Clifton Mo, Mark Roschewski, Kieron Dunleavy, and Wyndham Wilson
The term non-Hodgkin lymphoma (NHL) encompasses a diverse group of lymphoproliferative disorders of B-cell, T-cell, and NK-cell origin that together account for approximately 90% of all lymphomas diagnosed in the United States. Although unified in their histopathologic distinction from Hodgkin lymphoma, these disorders vary considerably in morphologic appearance, clinical behavior, therapeutic options, and prognosis. The past two decades have seen significant therapeutic advancements as well as progress in our understanding of the genetic and molecular basis of the different NHL subtypes.
EPIDEMIOLOGY
NHL is the seventh most common adult malignancy in the United States, with 70,130 new cases expected to be diagnosed in 2012. The overall incidence of NHL has increased substantially over the past several decades, almost doubling between 1975 and 1995. Since the mid-1990s, however, this trend has become progressively less pronounced, with overall incidence rates stabilizing between 2005 and 2009. Although incompletely understood, these changes in NHL incidence have been attributed to a variety of factors such as the emergence of (and subsequent advancements in therapy for) HIV/AIDS, improvements in detection and reporting of NHL, and reduction in mortality rates from other causes.
The risk of developing NHL increases with each decade of adult life. Certain subtypes of NHL, however, such as primary mediastinal B-cell lymphoma (PMBL) and Burkitt lymphoma (BL), tend to occur in younger patients. Although NHL occurs within all ethnic groups, it is most common in the Caucasian population. There is also considerable geographic disparity in NHL incidence, with the highest rates seen in North America, Australia, and Western Europe, and the lowest rates seen in Asia, South America, and the Caribbean.
There has long been speculation that certain environmental or lifestyle factors may contribute to the increased incidence of NHL. Although a variety of positive associations have been identified in recent years (i.e., exposure to organic solvents and hair dyes, smoking, BMI, high-fat diet, alcohol abstinence), these associations have generally been weak, inconsistent between studies, and confounded by various methodologic limitations. Consequently, the extent to which these external factors affect overall or subtype incidence rates remains unclear at this time, and further study is clearly warranted.
PATHOGENESIS AND MOLECULAR CHARACTERIZATION
The process of lymphomagenesis in NHL involves a complex interplay between genetic mutations that disrupt the normal cellular pathways of proliferation, differentiation, and apoptosis. These mutations lead to activation of proto-oncogenes and/or inactivation of tumor suppressor genes vital to the maintenance of regulated cellular proliferation. Balanced chromosomal translocations, thought to serve as inciting events in lymphomagenesis in NHL, are identified in a substantial percentage of cases (Tables 28.1 and 28.2). The notable exception is chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), which is characterized by a predominance of partial chromosomal deletions (13q–, 11q–, 17p–) and a conspicuous absence of balanced translocations.
Disorders of the immune system, often in conjunction with chronic viral infection, are also heavily implicated in lymphomagenesis and are associated with increased risk of NHL. Significantly higher rates of NHL are seen in patients with congenital and acquired immunodeficiencies as well as diseases of immune dysregulation. Though most of these lymphomas are of B-cell lineage, there are notable exceptions such as enteropathy-associated T-cell lymphoma (EATL), which occurs most commonly in patients with gluten enteropathy, and hepatosplenic T-cell lymphoma (HSTCL), which occurs in patients with inflammatory bowel disease or post–solid organ transplantation.
Epstein-Barr virus (EBV) is implicated in the pathogenesis of many different subtypes of NHL that occur in the immunocompromised host. Within the HIV-infected population, EBV is strongly associated with primary CNS lymphoma (PCNSL) and plasmablastic lymphoma, oral type. It is also seen in immunodeficient patients with primary effusion lymphoma (PEL), plasmablastic lymphoma, and posttransplant lymphoproliferative disorder (PTLD). EBV is also pathogenically implicated in a number of NHL subtypes in immunocompetent patients. In many of these lymphomas, EBV is thought to drive lymphomagenesis by constitutively activating NF-κB and other cell signaling pathways, while in other lymphomas its pathogenic role remains unknown.
Various other infectious pathogens have also been implicated in the development of NHL subtypes, such as HHV-8 and HTLV-1. Marginal zone lymphoma (MZL) is known to be antigenically driven by both viral and bacterial pathogens, to include hepatitis C virus (HCV) in splenic and nodal MZL variants, Helicobacter pylori in gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and Chlamydia psittaci in ocular adnexal MALT lymphoma (OAML).
CLASSIFICATION
NHL is classified according to the 2008 update of the World Health Organization (WHO) classification system. Initially established in 2001, this system constituted the first international consensus on diagnosis and classification of lymphoma. Within this system, NHL is classified primarily by cell lineage and maturity (B- vs. T/NK cell, mature vs. precursor cell of origin) and then further subcategorized according to a combination of morphologic, immunophenotypic, genetic, molecular, and clinical features. It is expected that the current classification system for NHL will continue to evolve as our knowledge of the genetic and molecular basis of these diseases continues to improve.
DIAGNOSIS
A properly evaluated and technically adequate excisional lymph node biopsy remains the gold standard for diagnosis of suspected lymphoma. In recent years, some centers have adopted the practice of obtaining a combination of core-needle biopsy and fine-needle aspiration as an alternative to surgical lymph node excision, reserving the latter for nondiagnostic cases. Although this approach is relatively sensitive and cost-effective, a definitive diagnosis is unobtainable in approximately 20% to 25% of patients. Consequently, multiple factors—including include perioperative risk, institutional experience with core-needle biopsy, and risk of possible delay in diagnosis—need to be considered when deciding upon the preferred approach to biopsy.
Diagnosis of NHL is achieved primarily through a combination of morphologic and immunohistochemical tissue analysis. Important additional studies for diagnostic confirmation and subclassification often include flow cytometry, cytogenetic analysis, and molecular studies. Testing for specific oncogenic chromosomal rearrangements or staining for overexpression of their corresponding oncoproteins can also be diagnostically useful in a number of NHL subtypes (see Tables 28.1 and 28.2).
WORKUP AND STAGING
Initial workup and staging evaluation of NHL should include a complete history and physical examination and clinical laboratory assessment of organ function. In addition, the following tests should be performed:
■Complete blood count with differential
■Complete metabolic panel to include lactate dehydrogenase (LDH)
■Serologies for HIV, HBV, HCV (regardless of exposure history)
■CT scan of the chest, abdomen, and pelvis
■Whole-body FDG-PET scan (strongly consider for aggressive lymphomas, or if concern exists for extranodal disease)
■Bone marrow (BM) aspirate and biopsy
■Lumbar puncture with CSF cytology and flow cytometry (patients at increased risk for central nervous system [CNS] disease: BL, ALL, intravascular lymphoma, elevated LDH, multiple extranodal sites, or involvement of BM, testis, or paranasal sinuses)
The Ann Arbor staging system, originally designed for Hodgkin lymphoma, also has prognostic and predictive utility in NHL, and its use is considered standard for newly diagnosed cases (Table 28.3). Although this system is often of limited prognostic value due to the lack of contiguous orderly spread through lymph node regions, it nevertheless remains an integral component of the validated international prognostic indices for aggressive NHL (IPI) and follicular lymphoma (FLIPI).
Restaging for Response Evaluation
Upon completion of therapy, staging studies should be repeated (CT scan and BM biopsy if positive previously). In accordance with the Revised Response Criteria for Malignant Lymphoma, FDG-PET is also useful for the evaluation of residual masses at the completion of therapy. In cases of suspected disease relapse or refractoriness to initial therapy, repeat biopsy should be performed whenever possible, both to exclude nonmalignant causes of the abnormal imaging or findings in question and to evaluate for possible transformation of disease.
PROGNOSTIC FEATURES
The International Prognostic Index (IPI) applies to untreated aggressive lymphoma. Five clinical factors comprise the IPI and 1 point is assigned to each factor:
–Age >60 years
–Eastern Cooperative Oncology Group (ECOG) performance status 2 or higher
–LDH level greater than normal
–Two or more extranodal sites
–Ann Arbor stage III or IV disease
Scores of 0 to 1, 2, and 3, and 4 to 5 correspond to 5-year survivals of 73%, 51%, 43%, and 26%, respectively. A validated clinical prognostic index has also been applied to patients with untreated follicular lymphoma. The Follicular Lymphoma International Prognostic Index (FLIPI) is scored according to age, stage, serum LDH level, hemoglobin, and the number of nodal areas, and has been found to reliably predict survival. In recent years, gene expression profiling has emerged as a useful means of identifying molecularly distinct subclassifications of NHL, and is likely to either augment or supplant current prognostic and predictive tools in the future. At this time, however, this technology remains investigational and not readily applicable to standard practice.
MANAGEMENT
Indolent B-Cell Non-Hodgkin Lymphoma
Follicular Lymphoma
FL is the most common of the indolent lymphomas, constituting approximately 70% of cases. Patients are typically older (median age of 60) with disseminated lymphadenopathy at diagnosis. Constitutional symptoms and extranodal involvement can occur, but are uncommon. Many patients are asymptomatic at diagnosis. Median survival is approximately 10 years. Histologic transformation to a more aggressive NHL subtype (typically DLBCL) occurs at an approximate cumulative rate of 3% per year. FL is graded (1–3) according to the number of centroblasts per high power field. Therapeutic approaches to grades 1 to 3A are similar, whereas grade 3B is considered a variant of DLBCL for the purposes of treatment.
FL is generally considered to be an incurable malignancy. Patients with early-stage FL, however, may achieve prolonged remissions and long-term survival with radiation treatment alone. Multiple studies have reported a 15-year overall survival rate of approximately 50% in these patients, with few relapses reported after 10 years. For patients with asymptomatic advanced-stage FL, chemotherapy has not been shown to improve OS compared to watchful waiting. In recent years, the anti-CD20 monoclonal antibody, rituximab, has demonstrated both safety and efficacy in follicular lymphoma with response rates of up to 73% in previously untreated patients. However, there is not yet evidence of a survival benefit to rituximab in the first-line setting in asymptomatic patients, and this approach is still considered investigational. In therapy-naive patients with symptomatic advanced FL by the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria, the addition of rituximab to chemotherapy is now considered the standard of care due to the significantly higher response rates and OS achieved over chemotherapy alone in multiple studies. Although no chemoimmunotherapy regimen has yet demonstrated superior survival over another, the combination of bendamustine and rituximab (BR), in an early report, demonstrated superior progression-free survival (PFS) and reduced toxicity compared to the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) in patients with low-grade NHL (predominantly FL). Patients not able to tolerate chemotherapy may be given single-agent rituximab. Extended treatment with rituximab, or “maintenance” rituximab, has been shown to extend PFS, although no OS advantage has yet been demonstrated.
Patients with relapsed/refractory FL can be treated with combination chemoimmunotherapy, single-agent rituximab, or radioimmunotherapy. The latter involves the delivery of targeted radiotherapy to tumor tissue by conjugating an anti-CD20 antibody to a radioactive isotope. In a randomized trial of relapsed or refractory follicular or transformed lymphoma, the overall response rate was better with ibritumomab tiuxetan than with rituximab (80% vs. 56%). However, a recently published phase III intergroup trial evaluating the role of radioimmunotherapy in newly diagnosed FL patients (R-CHOP versus CHOP followed by 131Iodine tositumomab) demonstrated similar PFS and OS in both groups at median 5 years of follow-up. Further studies of radioimmunotherapy in FL should better define the true benefit and optimal use of this treatment modality.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
SLL represents the less common lymphomatous/aleukemic phenotype of CLL and both diseases are considered to be biologically the same. Median age at diagnosis is 72, and many patients are asymptomatic at diagnosis. Similar to FL, treatment is only indicated for symptomatic disease.
CLL/SLL is a clinically heterogeneous disease, ranging from stability or slow progression for years without treatment (most commonly the 13q– variant) to rapidly progressive disease with a high degree of resistance to conventional therapy (17p– variant). Chemoimmunotherapy regimens containing fludarabine and rituximab are considered standard of care for first-line therapy. The OS benefit of adding rituximab to chemotherapy was recently demonstrated in the German CLL8 trial which randomized patients to fludarabine, cyclophosphamide, and rituximab (FCR) versus FC alone. FCR and FR are both acceptable first-line therapies; although rates of complete response and PFS seem to be superior with FCR, it is a more toxic regimen than FR and there has yet to be a proven survival benefit. In patients with the 11q deletion, however, recent data indicate that the inclusion of cyclophosphamide may overcome the adverse prognostic significance of this genetic lesion. In elderly patients and those unlikely to tolerate FCR, options include FR, “FCR-lite” (reduced doses of FC with higher doses of R), BR, lenalidomide, or alemtuzumab. In contrast to FL, single-agent rituximab does not possess sufficient activity to warrant its use in CLL/SLL.
For relapsed/refractory CLL/SLL, any of the aforementioned regimens or agents can be used. Additionally, the second-generation anti-CD20 monoclonal antibody, ofatumumab, was recently FDA approved for CLL/SLL refractory to fludarabine and alemtuzumab. Compared to rituximab, ofatumumab binds with higher affinity to CD20 and has a response rate of over 50% in these “double-refractory” CLL patients. Studies combining ofatumumab with chemotherapy are ongoing.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains an option for relapsed/refractory CLL/SLL. There is evidence of a strong and durable graft-versus-leukemia effect in patients transplanted for this disease, making it the only CLL therapy capable of achieving cure. Given the substantial risks and morbidity associated with this approach, however, it is generally reserved for patients who have failed conventional therapy and those with relapsed high risk (17p–) or transformed disease.
Lymphoplasmacytoid Lymphoma/Waldenström Macroglobulinemia
This is an indolent but incurable lymphoma composed of mature plasmacytoid lymphocytes that produce monoclonal IgM. It primarily affects older patients and is most common in the Caucasian population. Patients typically present with symptoms of increased tumor burden (cytopenias due to marrow involvement, hepatosplenomegaly, lymphadenopathy, constitutional symptoms) and/or symptoms attributable to the secreted monoclonal immunoglobulin (hyperviscosity syndrome, autoimmune neuropathy, mucocutaneous bleeding). Asymptomatic patients are considered to have “smoldering” WM and are observed. Symptomatic disease occurs in approximately 60% of patients within 5 years after diagnosis.
Options for therapy include single-agent rituximab, chemoimmunotherapy regimens such as FR or BR, and rituximab combined with novel agents such as bortezomib. When rituximab is used, the patient must be observed carefully for development or worsening of hyperviscosity symptoms, as serum IgM levels can increase abruptly and substantially prior to declining. Plasmapheresis prior to rituximab-containing therapy should be strongly considered for any patient presenting with symptoms of hyperviscosity or high baseline serum IgM.
Marginal Zone Lymphomas
These are indolent lymphomas, comprising approximately 10% of NHL, that occur primarily in extranodal MALT (EMZL or MALT lymphomas), and to a lesser extent within the spleen (splenic MZL) and lymph nodes (nodal MZL). The majority of EMZL occurs within the gastrointestinal tract (most commonly the stomach), but can also occur in the parotid and salivary glands, thyroid, lungs, ocular adnexae, and breast, among others. Most patients present with localized disease, and 5-year survival is approximately 90%. EMZL is highly antigen driven, and a history of chronic infection such as Helicobacter pylori-associated gastritis in gastric MALT lymphoma or Chlamydiphila psittaci in ocular adnexae MALT lymphoma is common. With current antibiotic regimens, the majority of patients with early-stage gastric MALT lymphoma will achieve sustained remission with bacterial eradication alone. Likewise, recent data indicate that eradication of C. psittaci with doxycycline can induce clinical remission in a substantial percentage of patients with ocular adnexae MALT lymphoma. For patients with advanced or antibiotic-refractory disease, or those with MALT subtypes not associated with known infectious agents, therapeutic options include rituximab, chemoimmunotherapy regimens similar to those used in FL, and radiation.
Splenic MZL accounts for approximately 20% of MZL, and typically presents with splenomegaly and BM involvement. Five-year overall survival is approximately 80%. Splenectomy has been the historical standard of care; however, rituximab is increasingly being used as an alternative or adjunct to surgical therapy, and in a recent prospective trial, was shown to significantly improve disease-free survival compared to splenectomy. Similar to EMZL, splenic MZL can also be antigen driven; approximately one-third of cases are associated with the HCV, and many of these patients can enter remission with antiviral therapy alone. Nodal MZL is the least common MZL, and is characterized by nodal disease in the absence of a mucosal component. The clinical course of nodal MZL tends to be less indolent than its extranodal or splenic counterparts, and 5-year overall survival is lower at just over 50%. Although it can also be associated with HCV, it is typically not associated with a known infectious etiology. The therapeutic approach for nodal MZL follows that of FL.
Aggressive B-Cell Non-Hodgkin Lymphoma
Diffuse Large B-Cell Lymphoma
DLBCL is the most common NHL subtype, accounting for approximately 30% of all cases. Although it is most commonly diagnosed in the seventh decade of life, DLBCL can occur at any age. DLBCL can occur either de novo or as a transformation from a more indolent NHL subtype. Gene expression profiling can classify most DLBCL into two molecularly distinct subtypes, germinal center B cell (GCB) and activated B cell (ABC), with the latter being less curable with standard therapies. Although novel agents targeting the B-cell receptor signaling pathway (such as ibrutinib, a first-in-class inhibitor of Bruton Tyrosine Kinase or BTK) are showing great promise in ABC-type DLBCL and may ultimately improve long-term outcomes in these patients, they have not been studied in the first-line setting and are not yet commercially available. Consequently, the GCB/ABC distinction cannot yet be used to guide choice of initial therapy for DLBCL.
Patients with both early-stage and advanced DLBCL are treated with systemic chemoimmunotherapy with curative intent. In multiple studies, R-CHOP given every 21 days (R-CHOP-21) has been shown to significantly improve response rates, PFS, and OS compared to CHOP alone in previously untreated patients with advanced disease, and consequently this regimen is now considered standard. The addition of IFRT to an abbreviated course of systemic therapy is considered an option in patients with early-stage DLBCL, although such an approach has failed to demonstrate survival benefit over chemoimmunotherapy alone and introduces the risk of long-term complications of radiation treatment. Likewise, the use of “dose-dense” R-CHOP with myeloid growth factor support (R-CHOP-14) has failed to demonstrate superiority over standard R-CHOP-21, with a trend toward increased toxicity. Dose intensity may still have a role in DLBCL, however, as the dose-intensive regimen of R-ACVBP recently demonstrated superior 3-year PFS and OS in untreated DLBCL patients aged 18 to 59 with low-intermediate IPI compared to R-CHOP. Although serious adverse events were more than twice as common with R-ACVBP, it nevertheless remains a promising regimen that can be considered for younger patients. Dose-adjusted (DA) EPOCH-R is another alternative regimen that has shown promising results in phase II trials and is currently being evaluated against R-CHOP-21 in the phase III setting. This regimen has a lower observed incidence of cardiac toxicity compared to R-CHOP and can be considered for patients in whom this is a concern.
Primary mediastinal B-cell lymphoma (PMBL) is a subtype of DLBCL that clinically and biologically more closely resembles classical Hodgkin lymphoma than other subtypes of DLBCL. Standard treatment approaches in the past have involved chemotherapy followed by mediastinal radiation. While combined modality therapy has been very effective in most patients, mediastinal radiation is associated with long-term sequelae and increased risks of cardiac disease and secondary tumors, particularly breast cancer in females. Recently, the DA-EPOCH-R regimen has demonstrated high efficacy in this disease, obviating the need for radiation in almost all patients.
Up to 10% of patients with DLBCL harbor t(8;14) with overexpression of MYC, and many of these patients are also positive for t(14;18) with overexpression of BCL2 (so-called “double-hit” lymphoma). Many of these tumors may fit into the WHO category of “B-cell lymphoma unclassifiable with features intermediate between BL and DLBCL.” In several retrospective studies, these patients have demonstrated inferior outcomes with standard therapies. The optimal management of patients with “double-hit” lymphoma is currently unknown.
Primary CNS Lymphoma
PCNSL is a rare and aggressive lymphoma that is confined to the CNS (brain parenchyma, meninges, cranial nerves, eyes, spinal cord). It is of DLBCL histology in over 95% of cases, and can occur in both immunocompetent and immunocompromised patients. It most commonly affects the brain parenchyma, although there can be concomitant or isolated leptomeningeal involvement in approximately 20% of cases. Intraocular involvement is also common, and in some cases can predate the development of brain lesions by months.
PCNSL is not effectively treated by standard DLBCL chemoimmunotherapy regimens due to inability of the component agents to penetrate effectively through the blood–brain barrier. High-dose methotrexate (3 to 3.5 g/m2) achieves therapeutic levels within the CSF and produces high response rates and 5-year OS of 20% to 40%. In a recent randomized trial, the addition of high-dose cytarabine to high-dose methotrexate improved both response rates and OS, and consequently this combination is now considered standard of care in medically fit patients. The role of radiotherapy as an adjunct to chemotherapy remains controversial, as it is associated with significant and sometimes disabling neurotoxicity. Patients not achieving CR to chemotherapy are generally offered WBRT. Studies assessing the utility of postchemotherapy WBRT in patients achieving CR to chemotherapy are ongoing.
Burkitt Lymphoma
BL is a highly aggressive but curable lymphoma, accounting for 1% to 2% of lymphomas in the United States. The majority of cases in the United States and Western countries are either sporadic or associated with immunodeficiency, typically affecting children and young adults and demonstrating EBV positivity in 30% to 50% of cases. Endemic BL, by contrast, is strongly associated with EBV infection and is highly prevalent in young children in equatorial Africa. Whereas endemic BL presents most commonly with jaw and facial bone disease, sporadic BL tends to present with bulky abdominal disease. Involvement of the BM, GI tract, and CNS are also common. All variants of BL are characterized by acute clinical onset and rapid disease progression without therapy.
Dose-intensive multiagent chemotherapy regimens incorporating high-dose methotrexate, high-dose cytarabine, and intrathecal chemotherapy (CODOX-M/IVAC, hyper-CVAD) are commonly used to treat BL, with approximately 60% to 80% of patients achieving long-term survival. The addition of rituximab to intensive chemotherapy was recently shown to improve EFS and OS in a randomized trial of over 250 patients with HIV-negative BL, and is now considered standard in most BL regimens. Additionally, a recent study of DA-EPOCH-R in BL yielded an event-free survival (EFS) of 97% at a median follow-up of 57 months. A confirmatory multicenter study of this regimen in BL and MYC+ DLBCL is ongoing.
Mantle Cell Lymphoma
MCL is an incurable and variably aggressive lymphoma. Median age at diagnosis is 60, and the majority of those affected are men. Patients commonly present with advanced disease, splenomegaly, and involvement of the BM, peripheral blood, and GI tract. Virtually all cases of MCL harbor t(11;14) with resultant overexpression of cyclin D1, although a small minority of MCL can be negative for this translocation.
Although response rates to chemotherapy are high in MCL, remissions tend to be short-lived and historic median survival is approximately 3 to 6 years. The recently developed mantle cell IPI (MIPI) classifies patients into prognostic categories based upon age, performance status, LDH, and WBC count, and can aid in therapeutic decision making. Given that a subset of MCL behaves in an indolent manner, watchful waiting is a reasonable approach in asymptomatic patients with a low risk MIPI. For symptomatic patients or those with a high risk MIPI, therapeutic options include standard chemotherapy (R-CHOP, BR, DA-EPOCH-R) or dose-intensive chemotherapy such as R-hyper-CVAD; although the latter approach has recently yielded impressive results (7-year OS of 68%), it has also been associated with considerable toxicity, especially in older patients.
High-dose chemotherapy with autologous stem cell rescue (HDT/ASCR) in first remission has been studied and may extend PFS over chemotherapy alone. However, this approach has not yet been shown to improve survival. Nonmyeloablative allogeneic SCT is still considered investigational, although at this time it remains the only potentially curative option. Novel agents such as bortezomib, lenalidomide, and temsirolimus have recently demonstrated significant activity in relapsed/refractory MCL, and are currently being studied in combination with chemotherapy and with each other in the first-line setting.
T/NK-Cell NHL
The term “peripheral T-cell lymphoma” (PTCL) encompasses the various lymphomas derived from mature T and natural killer (NK) cells, whereas “lymphoblastic lymphoma” (LBL) refers to the lymphomatous manifestation of acute lymphoblastic leukemia, a disorder of precursor/immature lymphocytes (most commonly of T-cell origin) that is addressed elsewhere in this handbook. T-cell lymphomas are less common than B-cell lymphomas, accounting for approximately 10% to 15% of NHL. Their behavior ranges from indolent to aggressive, although the majority are relatively aggressive lymphomas with poor response rates to chemotherapy and poor OS relative to B-cell lymphomas. There are notable exceptions, however, such as ALK-positive anaplastic large cell lymphoma (ALCL) and mycosis fungoides (MF) with limited skin disease, which have excellent prognoses. Although various distinct disease entities exist within the realm of PTCL, the most common subclassification remains “PTCL-not otherwise specified,” underscoring the need for further elucidation of the genetic and molecular basis of these diseases.
Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL-NOS)
This subclassification includes all T-cell lymphomas not identified as clinicopathologically distinct by the WHO classification. They are generally aggressive lymphomas that affect men disproportionately, present with both nodal and extranodal diseases, and respond poorly to CHOP-like chemotherapy, with 5-year OS of approximately 30% to 40%. Dose-intensive regimens such as hyper-CVAD have not been shown to improve outcomes over CHOP. A recent study of upfront HDT/ASCT in PTCL demonstrated good results, with long-term PFS of 44%. Although this approach is promising, randomized studies to assess the true benefit of HDT/ASCR are needed.
Several novel agents have demonstrated activity in relapsed/refractory PTCL in recent years, and are currently being evaluated in combination with chemotherapy and in the first-line setting. These include the histone deacetylase inhibitor, romidepsin, and the novel antifolate, pralatrexate, which have both been recently FDA approved for relapsed/refractory PTCL. Other agents being studied include alemtuzumab, vorinostat, denileukin deftitox, lenalidomide, and bortezomib.
Angioimmunoblastic T-Cell Lymphoma
AITL is one of the more common subtypes of PTCL, accounting for 15% to 20% of cases. Median age at diagnosis is 65, and patients typically present with diffuse lymphadenopathy, hepatosplenomegaly, extranodal involvement, systemic symptoms, rash, and hypergammaglobulinemia. Autoimmune phenomena, both hematologic and nonhematologic, are also common. Response rates to anthracycline-based chemotherapy are relatively poor, and 5-year OS is approximately 30%. High-dose chemotherapy with autologous stem cell rescue as first-line therapy for AITL is being studied; however, at this time the benefit of this approach remains unclear. Immunosuppressive therapy with cyclosporine has shown promising early results, and can be considered for select patients. Otherwise, the approach to treatment of AITL largely follows that of PTCL-NOS.
Anaplastic Large Cell Lymphoma
ALCL is a CD30-positive subtype of PTCL that encompasses two biologically distinct diseases: ALCL that overexpresses anaplastic lymphoma kinase (ALK), usually due to t(2;5), and ALK-negative ALCL. The former is typically a disease of children and young adults, while the latter tends to affect older individuals. Patients with both forms typically present with diffuse lymphadenopathy, extranodal disease, and systemic symptoms. ALK-positive ALCL has an excellent prognosis compared to most PTCL, with a 5-year OS of approximately 70% after anthracycline-based chemotherapy. ALK-negative ALCL has poorer outcomes, and the approach to therapy generally follows that of PTCL-NOS. Additionally, the anti-CD30 monoclonal antibody/cytotoxic conjugate, brentuximab vedotin, was recently FDA approved for relapsed/refractory ALCL after demonstrating a 57% CR rate. This promising agent is being further evaluated in combination with chemotherapy and in the first-line setting.
Primary cutaneous ALCL is a separate disease entity characterized by indolent behavior, predominantly dermatologic involvement, and excellent long-term survival. Additionally, a recent phenomenon of primary breast ALCL occurring in women with breast implants has been reported over the past decade. A recent FDA analysis concluded that breast implants are potentially associated with an increased relative risk, but still very low absolute risk, of primary breast ALCL.
NK/T-Cell Lymphomas
The two main subclassifications of NK/T-cell lymphoma are extranodal NK/T-cell lymphoma, nasal type (ENKL), and aggressive NK-cell leukemia (ANKL). These diseases are almost always EBV positive, and are extremely rare in North America and Europe but prevalent in Asia and Central/South America. ENKL typically involves the nasopharynx and nasal cavity, and palate, and can also affect the skin, gastrointestinal tract, and testis. Patients with disease confined to the nasal cavity can be successfully treated IFRT with or without chemotherapy, while those with extranasal disease and ANKL have a very poor prognosis. Encouraging results have recently been seen with L-asparaginase-based chemotherapy regimens, and further studies evaluating this agent in ENKL and ANKL are ongoing.
Hepatosplenic T-Cell Lymphoma
This is a rare and aggressive PTCL that typically affects young men and involves the liver, spleen, and BM. Histologic diagnosis can often be difficult to obtain. Prognosis is poor regardless of choice of therapy, with a 5-year OS of less than 10%. There is no standard of care, although most patients are treated with CHOP-like regimens with or without HDT/ASCR.
Enteropathy-Associated T-Cell Lymphoma
This is a rare and aggressive PTCL of the small intestine that typically affects older individuals with celiac disease, although many patients are diagnosed with EATL who have no known history of enteropathy. Patients typically present with abdominal pain and anorexia. Prognosis is poor, with a 5-year OS of 20% in patients treated with conventional chemotherapy. Although many patients are unable to tolerate multiagent chemotherapy, a recent study reported a 5-year OS of 60% in patients treated with chemotherapy followed by HDT/ASCR.
Cutaneous T-Cell Lymphoma/Mycosis Fungoides
CTCLs are typically mature T-cell neoplasms that originate within, and often remain confined to, the skin, with variable spread to the lymph nodes, BM, and peripheral blood. MF constitutes the majority of CTCL. Sezary syndrome (SS) is the much less common leukemic manifestation of MF, accounting for 3% of CTCL. MF is considered an indolent lymphoma, although behavior and prognosis are highly variable; patients with limited patch or plaque disease of the skin have excellent long-term survival, while prognosis is poorer for those with erythrodermal skin involvement and extracutaneous disease.
MF is staged according to the revised MFCG staging system, which incorporates extent of skin, nodal, visceral organ, and peripheral blood involvement. Patients with limited skin disease are typically treated with topical corticosteroids, topical retinoids, topical chemotherapy, phototherapy, or local radiation. Patients with more extensive skin involvement can be treated with the same modalities or with total skin electron beam therapy (TSEBT). Patients with more advanced disease are treated initially with systemic therapies such as extracorporeal photopheresis (ECP), oral retinoids, interferon, or HDAC inhibitors, with chemotherapy being reserved for patients who progress on these agents or for those with aggressive disease with visceral organ involvement.
Treatment Approaches for Relapsed Aggressive Lymphomas
Treatment for relapsed aggressive DLBCL generally involves salvage chemotherapy followed by HDT/ASCR in fit patients who demonstrate chemosensitive disease. Commonly used salvage chemotherapy regimens include R-ICE, R-DHAP, R-ESHAP, and EPOCH-R. Patients with chemoresistant disease do not benefit from HDT/ASCR and should be enrolled into clinical trials, considered for allogeneic HSCT, or treated palliatively. Additionally, the results of the recently published CORAL study indicate that the benefit of HDT/ASCR may be significantly limited in the rituximab era, as patients in this trial who were previously treated with rituximab had a 3-year EFS of only 21% after HDT/ASCR. This study also demonstrated a similarly poor 3-year EFS in patients who relapsed less than 12 months after initial diagnosis. Consequently, careful consideration of disease factors, as well as a frank discussion of treatment and available trial options, should precede referral for HDT/ASCR. Nontransplant candidates who are not eligible for a clinical trial can be treated palliatively with any of the aforementioned salvage regimens or with BR or lenalidomide.
The other aggressive B-cell lymphomas (MCL, BL) and the majority of aggressive T-cell lymphomas are rarely, if ever, cured with conventional salvage chemotherapy or HDT/ASCR, although studies of HDT/ASCR in relapsed PTCL have demonstrated a 5-year OS of approximately 40% and patients with ALK-positive ALCL can be cured with this approach. HDT/ASCR is considered an option in patients with PTCL who demonstrate chemosensitivity to salvage chemotherapy, although again careful consideration should be given to investigational therapies to include allogeneic HSCT.
REVIEW QUESTIONS
1.Which of the following statements are true concerning chromosomal abnormalities in NHL?
A.BL is associated with t(8;14), t(2;8), or t(8;22).
B.Virtually all cases of mantle cell lymphoma harbor t(11;14), leading to overexpression of bcl-2.
C.Cyclin D1 is overexpressed in the majority of follicular lymphoma and is associated with t(14;18).
D.Patients with anaplastic large cell lymphoma harboring t(2;5) have a worse prognosis than those without this translocation.
E.Patients with CLL/SLL harboring an 11q deletion have a relatively favorable prognosis compared to patients with normal cytogenetics.
2.Which of the following statements is false regarding the molecular biology of DLBCL?
A.Patients with ABC-DLBCL have inferior PFS and OS compared to those with GCB-DLBCL.
B.The NF-κB pathway is constitutively activated in GCB-ABCL.
C.PMBL has a molecular signature that is distinct from that of ABC- or GCB-DLBCL.
D.PCNSL is typically of DLBCL histology.
E.DLBCL cases that harbor both BCL-2 and MYC translocations constitute a highly aggressive subgroup that respond poorly to current therapies.
3.A 55-year-old man presents to his primary care physician with progressive fatigue and night sweats. Physical examination reveals cervical and axillary lymphadenopathy, and laboratory analysis is notable for a hemoglobin of 11 g/dL, serum LDH 1.5 × ULN, and normal renal and hepatic function. He is referred for excisional biopsy of an enlarged left cervical lymph node, which reveals DLBCL. Subsequent oncologic staging workup includes a BM aspiration/biopsy which reveals no evidence of large malignant lymphocytes, and a PET/CT scan which reveals hypermetabolic lymphadenopathy in the neck, axillae, hilum, and retroperitoneum, as well as multiple hypermetabolic lytic foci within non–weight-bearing bones. Serologic testing for chronic hepatitis and HIV are negative. MUGA scan demonstrates normal cardiac function. The patient has an ECOG performance status of 1, but does not wish to be referred for a clinical trial. Which of the following is the most appropriate approach to treating this patient?
A.R-CHOP-21 for six cycles followed by posttherapy PET/CT scan and BM biopsy.
B.R-CHOP-14 with filgrastim for six cycles followed by posttherapy PET/CT scan and BM biopsy.
C.R-CHOP-21 for six cycles followed by posttherapy CT scan and BM biopsy.
D.R-CHOP-21 for four cycles if PET/CT after cycle 2 demonstrates complete response.
E.R-hyper-CVAD for eight cycles, followed by posttherapy CT scan and BM biopsy.
4.A 50-year-old man with symptomatic stage III follicular lymphoma (histologic grade 2) is treated with six cycles of BR and obtains a complete remission. Two years later, he presents with worsening fatigue and frequent drenching night sweats. His examination reveals new anterior cervical and axillary lymphadenopathy and splenomegaly. Laboratory analysis reveals a hemoglobin of 9.5 g/dL, serum LDH 2 × the upper limit of normal, AST, and ALT 2× the upper limit of normal, and normal renal function. CT scan reveals multiple new enlarged cervical lymph nodes (2 cm maximal diameter), a 3 cm right axillary node, a 4 cm right external iliac node, splenomegaly (16 cm craniocaudal), and several enhancing foci within the liver (2 cm maximal diameter). Subsequent PET scan reveals moderate hypermetabolism (SUVs 5 to 10) within the cervical nodes and liver lesions, SUV of 14 within the right external iliac node, and SUV of 21 within the right axillary node. A surveillance CT scan performed 6 months ago revealed no abnormalities. What is the most appropriate next step?
A.Initiate salvage therapy for relapsed FL with R-CHOP.
B.Initiate salvage therapy for relapsed FL with ibritumomab tiutexan.
C.Initiate salvage therapy for relapsed FL with BR.
D.Obtain BM aspirate/biopsy.
E.Obtain BM aspirate/biopsy and excisional biopsy of the right axillary lymph node.
5.A 34-year-old woman presents to her primary care physician with progressive dyspnea on exertion and cough. Physical examination reveals mild facial plethora. Chest x-ray reveals mediastinal widening. Subsequent CT scan of the chest, abdomen, and pelvis is notable for a large mediastinal mass (13 cm in maximal diameter) compressing the SVC, and no other significant findings. Laboratory analysis reveals elevated LDH but is otherwise unremarkable. Tissue biopsy obtained via cervical mediastinoscopy reveals numerous large malignant lymphocytes in a sclerotic background that possess the following immunophenotype: CD20 strong+, CD23+, CD45+, CD79a+, Bcl6+, Mum1+, CD30 weak+, CD15–. What is the most likely diagnosis?
A.Hodgkin lymphoma
B.T-lymphoblastic lymphoma
C.PMBL
D.SLL
E.Mantle cell lymphoma
Suggested Readings
1.Amador-Ortiz C, Chen L, Hassan A, et al. Combined core needle biopsy and fine-needle aspiration with ancillary studies correlate highly with traditional techniques in the diagnosis of nodal-based lymphoma. Am J Clin Pathol. 2011;135:516-524.
2.Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomized controlled trial. Lancet. 2003;362:516-522.
3.Bassig B, Lan Q, Rothman N, et al. Current understanding of lifestyle and environmental factors and risk of non-Hodgkin lymphoma: an epidemiological update. J Cancer Epidemiol. 2012;2012:978930.
4.Clarke C, Glaser S. Changing incidence of non-Hodgkin lymphomas in the United States. Cancer. 2002;94:2015-2023.
5.Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242.
6.Connors JM, Yang Y, Sievers EL, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30:2190-2196.
7.Dave SS, Fu K, Wright GW, et al. Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med. 2006;354:2431-2442.
8.Delarue R, Tilly H, Salles G, et al. R-CHOP14 compared to R- CHOP 21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03-6B GELA study [abstract]. Blood. 2009;114:Abstract 406.
9.Dunleavy K, Pittaluga S, Janik J, et al. Primary mediastinal large b-cell lymphoma (PMBL) may be significantly improved by the addition of rituximab to dose-adjusted EPOCH and obviates the need for radiation: results from a prospective study of 44 patients. Blood (ASH Annual Meeting Abstracts). 2006;108:109.
10.Else M, Marin-Niebla A, de la Cruz F, et al. Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma. Br J Haematol. 2012;159:322-328.
11.Ferreri AJ, Reni M, Foppoli M, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374(9700):1512-1520.
12.Ferrucci PF, Zucca E. Primary gastric lymphoma pathogenesis and treatment: what has changed over the past 10 years? Br J Haemtaol. 2007;136:521-538.
13.Fischbach W, Goebeler-Kolve ME, Dragosics B, et al. Long term outcome of patients with gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series. Gut. 2004;53:34-37.
14.Frederico M, Rudiger T, Bellei M, et al. Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project. J Clin Oncol. 2013;31:240-246.
15.Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomized, open-label, phase 3 trial. Lancet. 2010;376:1164-1174.
16.Hiddemann W, Kneba M, Dreyling M, et al. Front-line therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphomas as compared to CHOP alone—results of a prospective randomized study of the German low grade lymphoma study group (GLSG). Blood. 2005;106:3725-32.
17.Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003;139:857-866.
18.Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med. 1998;339:21-26.
19.Roschewski M, Wilson WH. Biology and management of rare primary extranodal T-cell lymphomas. Oncology (Williston Park). 2010;24:94-100.
20.Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947.
21.Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany) [abstract]. Blood. 2009;114:405.
22.Salavoura K, Kolialexi A, Tsangaris G, et al. Development of cancer in patients with primary immunodeficiencies. Anticancer Res. 2008;28:1263-1270.
23.Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:42-51.
24.Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111:5496-5504.
25.Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124-4130.