3 lesions continue to show an inflammatory background, but contain frequent large atypical B cells that are CD20-positive. By in situ hybridization, EBV-positive cells are numerous (>50/high-power field).

Therapy and Prognosis

The clinical prognosis is variable in lymphomatoid granulomatosis with a median survival of 2 years.¹²³ Poor prognostic features include neurologic involvement and higher pathologic grade. The disease is uncommon and the optimal treatment regimen is unclear. In a prospective study, patients with grades I and II disease were treated with interferon-α, whereas those with grade III lesions received dose-adjusted R-EPOCH chemotherapy.¹²⁴ Among 27 patients with grade I or II disease treated with interferon-α, 56 percent were in continuous CR for a median of 52 months. Among grade III patients treated with dose-adjusted R-EPOCH, 40 percent achieved CR, with OS and PFS rates of 69 and 82 percent, respectively, after a median follow up of 46 months.

INTRAVASCULAR LARGE B-CELL LYMPHOMA

Definition

Intravascular large B-cell lymphoma is a rare type of extranodal large B-cell lymphoma characterized by selective growth of lymphoma cells within the lumina of vessels, sparing the large arteries and veins.²

Epidemiology

This tumor usually occurs in adults in the sixth and seventh decade. It occurs equally in men and women.

Clinical Features

The clinical manifestations of this lymphoma are extremely variable, with most symptoms related to the organs affected. Two major patterns of clinical presentation have been recognized: the first is in European countries with brain and skin involvement and the second in the Asian countries where patients typically present with multiorgan failure, hepatosplenomegaly, pancytopenia and hemophagocytic syndrome.^{125,126,127,128,129} B symptoms (fever, drenching sweats, and weight loss) are common in both types. An isolated cutaneous variant almost unique to Western countries has been identified in females and is associated with a better prognosis.¹²⁵ In this variant, skin lesions range from single to striking clusters of nodules and tumors which may appear as violaceous plaques, erythematous nodules, or ulcerating tumors, which are often painful. These lesions commonly appear on the arms and legs, abdomen and breasts, but may occur anywhere.

Laboratory Features

There are no laboratory findings specific for intravascular B cell lymphoma. Increased LDH and β₂-microglobulin levels are observed in most patients. An elevated erythrocyte sedimentation rate and abnormalities in hepatic, renal, and thyroid function are also common.¹³⁰ Tumor cells express B-cell–associated antigens and occasionally express CD5.

Therapy

Anthracycline-based chemotherapy is the standard of care for this type of lymphoma and retrospective studies suggest that the addition of rituximab improves clinical outcomes.^131,132 One study analyzed 106 patients who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57).¹³² The CR rate was 82 percent for patients in the R-chemotherapy group compared to 51 percent in the chemotherapy-alone group (p = 0.001). PFS and OS rates 2 years after diagnosis were 56 and 66 percent, respectively, in the R-chemotherapy group, compared with 27 and 46 percent for patients in the chemotherapy-alone group (p = 0.001 for PFS and p = 0.01 for OS). More intensive chemotherapy including high-dose methotrexate and/or high-dose cytarabine are recommended for patients with CNS involvement (e.g., R-CHOP with high-dose methotrexate). Many authorities believe that CNS prophylaxis is warranted even in cases of intravascular large cell lymphoma without demonstrable CNS disease at diagnosis, because of the high rate of CNS relapse.

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS

Definition

Posttransplantation lymphoproliferative disorders (PTLD) result from lymphoid or plasmacytic proliferations that develop in the setting of solid-organ or marrow transplantation. Although PTLD represents an uncommon complication in transplant patients, it is a significant cause of morbidity and mortality.¹³³

Epidemiology

The incidence of PTLD is approximately 1 to 2 percent in solid-organ transplant recipients, which is 30 to 50 times higher than the incidence of lymphoproliferative diseases in the immunocompetent general population.¹³⁴ There is a clear association between PTLD and the type of organ transplanted. Among the most commonly transplanted solid organs, heart, lung, and intestinal transplantation have the highest incidences of PTLD,¹³⁵ with the highest risk occurring in the first year after transplantation. The incidence of PTLD after blood or marrow transplantation is lower than after solid-organ transplantation and ranges from 0.5 to 1.0 percent in reported series.

Pathogenesis

The major risk factors that have been identified for the development of PTLD include EBV-positive serology pretransplantation, type of organ transplanted, and intensity of immunosuppressive regimen used.^136,137,138 The onset of posttransplantation lymphoma in most patients is related to B-cell proliferation induced by infection with EBV in the setting of chronic immunosuppression. The genome of the virus can be detected in the cells of the majority of cases.¹³⁹ However, in approximately 20 to 30 percent of cases the virus is undetectable in involved tissues.¹⁴⁰ Involvement of the lymph nodes, gastrointestinal tract, lungs, and liver are common with all types of allografts. The majority of PTLDs in solid-organ transplant recipients are of host origin. In contrast, the majority of PTLDs in hematopoietic stem cell allografts are of donor origin. Involvement of the grafted organ occurs in approximately 30 percent of patients and may lead to organ damage and fatal complications.¹⁴¹

Therapy

Management of PTLD is not uniform. A wide variety of approaches, including decreasing the dose of immunosuppressive drugs or administering antiviral therapy, interferon, intravenous immunoglobulin, adoptive therapy with EBV-specific cytotoxic T lymphocytes, chemotherapy, radiation, and rituximab therapy, have been reported. If feasible, reduction of immunosuppression is the first step in the management of such patients. Many cases of polyclonal PTLD resolve completely with a reduction in immunosuppressive therapy.¹⁴² Patients with late PTLD and more aggressive monoclonal PTLD are less likely to respond.¹⁴³ Rituximab has shown promising results in the treatment of CD20+ PTLD. In a multicenter prospective trial, 43 patients with previously untreated B-cell PTLD who failed to respond to tapering of immunosuppression, were treated with 4 weekly injections of rituximab at 375 mg/m².¹⁴⁴ The overall response rate was 44 percent, with an OS of 86 per cent after 80 days and 67 percent after 1 year. The only baseline factor predicting response at day 80 was a normal level of serum LDH. A retrospective study evaluated the efficacy and safety of chemotherapy salvage therapies in adult recipients of solid-organ transplants with a second progression of PTLD after initial therapy with rituximab.¹⁴⁵ CHOP therapy achieved a favorable overall response rate of 70 percent in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following initial therapy with rituximab.

A prospective trial evaluated a stepwise treatment approach beginning with reduction of immunosuppression, then interferon-α, and finally chemotherapy with ProMACE-CytaBOM plus granulocyte-monocyte colony-stimulating factor.¹⁴⁶ Sixteen eligible patients began treatment with reduced immunosuppression. The response rate to reduced immunosuppression was zero of 16 CR and one of 16 PR (6 percent). Six of the 16 patients (38 percent) had documented rejection of the transplanted organ during the period of reduced immunosuppression. Eight of the 16 patients had documented progressive disease during the period of reduced immunosuppression. Thirteen patients underwent treatment with interferon, with two patients achieving CRs (15 percent) and two achieving PRs (15 percent). Seven eligible patients proceeded to ProMACE-CytaBOM chemotherapy with five (67 percent) attaining CR. Four of the five CRs experienced remission durations of more than 2 years. The median survival for the treatment cohort as a whole was 19 months, with a range of 5 days to 60+ months. Overall survival was 50 percent at 2 years, 44 percent at 4 years, and 24 percent at 8 years.

The following sequence is currently recommended for PTLD: The first intervention should be reduction in immunosuppression, followed by four weekly cycles of rituximab if reduction of the immunosuppression by itself is ineffective. If PTLD does not regress with these measures, then six cycles of R-CHOP are recommended.

T-CELL–HISTIOCYTE-RICH LARGE B-CELL LYMPHOMA

Definition

T-cell–histiocyte-rich large B-cell lymphoma is characterized by effacement of the architecture of the lymph node by a lymphohistiocytic infiltrate with a diffuse or vaguely nodular growth pattern.^2,147 There are a limited number of large atypical B cells occurring singly or in small clusters with a predominant background infiltrate composed of T cells and histiocytes, the latter usually of the nonepithelioid type.

Epidemiology

T-cell–histiocyte-rich large B-cell lymphoma accounts for less than 5 percent of all cases of DLBCL and occurs at a younger age on average. The median age of onset is in the fourth decade, compared to the sixth decade for DLBCL.^{148,149,150,151} A male predominance is noted in most series, in contrast to DLBCL not otherwise specified, which occurs equally in men and women.

Clinical Features

This variant more often presents with advanced stage disease, B symptoms, an elevated LDH, splenic infiltration and multiple extranodal sites (especially the marrow and liver) compared to standard DLBCL.^{148,149,150,152}

Therapy and Prognosis

When treated with CHOP-like regimens, most series suggest that the outcome for these patients is similar to patients with typical DLBCL,^{149,151,152,153,154} with CR rates of approximately 60 percent, and 3-year and 5-year OS rates of 50 to 64 percent and 45 to 58 percent, respectively. Two case-control analyses have been performed comparing T-cell–histiocyte-rich large B-cell lymphoma and DLBCL with no differences in OS observed.^149,150 Based on these data, this subtype of large B-cell lymphoma should be treated in the same fashion as traditional DLBCL. Six cycles of R-CHOP for advanced disease is a reasonable initial approach to therapy.

PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA, LEG TYPE

Definition

This lymphoma is a primary cutaneous lymphoma composed solely of large transformed B cells that exhibits a predilection for the skin of the leg.²

Epidemiology

Primary cutaneous DLBCLs of the leg type constitute approximately 4 percent of all primary cutaneous B-cell lymphomas.^2,155 The median age at the time of presentation is 60 to 70 years.

Clinical Features

These lymphomatous tumors affect the skin of the legs in most cases, but approximately 10 percent arise at other sites.^156,157,158 Multiple tumors, sometimes ulcerating, are associated with poorer prognosis. There are frequent relapses and extracutaneous dissemination may occur.

Laboratory Features

The malignant B cells in this entity usually express CD20, BCL2, and FOX-P1. FISH of the lymphoma cells often detects translocations involving MYC, BCL6, or IGH genes. Amplification of the BCL2 gene is usually responsible for the high frequency of BCL2 overexpression. The t(14;18) translocation is generally not observed in this lymphoma variant. The gene-expression profile observed in this subtype suggests an activated B-cell origin.

Therapy

Anthracycline-containing chemotherapy with rituximab should be considered as initial therapy. The incorporation of rituximab improves the response rates and OS.^156,157,158 However, because of the advanced age of most patients with this variant at the time of diagnosis, aggressive combination chemoimmunotherapy may not be feasible due to patient frailty or comorbidities. In such circumstances, local radiation therapy or less-aggressive chemotherapy are reasonable.

ANAPLASTIC LYMPHOMA KINASE-POSITIVE LARGE B-CELL LYMPHOMA

Definition

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is an uncommon neoplasm of large immunoblast-like B cells that stain for nuclear and/or cytoplasmic ALK protein.

Epidemiology

The average age at presentation is in the fourth decade with a male predilection. Most patients present with advanced stage disease.

Clinical Features

Patients with anaplastic DLBCL usually present with widespread disease, with cervical and mediastinal nodes being the most frequent sites of adenopathy, and the liver, spleen, bone and gastrointestinal tract being the most common sites of extranodal involvement.^159,160

Laboratory Features

The immunoblastic cells of anaplastic DLBCL typically have a large central nucleolus and may exhibit maturation to plasmablastic cells. The lymphoma cells stain for the ALK protein by immunohistocytochemistry, usually with a granular cytoplasmic appearance though nuclear staining may also occur. These cells are usually negative for CD3, CD20, CD30, and CD79a. MUC1 mucin, a high-molecular-weight transmembrane glycoprotein, also known as epithelial membrane antigen and CD138 are usually strongly expressed by these cells. Monoclonal (light-chain restricted) IgA or IgG is generally present in the cytoplasm of the malignant cells. Occasional cases possess a t(2;17)(p23;q23) translocation that results in a clathrin-ALK fusion protein.

Therapy and Prognosis

The clinical course of ALK-positive large B-cell lymphoma is aggressive with a median survival time of 24 months. Because the tumors are usually negative for CD20, the utility of rituximab is dubious for this entity. Anthracycline-based chemotherapy is often inadequate and more intensive therapies should be considered.^159,160

HUMAN IMMUNODEFICIENCY RELATED DIFFUSE LARGE B-CELL LYMPHOMA VARIANTS

Primary effusion lymphoma, plasmablastic lymphoma, and large B-cell lymphoma arising in human herpesvirus-8–associated multicentric Castleman disease usually develop in the setting of acquired immunodeficiency induced by HIV and are discussed in Chap. 81.