Cancer Network - Non-Hodgkin Lymphoma - 2015-06-11

Non-Hodgkin Lymphoma
Published on Cancer Network (http://www.cancernetwork.com)
June 01, 2015 | Cancer Management [1]
By Andrew M. Evens, DO, MS [2], Jane N. Winter, MD [3], Leo I. Gordon, MD [4], Brian C. H. Chiu, PhD
[5], Richard Tsang, MD [6], and Steven T. Rosen, MD [7]
This management guide covers the risk factors, screening, diagnosis, staging, and treatment of
non-Hodgkin lymphoma.
Overview
Non-Hodgkin lymphoma (NHL) is the sixth most commonly diagnosed cancer in both men and
women in the United States. In 2015, it is estimated that there will be 71,850 new cases of NHL
(39,850 men and 32,000 women) and 19,790 deaths from NHL. The disease represents
approximately 4.3% of all cancer diagnoses (4.7% in males and 4% in females). Notably, incidence
rates of NHL almost doubled between 1970 and 1990 but have stabilized since the late 1990s among
general populations. Some of this increase may be artifactual, resulting from improved diagnostic
techniques and access to medical care, or directly related to the development of NHL in 25- to
54-year-old men with human immunodeficiency virus (HIV) infection. However, additional factors
must be responsible for this unexpected increase in frequency of NHL that has been observed
throughout the United States.
The increases have been more pronounced in whites, males, the elderly, and those with NHL
diagnosed at extranodal sites. Similar findings have been reported in other developed countries. In
the United States, incidence rates increased significantly during 2002-2011 for marginal zone
lymphoma (average 1.7% per year), mantle cell lymphoma (MCL) (1.7% per year), adult T-cell
leukemia/lymphoma (6.6% per year), and natural killer (NK)/T-cell lymphoma (3.5% per year) but
decreased for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (1.4% per
year).
Sidebar: Analysis of pre-diagnosis blood specimens for evidence of t(14;18) in patients with
follicular lymphoma revealed that progression to follicular lymphoma may occur up to 20 years later
in apparently healthy individuals carrying this marker. Investigators estimated that for individuals
with a high frequency of peripheral blood t(14;18), the risk of developing follicular lymphoma may be
as high as 23-fold that of controls. This marker of risk was present many years before diagnosis in
patients. (Roulland S et al: J Clin Oncol 32:1347-1355, 2014).
Epidemiology
Gender
The overall incidence of lymphoma is higher in men than in women. The age-adjusted incidence rate
between 2007 and 2011 was about 45% higher in males (23.9 per 100,000) than in females (16.3
per 100,000). Although the overall NHL incidence rates remained unchanged during 2002-2011
among men and women, rates for marginal zone lymphoma and adult T-cell leukemia/lymphoma
(ATLL) increased significantly in men, and to a lesser degree, in women.
Age
The incidence of NHL overall and of most histologic subtypes rises exponentially with increasing age.
In persons older than 65, the incidence was 91.6 (112.3 males and 76.9 females) per 100,000
persons in 2007-2011. Except for high-grade lymphoblastic and Burkitt lymphomas (the most
common types of NHL seen in children and young adults), the median age at presentation for all
subtypes of NHL exceeds 50 years.
Race/Ethnicity
The incidence of NHL varies by race/ethnicity, with non-Hispanic whites (20.6 per 100,000 persons)
at higher risk than blacks (14.3 per 100,000), Asian/Pacific Islanders (13.4 per 100,000), and
Page 1 of 42
Hispanics (17.7 per 100,000) during 2007-2011. Most histologies, particularly low-grade small
lymphocytic and follicular lymphomas, are more common in whites than in blacks. Only peripheral
T-cell lymphoma (PTCL), mycosis fungoides, and Szary syndrome are more common in blacks than
in whites.
Geography
NHL is most common in developed countries, with the United States having the highest rate
worldwide. The lowest NHL rates are found in eastern and south central Asia (2 to 3 per 100,000
population). Certain endemic geographic factors appear to influence the development of NHL in
specific areas. Human T-cell lymphotropic virus-1 (HTLV-1)-associated ATLL occurs more frequently
where HTLV-1 is endemic, in southern Japan and the Caribbean, and it occurs sporadically in Brazil,
sub-Saharan Africa, the Middle East, and the southeastern United States. The seroprevalence in
southwest Japan is 16%, although the lifetime risk of ATLL for these persons is 2% to 6%.
The incidence of Burkitt NHL in Africa (Nigeria and Tanzania) is 6 to 8, compared with 0.4 in the
United States. Further, the clinical features of Burkitt lymphoma in Africa differ from those of cases
reported to the American Burkitt Lymphoma Registry. Etiologic endemic factors include malaria as a
source of chronic B-cell antigenic stimulation and Epstein-Barr virus (EBV)-induced immortalization of
B lymphocytes. Heavy-chain disease is a disorder of B-lymphoid cells characterized by diffuse
thickening of the small intestine due to a lymphoplasmacytic infiltrate with secretion of incomplete
IgA heavy chains. Pathologically, it is a mucosa-associated lymphoid tissue (MALT) lymphoma of the
small bowel. This clinicopathologic entity is rarely encountered in individuals other than those of
Mediterranean ethnic origin.
Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean,
Africa, China, Japan, the Middle East, and Latin America. PTCLs are more common in Europe and
China than in North America. They represent about 4% of lymphomas in the United States.
Disease Sites
The NHLs are a heterogeneous group of neoplasms that usually arise or present in lymphoid tissues,
such as lymph nodes, spleen, and bone marrow, but they may arise in almost any tissue. The most
frequent sites for extranodal lymphomas, which constitute about 20% to 30% of all lymphomas
(peripheral T-cell NHL, 70% to 80%; follicular, 8% to 10%), are the stomach, skin, oral cavity and
pharynx, small intestine, and central nervous system (CNS). Although primary CNS lymphomas are
rare (3% to 4% of CNS), there has been a threefold increase in incidence from the 1960s to the
mid-1990s, even if patients with HIV infection and other types of immunosuppression are excluded.
However, there has been an overall decline in the incidence of primary CNS lymphomas in the United
States since 1995, driven mainly by the changing incidence in young and middle-aged men. The rate
has continued to increase in men older than 65 and in women. Each of these sites may be involved
singularly (ie, primary extranodal lymphoma) or as secondary extranodal sites concomitantly with
other systemic disease.
Survival
The potential curability of NHL varies among the different histologic subtypes and is related in part
to stage at presentation. The 5-year relative survival rate of patients with NHL increased from 47%
between 1975 and 1977 to approximately 71% between 2004 and 2010. These improvements in
survival occurred mainly in patients with intermediate- to high-grade histologies. The natural history
(survival rates) for indolent lymphomas was unchanged from the 1950s to the early 1990s; however,
recent Surveillance, Epidemiology, and End Results (SEER) and other data have shown improved
overall survival rates for patients with follicular lymphoma.
Sidebar: Investigators from the International Lymphoma Epidemiology Consortium (InterLymph)
pooled individual-level data from 17,471 NHL patients and 23,096 controls in 20 case-control studies
to estimate the associations between 11 NHL subtypes and self-reported medical history, family
history of hematologic malignancy, lifestyle factors, and occupation. In the 11 associated
monographs, they identified common risk factors among subtypes as well as risk factors that
appeared distinct among individual subtypes, suggesting both subtype-specific and shared
underlying mechanisms (Morton LM, et al: J Natl Cancer Inst Monogr. 2014:130-144, 2014).
Etiology, Pathogenesis, and Risk Factors

Chromosomal Translocations and Molecular Rearrangements
Page 2 of 42
Nonrandom chromosomal and molecular rearrangements play an important role in the pathogenesis
of many lymphomas and correlate with histology and immunophenotype (Table 1). The most
commonly associated chromosomal abnormality in NHL is the t(14;18)(q32;q21) translocation, which
is found in 85% to 90% of follicular lymphomas and 25% to 30% of higher-grade B-cell NHLs. This
translocation results in the juxtaposition of the BCL2 apoptotic inhibitor oncogene at chromosome
band 18q21 to the heavy-chain region of the immunoglobulin locus within chromosome band 14q32.
The t(11;14)(q13;q32) translocation results in overexpression of BCL1 (cyclin D1/PRAD 1), a
cell-cyclecontrol gene on chromosome 11q13, and is characteristically associated with MCL. The
t(3;16)(q27;p11) translocation makes the gene for the interleukin (IL)-2 receptor a partner of BCL6,
which is expressed in diffuse large B-cell lymphoma (DLBCL). Chromosomal translocations involving
8q24 lead to c-myc deregulation, which is seen in nearly all cases of Burkitt lymphoma, including
those associated with HIV infection, and a subset of DLBCL.
Next-generation sequencing studies have documented frequent mutations in NHL (many involve
alterations in epigenetic regulators), including EZH2, CREBBP, E300, MLL2, MEFB2 mutations in
follicular lymphoma; EZH2, MYD88, CREBBP, E300, MLL2, and MEFB2 mutations in DLBCL; NOTCH1,
MYD88, XPO1, KLHL6, and SF3B1 mutations in CLL; NOTCH1 mutation in MCL; and TET2, DNMT3A,
IDH2, RHOA, FYN, ATM, B2M, and CD58 mutations in PTCLs. In addition, recently presented data
further showed the functional importance of EZH2 in lymphomagenesis and its cooperation with
BCL6.
Sidebar: The Melnick laboratory published data showing that EZH2 is required for B lymphocytes to
form germinal centers and that EZH2 mutations convert EZH2 into a super-repressor that
permanently locks chromatin into a repressive state that causes lymphomas to arise from normal B
lymphocytes. Further, EZH2 had to cooperate with BCL6, which also serves as a gene repressor. The
combined and coordinated epigenetic actions of EZH2 and BCL6 appeared to be required for
lymphomagenesis (Bguelin W et al: Cancer Cell 23:677-692, 2013).
Environmental Factors
Environmental factors also may play a role in the development of NHL. Chemicals that have been
linked to the development of NHL include a variety of pesticides and herbicides
(2,4-D-organophosphates, chlorophenols) and solvents and organic chemicals (benzene, carbon
tetrachloride, trichloroethylene). There is some evidence that the association between pesticides and
NHL risk was limited to t(14;18)-positive NHL cases.
TABLE 1: Correlation
of chromosomal abnormalities in NHL with histology, antigen rearrangement, and oncogene
expression
Viruses
Several viruses have been implicated in the pathogenesis of NHL, including EBV, HTLV-1, Kaposi
sarcomaassociated herpesvirus (KSHV, also known as human herpesvirus 8), and hepatitis C virus
(HCV). Meta-analyses have shown a 13% to 15% HCV seroprevalence in certain geographic regions
among persons with B-cell NHL, especially marginal zone NHL.
EBV is a DNA virus that has been associated with Burkitt lymphoma (particularly in areas of Africa
where the virus is endemic), Hodgkin lymphoma, lymphomas in immunocompromised patients (ie,
Page 3 of 42
organ transplant recipients and HIV-infected persons), sinonasal lymphoma (Asia and South
America), and sporadically in other B- and T-cell lymphomas. In contrast to studies performed in
European patients, Mexican patients with intestinal lymphomas show a high frequency of EBV
positivity; this finding is not limited to T-cell NHLs but rather includes a significant portion of B-cell
NHLs. EBV can transform lymphocytes perpetually in culture. B lymphocytes from normal
EBV-positive subjects have been shown to grow as tumors in mice with severe combined
immunodeficiency.
HTLV-1 is a human retrovirus that establishes a latent infection via reverse transcription in activated
T-helper cells. A minority (3% to 5%) of carriers develop ATLL. An HTLV-1like provirus has been
detected in some patients with mycosis fungoides, although conflicting findings have been reported.
KSHV-like DNA sequences are frequently detected in primary effusion lymphomas, in patients with
Kaposi sarcoma, and in those with multicentric (plasma cell variant) Castleman disease. HCV
infection is associated with the development of clonal B-cell expansions and certain subtypes of NHL,
particularly in the setting of essential (type II) mixed cryoglobulinemia. HCV may predispose B cells
to malignant transformation by enhancing signal transduction on binding to the CD81 (TAPA-1)
molecule.
Sidebar: An international consortium examined the prognostic impact of EBV in more than 700
patients with DLBCL treated with R-CHOP. There were no significant survival differences observed in
EBV-positive DLBCL versus EBV-negative DLBCL; however, patients with EBV and CD30 coexpression
had inferior survival. Coexpression of EBV-encoded RNA and CD30 was characterized by increased
nuclear factor (NF)-B activity, cell proliferation, and cell-cycle progression (Ok CY et al: Clin Cancer
Res 20:2338-2349, 2014).
Bacterial Infections
Infection with Borrelia burgdorferi, the causative agent in Lyme disease, has been detected in about
35% of patients with peripheral cutaneous B-cell lymphoma in Scotland. A near-complete clinical and
histologic remission of a primary marginal zone B-cell lymphoma was observed after eradication of B
burgdorferi with antibiotic treatment. Gastric MALT lymphoma is seen most frequently, but not
exclusively, in association with Helicobacter pylori infection. Studies indicate that Campylobacter
jejuni and immunoproliferative small intestinal disease (-heavy chain disease) are related. Some
reports noted an association between infection with Chlamydophila psittaci and ocular adnexal
lymphoma. The infection was found to be highly specific and does not reflect a subclinical infection
widespread among the general population. Responses to antibiotics have been reported. Attempts to
confirm this association in the Western Hemisphere, however, have been unsuccessful.
Immune Modulation
Congenital and acquired states of immunosuppression that are associated with increased risk
include ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia,
X-linked lymphoproliferative syndrome, and severe combined immunodeficiency.
Acquired immunodeficiency states, such as HIV infection, are associated with relative increased risk
of NHL of 75 to 100 compared with the general population, although recent data in the post-HAART
(highly active antiretroviral therapy) era suggest it has decreased. These NHLs are usually
high-grade and often present with extranodal disease. Furthermore, iatrogenic immunosuppression
(eg, solid organ transplant [SOT] or hematopoietic stem cell transplant [SCT] recipients) have a
significantly increased risk of NHL. The absolute risk of NHL after SOT is 1% to 3% after kidney
transplant vs more than 10% after intestinal, cardiac, or multi-organ transplants; patients who have
had the latter warrant higher-dose immunosuppressive therapy.
An increased incidence of gastrointestinal (GI) lymphomas is seen in patients with celiac
(nontropical) sprue and inflammatory bowel disease, particularly Crohn disease. An aberrant clonal
intraepithelial T-cell population can be found in up to 75% of patients with refractory celiac sprue
before the development of overt T-cell lymphoma using immunophenotyping and T-cell receptor
gamma gene rearrangement polymerase chain reaction (PCR) techniques. Systemic lupus
erythematosus and rheumatoid arthritis have been associated with B-cell lymphoma. Sjgren
syndrome has been associated with NHL overall, DLBCL, and marginal zone lymphoma.
Patients who receive chemotherapy and/or radiation therapy are also at increased risk for
developing subsequent secondary NHL. Meta-analysis of cohort studies showed that blood
transfusion was associated with a 20% increase in the risk of NHL. The association was similar for
men and women as well as for transfusion given before or after 1992. In contrast, case-control
studies in general reported no association.
Page 4 of 42
Lifestyle Factors
Several studies have reported an excess risk of NHL in association with diets high in fat and meat
products. Some studies have suggested that ultraviolet radiation exposure and alcohol intake may
be linked inversely with NHL risk.
Genetic Susceptibility
Several reports have implicated a role for genetic variants in the risk of NHL, including genes that
influence DNA integrity and methylation; genes that alter B-cell survival and growth; and genes that
involve immune function/inflammation, oxidative stress, and xenobiotic metabolism. Recent
genome-wide association studies (GWAS) conducted by investigators in the International Lymphoma
Epidemiology Consortium (InterLymph) have identified a number of predisposing single nucleotide
polymorphisms (SNPs) for NHL, including 11q23.3 (CXCR5), 11q24.3 (ETS1), 3q28 (LPP), 18q21.33
(BCL2), and 8q24.21 (PVT1) linking variants outside the HLA region to follicular lymphom risk; 6p25.3
(EXOC2), 6p21.33 (HLA-B), 2p23.3 (NCOA1), and 8q24.21 (PVT1) supporting the role of immune
recognition and immune function in the pathogenesis of DLBCL; rs9461741 (BTNL2) and rs2922994
(HLA-B) suggesting that genetic variation in the HLA region influences susceptibility to marginal zone
lymphoma; and 10q23.31 (ACTA2/FAS), 18q21.33 (BCL2), 11p15.5 (C11/F21), 4q25 (LEF1), 2q33.1
(CASP10/CASP8), 9p21.3 (CDKN2B-AS1), 18q21.32 (PMAIP1), 15q15.1 (BMF), and 2p22.2 (QPCT)
pointing to genes involved in apoptosis and CLL risk.
Sidebar: Investigators in the InterLymph conducted a comprehensive multi-stage GWAS on 5,216
patients with DLBCL and 12,223 controls. The authors identified five independent SNPs in four loci
that achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2); rs2523607 at
6p21.33 (HLA-B); rs79489871 at 2p23.3 (NCOA1); and two independent SNPs, rs13255292 and
rs4733601, at 8q24.21 (PVT1). These data provide substantial new evidence for genetic
susceptibility to DLBCL and suggest pathways involved in immune recognition and immune function
in the pathogenesis of this B-cell malignancy (Cerhan JR et al: Nat Genet 46:1233-1238, 2014).
Signs and Symptoms

Fever, weight loss, and night sweats, referred to as systemic B symptoms, as well as fatigue and
weakness, are more common in advanced or aggressive NHL, but may be present in all stages and
histologic subtypes.
Low-Grade Lymphomas
Painless, slowly progressive peripheral adenopathy is the most common clinical presentation in
patients with low-grade lymphomas. Patients sometimes report a history of waxing and waning
adenopathy before seeking medical attention. Spontaneous regression of enlarged lymph nodes can
occur and can cause a low-grade lymphoma to be confused with an infectious condition.
Primary extranodal involvement and B symptoms are uncommon at presentation; however, both are
more common in advanced or end-stage disease. Bone marrow is frequently involved, sometimes in
association with cytopenias. Splenomegaly is seen in about 40% of patients, but the spleen is rarely
the only involved site at presentation (eg, splenic marginal zone lymphoma).
Aggressive-Histology Lymphomas
The clinical presentation of aggressive-histology lymphomas is more varied. Although the majority of
patients present with adenopathy, more than one-third present with extranodal involvement, the
most common sites being the GI tract (including Waldeyer ring), skin, bone marrow, sinuses, bone,
and CNS. B symptoms are more common, occurring in about 30% to 40% of patients. Lymphoblastic
lymphoma often typically presents with an anterior superior mediastinal mass with possible superior
vena cava (SVC) syndrome, and leptomeningeal disease with possible cranial nerve palsies.
American patients with Burkitt lymphoma often present with a large abdominal mass and symptoms
of bowel obstruction.
Screening and Diagnosis

No effective methods are available for screening or identifying populations at high risk for
developing NHL. A definitive diagnosis can be made only by biopsy of pathologic lymph nodes or
tumor tissue. It is critical to perform an excisional lymph node biopsy (fine-needle aspiration [FNA] is
Page 5 of 42
insufficient for diagnostic purposes) to avoid false-negative results and inaccurate histologic
classification. One study showed that when FNAs and biopsy results for the diagnosis of NHL and
Hodgkin lymphoma were compared, only 12% of FNAs correlated with subsequent excisional biopsy
results. When clinical circumstances make surgical biopsy of involved lymph nodes or extranodal
sites prohibitive, a core biopsy obtained under computed tomographic (CT) or ultrasonographic
guidance may suffice, but this requires the integration of immunophenotypic analysis
(immunohistochemistry [IHC] and/or flow cytometry) and often genotypic analysis (cytogenetics
and/or molecular studies, such as fluorescent in situ hybridization [FISH] and PCR) for accurate
diagnosis. A formal review by an expert hematopathologist is mandatory.
Initial Diagnostic Evaluation
Initial diagnostic evaluation for lymphoproliferative malignancy should include the following:
Careful history (night sweats, weight loss, fever; neurologic, musculoskeletal, or GI symptoms).
Physical examination (lymph nodes, including submental, infraclavicular, epitrochlear, iliac,
femoral, and popliteal nodes; pericardial rub, pleural effusion, distended neck and/or upper
extremity veins in SVC syndrome; breast masses; hepatosplenomegaly, bowel obstruction, renal
mass, and testicular or ovarian mass; focal neurologic signs, such as plexopathy, spinal cord
compression, nerve root infiltration, and meningeal involvement; skin lesions).
Biopsy of peripheral lymphadenopathy (excisional biopsy recommended).
CT scan of the neck (cervical lymph nodes, Waldeyer ring) and chest (mediastinal, hilar, or
parenchymal pulmonary disease).
CT scan of the abdomen and pelvis (enlarged lymph nodes, splenomegaly, filling defects in the
liver and spleen).
Bone marrow biopsy and aspirate.
FDG-PET (fluorodeoxyglucose positron emission tomography) scans (select cases: aggressive NHL
histologies) for staging at diagnosis, response, assessment, and relapse; off of a clinical trial, early
repeated PET scans (eg, following two cycles) are not advocated, in part because of the frequent
disparate interpretation of PET scans as well as lack of predictability of impact of modification of
treatment.
Sidebar: An imaging working group composed of representatives from major international
cooperative groups published revised guidelines on imaging for staging and response assessment of
lymphoma. This included re-assessment of use (and methods) of FDG-PET/CT scanning, re-appraisal
of bone marrow biospy, and post-remission surveillance scanning (Barrington SF et al: J Clin Oncol
32:3048-3058, 2014).
Complete blood cell count with differential and platelet count (peripheral blood lymphocytosis with
circulating malignant cells is common in low-grade lymphoma and MCL). Bone marrow and
peripheral blood involvement may be present, and the distinction between leukemia and lymphoma
is difficult to make in some cases.
TABLE 2: Immunophenotypic and

histochemical markers of B-cell lymphomas/leukemias
General chemistry panel (including lactate dehydrogenase [LDH] level determination) is
mandatory.
Hepatitis B virus (HBV) and HCV panels should be considered, especially in patients anticipated to
receive monoclonal antibody therapy and/or chemotherapy (HBV: at least HBV surface antigen and
HBV core antibody; HCV: HCV antibody).
HIV serology in at-risk patients with DLBCL and other aggressive and Burkitt histologies; HTLV-1
serology in select patients with cutaneous T-cell lymphoma (CTCL), especially if they have
hypercalcemia.
Page 6 of 42
Cytogenetic and molecular analyses of lymph node, bone marrow, and peripheral blood (select
cases).
Immunophenotyping can be of particular benefit in distinguishing B-cell CLL/SLL from other
lymphomas (Table 2). Immunophenotyping and histochemical markers may also be of benefit in
distinguishing T-cell lymphomas/leukemias (Table 3).
TABLE 3:
Immunophenotypic and histochemical markers of T-cell lymphomas/leukemias
Examination of cerebrospinal fluid and consideration of intrathecal chemotherapy prophylaxis in
patients with (1) diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus,
breast, or multiple extranodal sites; (2) high-grade lymphoblastic lymphoma and Burkitt lymphoma
and its variants; (3) primary CNS lymphoma if no evidence of increased intracranial pressure.
Upper GI endoscopy in patients with head and neck involvement (tonsil, base of tongue,
nasopharynx) and those with a GI primary NHL; MCL is associated with a high incidence of occult GI
involvement.
Ultrasonography of opposite testis in patients with a testicular primary.
Spinal magnetic resonance imaging (MRI) scan for epidural disease when clinically indicated
(critical in the evaluation of suspected spinal cord involvement).
Pathology
The Working Formulation was proposed in 1982 as a modification of the Rappaport classification of
NHL based on morphology and biologic aggressiveness. Although many subtypes were not
recognized, including T-cell lineage lymphomas, a revised European-American classification of
lymphoid neoplasms (REAL classification) was introduced in 1994 incorporating T-cell malignancies,
subtypes of Hodgkin lymphoma, and newer defined lymphoma-proliferative disorders. The World
Health Organization (WHO) classification for lymphomas (introduced in 1999 and updated in 2008)
uses the principles of the REAL classification, defining each entity according to morphologic features,
immunophenotype, genetic features, postulated normal counterpart, and clinical features.
WHO Classification
The modifications in the 2008 WHO classification included incorporation of further site-specific
lymphoma subtypes, recognition of age as a defining feature of some diseases, and inclusion of
several borderline and provisional categories (Table 4). The most frequently occurring clinical
entities recognized within the WHO classification are DLBCL (31%), follicular lymphoma (22%),
marginal zone/MALT lymphoma (8%), SLL (7%), and MCL (6%), whereas all noncutaneous T-cell
lymphomas represent approximately 10% of NHL diagnoses in the United States.
Page 7 of 42
TABLE 4: WHO classification of the mature B-cell, T-cell, and NK-cell neoplasms (2008)
The WHO classification includes three types of follicular lymphoma (grades 1/2, 3a, and 3b). Grading
of follicular lymphoma is based in part on the number of centroblasts or large cells per high-power
field. Notably, the presence of any diffuse areas (ie, non-follicular pattern) with large B cells should
be designated as DLBCL. Further, some cases may include a composite of different histologic
subtypes within the same lymph node excision (eg, follicular lymphoma and DLBCL). Grade 3b
follicular lymphoma indicates sheets of large cells within a follicle (ie, maintained follicular
architecture). Grade 3b follicular lymphoma more closely resembles DLBCL at the molecular level.
In the revised WHO classification, further clinicopathologic subtypes were added, namely DLBCL
associated with inflammation and EBV and DLBCL in the elderly. In terms of T-cell lymphomas,
anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive, is considered a
distinct disease, which is distinguished from the provisional entity of ALCL, ALK-negative. Three new
variants of primary cutaneous T-cell lymphoma were also introduced (Table 4). In addition, an
indolent T-cell lymphoproliferative disease of the GI tract has been described .
Staging and Prognosis

Determining the extent of disease in patients with NHL provides prognostic information and is useful
in treatment planning. However, histologic subclassification (WHO classification) is the primary
determinant of survival and potential for cure. Compared with patients with limited disease, those
with extensive disease usually require different therapy, and certain extranodal sites of involvement,
such as the CNS and testes, require specific treatment modalities.
Ann Arbor System
Although initially devised for Hodgkin lymphoma, the Ann Arbor system has been routinely applied to
NHL (Table 5). Because Hodgkin lymphoma commonly spreads via contiguous lymph node groups,
this system is based primarily on the distribution of lymphatic involvement with respect to the
diaphragm and the presence of extralymphatic organ involvement. The Ann Arbor system does not
reflect the noncontiguous nature of disease spread in NHL, does not discriminate well between
stages III and IV disease, and fails to account for tumor bulk or number of extranodal sites.
Some trials in Burkitt and Burkitt-like lymphoma use the St. Jude/Murphy staging system, in part to
more completely describe the extent of extranodal disease. Unlike the current WHO classification,
this staging system recognizes Burkitt leukemia as a separate entity. Moreover, this system was
developed when surgery was used for diagnostic and therapeutic purposes. Patients are also
typically stratified into two risk groups, with low-risk patients defined as having a normal LDH level
and a single focus of disease measuring less than 10 cm and all others considered to be
high-risk.
Page 8 of 42
TABLE 5: Ann Arbor staging classification for NHL

Prognostic Factors
Histology (by WHO classification) remains the major determinant of treatment outcome and
prognosis. Newer pathologic technologic methods, such as gene expression profiling, have emerged
as important determinants of outcome. However, these currently remain research-based; routine
clinical factors continue to be prognostically important in indolent and aggressive NHLs.
The International Prognostic Index
The International Prognostic Index (IPI) was developed in the pre-rituximab (R) era.
TABLE 6: NCCNInternational Prognostic Index

It has served as a useful guide for prognosis in patients with aggressive DLBCL treated with
cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisone (CHOP)-like
therapy. Because younger patients are more likely to be considered for more intensive
investigational regimens, an age-adjusted model for patients 60 years and younger was developed
that required only three clinical factorsstage (III or IV), high LDH level, and performance statusto
predict survival. Notably, the IPI has remained a valid prognostic index in the rituximab era, but it
has lost much of its capacity to discriminate between risk groups in the setting of R-CHOP
chemotherapy. On the basis of raw data from the National Comprehensive Cancer Network (NCCN)
lymphoma database, a new prognostic model was built based solely on clinical factors (Table 6). The
NCCN-IPI identifies low- and high-risk cohorts with 5-year overall survivals of 96% and 33%,
respectively; is easy to use; and is more powerful than its predecessor, the IPI.
A prognostic factor model was devised based on 919 cases of follicular lymphoma, known as the
Follicular Lymphoma IPI (FLIPI; Table). Multivariate analysis showed that age, Ann Arbor stage,
number of nodal sites, LDH level, and hemoglobin level were predictors of overall survival. An
analysis of the FLIPI in the post-rituximab era has been reported (FLIPI-2). Multivariate analysis
showed that elevated beta2-microglobulin level, longest nodal diameter over 6 cm, bone marrow
involvement, anemia, and age over 60 years independently predicted survival. Including all patients
(N = 832) with 0, 1 or 2, or 3 to 5 factors, the 3-year progression-free survival was 91%, 69%, and
51%, respectively (P = .00001), whereas the 5-year progression-free survival was 79%, 51%, and
20%, respectively (P = .00001). Among patients treated with rituximab-containing regimens only (n
= 559), the FLIPI-2 remained predictive of outcome (3-year progression-free survival of 89%, 73%,
and 57%, respectively; P = .001).
The MCL International Prognostic Index (MIPI) was created from 455 advanced-stage MCL patients
treated within three German clinical trials. It consisted of several clinical factors. The simplified MIPI
(sMIPI) is the sum of increasing points for grouped values of age, performance status, LDH level
greater than the upper limit of normal, and leukocyte count and is scored as low-risk (0-3 points),
intermediate-risk (4-5 points), and high-risk (> 5 points; Table 8). Patients with low or intermediate
risk according to the sMIPI had a 5-year overall survival of more than 75% to 80% compared with
38% for patients with high risk (> 5 factors).
Immunobiologic Factors
Page 9 of 42
Various immunobiologic factors have been suggested as predictors of outcome in NHL.
TABLE 7: Follicular lymphoma International Prognostic Indices

Immunophenotype
A number of studies have suggested that patients with aggressive T-cell NHL have a higher relapse
rate and decreased overall survival compared with patients who have B-cell disease, especially in
the postrituximab era. The Lunenberg Biomarker Consortium has shown that Ki-67 greater than
75% and CD5 expression greater than 75% predict inferior survival, and the integration of these two
markers in addition to high BCL2 expression improved the prognostication of the IPI. Studies using
the Ki-67 antibody, a marker of nuclear proliferation, have shown that increased tumor cell
proliferation is a poor prognostic factor in MCL.
Cytogenetic abnormalities and oncogene expression
Mutations of p53 are associated with histologic transformation in follicular NHL, which is a
phenomenon frequently associated with a poor prognosis. Expression of BCL2 in DLBCL has also
been associated with inferior survival, whereas BCL6 expression is a marker of germinal center
derivation, a predictor of a favorable outcome with CHOP-like therapy. Expression of MYC in DLBCL
as a sole abnormality has been shown to portend an inferior prognosis, while concurrent molecular
expression of BCL2, MYC, and/or BCL6 in B-cell lymphomas (the so-called double-hit or triple-hit
lymphomas) is a particularly poor prognostic sign. The MYD88 L265P somatic mutation has been
shown to occur frequently in Waldenstrms macroglobulinemia.
TABLE 8:
Simplified MCL International Prognostic Index
Molecular Profiling
DNA microarray technology for gene expression profiling (GEP) has identified distinct prognostic
subgroups in DLBCL and follicular NHL. Studies in DLBCL have characterized patients into the
following subgroups: germinal center B-like DLBCL, activated B-like DLBCL, and a heterogeneous
subgroup termed type-3 DLBCL. In the prerituximab era, patients with germinal center B-like
DLBCL had a significantly improved overall survival compared with patients who had the other
molecular profiles. In the post-rituximab era, this prognostic difference is less, but still apparent.
Studies in follicular NHL identified two gene expression signatures that predicted survival:
immune-response 1 and immune-response 2. Interestingly, the genes that defined the prognostic
signatures, however, were not expressed in the tumor cells but were expressed by the nonmalignant
tumor microenvironment (primarily T cells, macrophages, and dendritic cells). A variety of
immunologically active cell types, including specific T-cell subsets and tumor-associated
macrophages, have been associated with prognosis in some studies.
Similar data are available in DLBCL regarding gene-expressing studies of the surrounding
(nonmalignant) microenvironment. Lenz et al showed that the stromal-1 signature (composed of
extracellular-matrix deposition and histolytic infiltration) was associated with a significantly
improved outcome compared with stromal-2 (tumor blood-vessel density) in CHOP- and
R-CHOPtreated populations. GEP is now able to be performed on formalin-fixed paraffin-embedded
tissue, and data continue to be generated linking unique molecular signatures with patient outcome.
Treatment
The therapeutic approach for NHL differs for each subtype. Chemotherapy remains the most
important modality (Tables 9 and 10). However, in select instances, radiation therapy or, rarely,
surgical resection plays a critical role. Biologic approaches, including monoclonal antibodies (Table
11) and recombinant conjugates, have shown significant clinical activity and are now incorporated
into treatment paradigms. In addition, several novel therapeutics targeted against various oncogenic
Page 10 of 42
and signaling pathways have been approved, and they continue to be evaluated as a component of
front-line treatment (Table 12). Autologous and allogeneic SCTs, traditionally reserved for recurrent
or refractory disease, are being evaluated as part of initial therapy in high-risk settings. This section
will be organized by NHL subtype to best illustrate the biologic characteristics and therapeutic
considerations that determine the management strategy for individual patients. Common NHLs will
be covered in depth, whereas less frequent entities will be described in limited detail.
Follicular Lymphoma
Follicular lymphoma accounts for 22% of all NHLs; only DLBCL is more common. The clinical
presentation may be nodal or extranodal, and bone marrow involvement occurs in the majority of
cases. Extensive intra-abdominal adenopathy without peripheral node enlargement is not
uncommon. Clinical behavior is variable, reflecting the heterogeneity of the underlying biology; some
patients survive decades, whereas others progress rapidly to resistant disease or transform to a
more aggressive histology. There are rare spontaneous remissions. Transformation is common,
occurring in 2% to 5% of patients each year and ultimately 30% to 40% of all patients. A recent
report suggests that the risk may be lower than previously reported, plateauing after 5 years.
Although follicular lymphoma is generally responsive to treatment, the clinical course is
characterized by repeated relapses. Even though there was no improvement in survival for patients
with follicular lymphoma for many years, there is now evidence that outcomes are improving.
Median survival has reached more than 18 years in some series. It is likely that this is at least in part
attributable to use of rituximab in combination with chemotherapy, but survival was already
improving before the approval of rituximab.
It is crucial to distinguish between reactive follicular hyperplasia and follicular lymphoma, because
the former is a benign condition. Morphologic features as well as the absence of BCL2 staining within
the follicle and the absence of CD10 and/or BCL6 protein expression in the interfollicular areas help
distinguish reactive follicular hyperplasia from follicular lymphoma. Follicular lymphoma is graded
according to the number of admixed centroblasts within the neoplastic follicles. Grade 3 follicular
lymphoma, previously known as follicular large cell lymphoma, is now subdivided into two subtypes:
Grade 3a is characterized by a mixture of centrocytes and centroblasts within the follicle, whereas
grade 3b has only sheets of centroblasts with no residual centrocytes.
The neoplastic lymphocytes in follicular lymphoma express the pan-B markers CD19, CD20, CD22,
and CD79a and antigens of the germinal center (including CD10 and BCL6). Most follicular
lymphomas express BCL2 protein, which is highly correlated with the t(14;18)(q32;q21). This
translocation results in the juxtaposition of the BCL2 oncogene into the immunoglobulin H
heavy-chain locus on chromosome 14, resulting in its constitutive expression. Follicular lymphoma
grade 3b with BCL6 rearrangement but no t(14;18)(q32;21) may be more closely related to DLBCL
than to other follicular lymphomas and is treated as such.
As previously mentioned, the FLIPI is a prognostic index designed specifically for follicular
lymphomas based on five adverse prognostic factors (Table 7). Age is the most important factor.
Three risk categories have been defined, each consisting of approximately one-third of patients.
More than two-thirds of low-risk patients but only one-third of high-risk patients survive 10 years. A
modern prognostic scoring system, the FLIPI2, is based on prospectively collected data from the
rituximab era (Table 7) and has progression-free survival rather than overall survival as its principal
endpoint. Among patients receiving rituximab-containing therapy, it is a robust predictor of clinical
outcome. Whereas clinical parameters are surrogates for biologic characteristics, biologic correlates
may soon supersede clinical prognostic indicators.
As noted before, investigators from the National Cancer Institute (NCI) previously described
gene-expression signatures representing immunomodulatory genes in the microenvironment with
prognostic significance. Others have reported that the number of tumor-associated macrophages,
specific T-cell subsets, and serum cytokine and chemokine levels are independent predictors of
overall survival in follicular lymphoma, underscoring the importance of host response in determining
clinical outcome. Consistent with these findings, promising new agents targeting regulators of the
T-celldependent anti-tumoral effect are now under investigation.
Sidebar: The presence of BCL2 coding sequence mutations has been identified recently as a
powerful indicator of poor prognosis, independent of the FLIPI. BCL2 coding sequence mutations
correlated with an increased risk of transformation (hazard ratio [HR] = 3.6; 95% confidence interval
[CI], 2.06.2; P< .001) and risk of lymphoma-related death (median survival: 20.4 years versus 9.5
years; P=.012) and may serve as a supplement to the FLIPI, enhancing its capacity to predict
outcome (Correia C et al: Blood 125:658-667, 2015).
Page 11 of 42
Sidebar: Investigators from the MD Anderson Cancer Center reported results of a phase II trial with
the humanized anti-PD1 monoclonal antibody, pidilizumab, in combination with rituximab for
patients with relapsed follicular lymphoma. Among 32 patients and with 15-month median follow-up,
66% of patients achieved a response, with 52% of responses being complete. Therapy was overall
well tolerated, with the most common adverse event being grade 2 respiratory infection in 16% of
patients (Westin JR et al: Lancet Oncol 15:69-77, 2014).
TABLE 9:
Chemotherapeutic regimens for NHL
TABLE 10: Commonly used salvage regimens for NHL
TABLE 11: Examples of monoclonal antibodies for lymphoid

malignancies
Treatment of early-stage disease
For patients with stage I or II follicular lymphoma, radiotherapy continues to be the recommended
approach because of the potential for long-term disease-free survival and possible cure. Results from
the Princess Margaret Hospitals series of involved-field radiotherapy (IFRT) for early-stage disease
show cumulative relapse rates of 54% and 56% at 15 and 25 years, respectively, with only a 2% risk
Page 12 of 42
of relapse beyond 15 years. Analysis of the SEER database for adults with stage I or II follicular
lymphoma diagnosed between 1973 and 2004 showed improved disease-specific survival and overall
survival with upfront IFRT, compared with all other approaches.
Irradiation alone for clinical stages I and IIA low-grade follicular lymphoma was, in the past, directed
to the entire involved lymphoid region, as defined by Kaplan and coworkers, or the involved region
plus one additional uninvolved region on each side of the involved nodes. However, targeting just
the involved lymph nodes with a margin up to 5 cm, compared with routinely covering the entire
lymph node region has been shown by a Canadian study to give equally good results and may
reduce long-term risks. Current guidelines for radiation planning utilize target definition with CT
simulation and is termed involved-site radiotherapy (ISRT). It is important to note that radiation to
large intra-abdominal or pelvic fields may be associated with increased morbidity and thus must be
judiciously considered. Conformal or intensity-modulated radiation therapy (IMRT) may be required
to spare sensitive organs such as the kidneys and liver. The recommended dose is approximately 30
Gy for nonbulky disease showing prompt regression and 36 Gy for bulky or slowly regressive disease,
in 1.75 to 2 Gy daily fractions. A trial from the United Kingdom showed equivalent results comparing
24 Gy with 40 Gy. Because the majority of subsequent relapses occur outside previous radiation
fields, often in adjacent or distal lymph nodes, extended-field or total lymphoid irradiation has been
used to try to improve cure rates. Clinical series have shown improvement in freedom from relapse
only, with no significant difference in long-term survival.
Despite the excellent outcomes associated with radiotherapy, the National Lymphocare Study
revealed that the majority of patients in the United States either are observed or are treated with
rituximab alone or in combination with chemotherapy, foregoing the potential for cure, even in
young patients. Use of functional imaging with PET may improve the results of IFRT by more
accurately identifying patients with truly localized disease. Combined-modality therapy has also
resulted in excellent disease control, but there is no evidence that this approach improves outcomes
compared with radiotherapy alone.
Treatment of advanced-stage disease
The asymptomatic patient. The standard management of asymptomatic patients with follicular
lymphoma has been a watch-and-wait approach. Treatment is delayed until symptoms or
cytopenias intervene or there is impending compromise of vital organs. In the pre-rituximab era,
multiple phase III randomized trials comparing immediate chemotherapy with observation for
asymptomatic patients with advanced-stage follicular lymphoma showed no difference in outcomes.
A phase III trial comparing the watch-and-wait approach with rituximab therapy for asymptomatic
lowtumor burden advanced-stage disease has been completed in Europe. Although the median time
to new therapy had not been reached at 4 years, there was no survival benefit to initiating therapy
with rituximab in asymptomatic patients compared with the watch-and-wait strategy. Although an
increasing number of asymptomatic patients with low-burden disease and their physicians are opting
to start treatment with rituximab before they are symptomatic or meet standard criteria for therapy,
the watch-and-wait strategy continues to be the recommended approach.
An American intergroup trial (E4402) compared two different rituximab dosing regimens in
asymptomatic patients with lowtumor burden indolent lymphoma. All patients received rituximab
375 mg/m2 weekly for 4 weeks and responders were randomized to either maintenance rituximab
(one dose every 3 months until progression) or re-treatment with four weekly doses of rituximab at
the time of progression. Each strategy was continued indefinitely until treatment failure. There was
no difference between the two strategies in time to treatment failure. Although time to cytotoxic
therapy was slightly longer in patients receiving maintenance rituximab, this came at a cost of four
times more rituximab and without an improvement in quality of life. The authors concluded that
rituximab re-treatment was the preferred strategy over ongoing maintenance rituximab, if patients
and their physicians elect rituximab monotherapy for lowturmor burden follicular lymphoma.
TABLE 12: Examples of targeted treatment agents (non-antibody) for the treatment of lymphoid
malignancies
Rituximab. For patients with symptoms or other reasons for treatment, there are many treatment
options, including single- or multi-agent chemotherapy, monoclonal antibodies or
radioimmunoconjugates, combinations of chemotherapy and immunotherapy with anti-idiotype
Page 13 of 42
vaccines, and newer agents such as bortezomib (Velcade) and bendamustine (Treanda). There are
few data on the treatment of hightumor burden disease with single-agent rituximab. Among
patients with low-burden disease, overall response rates have ranged from 47% to 74%.
In relapsed or refractory indolent lymphomas, treatment with rituximab results in overall response
rates of nearly 50%, with a median response duration of approximately 1 year. To improve on
response rates and duration of response, additional doses of rituximab have been administered as
maintenance therapy. The median event-free survival is prolonged with this approach, especially
for previously untreated patients. With a median follow-up of more than 9 years, an early trial of
single-agent rituximab has shown that among untreated patients who responded to rituximab, 45%
of those who received an additional four doses of rituximab were without progression or other events
at 8 years. In previously treated patients, the total duration of benefit from rituximab appears to be
the same whether patients receive maintenance rituximab on a scheduled basis or reinduction with
rituximab only at the time of disease progression. A confirmatory trial (ECOG 4402, described above)
in asymptomatic untreated patients with a low tumor burden has not shown an overall advantage to
the maintenance strategy. Maintenance regimens have varied, and the impact of the frequency of
administration on the duration of response is unknown.
Rituximab maintenance also impacts progression-free survival among patients treated with
chemotherapy alone and those receiving rituximab plus chemotherapy. Among previously untreated
patients with follicular lymphoma who responded to immunochemotherapy (R-CVP [rituximab,
cyclophosphamide, vincristine, prednisone], R-CHOP, or R-FCM [rituximab, fludarabine,
cyclophosphamide, mitoxantrone]), rituximab maintenance resulted in a significant improvement in
progression-free survival over observation in the PRIMA phase III trial (6-year; 59% vs 43%; P <
.0001), recently updated by Salles and colleagues. Of note, no differences in the response to
second-line therapy were noted. The most common grade 3/4 adverse event was infection (39% for
rituximab maintenance vs 24% for observation). Among relapsed/refractory patients treated with
CHOP or R-CHOP maintenance, rituximab also improved progression-free survival. Whether these
results will translate into an overall survival benefit remains to be seen. Questions also remain
regarding the impact of maintenance rituximab on the quality of life and the cost of care. Compared
with observation, maintenance rituximab has been associated with an increased risk of infectious
complications.
Chemotherapy with and without rituximab. For patients with hightumor burden disease and/or
symptoms, the addition of rituximab to chemotherapy has resulted in major improvements in clinical
outcome, including overall survival. Four phase III trials comparing combinations of chemotherapy
and rituximab with chemotherapy alone in previously untreated patients have all shown benefit for
the combination, establishing chemoimmunotherapy as the standard of care for symptomatic
patients or those with hightumor burden disease. Overall response rates and either median time to
treatment failure or event-free survival were superior in the chemoimmunotherapy arm in every
series. An overall survival benefit has been demonstrated in three of the four trials and in the
high-risk subset of the fourth study.
The combination of bendamustine (Treanda) and rituximab was compared with R-CHOP as first-line
therapy in previously untreated patients with follicular, indolent, and mantle cell lymphomas,
resulting in significantly longer median progression-free survival (69.5 months vs 31.2 months; HR =
0.58). Bendamustine plus rituximab was less myelosuppressive than R-CHOP and resulted in fewer
infections, less peripheral neuropathy, and fewer episodes of stomatitis. This combination has
become the backbone for the new US intergroup trial in which rituximab-bortexomib-bendamustine
is compared with rituximab-bendamustine. The importance of minimal residual disease in follicular
lymphoma is not known. There have been recent studies analyzing minimal residual disease, and
other prospective trials are ongoing.
Radioimmunotherapy. The anti-CD20 radioimmunoconjugates Y-90 ibritumomab (Zevalin) and
I-131 tositumomab (Bexxar) both deliver ionizing radiation to target cells and their neighbors and
have proved to be relatively easy to administer, safe, and effective. Response rates are higher and
remissions more durable when radioimmunoconjugates are used early in the clinical course. Both
agents are likely to have their greatest impact when used earlier in the disease course.
In previously treated patients, Y-90 ibritumomab, a high-energy beta-emitter, yielded an overall
response rate of 80% for relapsed or refractory follicular or transformed CD20+ B-cell NHL, with a
median duration of response of 14 months. For patients whose disease is refractory to rituximab,
response rates with Y-90 ibritumomab are high (74% overall response rate), but the median duration
of response is relatively short (6.4 months; range, 0.5 months to 25+ months). The dose-limiting
feature of this approach is hematologic toxicity. Short-lived myelosuppression occurs 7 to 9 weeks
Page 14 of 42
posttreatment. Dosing is based on weight (0.4 mCi/kg), with a reduction (0.3 mCi/kg) for those with
mild thrombocytopenia (platelet count < 100,000/L). When used to consolidate first partial or
complete remission, Y-90 ibritumomab prolonged progression-free survival from 1.1 to 4.1 years.
However, only 14% of the 414 patients enrolled on this randomized phase III trial received a
rituximab-containing regimen for induction. Now that the addition of rituximab to chemotherapy has
become standard of care based on demonstrated improvement in progression-free and overall
survival rates, the benefit of consolidation with radioimmunotherapy will need to be evaluated in
large numbers of patients treated first with chemoimmunotherapy.
I-131 tositumomab is both a gamma- and a beta-emitter and is individually dosed on the basis of
dosimetry to deliver 75 cGy of total-body irradiation. Similar to Y-90 ibritumomab, it is effective in
both heavily pretreated relapsed and refractory patients. Heavily pretreated patients with refractory
low-grade or transformed NHL had an overall response rate of 65% (20% complete response rate),
with a median duration of response of 6.5 months. These rates were notable in view of a response
rate of only 28% in the preceding chemotherapy regimen. Like Y-90 ibritumomab, I-131 tositumomab
is associated with predictable myelosuppression. Secondary myelodysplasia and leukemia have
occurred in patients treated with radioimmunotherapy, but only in patients previously treated with
chemotherapy and thereby already at risk. In previously untreated patients, the complete response
rate was 75%, with a 5-year progression-free survival of 59%. These data must be interpreted
carefully, because this study enrolled a relatively young patient population (median age, 49 years)
with low-bulk disease, a group that some physicians would choose to observe rather than treat.
The American intergroup completed a phase III trial comparing CHOP followed by I-131 tositumomab
with R-CHOP in treatment-naive patients. Outcomes were excellent with either strategy. R-CHOP and
CHOP followed by radioimmunotherapy produced similar response rates, progression-free survival,
and overall survival. Furthermore, there were no major differences in toxicities. The future role of
radioimmunotherapy in induction and consolidation for follicular lymphoma remains to be
determined. New strategies to enhance tumoricidal effects and reduce toxicity of
radioimmunoconjugates are under study, including the use of radiosensitizers, fractionation,
pretargeting, and production of humanized antibodies.
Interferon-. The use of interferon (IFN)- in follicular lymphoma has been extensively investigated
both in combination with chemotherapy and as maintenance therapy, with varying results. In most
studies, IFN- was associated with a prolongation of remission, but not overall survival. A notable
exception was the GELF86 trial, in which overall survival was prolonged. The Southwest Oncology
Group (SWOG) reported results of a large phase III trial in which patients with indolent lymphomas
were randomized to receive IFN- or observation following induction with an intensive
anthracycline-containing regimen and in some cases radiotherapy. Post-remission therapy did not
prolong progression-free survival or overall survival.
Irradiation. Radiation therapy is not typically used in conjunction with systemic therapy. However,
irradiation may be effective when used locally for palliation of symptomatic sites of disease.
Abbreviated fractionated schedules (25 to 30 Gy in 2.5 to 3 Gy daily fractions, respectively) are often
used. A low-dose regimen of 4 Gy in 2 fractions has been shown to be effective, with an overall
response rate of approximately 80% in the palliation of symptoms, and is well tolerated. A phase III
trial from the UK that compared 4 Gy with 24 Gy showed good symptom control with 4 Gy, but the
progression-free rate is lower than with 24 Gy. Total-body irradiation, usually consisting of 12 Gy in 2
Gy fractions twice a day, is used as part of preparative regimens for bone marrow transplant.
Anti-idiotype vaccines. Lymphoma-specific idiotypes serve as tumor-specific antigens in follicular
lymphoma and constitute the basis for vaccine therapy. In early vaccine trials, immunized patients
who generated an anti-idiotype response experienced longer remissions than those who failed to
mount a response. In phase I trials, vaccination resulted in tumor shrinkage in some patients, and in
a phase II trial, anti-idiotype vaccine eliminated minimal residual disease detectable only by PCR
after intensive chemotherapy.
A phase III randomized trial comparing vaccination plus KLH (keyhole limpet hemocyanin, a
nonspecific immunostimulant) with KLH alone in previously untreated patients who achieved a
complete remission with intensive anthracycline-containing combination chemotherapy was
conducted. Patients who received the vaccine who were in complete remission for 6 months after
intensive chemotherapy experienced a marginally significant prolongation of cancer-free survival.
However, disease-free survival was prolonged significantly for those patients who received an IgM-Id
but NOT for those who received an IgG-Id vaccine, compared with isotype controls. In contrast, two
other placebo-controlled trials of anti-idiotype vaccination have shown no benefit. Compared with
placebo, vaccination following induction chemotherapy with CVP, or induction immunotherapy with
Page 15 of 42
rituximab did not impact progression-free or overall survival. Differences in study design are likely
responsible for the differences in outcomes among the trials. New directions in vaccination include
idiotype-pulsed dendritic cell and membrane proteoliposomal vaccines.
Novel agents. New agents targeting specific molecular targets such as Bruton tyrosine kinase (BTK)
receptor, the phosphoinositide 3kinase pathway, the ubiquitin-proteasome pathway, histone
deacetylase, the mammalian target of rapamycin, the microenvironment, and BCL2 have shown
promise in the treatment of follicular lymphoma (Table 12). Novel antibody approaches to follicular
lymphoma include new and improved anti-CD20s, antibodies that bind to alternative targets,
antibody-drug conjugates, and radioimmunoconjugates.
Sidebar: Patients with indolent lymphoma refractory to both rituximab and an alkylating agent were
treated with idelalisib daily, with promising results. Ninety percent of the 125 patients experienced a
decrease in tumor burden with an overall response rate of 57% and median progression-free survival
of 11 months. Responses were observed in all histologies and treatment was overall well-tolerated
(Gopal AK et al: N Engl J Med 370:1008-1018, 2014).
SCT. The natural history of follicular lymphoma is characterized by response to therapy, but also by
repeated relapses and progressively shorter and shorter remissions that ultimately result in death
from progressive disease. Autologous and allogeneic SCTs are alternative strategies often associated
with durable remissions that may impact overall survival. Unfortunately, immediate and long-term
toxicities are significant and must be considered when assessing the appropriate role of transplant in
the overall treatment plan for individual patients. Whether any of the new therapeutic strategies will
prove to be as effective as autologous SCT in the relapsed setting remains to be seen.
Several groups have investigated the role of autologous SCT as consolidation therapy for patients in
first complete or partial remission. Although progression-free survival may be prolonged, an impact
on survival has not been demonstrated consistently. An increased incidence of secondary
myelodysplasia following autologous SCT in first remission has reduced enthusiasm for this
approach. Contemporary trials evaluating the role of autologous SCT for follicular lymphoma in first
remission induced with rituximab-containing regimens are needed. The results of a German
Lymphoma Study Group trial comparing IFN maintenance with myeloablative chemotherapy with
autologous SCT after induction with CHOP or R-CHOP are awaited.
An alternative approach to consolidating complete and partial remissions achieved with conventional
induction therapy is the use of a sequential high-dose chemotherapy program, which culminates in
an autologous SCT. The Italian cooperative groups have reported results of a phase III randomized
trial comparing R-CHOP for six cycles with sequential high-dose chemotherapy with autologous SCT.
Again, there was a significant difference in event-free survival, but no difference in overall survival.
Single-institution studies as well as analysis of registry data suggest that a tumor-free graft is an
important determinant of outcome in follicular lymphoma. Administration of rituximab during stem
cell mobilization provides an in vivo purge, reducing contamination of the autograft with malignant
lymphocytes; however, a recent randomized trial showed no overall survival benefit.
Sidebar: Investigators from the United Kingdom randomized 280 relapsed/refractory follicular
lymphoma patients in a factorial design who were undergoing autologous SCT to rituximab purging
before SCT or rituximab maintenance after SCT. Pre-SCT rituximab purge had no effect on
progression-free survival or overall survival, whereas rituximab maintenance was associated with
improved 10-year progression-free survival (54% vs 37%, respectively; P = .01). However, overall
survival was not improved with this treatment strategy (Pettengell R et al: J Clin Oncol 31:1624-1630,
2013).
Allogeneic SCT has been investigated primarily in young patients with HLA-identical sibling donors
and extensive disease and/or marrow involvement. Low relapse rates suggest that this approach is
potentially curative but is associated with treatment-related morbidity and mortality.
Reduced-intensity transplant is based on the assumption that a graft-vs-lymphoma effect is
operative and has the potential to cure follicular lymphoma. A recent update of nonmyeloablative
allogeneic transplant for relapsed follicular lymphoma with a median follow-up of 107 months
showed excellent long-term outcomes and is supportive of the trend to replace myeloablative
conditioning regimens with regimens that are either reduced-intensity or strictly nonmyeloablative.
Overall treatment strategy
Whereas treatment choices were once limited to single or combination alkylator-based treatment,
we now are faced with choosing among a wide variety of strategies. There are many unanswered
questions that can only be addressed through well-designed clinical trials. Hence, whenever
possible, every patient with follicular lymphoma should be enrolled in prospective clinical studies. In
Page 16 of 42
the absence of symptoms or other indications for treatment, patients should be observed. A
combination of rituximab and chemotherapy is recommended in the absence of a clinical trial for
those who require treatment, which may be followed by 2 years of maintenance rituximab. Select
patients with comorbidities may be best served with rituximab-alone induction therapy.
Radioimmunotherapy is a good option at the time of relapse, with transplant reserved for select
patients in first or subsequent relapse.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
CLL/SLL (also see Chronic Lymphocytic Leukemia and Hairy-Cell Leukemia chapter) is a
malignancy of small, round, B lymphocytes involving peripheral blood, bone marrow, and lymph
nodes. The term SLL is reserved for cases in which there are no circulating malignant lymphocytes.
SLL generally presents with lymph node and splenic involvement. Involvement of the bone marrow
and peripheral blood may develop later in the course of disease. At the time of presentation, patients
may be asymptomatic, complain of only fatigue, or have symptoms related to cytopenias (including
autoimmune hemolytic anemia, lymphadenopathy, or splenomegaly).
The immunophenotype helps distinguish CLL/SLL from other B-cell leukemias/lymphomas, including
mantle cell and leukemic forms of follicular lymphoma. Typically, the malignant lymphocytes stain
weakly with surface immunoglobulin, CD20, CD22, and CD79b; they are CD5+, CD23+, and FMC7.
Cytogenetic abnormalities are detected in the majority of cases when FISH analysis is used. Trisomy
12, deletions at 13q14, and deletions at 11q22-23 are common. Many molecular markers of
prognosis have been studied in CLL, including Zap-70, but their value in SLL is unknown.
Given the relatively small numbers of patients with SLL, they have generally been included in clinical
trials of indolent lymphoma. Conventional alkylator-based regimens with rituximab as well as
purine analogues and combinations including bendamustine have been used when patients become
symptomatic. Anthracyclines have not been shown to benefit patients with CLL/SLL. When compared
with follicular lymphoma, CLL/SLL is less likely to respond to rituximab as a single agent.
Alemtuzumab (Campath), a potent therapy for CLL, is less effective in treating nodal disease than
peripheral blood and bone marrow involvement. SCT, both autologous and allogeneic, has been
studied in select patient populations but should be reserved for relapsed young patients with a good
performance status.
As discussed in the CLL chapter, there are two additional CD20 monoclonal antibodies now Food and
Drug Administration (FDA)-approved for the treatment of CLL (ie, ofatumumab [Arzerra] for CLL
refractory to fludarabine and alemtuzumab; and obinutuzumab [Gazyva] for use in combination with
chlorambucil for untreated CLL) and other novel therapeutic agents with very encouraging clinical
activity (eg, the BTK inhibitor, ibrutinib [Imbruvica], and the PI3K delta inhibitor, idelalisib). An
international randomized phase III study (RESONATE study) comparing ibrutinib with ofatumumab for
patients with relapsed/refractory CLL or SLL was stopped early because an interim analysis showed a
statistically significant improvement in progression-free survival and overall survival for patients
receiving ibrutinib. OBrien and colleagues recently reported results with single-agent ibrutinib in 29
older patients (age 70 years) with untreated CLL/SLL. At a median follow-up of approximately 2
years, the overall response rate was 71% (complete remission, 13%).
Sidebar: Goede and colleagues presented final results from the German CLL11 trial studying
obinutuzumab plus chlorambucil in treatment-naive CLL patients with comorbidities. The phase III
trial assigned 780 CLL patients with a Cumulative Illness Rating Scale score greater than 6 and/or an
estimated creatinine clearance of less than 70 mL/min to obinutuzumab plus chlorambucil, rituximab
plus chlorambucil, chlorambucil alone. Corresponding median progression-free survival was 26.7,
16.3, and 11.1 months, respectively (P < .0001). The overall survival was superior for obinutuzumab
plus chlorambucil over chlorambucil (HR = 0.41; P = .002) (Goede V et al: N Engl J Med
370:1101-1110, 2014).
Splenic Marginal Zone Lymphoma
Splenic marginal zone lymphoma (SMZL) is a rare disorder accounting for less than 1% of NHLs.
Clinically, this lymphoma most often presents as splenomegaly with splenic hilar node involvement
but without peripheral adenopathy. The bone marrow is commonly involved, and malignant villous
lymphocytes may be detected in the peripheral blood. Cytopenias are a common presenting feature,
often related to hypersplenism and less frequently to an autoimmune process or marrow
replacement. Sometimes confused with CLL or MCL, SMZL may be distinguished by its
immunophenotype. Typically, cells are CD20+, CD79a+, CD5, CD10, CD23, and CD43.
Staining for cyclin D1 is negative, excluding MCL. The absence of CD103 helps exclude hairy cell
Page 17 of 42
leukemia. Complex karyotypes are common. The clinical course is indolent. Cytopenias may respond
to splenectomy with long-lasting remissions. High response rates have been reported with rituximab,
and maintenance appears to delay relapse. Transformation to more aggressive histologies may
occur. Fludarabine alone or with rituximab appears to be more effective than alkylators, which are
relatively ineffective in this disease, but may be associated with significant toxicity.
Nodal Marginal Zone Lymphoma
Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell disorder that resembles lymph
nodes involved by marginal zone lymphomas of extranodal or splenic origin without extranodal or
splenic involvement. Lymphadenopathy (either localized or generalized) is the presenting complaint
in most cases. Extranodal lymphoma may be uncovered in the evaluation of many cases of
suspected NMZL. The clinical course is usually indolent, similar to that of other marginal zone
lymphomas.
Extranodal Marginal Zone B-Cell Lymphoma of MALT Type
MALT lymphomas account for only 7% to 8% of B-cell lymphomas but nearly 50% of all gastric
lymphomas. Although the GI tract is most often involved, other common sites include the lungs,
head and neck, ocular adnexae, skin, thyroid, and breasts. There often is an associated history of
autoimmune disorders, such as Sjgren syndrome or Hashimoto thyroiditis, or chronic inflammatory
processes secondary to infectious agents (H pylori, B burgdorferi, or C psittaci). A form of MALT
involving the small bowel (immunoproliferative small intestinal disease, previously known as -heavy
chain disease) has been associated with C jejuni. The majority of patients present with stage I or II
disease. The frequency of bone marrow involvement appears to differ depending on the primary site
of involvement. Multiple extranodal sites may be involved at the time of presentation.
Transformation to a high-grade lymphoma may occur in approximately 8% of cases.
The malignant lymphocytes of MALT lymphoma are typically CD20+, CD79a+, CD5, CD10, and
CD23. The t(11;18)(q21;q21) is characteristic of MALT lymphomas, particularly those involving the
stomach or lungs. The translocation creates a fusion between the MALT-1 gene, which is an essential
regulator of BCL10mediated NF-B signaling, and the API2 gene, which inhibits apoptosis. This
genetic abnormality is a marker of MALT lymphomas that do not respond to antibiotic therapy for H
pylori infection, are associated with a more advanced stage, and do not transform into more
aggressive NMZLs, SMZLs, or other types of lymphoma. Additional characteristic translocations have
been discovered (Table 1), but their clinical significance is uncertain at this time.
Treatment of H pylori infection with triple therapy (eg, omeprazole, metronidazole, and
clarithromycin) results in regression in the majority of early lesions. However, tumors invading
beyond the submucosa and lesions with t(11;18) are associated with a failure to respond to H pylori
eradication, deep penetration, and distant spread. Localized MALT gastric lymphoma that does not
respond to antibiotics may be cured with local irradiation, with a field including the stomach and
perigastric lymph nodes. This treatment is safe, extremely effective, and preserves the stomach. If
local irradiation fails, chemotherapy or rituximab, and in some instances surgery, can be used.
Alkylator-based therapy or purine analogues have been used with success for persistent or
disseminated disease.
Lymphoplasmacytic Lymphoma/Waldenstrm Macroglobulinemia
Lymphoplasmacytic lymphoma/Waldenstrm macroglobulinemia is a disorder of small B
lymphocytes, plasmacytoid lymphocytes, and plasma cells, typically involving the bone marrow,
lymph nodes, and spleen. It is usually associated with a serum monoclonal protein (usually IgM) with
associated hyperviscosity or cryoglobulinemia. The clinical presentation is usually related to
hyperviscosity with visual symptoms, stroke, or congestive heart failure. In approximately 10% of
patients, peripheral neuropathies occur, which are related to reactivity of IgM with myelin-associated
glycoprotein or gangliosides. An association with HCV infection has been demonstrated.
Characteristically, the immunophenotypic analysis reveals surface and cytoplasmic immunoglobulin,
usually IgM type, and B-cellassociated antigens (such as CD19, CD20, CD22, and CD79a). The
malignant cells are CD5, CD10, and CD23.
The clinical course is generally indolent. Asymptomatic patients may be observed. Plasmapheresis
may be appropriate first therapy for those who present with hyperviscosity. The clinical status of the
patient, not the level of the protein, determines when treatment is initiated. Choice of therapy
depends on many individual factors, including age, comorbidities, and the particular indication for
Page 18 of 42
therapy. Rituximab and nucleoside analogues (cladribine and fludarabine) as well as the traditional
oral alkylators have shown efficacy, whereas anthracyclines are not beneficial. Rituximab
monotherapy may be associated with a rapid rise in IgM levels associated with increased serum
viscosity requiring plasmapheresis. Combinations of these agents are also under study. Bortezomib,
lenalidomide, and alemtuzumab have shown activity in Waldenstrm macroglobulinemia. SCT, both
autologous and allogeneic, is being investigated in younger patients with relapsed or refractory
disease. In addition, the BTK inhibitor ibrutinib is associated with encouraging clinical activity in
patients with Waldenstrm macroglobulinemia, prompting expanded approval of this agent.
Sidebar: Ibrutinib was granted breakthrough therapy designation for Waldenstrm
macroglobulinemia by the FDA January 29, 2015. The approval was based in part on a multicenter
phase II study of ibrutinib 420 mg once daily for 63 patients with previously treated Waldenstrm
macroglobulinemia. The overall response rate was 62% with median duration not reached and
median time to response of 1.2 months. In addition, responses were impacted by mutations in
CXCR4, but not MYD88 L265P, as predicted in laboratory studies (Cao Y et al. Br J Haematol 2015,
Epub ahead of print; Cao Y et al: Leukemia 29:169-176, 2015).
Diffuse Large B-Cell Lymphoma
Clinical presentation
DLBCL makes up about one-third of the cases of NHL and is classified as a mature peripheral B-cell
neoplasm by the WHO. The clinical presentation is variable, but generally patients present with
either peripheral lymphadenopathy (neck, axillae) or enlarged nodes in the mediastinum, the
mesenteric region, or the retroperitoneum. These sites predict symptoms, which may include chest
pain; facial swelling and suffusion of the eyelids (SVC syndrome from mediastinal disease);
abdominal discomfort, ascites (mesenteric), or back pain; or renal obstruction (retroperitoneal
presentations). More than 30% of patients present with disease in extranodal sites, such as the GI
tract (including Waldeyer ring), skin, bone marrow, sinuses, genitourinary tract, thyroid, and CNS. B
symptoms, consisting of fever, sweats, and weight loss, are more common in DLBCL than in the
indolent lymphomas and occur in about 30% of patients. The median age at presentation is 60 years.
Once the diagnosis is clearly established, staging studies are carried out to determine treatment and
define parameters for follow-up. Generally, imaging studies of the chest, abdomen, and pelvis are
obtained, and CT scans provide the most accurate anatomic information. Functional imaging using
PET scans provides important information, including the diffferentiation between residual scar and
active disease after treatment. Further, bone marrow biopsy and aspirate and LDH serum levels
should be performed. Additional staging studies (eg, brain MRI, lumbar puncture,
esophagogastroduodenoscopy) should be guided by clinical symptoms.
Pathology/immunology
The diagnosis should be made by incisional or excisional biopsy of an available lymph node, with
adequate tissue for immunologic studies, such as flow cytometry or IHC, to identify the characteristic
B-cell clonality (kappa or lambda restriction). The use of FNA or core biopsy should be discouraged; it
is acceptable only when tissue cannot be safely obtained by other means and only if flow cytometry
is used to help classify the disease (including ruling out composite lymphomas) and to distinguish it
from other malignancies that may masquerade as lymphoma. In many cases of DLBCL, CD10 is
present, indicating a germinal center origin. The CD20 antigen is present in almost all cases.
Markers for BCL2 and BCL6 help determine cell of origin (COO) and may offer prognostic information,
although continued investigation and research are needed to refine the COO classification as
demonstrated by the Gribben laboratory. In addition, molecular testing is encouraged because
identification of c-MYC oncogene in DLBCL has been shown to predict for increased risk of CNS
dissemination and overall inferior survival (compared with MYCnegative DLBCL). Two 2012 studies
by Green et al and Johnson et al showed that DLBCL patients with MYC and BCL2 coexpression by
IHC have a poorer prognosis when treated with R-CHOP therapy. This finding was corroborated in the
International DLBCL Rituximab-CHOP Consortium Program; however, the most appropriate therapy
for patients with double-positive protein expression is not known. Recent data have been
published regarding the presence of molecular double-hit DLBCL, which is characterized by
rearrangements in MYC with BCL2 and/or BCL6.
Sidebar: A large, multicenter retrospective study examined features and outcomes of 311 patients
with untreated double-hit lymphoma. At 2 years, 40% of patients remained disease-free and 49%
were alive. Intensive induction was associated with improved progression-free survival, but not
overall survival. Further, a double-hit lymphoma prognostic risk score was developed (Petrich AM et
Page 19 of 42
al: Blood 124:2354-2361, 2014).
Prognostic factors
Clinical predictors of response have been identified and are now widely used to help design
therapeutic plans and clinical trials. These predictors include patient age (younger than or older than
60 years), performance status (0, 1 vs 2-4), number of extranodal sites (more than two), Ann Arbor
stage (I or II vs III or IV), and serum LDH level (higher than normal; Table 6). Older patients, higher
stage, poorer performance status, higher number of extranodal sites, and higher LDH level all predict
a worse outcome, and this model has been validated in more than 3,000 patients. These parameters
have been called the IPI; this index is used to plan therapy and clinical trials in the United States and
abroad and may be used to predict survival. Updated analyses of the IPI in the post-rituximab era
have validated the IPI as an important prognostic tool (Table 13).
Genomics have also been used to help predict outcome on the basis of molecular signature (see
subsection on Molecular profiling). This molecular system provides prognostic information
independent of the IPI.
Treatment
Before the 1970s, most patients with stage I/II large cell lymphoma (intermediate grade in the
Working Formulation) were treated with irradiation alone, with overall cure rates of 40% to 50%.
Patients with pathologically favorable stage I/II disease had even better outcomes, but relapse rates,
even in these patients, were still 20% to 30%. Pathologic staging, therefore, selected a group
suitable for irradiation alone. This approach is no longer appropriate, in view of the success of
combined chemotherapy and irradiation in clinically staged patients.
TABLE 13: Outcomes according to International Prognostic Index (IPI) factors and the NCCN-IPI in
patients with de novo DLBCL treated with R-CHOP in British Columbia Cancer Agency database
Coiffier et al (N Engl J Med 2000) found that the addition of rituximab improved results in elderly
patients with DLBCL, and recent data confirm these observations for younger patients as well. For
patients with clinical stage I or II disease (by the Ann Arbor criteria), most studies suggest that
chemotherapy (CHOP) with rituximab for three or four cycles followed by localized radiation therapy
is preferred. Excellent local and systemic tumor control is obtained with combined-modality therapy.
In an Eastern Cooperative Oncology Group (ECOG) phase III trial, Horning et al showed that eight
cycles of CHOP and irradiation produced a 10-year disease-free survival rate of 57%, compared with
46% with CHOP alone (P = .04). Overall survival was 64% vs 60%, respectively (P = .23), and time to
disease progression was 73% vs 63%, respectively (P = .07).
Miller et al showed that CHOP (three cycles of CHOP and irradiation) produced a progression-free
survival at 5 years of 77%, vs 64% for eight cycles of CHOP alone (P = .03). Overall survival at 5
years was 82% vs 72%, respectively (P = .02). Update of this SWOG study was reported by Miller et
al, with an 8.2-year median follow-up. The 5-year estimates for CHOP for three cycles plus irradiation
vs CHOP for eight cycles remained unchanged. Kaplan-Meier estimates, however, now show
overlapping curves at 7 years for failure-free survival and 9 years for overall survival. The treatment
advantage for CHOP (for three cycles plus irradiation) for the first 7 to 9 years was diminished
because of excess late relapses and NHL deaths occurring between 5 and 10 years. Patients with
good IPI risk factors had a 5-year overall survival of 94%; patients with one adverse risk factor had
an overall survival of 70%; those with three adverse risk factors had a 5-year survival of 50%.
These results were confirmed by a single-arm (doxorubicin-containing chemotherapy) approach
followed by IFRT conducted by the British Columbia Cancer Agency. However, two reports from
European investigators question the value of consolidation irradiation in early-stage disease. These
studies did not use rituximab or FDG-PET staging, and details on the irradiation technique used were
not available. The necessity of consolidation radiation therapy after complete response to R-CHOP
chemotherapy is now being tested in a randomized study in Germany (the UNFOLDER trial).
Until further studies define the optimal therapy for stages IA to IIA DLBCL (nonbulky), many
investigators consider three or four cycles of R-CHOP and IFRT the initial treatment of choice. For
Page 20 of 42
patients with bulky disease, a minimum of six cycles of R-CHOP is typically administered. Irradiation
doses of 30 to 36 Gy, delivered in 1.75 to 1.8 Gy over 3 to 4 weeks after completion of systemic
therapy, appear to be adequate. Radiation fields usually include involved lymph node sites or an
involved extranodal site and its immediate lymph node drainage areas. Volumetric definitions of
radiation target volumes are now used with 3-dimensional CT planning, and when gross target
volume, clinical target volume, and planning target volume are outlined, such planning methods to
treat the involved site(s) are now termed involved-site radiation therapy (ISRT). For the most
common presentations of stage I-II lymphoma, the disease is encompassed in a planning target
volume with acceptable toxicity.
Disease site or potential toxicities may influence the treatment plan:
Lymphomas of the head and neck may be managed with chemotherapy alone to avoid the acute
mucositis and long-term xerostomia associated with radiation therapy fields that are large and
include both parotid glands. Alternatively, precise radiation therapy techniques can be employed
with intentional sparing of salivary glands, using IMRT.
Fully resected gastric or small intestinal lymphoma may be treated with chemotherapy alone.
Patients at high risk for perforation or life-threatening hemorrhage may require surgical resection.
Alternatively, chemotherapy followed by local irradiation allows gastric preservation and is preferred
in most patients.
For patients with advanced stage (III or IV) disease, CHOP continues to be the standard combined
with rituximab for six cycles. Preliminary results from three randomized studies using dose-dense
therapy (ie, shortening the interval between cycles from 3 weeks to 2 weeks with growth factor
support) have shown no benefit to this strategy. Mature data are needed to confirm these
preliminary results. The addition of rituximab to CHOP chemotherapy has been shown to be
associated with improved response rate, disease-free survival, and overall survival. There appears to
be no advantage to maintenance therapy with rituximab in this setting as long as rituximab is
included in the induction. Responses are seen in upward of 90% of patients, and approximately 60%
to 65% of patients are cured. Several studies have shown that early complete remission by PET (ie,
after two or three cycles) predicts for favorable outcome, while persistent metabolic uptake predicts
for high risk of relapse. Further, phase II studies have shown that modification of chemotherapy (eg,
from CHOP to ICE [ifosfamide, carboplatin, etoposide]) for patients with positive early PET findings
may improve outcomes. However, this is not recommended outside of a clinical trial, in part because
of the poor reproducibility in the interpretation of PET scans and nonrandomized data. Data
published by the German High-Grade Non-Hodgkin Lymphoma Study Group in successive DLBLC
studies have suggested that sex and age may impact the benefit to rituximab therapy (see sidebar).
Continued prospective studies are needed to define the most optimal dose and dosing schedule of
rituximab (based in part on age and sex).
Sidebar: The German High-Grade Non-Hodgkin Lymphoma Group showed that compared with
elderly women, all other subgroups had significantly faster clearance of rituximab and thus appear to
be suboptimally dosed when rituximab is given at 375 mg/m2 (Pfreundschuh M et al: Blood
123:640-646, 2014). They followed this observation with the prospective SMARTE-R-CHOP-14 trial,
which showed improved pharmacokinetics in older men (Pfreundschuh M et al: J Clin Oncol
32:4127-4133, 2014).
As described before, DLBCL patients with double-positive MYC and BCL2 protein expression and
especially molecular double-hit DLBCL (MYC with BCL2 and/or BCL6) have inferior outcomes when
treated with R-CHOP therapy. Ideal therapy for these patient populations is not known. Continued
treatment strategies, such as more intensive chemotherapy (eg, DA-EPOCH-R [dose-adjusted
etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin with rituximab]),
consolidative therapy (eg, autologous SCT), and the integration of rational targeted therapeutic
agents, continue to be explored.
For patients who either do not have a complete remission or who relapse, alternative therapies are
possible, but long-term responses have been seen mostly with autologous or allogeneic SCT. The
impact of posttransplant therapy is not standard, although several investigational efforts are
examining this. Patients who do not have responsive disease before SCT generally do poorly. The IPI
has been used to predict outcome for transplant in DLBCL. The role of autologous SCT for high-risk
patients remains open to debate. A randomized clinical trial of early vs delayed high-dose therapy
for patients with high- and high-intermediaterisk diffuse aggressive lymphoma conducted by the US
intergroup showed no benefit to this approach; however, the subgroup of patients with high risk
according to the IPI may not have been powered to detect a small difference. Outside of a clinical
trial, consolidative SCT is not recommended. Investigational treatments include novel antibodies,
Page 21 of 42
radioimmunotherapy, single-agent chemotherapy drugs, and the integration of novel therapeutic
agents (eg, ibrutinib, lenalidomide). Nonmyeloablative SCT continues to be evaluated in patients
with recurrent or refractory disease.
Some investigators believe that irradiation for stages III and IV (advanced or extensive) DLBCL may
be added after the completion of definitive chemotherapy if there is localized residual disease, to
improve local tumor control. Irradiation may also be delivered after chemotherapy to areas of
initially bulky disease, again to enhance local tumor control. These recommendations are based on
the observation that when DLBCL relapses after definitive chemotherapy, it usually does so in
initially involved or bulky areas of disease. The benefits and potential adverse effects of irradiation
should be weighed against the use of alternative chemotherapy salvage regimens.
Mantle Cell Lymphoma
By comparison with patients with low-grade NHL, patients with MCL are older (median age, 64
years), mostly male (75%), and more likely to have peripheral blood involvement (about 30%) and
extranodal involvement (mostly the GI tract and CNS, as discussed below). The clinical course in MCL
is characterized by features of the aggressive lymphomas (an aggressive course) and the indolent
lymphomas (frequent recurrences). The disease is often widespread at diagnosis, and marrow
involvement and splenomegaly are common. GI tract involvement is also common, and many
centers suggest evaluation of the GI tract at the time of diagnosis. CNS recurrences are frequent (up
to 20%), but isolated CNS disease is a rare occurrence. Leukemic presentations are not uncommon,
especially in patients with blastic MCL.
It is also important to recognize that a subset of MCL patients may present with indolent disease and
may not warrant immediate therapy. Among 97 MCL patients seen over a 10-year period at Cornell,
Martin and colleagues (J Clin Oncol 2009) observed 32% of patients more than 3 months before start
of systemic therapy. Median time to treatment for this group of patients was 12 months (range, 4 to
128 months). Better performance status and lower-risk IPI scores were characteristic of the patients
who could be observed. Altogether, this finding suggests that a deferred approach to treatment is
acceptable in a select group of patients with MCL.
This disorder was originally classified as diffuse, small, cleaved lymphoma by the REAL classification
and represents less than 10% of all NHLs. In this disease, a homogeneous population of small
lymphoid cells with irregular nuclear borders arises from and expands the mantle zone surrounding
the germinal centers of the lymph nodes, spreading diffusely through the node as the germinal
centers are overrun. The lymphocytes express IgM or IgD, as in CLL, but in much greater density. It
was recognized that the cells carry a translocation of the long arms of chromosomes 11 and 14,
notated as t(11;14)(q13;q23). This molecular event juxtaposes the BCL1 gene on chromosome 11 to
the immunoglobulin heavy-chain gene on chromosome 14, leading to overexpression of BCL1. This
gene encodes the cell-cycle regulatory protein cyclin D1, which is believed to play a role in
checkpoint control in DNA synthesis. The immunophenotype is characteristic, and MCLs are usually
CD5+, CD20+, CD10, CD23, and FMC7+. This immunophenotype is similar to that seen with
CLL/SLL, except that CD23 is most often expressed in CLL/SLL but usually is not expressed in MCL.
The key to the diagnosis is the demonstration in tumor tissue or peripheral blood of the t(11;14) by
FISH or the cyclin D1 protein by IHC. Inactivation of the ATM gene has been described in MCL. Data
also show that MCL cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d), suggesting a
relationship with the stromal environment.
The role of SOX11 in MCL biology has been debated, and its importance as a prognostic factor
remains uncertain. Vegliante and colleagues found that SOX11 directory regulates the expression of
PAX5, a transcription factor that maintains B-cell identity and represses plasma cell differentiation,
thus preventing MCL cells from completing their normal differentiation process. These data suggest
that the development of MCL may be related to a combination of cyclin D1 overexpression,
deregulation of cell proliferation, and the block of normal B-cell differentiation, which prevents
further development through the SOX11-PAX5-BLIMP-1 regulatory axis.
Sidebar: Investigators evaluated t(11;14)-positive B-PLL patients and 6 t(11;14)-negative B-PLL
patients. There was high similarity in immunophenotype and gene expression profile between
t(11;14)-positive B-PLL and MCL. Furthermore, the t(11;14)-negative B-PLL cases appeared as a
subgroup of MCL, while a third group clustered close to nodal MCL and was associated with short
survival (van der Velden VH et al: Blood124:412-419, 2014).
Page 22 of 42
Treatment
The NCCN guidelines recommend clinical trials for patients with MCL (there is no standard
therapy); however, a number of exciting breakthroughs have been seen recently in the treatment of
MCL. Responses to aggressive chemotherapy alone (CHOP or R-CHOP) are seen, but patients relapse
frequently, and median survival is short (typically <16 months). Recent data suggest an advantage
to autologous SCT while patients are in first remission, but more data are required to validate these
results. Patients who have relapsed after autologous SCT have been successfully rescued and
potentially cured by allogeneic SCT.
Sidebar: External validation of the MIPI was performed on 958 patients with MCL who were treated
in two recent randomized trials of the European MCL Network. Five-year overall survival rates in MIPI
low-, intermediate-, and high-risk groups were 83%, 63%, and 34%, respectively. The prognostic
significance was independent of patient age or treatment strategy (Hoster E et al: J Clin Oncol
32:1338-1346, 2014).
Sidebar: Recently Robak and colleagues described the substitution of bortezomib for vincristine in
R-CHOP (VR-CAP) in patents with newly diagnosed MCL. In a randomized study, they reported an
improvement in the primary endpoint of the study, which was progression-free survival, from 16.1
months to 30.7 months (HR = 0.51; P < .001). Secondary endpoints, including complete response
rates (42% vs 53%), duration of CR (18 months vs 42.1 months), median treatment-free interval
(20.5 months vs 40.6 months), and 4-year overall survival rate (54% vs 64%), were all in favor of the
VR-CAP regimen over the R-CHOP regimen. These studies need further validation. Furthermore, the
role of maintenance therapy with rituximab or consolidation with SCT were not addressed in this
study (Robak T et al: N Engl J Med 372:944-953, 2015).
A number of studies over the past 5 to 10 years have examined intensive treatment strategies for
patients with newly diagnosed MCL. Investigators have shown that aggressive hyperfractionated
chemotherapy with rituximab (R-hyper-CVAD [cyclophosphamide, vincristine, doxorubicin,
dexamethasone]) may result in long-term responses in patients with MCL.
The Nordic group compared their prior experience (1996-2000) using a high-dose CHOP regimen for
four cycles followed by an autologous SCT with BEAM (carmustine [BiCNU], etoposide, cytarabine
[Ara-C], methotrexate) or BEAC (carmustine [BiCNU], etoposide, cytarabine [Ara-C],
cyclophosphamide) conditioning with a newer regimen (2000-2006). Patients were then followed up
using patient-specific primers as markers for molecular relapse; those who showed molecular
recurrence were treated with rituximab preemptively. Only morphologic relapse was considered a
relapse for the purposes of this trial. The results of the two trials were compared and showed that
5-year event-free survival improved from 15% to 41% and overall survival, from 63% to 75%. Further
studies are needed to verify these data.
A number of MCL patients cannot tolerate aggressive induction therapeutic regimens such as
hyper-CVAD/Ara-C-MTX or autologous SCT. Thus, more tolerable treatment regimens are needed.
The combination of bendamustine and rituximab (BR) has been shown to be a well-tolerated and an
active treatment regimen. A subset of patients from the Study group indolent Lymphomas (StiL)
study had MCL; the median progression-free survival for patients treated with BR was 35 months
compared with 22 months for patients who received R-CHOP (P = .004). The Mayo Clinc has reported
an additional low-intensity chemotherapeutic regimen for frontline treatment of MCL that includes
cladribine.
The potential benefit of maintenance therapy for MCL, in particular rituximab, has been hotly
debated. The German Mantle Cell Group randomized 560 older MCL patients to R-CHOP or to
fludarabine, cyclophosphamide, and rituximab induction therapy, which was followed by a second
randomization to maintenance therapy with either rituximab or IFN. Results showed that
maintenance rituximab resulted in better progression-free survival compared with IFN in patients
who were initially treated with R-CHOP but not in patients who were treated with purine
analoguecontaining regimens. Moreover, among patients treated with R-CHOP induction therapy,
maintenance therapy with rituximab significantly improved overall survival (4-year overall survival
rates of 87% vs 63% with IFN; P = .005).
There have been several recent clinical breakthroughs in MCL. The oral immunomodulatory agent,
lenalidomide, was FDA-approved in June 2013 for the treatment of patients with MCL whose disease
has relapsed or progressed after two prior therapies, one of which included bortezomib. This
approval was based on the results of the single-arm phase II EMERGE study of 134 patients with
relapsed/refractory MCL. The overall response rate was 28%, with median time to response of 2.2
months and a median duration of response of 16.6 months.
More recently, the oral BTK inhibitor, ibrutinib, was approved by the FDA for patients with
Page 23 of 42
relapsed/refractory MCL who have received at least one prior therapy. Wang and colleagues from MD
Anderson Cancer Center reported an overall response rate of 68% in heavily pretreated MCL
patients; the median duration of response was 15.3 months. There are now multiple ongoing studies
examining both of these targeted treatment agents, in addition to bortezomib (FDA-approved in
2006 for relapsed/refractory MCL) and other therapeutics, as a part of up-front therapy for MCL (eg,
NCT01415752 and NCT01776840). All of these novel therapeutics have the potential to change the
landscape of treatment approaches for MCL.
Burkitt and Burkitt-Like Lymphoma
These diseases present as three distinct clinical entities: endemic, sporadic, and
immunodeficiency-related types. Endemic Burkitt lymphoma most often presents in young children
or adolescents with large nodes in the neck, often involving the maxilla or mandible. These cases are
most often seen in equatorial Africa and follow the distribution of endemic malaria, hence its
designation as endemic Burkitt lymphoma. In American, or sporadic, Burkitt or Burkitt-like
lymphomas, the disease presents in the abdomen and extranodal sites, especially in the GI tract.
Sporadic Burkitt lymphoma accounts for 1% to 2% of all adult lymphomas in Western Europe and the
United States. The immunodeficiency type is seen in the setting of HIV infection but can be seen in
patients with CD4 cell counts greater than 200/L. In both endemic and sporadic Burkitt and
Burkitt-like lymphomas, males are affected more often than females.
The LDH level is often elevated, owing to the high turnover rate of these cells and the bulk of
disease. The bone marrow and CNS are often involved, and if not involved initially, they are at risk,
so CNS prophylaxis is needed. A staging system for Burkitt and Burkitt-like lymphomas has been
developed by Murphy and associates.
These lymphomas are the most rapidly proliferating (doubling time of 25 hours) NHLs. Under the
microscope, it is difficult to distinguish Burkitt from Burkitt-like lymphomas and from the B-cell
French-American-British L3 variant of acute lymphoblastic leukemia. Indeed, the WHO classification
recognizes the lymphoma and leukemic phases as a single entity, a mature B-cell neoplasm. The
disease is characterized by medium-sized cells with an abundant basophilic cytoplasm with lipid
vacuoles. There are round nuclei with clumped chromatin and multiple nucleoli; a diffuse pattern of
infiltration is seen and is classic for Burkitt lymphoma. The numerous macrophages that are usually
seen in the lymph node biopsy specimens give rise to the so-called starry-sky appearance.
The proliferative rate of this tumor is high, and there are frequent apoptotic cells. In the Burkitt-like
variant, there is greater pleomorphism in nuclear size and shape, and the nuclei have fewer nucleoli.
There is a low level of concordance among pathologists (about 53%) when they attempt to
distinguish Burkitt from Burkitt-like lymphomas, and even by clinical criteria, that distinction is
difficult. The cells express surface IgM, CD19, CD20, CD22, CD10, and CD79a and do not express
CD5, CD23, and TdT. BCL6, a zinc finger protein, is usually expressed. The major consideration in the
differential diagnosis is precursor B-cell lymphoma/leukemia, which in contrast expresses TdT;
surface immunoglobulin is mostly negative. CD20 may also be negative in this disorder. In Burkitt
lymphoma, the expression of CD10 and BCL6 protein suggests that these cells originate from the
germinal center and, indeed, this is confirmed by sequence analysis of the immunoglobulin variable
heavy-chain and light-chain genes. Somatic hypermutation of these genes has been described. Gene
expression and microRNA profiles from each of the Burkitt lymphoma subtypes are homogeneous
and distinct compared with DLBCL.
Genetics
The distinguishing genetic abnormality in Burkitt lymphoma is overexpression of the c-myc

oncogene; in 80% of cases, this abnormality results from a balanced translocation between
chromosomes 8 and 14, notated as t(8;14), where the c-myc oncogene on chromosome 8 is
juxtaposed to immunoglobulin heavy-chain enhancer elements on chromosome 14. In the remaining
20% of cases, there are other translocations, including t(2;8)(p12;q24) and t(8;22)(q24;q11). There
have been different breakpoints identified in Burkitt lymphoma, and they have been associated with
the sporadic and immunodeficiency subtypes.
Sidebar: An analysis of cytogenetic and molecular features in Burkitt lymphoma cell lines and
patient samples has recently been completed by Murga Penas et al. It appears that most of the cell
lines remained stable over years of passages. The most frequent structural changes were dup (1q)
Page 24 of 42
and del (13q), and the most frequent numerical changes were +7 and +13. Interestingly, the
frequency of 1q gains and 13q losses was higher in the EBV-negative than in EBV-positive Burkitt cell
lines (Murga Penas EM et al: Genes Chromosomes Cancer 53:497-515, 2014).
Sidebar: Recent studies identified MYC-negative Burkitt-like lymphoma, characterized by a
recurrent focal homozygous deletion in 11q24.2-q24.3, including the ETS1 gene, which was shown to
be mutated in 4 of 16 cases that were investigated. These data suggest the existence of a B-cell
lymphoma similar to Burkitt lymphoma that is identified by deregulation of genes in 11q (Salaverria I
et al: Blood 123:1187-1198, 2014).
EBV
EBV, a member of the herpesvirus family, has the ability to infect resting B cells and transform them
into proliferating blasts, most likely by bypassing antigens on lymphocytes and activating signaling
molecules. By contrast, certain viruses (HCV) and bacteria (H pylori) may cause lymphoma by
activating lymphocytes in an antigen-specific manner. EBV infection results in a polyclonal
proliferation of lymphoblasts that are latently infected with the virus, as opposed to the infection
seen in infectious mononucleosis, which is a lytic infection. This process is regulated by the
expression of up to nine latent viral proteins, which are under the control of the transcription factor
EBV nuclear antigen 2. It appears that the type and result of EBV infection in lymphoid tissue are
controlled by various growth programs, each causing expression of different viral proteins, which
then determine the fate of the infected cell. These in vitro events are different from what occurs in
healthy carriers of EBV (up to 90% of the population have been exposed), where the viral proteins
are not expressed because all of the latently infected cells are resting memory B cells.
Although EBV was found in patients with Burkitt lymphoma over 40 years ago, the role of EBV in the
disease still remains uncertain. The exact role of c-myc overexpression in the pathogenesis of the
disease is also not known, but c-myc is known to play a role in cell-cycle progression and cellular
transformation. EBV is found in more than 95% of cases of endemic Burkitt lymphoma, which
occurs in Africa, but its role in the pathogenesis of the disease is still not clear. The reason therapy
with antiviral agents (ganciclovir or acyclovir) cannot be used to treat EBV-associated lymphomas is
that the required thymidine kinase gene is not expressed in latent EBV infection. Recent studies
using the small molecule arginine butyrate, to up-regulate the thymidine kinase gene and protein
expression, with concomitant antiviral antibiotics have met with some success.
Treatment
Patients must be treated quickly after diagnosis, which should be made on a full biopsy so that
adequate tissue is obtained. Tumor lysis syndrome occurs most often with Burkitt lymphoma, and
attempts to reduce uric acid production with allopurinol or to degrade it with the enzyme rasburicase
(Elitek) should be part of the management, as should aggressive hydration. Patients should be
managed in a facility with access to support such as urgent dialysis, because it may be necessary if
tumor lysis syndrome occurs. In addition, it is often beneficial to institute a pre-phase of therapy
using pulse steroids with lower-dose fractionated cyclophosphamide with or without vincristine.
Treatment has typically included aggressive chemotherapy, with anthracyclines and
cyclophosphamide as the cornerstone. Regimens incorporating hyperfractionated cyclophosphamide
such as hyper-CVAD, developed by Murphy and adopted by the M. D. Anderson group, have been
used. Other published regimens include CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin,
high-dose methotrexate/ifosfamide, etoposide, and high-dose Ara-C) and the French regimen, which
incorporate intensive therapy given weekly in various combinations, and intrathecal chemotherapy
and systemic high-dose methotrexate or high-dose Ara-C to facilitate CNS penetration. Evens et al
have shown excellent response rates and disease-free survival in patients treated with a modified
CODOX-M/IVAC regimen that substituted Doxil for Adriamycin and integrated high-dose rituximab. In
addition, excellent outcomes were recently reported for rituximab combined with DA-EPOCH therapy.
The treatment of Burkitt lymphoma in adults has been reviewed recently by Jacobson and LaCasce.
Sidebar: It has become clear now that rituximab should be included as a part of the aggressive
regimens that are used to treat Burkitt lymphoma (Wildes TM et al: Ther Adv Hematol 5:3-12, 2014;
Shahbazi S et al: Cancer Biol Ther 15:1117-1119, 2014; Rizzieri DA et al: Br J Haematol 165:102-111,
2014).
Primary Mediastinal Large B-Cell Lymphoma
Primary mediastinal large B-cell lymphoma (PMLBCL) occurs most often in young women (female to
Page 25 of 42
male ratio is 2:1) who present with mediastinal masses only. These masses are usually bulky and
often invade surrounding structures, such as the pleura, lungs, pericardium, and chest wall, but
disease is infrequently found outside the chest cavity. At recurrence, however, extranodal sites such
as the lungs, adrenal glands, liver, or kidneys may be involved. Because of the location and bulk of
the disease, patients complain of chest pain, cough, and shortness of breath and are often found to
have SVC syndrome. This can be subtle, with unexplained breast enlargement the only symptom in
some cases. The diagnosis can be delayed if the clinician does not recognize the signs and
symptoms of SVC syndrome. This clinical presentation is similar to that of classic Hodgkin
lymphoma, and indeed, that is the primary differential diagnostic consideration when these patients
are evaluated.
The pathology is characterized by a diffuse proliferation of large cells with clear cytoplasm, often
accompanied by extensive sclerosis. The cells are mostly of B-cell origin and express CD20 and other
B-cell markers but do not express surface immunoglobulin (Ig). Indeed, the discordant expression of
CD79a and Ig expression are distinguishing features of PMLBCL. There are data that describe gains
of chromosomal material in tissue specimens, most often 2p, 9p, 12q, and Xq. The rel, mal, and fig1
(IL4 gene) oncogenes are overexpressed in tissue specimens. Ig genes have a high level of somatic
hypermutation. All of these observations suggest that this entity is unique, especially compared with
B-cell lymphomas that arise in peripheral nodes. IL-13 expression and downstream effectors of IL-13
signaling pathways are overexpressed, along with tumor necrosis factor (TNF) family members and
TNF receptorassociated factor-1.
Sidebar: Recenlty, Shi et al described the expression of the programmed cell death ligand PDL-2 in
primary mediastinal B-cell lymphoma; mutations of PTPN1 have also been described by
Gunawardana et al. In the Gunawardana study, the mutations were found in 17 of 77 cases (22%),
while the same mutations were found in 6 of 20 of Hodgkin lymphoma cases (20%). The
consequences of these mutations are reduced phosphatase activity and increased phosphorylation
of JAK-STAT pathway members. These biology studies identify potential therapeutic targets in
PMLBCL (Shi M et al: Am J Surg Pathol 38:1715-1723, 2014; Gunawardana J et al: Nat Genet
46:329-335, 2014).
The overexpression of the rel oncogene, previously described, has been associated almost
exclusively with the nucleus, consistent with NF-B pathway activation, and mal gene overexpression
has been confirmed in gene array studies. These data help us to reorder our thinking about these
clinically unique lymphomas and to begin to build a molecular story that is consistent with the
clinical observation that PMLBCL is more like classic Hodgkin lymphoma than like DLBCL.
Furthermore, the observations that certain signaling pathways are involved provide a rationale to
attack these pathways specifically in a targeted approach.
As we learn more about this disorder, similarities to classic Hodgkin lymphoma become more clear.
The WHO recognizes a category as B-cell lymphoma, unclassifiable, with features intermediate
between DLBCL and classic Hodgkin lymphoma, which is commonly referred to as gray zone
lymphoma. A recent prospective study using DA-EPOCH-R for patients with gray zone lymphoma was
reported (Sidebar).
Sidebar: The NCI group treated 24 patients with mediastinal gray zone lymphoma in a prospective
study using infusional DA-EPOCH-R. The event-free survival and overall survival rates for these
patients were 62% and 74%, respectively, which were more modest than were outcomes for patients
with primary mediastinal DLBCL (Wilson WH et al: Blood 124:1563-1569, 2014).
Treatment
The clinical course is variable; some report a poor outcome with conventional, CHOP-based
chemotherapy regimens and irradiation, and some report an excellent outcome. It seems clear that
bulk of disease and LDH level are important prognostic factors and that prediction of the outcome by
the IPI is useful. A variety of chemotherapy regimens have been evaluated, including CHOP and
MACOP-B/VACOP-B (methotrexate or etoposide, Adriamycin, [doxorubicin], cyclophosphamide,
Oncovin [vincristine], prednisone, bleomycin), and more recently rituximab has been incorporated
into the management. Usually, radiation therapy is a part of the initial treatment; however, recent
data suggest that radiation therapy may not be necessary in all patients. In general, patients receive
anthracycline-containing chemotherapy with rituximab, and after four to six courses, radiation
therapy may be given to patients with bulky disease. There is currently one randomized trial,
conducted by the International Extranodal Lymphoma Study Group (IELSG), that compared radiation
Page 26 of 42
therapy with no radiation therapy in this setting; complete metabolic response was achieved in
patients who completed R-CHOP chemotherapy (or equivalent). However, in the subgroup of patients
with PMLBCL treated with DA-EPOCH-R (n = 51), radiation was not necessary to achieve high rates of
long-term disease-free survival and was comparable to that found in historical data using radiation.
PET scanning and early PET response may influence the use of consolidation radiation therapy in the
future.
Sidebar: Recently, the role of PET imaging in the management of patients with PMBCL has been
evaluated and is the subject of active clinical trials. In 2015, there were three studies that evaluated
PET scans in PMBCL and the conclusion of all was the same: the PET scan as an interim or end of
treatment test had excellent negative predictive value, but positive PET scans need to be confirmed
by biopsy before second-line therapy is instituted. The role of PET in the management of patients
with lymphoma is in evolution, and further studies standardizing response criteria are still needed
(Nagle SJ et al: Cancer Med 4:7-15, 2015; Vassilakopoulos TP et al: Leuk Lymphoma 56:3-5, 2015;
Cheah CY et al: Leuk Lymphoma 56:49-56, 2015).
Peripheral T-Cell Lymphoma, Unspecified
PTCL, unspecified is predominantly a nodal lymphoma that represents the most common T-cell
lymphoma subtype in Western countries, accounting for approximately 50% to 60% of T-cell
lymphomas and 5% to 7% of all NHLs. PTCL usually affects male adults (male to female ratio, 1.9:1),
with a median age of 61 years (range, 17 to 90 years); 25% of patients present in stage I or IIE, 12%
in stage III, and 63% in stage IV. Patients with PTCL commonly present with unfavorable
characteristics, including B symptoms (40%), elevated LDH level (66%), bulky tumor 10 cm or larger
(11%), nonambulatory performance status (29%), and extranodal disease (56%), leading to the
majority of patients (53%) falling into the unfavorable IPI category (score of 3 to 5). In addition, gene
signature clusters predictive of survival have been identified.
Most T-cell NHL patients are treated in the same manner as aggressive B-cell patients, with
anthracycline-based combination chemotherapy such as CHOP; however, the results are inferior.
Randomized trials comparing CHOP with other combination regimens have failed to identify a
superior regimen. Rituximab should not be included in the treatment of PTCL (unless other
conditions such as immune thrombocytopenic purpura exist), because CD20 is not expressed.
Denileukin diftitox is a novel recombinant fusion protein consisting of peptide sequences for the
enzymatically active and membrane translocation domains of diphtheria toxin with recombinant IL-2
(CD25 receptor); it has been studied mostly in cutaneous T-cell NHL, although clinical benefit has
been reported in other T-cell NHL patients. The histone deacetylase inhibitors romidepsin (Istodax)
and belinostat (Beleodaq) have shown activity against PTCL and are FDA-approved medications for
patients who have received at least one prior therapy. The novel antifolate pralatrexate (Folotyn) is
also FDA-approved for the treatment of patients with relapsed or refractory PTCL, brentuximab
vedotin (Adcetris) has efficacy in tumors expressing CD30, while recent phase I/II studies of an
Aurora-A kinase inhibitor, alisertib, have shown activity against PTCL. In addition, both gemcitabine
(Gemzar) and Doxil are active agents against PTCL. Recently, the Center for International Blood and
Marrow Transplant Research examined and demonstrated a role of SCT for patients with newly
diagnosed and relapsed/refractory PTCL.
Sidebar: Belinostat, a histone deacetylase inhibitor (HDACi), was approved by the FDA in 2014 for
use in patients with relapsed/refractory PTCL. An overall response rate of 25.8% was seen in a
clinical study involving 120 patients with relpased or refractory PTCL. Common adverse effects were
similar to those seen with other previously approved HDACi agents (OConnor OA et al: J Clin Oncol
31(suppl):abstract 8507, 2013); Foss F et al: Br J Haematol 168:811-819, 2015).
Angioimmunoblastic T-Cell Lymphoma
Angioimmunoblastic T-cell lymphoma (AITL), also known as angioimmunoblastic lymphadenopathy
with dysproteinemia, is one of the more common T-cell lymphomas, accounting for 15% to 20% of
cases and 3% to 4% of all lymphomas. Pathologically, AITL has distinct features, with a diffuse
polymorphous infiltrate, prominent arborizing blood vessels, perivascular proliferation of follicular
dendritic cells, and the presence of large B-cell blasts often infected with EBV. The malignant cells
are mature follicular helper CD4 T cells. The mean age at presentation is 57 to 65 years, with a
slight male predominance, and the majority of patients present with stage III or IV disease. AITL is
commonly a systemic disease with nodal involvement with various associated disease features, such
as organomegaly, B symptoms (50% to 70%), rash, pruritus, pleural effusions, arthritis, eosinophilia,
and varied immunologic abnormalities (positive Coombs test, cold agglutinins, hemolytic anemia,
Page 27 of 42
antinuclear antibodies, rheumatoid factors, cryoglobulins, and polyclonal hypergammaglobulinemia).
Spontaneous disease regression is seen on rare occasions, although AITL typically follows an
aggressive clinical course. Treatment with anthracycline-based combination chemotherapy results in
complete remission rates of 50% to 70% for AITL patients, although only 10% to 30% of patients are
long-term survivors.
In one prospective, nonrandomized, multicenter study, patients with newly diagnosed stable AITL
were treated with prednisone with or without combination chemotherapy. Patients who had a
complete remission after initial treatment with prednisone received no further treatment. Patients
with relapsed/refractory disease were given combination chemotherapy. Patients who had
life-threatening disease at diagnosis also received combination chemotherapy initially. The
complete remission rate was 29% for patients who received single-agent prednisone, whereas the
complete remission rates for patients with relapsed/refractory disease or patients who initially
received combination chemotherapy were 56% and 64%, respectively. With a median follow-up of 28
months (range, 7 to 53 months), the overall and disease-free survival rates were 40.5% (CI, 24% to
56%) and 32.3% (CI, 17% to 47%), respectively, although the median overall survival was 15
months.
There are anecdotal reports of relapsed AITL patients who have responded to immunosuppressive
therapy, such as low-dose methotrexate/prednisone, as well as reports of responses to purine
analogue treatment. Furthermore, cyclosporine has demonstrated activity in relapsed AITL patients
in case reports. There are also anecdotal reports of responses to thalidomide plus steroid and to
lenalidomide in AITL. In addition, long-term remissions have been seen with romidepsin treatment for
AITL. Brentuximab vedotin has been effective in AITL patients overexpressing CD30 (approximately
20% of patients). Both autologous and allogeneic SCT have shown benefit in AITL, although the
optimal timing remains open to debate.
Anaplastic Large Cell Lymphoma, T-/Null-Cell, Primary Systemic Type
ALCL, primary systemic type, is a CD30-positive T-cell lymphoma that accounts for approximately
2% to 3% of all NHLs. This disease mainly involves lymph nodes, although extranodal sites may be
involved (not exclusively the skin; see subsection on ALCL, CD30+ cutaneous type). This disease
may be divided, in part, on the basis of the expression of the tyrosine kinase ALK, created from a
balanced chromosomal translocation t(2;5) and other less common translocations involving 2p23
(see Table 1). When heterogeneous patient populations are analyzed, the prevalence of ALK
positivity in primary systemic ALCL cases is 50% to 60%. ALK-positive ALCL is typically diagnosed in
men before age 35 (male to female ratio, 1.7:1), with frequent systemic symptoms and extranodal
and advanced-stage disease. ALK-negative patients are usually older (median age, 61 years), with a
male to female ratio of 1.5:1, with a similar high incidence of extranodal disease. In addition to the
prognostic importance of ALK positivity, the IPI has been identified as an independent prognostic
factor within the group of ALK-positive ALCL patients, with a reported 5-year overall survival of 94%
vs 41% for IPI 0 or 1 and 2 to 4, respectively.
Therapy for pediatric ALCL is often based on prognostic risk factors, with treatment regimens
modeled after high-grade B-cell NHL protocols. Following a brief cytoreductive prephase, short,
intensified polyagent chemotherapy is administered, with the number of cycles dependent on the
stage of disease. Therapy for adult ALCL, primary systemic type, has commonly included
anthracycline-based regimens such as CHOP. Autologous hematopoietic SCT in first complete
remission for ALK-negative ALCL has been advocated by some groups, although this approach
warrants prospective validation. The immune antibody drug conjugate brentuximab vedotin, an
anti-CD30 antibody linked to the antitubulin agent monomethyl auristatin E (MMAE), has shown
remarkable clinical activity against this disease and is FDA-approved for this indication. In addition,
the oral ALK and ROS1 inhibitor crizotinib (FDA-approved for treatment of some patients with
nonsmall-cell lung cancer) has significant activity against ALK-positive ALCL.
Hepatosplenic T-Cell Lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon T-cell lymphoma that is seen mainly in
young males (median age, 35) presenting with B symptoms, prominent hepatosplenomegaly, mild
anemia, neutropenia, thrombocytopenia (commonly severe), significant peripheral blood
lymphocytosis, and rare lymphadenopathy. It is associated with an aggressive clinical course
(median survival, 12 to 14 months).
The tumor cells are usually negative for CD4 and CD8 (85%); positive for CD2, CD3, and CD7
(negative for CD5); and express CD56 in 70% to 80% of cases. TIA-1 is present in almost all cases,
Page 28 of 42
but commonly granzyme B and perforin are not present, an indication of a nonactivated cytotoxic
T-cell phenotype. Cells usually express the / T-cell receptor (Vd1+/Vd2/Vd3) but are negative
for EBV.
Historically, patients with HSTCL have been treated with CHOP-like regimens. Early autologous SCT
has been favored by some investigators on the basis of anecdotal cases; however, if feasible, an
allogeneic transplant may be more appropriate. A recent report described activity with the purine
analogue pentostatin in relapsed HSTCL patients. Approximately 10% to 20% of HSTCL cases arise in
immunocompromised patients, predominantly in the SOT setting.
Extranodal NK/T-Cell Lymphoma, Nasal Type
Extranodal NK/T-cell lymphoma, nasal-type, formerly known as angiocentric lymphoma, is rare in
Western countries; it is more prevalent in Asia and Peru. The disease commonly presents in men at
the median age of 50 years. This entity is associated with EBV and is typically characterized by
extranodal presentation and localized stage I/II disease but with angiodestructive proliferation and
an aggressive clinical course. These tumors have a predilection for the nasal cavity and paranasal
sinuses (nasal), although the nasal-type designation encompasses other extranodal sites of
NK/T-cell lymphomatous disease (skin, GI tract, testis, kidneys, upper respiratory tract, and rarely
orbit/eyes).
Combined-modality therapy incorporating platinum-based chemotherapy (minimum of six cycles for
patients with stage III or IV disease) and IFRT (minimum 50 Gy) is recommended for patients with
extranodal NK/T-cell lymphoma, nasal type, although the benefit of the addition of chemotherapy to
radiation therapy remains open to debate for limited-stage disease. A phase I/II study of concurrent
chemoradiotherapy for untreated localized NK/T-cell lymphoma was conducted in Japan; it showed a
2-year overall survival of 78%, although confirmatory studies are warranted. Patients with systemic
disease have poor long-term survival (5-year overall survival, 20% to 25%), with high locoregional
(over 50%) and systemic (over 70%) failure rates. Asparaginase (Elspar) has been shown to have
significant activity against this lymphoma, typically integrated with other agents, such as the
regimen SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide).
Enteropathy-Associated T-Cell Lymphoma
Enteropathy-associated T-cell lymphoma (EATL; also known as intestinal T-cell lymphoma) is a rare
T-cell lymphoma of intraepithelial lymphocytes that commonly presents with multiple circumferential
jejunal ulcers in adults with a brief history of gluten-sensitive enteropathy. EATL accounts for less
than 1% of NHLs, according to the International Lymphoma Study Group, and has been recognized to
have a poor prognosis, with reported 5-year overall and disease-free survival rates of 20% and 3%,
respectively. This finding is in part related to many patients presenting with a poor performance
status and varied complications of locally advanced disease by the time a diagnosis of EATL has
been confirmed.
EATL may present without an antecedent celiac history, but most patients have abdominal pain and
weight loss. Evidence of celiac serologic markers such as positive antigliadin antibodies and/or HLA
types such as DQA1*0501/DQB1*0201/DRB1*0304 may be present at diagnosis of EATL. Moreover,
these genotypes may represent celiac patients at higher risk for development of EATL. Small-bowel
perforation or obstruction, GI bleeding, and enterocolic fistulae are recognized complications of this
disease. The immunophenotype consists of panT-cell antigens, usually CD8+, and the mucosal
lymphoid antigen CD103 is often expressed.
Following diagnosis of EATL, doxorubicin-based combination chemotherapy should be considered for
all patients, and aggressive nutritional support with parenteral or enteral feeding is critical in the
care of these patients. Responding patients could potentially benefit from consolidation autologous
SCT in first remission. Patients with known celiac disease should adhere to a gluten-free diet.
Adult T-Cell Leukemia/Lymphoma
The retrovirus HTLV-1 has been documented to be critical to the development of ATLL. HTLV-1 is
known to cause diseases other than ATLL, including tropical spastic paraparesis/HTLV-1associated
myelopathy, infective dermatitis, and uveitis. In areas in Japan where HTLV-1 is endemic,
approximately 10% to 35% of the population is infected with the virus. Among these carriers, the
overall risk of ATLL is approximately 2.5% in patients who live to age 70. Of the Caribbean
population, 2% to 6% are HTLV-1 carriers, whereas less than 1% of the population in lower-risk
areas, such as the United States and Europe, are seropositive. HTLV-1 is transmitted through sexual
Page 29 of 42
intercourse, transfused blood products (products containing white blood cells, not fresh frozen
plasma), shared needles, breast milk, and vertical transmission. Transfusion of HTLV-1contaminated
blood products results in seroconversion in approximately 30% to 50% of patients, at a median of 51
days.
The clinical features of 187 ATLL patients included a median age at onset of 55 years and
lymphadenopathy (72%), skin lesions (53%), hepatomegaly (47%), splenomegaly (25%), and
hypercalcemia (28%) present at diagnosis. The differential diagnosis between cutaneous ATLL and
mycosis fungoides is often difficult. ATLL is separated into four subtypes divided by clinicopathologic
features and prognosis: acute, lymphoma, chronic, and smoldering. Shimoyama and colleagues (Br J
Haematol 1991) reported on the characteristics of 818 ATLL patients. Patients with acute-type ATLL
present with hypercalcemia, leukemic manifestations, and tumor lesions and have the worst
prognosis, with a median survival of approximately 6 months. Patients with lymphoma-type ATLL
present with low circulating abnormal lymphocytes (< 1%) and nodal, liver, splenic, CNS, bone, and
GI disease; the median survival is 10 months. Patients with chronic-type ATLL present with more
than 5% abnormal circulating lymphocytes and have a median survival of 24 months, whereas the
median survival of patients with smoldering-type ATLL has not yet been reached.
ATLL is an aggressive neoplasm with resistance to conventional chemotherapy, in part due to the
viral protein Tax-mediated resistance to apoptosis and overexpression of p-glycoprotein (the product
of the multidrug resistance-1 gene). Patients may initially respond to combination chemotherapy,
but unfortunately, response durations are brief (5 to 7 months). El-Sabban and colleagues (Blood
2000) combined arsenic trioxide (Trisenox) with IFN-, which induced cell-cycle arrest and apoptosis.
Response rates of 70% to 90% with combination IFN- and zidovudine therapy have been
demonstrated in ATLL, with associated increased median survival rates compared with those of
historic controls. The Japanese Clinical Oncology Group Study randomized patients with untreated
aggressive ATLL to VCAP-AMP-VECP (vincristine, cyclophosphamide, Adriamycin [doxorubicin],
prednisone-Adriamycin [doxorubicin], MCNU [ranimustine], prednisone-vindesine, etoposide,
carboplatin, prednisone) chemotherapy or biweekly CHOP. They reported a higher complete
remission rate and improved survival rates with VCAP-AMP-VECP, although treatment-related toxicity
was high. Allogeneic SCT has been successfully employed in select patients.
Other agents with anecdotal activity in ATLL include irinotecan and the purine analogues
(pentostatin and 2-chlorodeoxyadenosine, although pentostatin did not appear to improve outcomes
when added to combination chemotherapy). Recently, the anti-CCR4 monoclonal antibody
(mogamulizumab) was approved in Japan as monotherapy for ATLL, with a response rate of 50% and
a median progression-free survival of 5.2 months.
Cutaneous T-Cell Lymphomas
CTCLs constitute a group of cutaneous NHLs with clonal expansion of T lymphocytes into the skin.
Several entities are recognized by the combined European Organisation for Research and Treatment
of Cancer (EORTC) and WHO classification, which is based on morphologic, histopathologic, and
molecular features (Table 14). The frequency and disease-specific survival rates differ for each
entity.
Mycosis Fungoides/Szary Syndrome
Mycosis fungoides and its variants represent the most common type of CTCL, accounting for 50% of
CTCLs, with a male predominance of approximately 2:1 and a predominance of African American
patients of 1.6:1. It has a yearly incidence of 0.36 cases per 100,000 population that has remained
constant over the past decade. Clinical and histologic diagnosis of mycosis fungoides has proved to
be difficult, because in early stages, it may resemble other dermatoses, such as eczematous
dermatitis, psoriasis, and parapsoriasis.
Clinically, mycosis fungoides is characterized by erythematous patches, evolving into plaques or
tumors; however, the progress is variable. It is classified as an indolent lymphoma by the EORTC.
The neoplastic cells have a mature CD3+, CD4+, CD45RO+, CD8 memory T-cell phenotype. Szary
syndrome is the aggressive, leukemic, and erythrodermic form of CTCL, which is characterized by
circulating atypical malignant T lymphocytes with cerebriform nuclei (Szary cells) and
lymphadenopathy. Circulating Szary cells also have a mature memory T-cell phenotype with loss of
CD7 and CD26. For staging purposes, the tumor node metastasis system is most commonly used
(Table 15).
Investigative and recently approved options that have shown activity against mycosis
fungoides/Szary syndrome include the histone deacetylase inhibitors vorinostat (Zolinza,
Page 30 of 42
FDA-approved), romidepsin (Istodax, FDA-approved), and panobinostat; the novel antifolate
pralatrexate (Folotyn, FDA-approved); the proteasome inhibitor bortezomib; and monoclonal
antibodies targeting CD4 (zanolimumab), CCR4 (mogamulizumab), and CD30 (brentuximab vedotin)
in select patients.
Treatment of early-stage disease
At present, CTCLs are regarded as incurable. In early CTCL, the cell-mediated immune response is
usually normal. Therefore, the majority of these cases can be treated successfully with topical
modalities. Early aggressive therapy does not improve the prognosis of patients with CTCL. The
skin-targeted modalities include psoralen plus ultraviolet A (PUVA); narrow-band ultraviolet B; skin
electron beam radiation therapy; spot radiation therapy; and topical preparations of steroids,
retinoids, carmustine, or nitrogen mustard (Table 16). Radiation therapy prescriptions may be similar
to those for other lymphomas or may be delivered at high doses in limited fractions. Excimer laser
treatment can also be used for discrete lesions.
Treatment of advanced-stage disease
A limited number of patients progress to more aggressive and advanced disease with either
cutaneous or extracutaneous tumor manifestations. Treatment goals in advanced stages should be
to reduce the tumor burden, relieve symptoms, and potentially decrease the risk of transformation
into aggressive lymphoma. Established treatment options are monochemotherapy (ie, gemcitabine,
doxil) and polychemotherapy, including CVP, CHOP, and ESHAP (etoposide, methylprednisolone,
high-dose cytarabine, cisplatin) regimens; extracorporeal photopheresis; IFNs; retinoids and
rexinoids (bexarotene [Targretin] capsules); histone deacetylase inhibitors (vorinostat and
romidepsin); novel antifolates (pralatrexate); monoclonal antibodies (alemtuzumab); and
recombinant toxins (denileukin diftitox). Combinations are frequently used (Table 16). Encouraging
results with an anti-CD3 immunotoxin have been reported. Select patients with progressive and
recalcitrant disease have been cured with an allogeneic SCT.
TABLE 14:
The WHOEORTC consensus classification for primary cutaneous lymphomas with relative frequency
and 5-year survival
Primary Cutaneous CD30+ Lymphoproliferative Disorders
Primary cutaneous CD30+ lymphoproliferative disorders are the second most common group of
CTCL, representing approximately 30% of CTCLs. This spectrum of diseases includes lymphomatoid
papulosis, ALCL CD30+ cutaneous type, and borderline disorders. The distinction between these
entities can be challenging and is often made on the basis of clinical behavior.
Lymphomatoid Papulosis
Page 31 of 42
TABLE 15: Stage classification for mycosis fungoides and Szary

syndrome
Lymphomatoid papulosis is most commonly associated with mycosis fungoides, CD30+ large T-cell
lymphoma, and Hodgkin lymphoma. Four histologic types have been identified, characterized as
types A, B, C, and D. Types A and C consist of large lymphocytes resembling Reed-Sternberg cells.
Type A cells are embedded in a dense inflammatory background, whereas type C cells form large
sheets imitating CD30+ large T-cell lymphoma. Type B simulates classic features of mycosis
fungoides, with epidermotropism and a dermal band-like infiltrate composed of small to
medium-sized cells. Type D is CD8+. Lymphomatoid papulosis lesions occasionally exhibit clonal
gene rearrangements.
Lymphomatoid papulosis represents a benign, chronic recurrent, self-healing, papulonodular, and
papulonecrotic CD30+ skin eruption. However, a lymphoid malignancy may develop in 10% to 20%
of patients, but the prognosis for patients with lymphomatoid papulosis is otherwise excellent, with a
5-year survival of 100%. There is no curative treatment available. Lymphomatoid papulosis is
managed by observation, intralesional steroid injection, topical bexarotene, ultraviolet light therapy,
or low-dose methotrexate. For select patients brentuximab vedotin is an option.
Anaplastic Large Cell Lymphoma, CD30+ Cutaneous Type
TABLE 16: Treatment options for cutaneous T-cell lymphoma by stage

Primary systemic CD30+ ALCL and primary cutaneous CD30+ ALCL represent identical morphologic
entities, but they are clinically distinct diseases.
The neoplastic cells of primary cutaneous CD30+ ALCL are of the CD4+ helper T-cell phenotype with
CD30 expression. It represents 9% of CTCLs and typically presents with solitary or localized nodules.
This tumor has an excellent prognosis, as confirmed in several studies, in contrast to the
transformation of mycosis lymphoma to a CD30 large cell variant. It shows histologic and
immunophenotypic overlap with lymphomatoid papulosis. In most cases, tumor cells show anaplastic
features, less commonly a pleomorphic or immunoblastic appearance. However, there is no
difference in the prognosis and survival rate. Primary CD30+ ALCL rarely carries the t(2;5)
translocation and is usually ALK-negative. These lesions may undergo spontaneous regression, as do
Page 32 of 42
the lesions of lymphomatoid papulosis. The mechanism of tumor regression remains unknown.
Local radiation therapy (30-40 Gy) or surgical excision is the preferred treatment, with systemic
chemotherapy reserved for cases with large tumor burden and extracutaneous involvement. More
recently, there has been reported efficacy of recombinant IFN--1b (Actimmune) and combined
treatment with bexarotene and IFN--2a (Roferon-A). Brentuximab vedotin treatment can provide
sustained remissions. Durable responses have also been witnessed after treatment with liposomal
doxorubicin (Doxil).
Subcutaneous Panniculitis-Like T-Cell Lymphoma
Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) is a rare T-cell lymphoma that infiltrates
the subcutaneous fat without dermal and epidermal involvement, causing erythematous to
violaceous nodules and/or plaques. Approximately 20% of patients have an associated autoimmune
disease, most commonly systemic lupus erythematosus. Systemic symptoms are frequent and
include weight loss, fever, and fatigue. The disease may be complicated by the hemophagocytic
syndrome. SCPTCL may be preceded by a benign-appearing panniculitis for years. The infiltrate is
pleomorphic and associated with inflammation and necrosis. The T-cell phenotype is /+ with
CD4(+/), CD8+, and CD56(/+). Standard treatment has historically included CHOP-like
chemotherapy. However, recent data suggest that patients can be controlled for long periods with
local radiation treatment and/or steroids. Five-year survival rates exceed 80%.
Cutaneous / T-Cell Lymphoma
Cutaneous / T-cell lymphoma is a rare panniculitis presenting with disseminated (ulcerated)
plaques, nodules, or tumors. Involvement of mucosal or extranodal sites is common. Systemic
symptoms, including weight loss, fever, and fatigue, are almost always present. The hemophagocytic
syndrome is often noted. The /+ T cells are characteristically CD2+, CD3+, CD4, CD5,
CD7(/+), CD8(/+), and CD56+. Aggressive chemotherapy is indicated, with consideration of
autologous or allogeneic SCT incorporated into the initial treatment schema. The median survival is
less than 2 years.
Pleomorphic T-Cell Lymphomas With Small/Medium Cells
The small/medium pleomorphic CTCL type appears clinically with single erythematous to violaceous
nodules or tumors and accounts for less than 3% of CTCL cases. Most advanced cases have an
unfavorable prognosis, with a median survival of 24 months or less; however, the CD3+, CD4+,
CD8, CD30 subtype with limited lesions often of the face and upper trunk has a favorable
prognosis with a 5-year survival rate exceeding 90%.
The optimal therapy for pleomorphic T-cell lymphomas with small/medium cells has not been
defined. Localized lesions have been treated with radiation therapy or surgical excision. Patients with
generalized skin disease or progression have been treated effectively with systemic treatments,
including multiagent chemotherapy, retinoids, IFNs, and monoclonal antibodies.
Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma is currently a
provisional entity in the WHO classification of mature T-cell and NK-cell neoplasms. It is a rare
disease accounting for less than 1% of CTCL. Most patients are adults and present with generalized
papules, nodules, hyperkeratotic patches, and/or plaques. Central ulceration and necrosis is
common. Dissemination to other visceral sites, including lung, testis, oral mucosa, and the CNS, is
common; the lymph nodes are usually spared. The histologic appearance, although quite variable,
includes proliferation of epidermotropic CD8+ cytotoxic malignant clonal T-cells. Invasion and
destruction of adnexal skin structures and angiocentricity are common.
An aggressive clinical course is typical with a median survival of less than 3 years. Combination
chemotherapy rarely provides a sustained remission. Antifolates can be effective in some patients.
Allogeneic SCT should be a consideration in medically fit patients.
Cutaneous B-Cell Lymphomas
Primary cutaneous B-cell lymphomas (CBCLs) are rare entities. They constitute up to 25% of all
cutaneous lymphomas. However, the incidence of CBCLs has been underestimated because of the
absence of immunologic and molecular markers. In addition, their terminology and classification
remain controversial, with, until recently, separate and distinct terminology promoted by WHO and
Page 33 of 42
EORTC. Primary CBCLs are distinct from nodal lymphomas, and the majority of them have an
excellent prognosis. Several types are recognized, with the most common types being follicular
center lymphoma and marginal zone lymphoma.
Primary cutaneous follicular center lymphoma
Primary cutaneous follicular center lymphoma (PCFCL) is defined as a proliferation of centrocytes

(small to large cleaved cells) and centroblasts (large round cells with prominent nuclei) that show a
nodular or diffuse infiltrate in the majority of cases and presenting only rarely a true follicular
pattern. PCFCL is the most common subtype of CBCLs, accounting for 40% of CBCLs. PCFCL shows a
predilection for the head, neck, and trunk in elderly patients, with a median age of 60 years and a
male predominance of approximately 1.5:1. The clinical course is usually indolent, with an excellent
overall survival of up to 97%. However, relapses occur frequently. The large round cell morphology
might be associated with a higher rate of disease progression and poorer prognosis.
Small centrocytes predominate in low-grade PCFCL, whereas an increased number of large cells
occurs in high-grade PCFCL; however, lesions with pure high-grade disease may behave indolently
and should not by themselves drive the treatment administered. In contrast to their nodal
counterpart, BCL2 is usually not expressed in neoplastic cells, and the t(14;18) translocation is rarely
detected. More recently, low rates of BCL2 expression have been reported. In addition to CD10+ and
BCL6+ expression, PCFCL also has an aberrant expression of CD45 RA and CD43 and thus provides a
helpful clue to distinguish it from pseudolymphomas. Radiation therapy (24-30 Gy) is often the
preferred therapy for solitary or localized group lesions. Surgical excision can be considered for small
lesions. Chemotherapy, although effective, rarely results in cure. Rituximab has proved to be
effective for palliation. Observation is a reasonable alternative in many instances.
Primary cutaneous marginal zone lymphoma
Primary cutaneous marginal zone lymphoma (PCMZL) is a recently recognized low-grade lymphoma
and represents the second most common subtype of CBCLs. It predominantly occurs on the upper
and lower extremities. The median age at presentation is 55 years, and females are affected more
often than males. The reported survival rates are 97% to 100%, although relapses commonly occur.
Histologically, PCMZL has features of MALT lymphomas and shows a nodular or diffuse dermal
infiltrate with a heterogeneous cellular infiltrate of small lymphocytes, lymphoplasmacytoid cells,
plasma cells, intranuclear inclusions (Dutcher bodies), and reactive germinal centers that may be
infiltrated by neoplastic cells. Diagnosis can be difficult, because of the variable composition of the
infiltrate that may be interpreted as a reactive process or as PCFCL. In contrast to PCFCL, marginal
zone lymphoma is negative for BCL6 and CD10. In 50% of cases, CD43 is highly expressed.
Large-cell transformation and a head and neck presentation may be associated with a worse
prognosis. Therapeutic alternatives are similar to those described for PCFCL.
Primary cutaneous diffuse large B-cell lymphoma, leg type
EORTC and the International Society for Cutaneous Lymphomas consensus recommendations for the
management of CBCLs have been published by Senff and coworkers. Primary cutaneous diffuse large
B-cell lymphoma, leg type (PCLBCL, LT) forms a separate category in the WHO-EORTC classification,
as a more aggressive type seen in elderly patients, with a median age of 76 years at diagnosis and a
female predominance of 7:2. Most cases have a follicle center cell origin, and histologic evaluation
shows a diffuse dermal infiltrate with predominance in large B cells with multilobulated nuclei,
consisting of centroblasts and immunoblasts, with the presence of small, cleaved cells and a minor
admixed infiltrate component. Eosinophilic intranuclear (Dutcher body) or intracytoplasmic (Russell
body) inclusions of immunoglobulin are common. Unlike PCFCL, PCLBCL, LT consistently expresses
BCL2, although it is not associated with the t(14;18) translocation.
The prognosis is less favorable for PCLBCL, LT than for other CBCLs, with a 5-year survival rate of
50% to 60%. Prognostic factors identified with a poor outcome include the predominance of round
cells (centroblasts/immunoblasts) over cleaved cells (centrocytes) in the tumor infiltrate, MUM1
expression, and multiple lesions at presentation. The use of an IPI-based model is required to
investigate whether PCLBCL, LT is associated with a poorer prognosis. These lymphomas should be
treated as systemic DLBCLs with anthracycline-based chemotherapy. In patients who present with a
single, small skin tumor, radiotherapy is a consideration. Rituximab has also been incorporated into
combination regimens.
Intravascular large B-cell lymphoma
WHO and EORTC have proposed intravascular large B-cell lymphoma (IVLBCL), or angiotropic B-cell
Page 34 of 42
lymphoma, as a provisional entity. This subtype is rare and corresponds to the proliferation of
malignant lymphocytes within lumina of small vessels, involving most frequently the skin and CNS. It
was previously considered a vascular tumor and referred to as malignant angioendotheliomatosis.
Although the majority of cases are of B-cell origin, a few cases of T-cell lineage have been reported.
The reason for intravascular localization is not clear, but association with an unknown surface
receptor or dysfunction of lymphocyte-endothelial interaction affecting adhesion molecules has been
suspected.
IVLBCL is clinically characterized by tender erythematous, purpuric, indurated patches and plaques
located on the trunk and thighs, where it can resemble panniculitis. Cases of generalized
telangiectasia over normal skin have been reported. Cytomorphology reveals intravascular occlusion
of small vessels, filled with large atypical centroblast-like B lymphocytes. IHC shows CD19, CD20,
CD45, and CD79a expression. Genotypic analysis has demonstrated clonality, although it may not be
positive in every case. Generally, the prognosis of this aggressive type of lymphoma is poor despite
the use of combination chemotherapy, because of the initial or secondary CNS involvement.
However, rituximab appears to have had a significantly favorable impact on the outcome of patients
with IVLBCL.
CD4+/CD56+ Hematodermic Neoplasm
The CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) commonly presents in the
skin, with nodular and extracutaneous systemic involvement. This rare disorder appears to be
derived from a plasmacytoid dendritic cell precursor. T-cell receptor genes are in germline
configuration. This entity causes a dismal prognosis (median survival, 14 months) despite intensive
chemotherapy. For this reason, this disease is often treated as an acute leukemia. The novel IL-3
(CD123) receptor-directed recombinant diphtheria toxin protein, SL-401, has received orphan drug
designation from the FDA.
Plasmacytoma
Primary cutaneous involvement of plasmacytoma is uncommon and generally develops as a
consequence of direct spread from an underlying multiple myeloma. It represents 4% of
extramedullary plasmacytomas and affects predominantly elderly men, with a median age of 60
years at diagnosis. It is characterized by a monoclonal proliferation of mature plasma cells.
Cutaneous plasmacytomas are potentially curable, with a 5-year survival rate of more than 90%.
However, the presentation of multiple lesions is an important adverse prognostic factor.
Histopathology shows a dense monomorphous dermal infiltrate of plasma cells with a varying degree
of maturation and atypia, admixed with few lymphocytes and histiocytes. Neoplastic plasma cells
express clonal immunoglobulin, CD38, and CD79a but are negative for CD20. Rarely, amyloid
deposition within the tumor is demonstrated, which is more common in secondary cutaneous
involvement of plasmacytoma. A recent organized workshop on plasma cell dyscrasias questioned
whether these cases are true cutaneous plasmacytomas, represent reactive B-cell infiltrates
associated with an infectious etiology, or represent a variant of marginal zone lymphoma with a
predominant population of plasma cells. Diagnosis may rely on demonstration of monoclonality by
restriction of immunoglobulin light-chain expression. Excision or radiation treatment is most
commonly used.
HIV-Related Lymphomas
Most lymphomas seen in patients who have HIV infection are of an aggressive histology and
advanced stage at presentation. Extranodal disease is common, with unusual sites of presentation,
including the GI tract, CNS, and multiple soft tissue masses. Some patients present with primary CNS
lymphoma. Poor-risk factors include a high LDH level, large tumor bulk, extranodal disease, and low
CD4 cell counts (< 100/L). Because of their increased risk of opportunistic infections and impaired
hematologic reserve, many patients with HIV-related lymphomas historically have been unable to
tolerate aggressive chemotherapy regimens. Current antiviral medications have allowed for the use
of more traditional regimens, including R-CHOP and EPOCH-R, with results comparable to those of
other NHL patients with similar histologies and presentations. CNS prophylaxis with intrathecal
chemotherapy is necessary to prevent meningeal dissemination. (For a more detailed discussion of
HIV-related NHL, see the AIDS-Related Malignancies chapter.)
Posttransplant Lymphoma
Page 35 of 42
Posttransplant lymphoproliferative disorders (PTLDs) remain a morbid complication associated with
SOT. The incidence varies from 1% to 2% in renal transplant recipients and up to 12% to 14% in
heart or multi-organ transplant recipients; the latter patient groups require more potent
immunosuppressive therapy.
The pathologic spectrum of PTLD is heterogeneous, comprising a spectrum ranging from
hyperplastic-appearing lesions to frank aggressive lymphoma. The most frequent subtype seen is
monomorphic, of which the most common histology is akin to DLBCL. PTLDs are fully depicted in the
updated WHO classification (see Table 4). Historically, PTLDs were reported to occur at a median of 6
months from SOT, although recent data suggest this interval is likely longer (ie, median 40 to 50
months). Early PTLD cases (ie, < 12 months after SOT) more often express EBV, whereas late-onset
cases are typically EBV-negative.
Recent evidence suggests improved outcomes for PTLD in the modern era. Treatment initially
involves the reduction of immunosuppression (usually by at least 50%), especially for early
EBV-positive cases. EBV-negative PTLD will respond to immunosuppression reduction, but less
frequently than EBV-positive cases. In addition, the status of the transplanted organ will in part
dictate the amount of immunosuppression safely allowable to avoid organ rejection. The exact role
of rituximab in B-cell PTLD continues to be defined. Single-agent rituximab was evaluated in two
phase II studies of patients in whom reduction of immunosuppression failed, with reported overall
response rates of 42% and 73% and modest survival rates. A retrospective series using frontline
rituximab-based therapy, in conjunction with reduced immunosuppression, was associated with
significantly improved survival compared with prior reports. In addition, a recent prospective PTLD
clinical trial using sequential rituximab followed by CHOP therapy showed good outcomes. Final
results of the latter trial, which studied a response-adapted therapeutic strategy with frontline
single-agent rituximab, are eagerly awaited.
The decision of initially treating with rituximab alone vs concurrent or sequential rituximab with
chemotherapy (eg, R-CHOP) is often determined on a patient-by-patient basis. Factors in small
studies associated with lower response to rituximab in PTLD include EBV-negative disease and
elevated LDH levels. In addition, chemotherapy may be needed as initial therapy for patients who
have a large tumor burden warranting rapid response of disease. Of note, during chemotherapy,
immunosuppressant medication doses should be either significantly reduced or carefully stopped
completely, in part to avoid infectious complications. Carefully selected patients with
relapsed/refractory monomorphic PTLD are able to receive high-dose chemotherapy followed by
autologous SCT, with long-term survival noted in some reports.
Anecdotal reports have described the activity of thymidine kinase inhibitor antiviral therapies such
as ganciclovir and acyclovir to prevent and/or treat PTLD, although the data are not convincing. This
finding is not surprising, because EBV survives as an episome outside the lymphocyte genome, and
these drugs do not eradicate latently infected B cells. However, one group has shown that arginine
butyrate was able to induce EBV tyrosine kinase activity in EBV-immortalized B cells and convert
patient-derived latently infected B-cell lymphoma tumor cells that were resistant to ganciclovir to a
sensitive phenotype. A phase I/II study with encouraging clinical results was reported. In
hematopoietic SCT-related PTLD, EBV-specific cytotoxic T lymphocytes (CTLs) have been used with
encouraging results. In addition, the use of adoptive immunotherapy with EBV-specific CTLs
continues to be explored in PTLD (Sidebar).
Sidebar: Recent studies from the Baylor group have shown the utility of T cells primed against EBV
and other viruses in patients with EBV-related immune deficiency associated lymphomas. In novel
studies, the Baylor group has used genetically modified expanded CTLs that were enriched for
specificity against type II latency latent membrane protein (LMP) antigens. When these were infused
into 50 patients with EBV-associated lymphoma, there were no infusion-related toxicities.
Furthermore, 28 of 29 high-risk or multiply-relapsed patients receiving LMP-CTLs as adjuvant therapy
remained in remission a median of 3.1 years after infusion. Of 21 patients who had active disease at
the time of infusion, 13 had responses, including 11 complete responses. Duration of the responses
in patients with active disease were not described. It is clear from these and similar studies that this
approach to EBV-mediated and other virus-mediated lymphomas may be addressed by
T-cellmediated, immunotherapy-based approaches (Bollard CM et al: J Clin Oncol 32:798-808, 2014;
Papadopoulou A et al: Science Transl Med 6:242ra83, 2014; Leen AM et al: Immunol Rev 258:12-29,
2014).
Primary CNS Lymphoma
Primary CNS lymphoma is a rare form of NHL, arising within and confined to the CNS. Histologically,
Page 36 of 42
primary CNS lymphomas are indistinguishable from systemic NHLs. A stereotactic needle biopsy is
the procedure of choice for diagnosis. Resection does not appear to improve survival. More than 40%
of patients have evidence of leptomeningeal dissemination, and 15% have ocular disease at
presentation. Thus, examination of the eyes for lymphoma (slit lamp) at diagnosis is important, as is
MRI of the entire neurospinal axis, to rule out multifocal disease.
The two most important prognostic factors in primary CNS lymphoma are age (> 50 years) and poor
performance status (Karnofsky performance score < 70). Retrospective studies have documented
that treatment of primary CNS lymphoma with whole-brain radiotherapy (WBRT) alone (with or
without corticosteroids) results in a median survival of 10 to 15 months, with a 5-year survival of 3%
to 4%. Current standard therapy for newly diagnosed primary CNS lymphoma is systemic
chemotherapy, including high-dose intravenous methotrexate-based therapy (at least 2,500 to 3,500
mg/m2 per cycle) commonly combined with agents that penetrate the CNS (vincristine, procarbazine,
and high-dose cytarabine). This regimen results in median survival rates of 50 to 60 months. The
most important component in the treatment of primary CNS lymphoma is the use of high-dose
methotrexate therapy (at least 2,000 mg/m2 and up to doses of 8,000 mg/m2). WBRT had been
considered a standard component following chemotherapy; however, long-term neurotoxicity
remains a major concern, especially for patients older than 60 years.
A study by Morris and colleagues reported encouraging results for primary CNS lymphoma patients
who achieved complete remission following five to seven cycles of high-dose methotrexate-based
chemoimmunotherapy and subsequently received reduced-dose WBRT (23.4 Gy) compared with the
standard WBRT of 45 Gy. A German study randomized 551 patients, of whom 318 were treated per
protocol, to high-dose methotrexate and ifosfamide with or without WBRT. The non-inferiority
hypothesis was not proved statistically; however, the median overall survival in the WBRT population
was 32.4 months vs 37.1 months without WBRT. In addition, the Alliance US Cooperative Group
recently reported outcomes using a nonradiation-based therapeutic regimen.
Long-term survival data are also available using autologous or allogeneic SCT for relapsed/refractory
primary CNS lymphoma, although an important prognostic factor is control of CNS disease
immediately before transplant. Further, most transplant conditioning regimens for CNS lymphoma
have incorporated thiotepa-based therapy (eg, busulfan, cyclophosphamide, and thiotepa).
Sidebar: Rubenstein and colleagues used a treatment regimen consisting of methotrexate,
temozolomide, and rituximab induction followed by high-dose consolidation with etoposide plus
cytarabine for patients with untreated primary CNS lymphoma. With median follow-up of nearly 5
years, the 2-year progression-free survival was 57%, which appears comparable with
radiation-related regimens. In addition, older patients appeared to fare as well as younger patients,
while high tumor BCL6 expression correlated with inferior survival (Rubenstein JL et al: J Clin Oncol
31:3061-3068, 2013).
Tumor Lysis Syndrome
Tumor lysis syndrome is a common complication after treatment of high-grade, bulky NHLs (because
of their exquisite sensitivity to therapy and high proliferative capacity). The syndrome is
characterized by renal failure, hyperkalemia, hyperphosphatemia, and hypocalcemia. Measures to
prevent this complication include aggressive hydration; allopurinol; alkalinization of the urine; and
frequent monitoring of electrolytes, uric acid, and creatinine. Dialysis is sometimes required.
Rasburicase, a recombinant urate-oxidase enzyme, is now available for the prevention and
treatment of hyperuricemia. (For a more comprehensive discussion of the tumor lysis syndrome, see
the Oncologic Emergencies and Paraneoplastic Syndromes chapter.)
Lymphoma During Pregnancy
Lymphoma is one of the most common cancers diagnosed during pregnancy, occurring in
approximately 1 in every 5,000 gestations. Evens and colleagues recently reported outcomes from a
retrospective analysis of 50 patients with NHL that occurred during pregnancy. Median age at
diagnosis for B-cell NHL was 29.5 years vs 34 years for T-cell lymphoma (P = .09). The most common
NHL diagnosis was DLBCL, which accounted for 56% of all NHLs and 73% of B-cell NHLs. Fifty-four
percent of NHL patients had advanced-stage disease, although functional imaging was not
performed in any patient. Interestingly, extranodal disease was still frequently identified, with 26% of
patients having more than one extranodal site, with several atypical sites seen (eg, vaginal, breast).
Diagnosis of lymphoma occurred at a median of 23 weeks, with all but one patient having untreated
disease. Pregnancy was terminated in six NHL patients; among the remaining patients, 15 (32%) had
therapy deferred until postpartum. In the latter patients, a diagnosis was made at a median of 30
Page 37 of 42
weeks gestation compared with 22 weeks gestation for patients who received antenatal therapy (P
< .001).
Antenatal treatment was started at a median of 25 weeks gestation (range, 13 to 37 weeks). Four of
the five NHL patients who received antenatal radiotherapy had supra-diaphragmatic stage I-II
disease, while most patients who received antenatal therapy were treated with conventional
non-antimetabolite chemotherapy regimens (eg, CHOP). The overall response rate for NHL patients
who received antenatal therapy was 71% (complete remission 50%). The most common preterm
complication was induction of labor (33%), while gestation went to full term in 56% of patients, with
delivery occurring at a median of 37 weeks. Interestingly, there were no differences in maternal
complications, perinatal events, or median infant birth weight based on deferred vs antenatal
therapy. At a median follow-up of 41 months, 3-year progression-free survival and overall survival for
NHL patients were 53% and 82%, respectively. On univariate analysis for NHL, radiotherapy
predicted inferior progression-free survival, and increased LDH levels and poor ECOG performance
status portended worse overall survival. It is highly advocated that patients be managed
concurrently with high-risk maternal-fetal medical consultation.
Follow-Up of Long-Term Survivors

Relapse
Among patients with aggressive lymphoma subtypes, most recurrences are seen within the first 2
years after the completion of therapy, although later relapses may occur. Physical examination and
laboratory testing at 2- to 3-month intervals and follow-up CT scans (with or without PET scan) at
6-month intervals for the first 2 years following diagnosis are recommended. However, it is
recognized that on relapse of disease, the patient usually presents with symptoms rather than the
relapse being diagnosed purely on the basis of surveillance scans or routine clinic visits. Early
detection of recurrent disease is important because these patients may be candidates for potentially
curative high-dose therapy and SCT. Patients with advanced low-grade NHL are at a constant risk of
relapse, and late recurrence of disease may be seen, sometimes after more than a decade-old
remission.
Treatment Complications
There has been a more selective use of irradiation as part of the initial therapy for NHL; therefore,
the risk of certain radiation-induced complications has been reduced or eliminated in patients with
more recently diagnosed NHL. Nevertheless, total-body irradiation may be used as a component of
myeloablative conditioning regimens. Also, transplant recipients are at increased risk for secondary
myelodysplasia and acute myeloid leukemia, regardless of whether they received a
radiation-containing conditioning regimen. All individual chemotherapy agents have their own
potential long-term morbidity, such as late cardiovascular disease with anthracycline therapy.
Secondary Malignancies
Long-term survivors are at increased risk for second cancers. In a survey of 6,171 patients with NHL
who survived 2 or more years, nearly 1,000 patients lived 15 or more years after diagnosis. Second
cancers were reported in 541 patients, with significant excesses seen for all solid tumors; acute
myeloid leukemia; melanoma; Hodgkin lymphoma; and cancers of the lungs, brain, kidneys, and
bladder. The actuarial risk of developing a second malignancy at 3 to 20 years after diagnosis of NHL
was 21%, compared with a population-expected cumulative risk of 15%.
Long-term survivors need continued follow-up for possible treatment-related complications. Some of
these toxicities may still be unknown. Careful documentation of late complications will be important
in the design of future treatment strategies aimed at preserving or improving response rates and the
duration of remission while reducing toxicity.
Suggested Reading
Abe S, Oda I, Inaba K, et al: A retrospective study of 5-year outcomes of radiotherapy for gastric
mucosa-associated lymphoid tissue lymphoma refractory to Helicobacter pylori eradication therapy.
Jpn J Clin Oncol 43:917922, 2013.
Barta SK, Xue X, Wang D, et al: Treatment factors affecting outcomes in HIV-associated
non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood 122:32513262, 2013.
Bdr C, Grossmann V, Popov N, et al: EZH2 mutations are frequent and represent an early
Page 38 of 42
event in follicular lymphoma. Blood 122:31653168, 2013.
Cerhan JR, Berndt SI, Vijai J, et al: Genome-wide association study identifies multiple
susceptibility loci for diffuse large B cell lymphoma. Nat Genet 46:12331238, 2014.
Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J
Clin Oncol 25:579586, 2007.
Coutinho R, Clear AJ, Owen A, et al: Poor concordance among nine immunohistochemistry
classifiers of cell-of-origin for diffuse large B-cell lymphoma: Implications for therapeutic strategies.
Clin Cancer Res 19:66866695, 2013.
Delabie J, Holte H, Vose JM, et al: Enteropathy-associated T-cell lymphoma: Clinical and
histological findings from the International Peripheral T-Cell Lymphoma Project. Blood 118:148155,
2011.
de Masson A, Beylot-Barry M, Bouaziz JD, et al: Allogeneic stem cell transplantation for
advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow
Transplantation and French Study Group on Cutaneous Lymphomas. Haematologica 99:527534,
2014.
Dunleavy K, Pittaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab therapy in primary
mediastinal B-cell lymphoma. N Engl J Med 368:14081416, 2013.
Dunleavy K, Pittaluga S, Shovlin M, et al: Low-intensity therapy in adults with Burkitts
lymphoma. N Engl J Med 369:19151925, 2013.
Evens AM, Advani R, Press OW, et al: Lymphoma occurring during pregnancy: Antenatal
therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 31:41324139,
2013.
Evens AM, David KA, Helenowski I, et al: Multicenter analysis of 80 solid organ transplantation
recipients with post-transplantation lymphoproliferative disease: Outcomes and prognostic factors in
the modern era. J Clin Oncol 28:10381046, 2010.
Federico M, Bellei M, Marcheselli L, et al: Follicular lymphoma international prognostic index 2:
A new prognostic index for follicular lymphoma developed by the international follicular lymphoma
prognostic factor project. J Clin Oncol 27:45554562, 2009.
Fenske TS, Zhang MJ, Carreras J, et al: Autologous or reduced-intensity conditioning allogeneic
hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of
transplantation timing and modality. J Clin Oncol 32:273281, 2014.
Fernndez V, Salamero O, Espinet B, et al: Genomic and gene expression profiling defines
indolent forms of mantle cell lymphoma. Cancer Res 70:14081418, 2010.
Foss FM, Zinzani PL, Vose JM, et al: Peripheral T-cell lymphoma. Blood 117:67566767, 2011.
Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic
lymphocytic leukemia. N Engl J Med 370:9971007.
Gopal AK, Kahl BS, de Vos S, et al: PI3K inhibition by idelalisib in patients with relapsed indolent
Goy A, Sinha R, Williams ME, et al: Single-agent lenalidomide in patients with mantle-cell
lymphoma who relapsed or progressed after or were refractory to bortezomib: Phase II MCL-001
(EMERGE) study. J Clin Oncol 31:36883695, 2013.
Green TM, Young KH, Visco C, et al: Immunohistochemical double-hit score is a strong predictor
of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus
cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30:34603467, 2012.
Herrmann A, Hoster E, Zwingers T, et al: Improvement of overall survival in advanced stage
mantle cell lymphoma. J Clin Oncol 27:511518, 2009.
Heslop HE, Slobod KS, Pule MA, et al: Long-term outcome of EBV-specific T-cell infusions to
prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood
115:925935, 2010.
Hu S, Xu-Monette ZY, Tzankov A, et al: MYC/BCL2 protein coexpression contributes to the
inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates
high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP
Consortium Program. Blood 121:40214031, 2013.
Illidge T, Specht L, Yahalom J, et al: Modern radiation therapy for nodal non-Hodgkin
lymphoma-target definition and dose guidelines from the International Lymphoma Radiation
Oncology Group. Int J Radiat Oncol Biol Phys 89:4958, 2014.
Jegalian AG, Eberle FC, Pack SD, et al: Follicular lymphoma in situ: Clinical implications and
comparisons with partial involvement by follicular lymphoma. Blood 118:29762984, 2011.
Jacobson C, LaCasce A: How I treat Burkitt lymphoma in adults. Blood 124:29132920, 2014.
Page 39 of 42
Johnson NA, Slack GW, Savage KJ, et al: Concurrent expression of MYC and BCL2 in diffuse large
B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and
prednisone. J Clin Oncol 30:34523459, 2012.
Kahl BS, Hong F, Williams ME, et al: Results of Eastern Cooperative Oncology Group Protocol
E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies
for low tumor burden follicular lymphoma. In: Proceedings from 53rd American Society of
Hematology Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. Abstract LBA-6.
Kchour G, Tarhini M, Kooshyar MM, et al: Phase 2 study of the efficacy and safety of the
combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult
T-cell leukemia/lymphoma (ATL). Blood 113:65286532, 2009.
Kluin-Nelemans HC, Hoster E, Hermine O, et al: Treatment of older patients with mantle-cell
Kyriakou C, Canals C, Finke J, et al: Allogeneic stem cell transplantation is able to induce
long-term remissions in angioimmunoblastic T-cell lymphoma: A retrospective study from the
lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol
27:39513958, 2009.
Ladetto M, Lobetti-Bodoni C, Mantoan B, et al: Persistence of minimal residual disease in bone
marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program. Blood
122:37593766, 2013.
Lenz G, Wright G, Dave SS, et al: Stromal gene signatures in large B-cell lymphomas. N Engl J
Med 359:23132323, 2008.
Link BK, Maurer MJ, Nowakowski GS, et al: Rates and outcomes of follicular lymphoma
transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic
Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol
31:32723278, 2013.
Martin PJ, Counts GW Jr, Appelbaum FR, et al: Life expectancy in patients surviving more than
5 years after hematopoietic cell transplantation. J Clin Oncol 28:10111016, 2010.
Morin RD, Mungall K, Pleasance E, et al: Mutational and structural analysis of diffuse large B-cell
lymphoma using whole-genome sequencing. Blood 122:1256-1265, 2013.
Morris PG, Correa DD, Yahalom J, et al: Rituximab, methotrexate, procarbazine, and vincristine
followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed
primary CNS lymphoma: Final results and long-term outcome. J Clin Oncol 31:39713979, 2013.
Mullighan CG: Genome sequencing of lymphoid malignancies. Blood 122:38993907, 2013.
OBrien S, Furman RR, Coutre SE, et al: Ibrutinib as initial therapy for elderly patients with
chronic lymphocytic leukaemia or small lymphocytic lymphoma: An open-label multicentre, phase
1b/2 trial. Lancet Oncol 15:4858, 2014.
Ott G, Rosenwald A, Campo E: Understanding MYC-driven aggressive B-cell lymphomas:
pathogenesis and classification. Blood 122:38843891, 2013.
Prez-Galn P, Dreyling M, Wiestner A: Mantle cell lymphoma: Biology, pathogenesis, and the
molecular basis of treatment in the genomic era. Blood 117:2638, 2011.
Perry AM, Warnke RA, Hu Q, et al: Indolent T-cell lymphoproliferative disease of the
gastrointestinal tract. Blood 122:35993606, 2013.
Pettengell R, Schmitz N, Gisselbrecht C, et al: Rituximab purging and/or maintenance in
patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective
randomized trial from the lymphoma working party of the European group for blood and marrow
transplantation. J Clin Oncol 31:16241630, 2013.
Poulain S, Roumier C, Decambron A, et al: MYD88 L265P mutation in Waldenstrom
macroglobulinemia. Blood 121:45044511, 2013.
Pugh TJ, Ballonoff A, Newman F, et al: Improved survival in patients with early stage low-grade
follicular lymphoma treated with radiation. Cancer 116:38433851, 2010.
Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus
rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An
open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:12031210, 2013.
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 377:4251, 2011.
Senff NJ, Noordijk EM, Kim YH, et al: European Organization for Research and Treatment of
Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the
management of cutaneous B-cell lymphomas. Blood 112:16001609, 2008.
Page 40 of 42
Shiels MS, Engels EA, Linet MS, et al: The epidemic of non-Hodgkin lymphoma in the United
States: disentangling the effect of HIV, 1992-2009. Cancer Epidemiol Biomarkers Prev 22:10691078,
2013.
Shimada K, Matsue K, Yamamoto K, et al: Retrospective analysis of intravascular large B-cell
lymphoma treated with rituximab-containing chemotherapy as reported by the IVL Study Group in
Japan. J Clin Oncol 26:31893195, 2008.
Smith SM, Burns LJ, van Besien K, et al: Hematopoietic cell transplantation for systemic mature
T-cell non-Hodgkin lymphoma. J Clin Oncol 31: 31003109, 2013.
Styczynski J, Gil L, Tridello G, et al: Response to rituximab-based therapy and risk factor analysis
in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in
children and adults: a study from the Infectious Diseases Working Party of the European Group for
Blood and Marrow Transplantation. Clin Infect Dis 57: 794802, 2013.
Suzumiya J, Ohshima K, Tamura K, et al: The International Prognostic Index predicts outcome in
aggressive adult T-cell leukemia/lymphoma: Analysis of 126 patients from the International
Peripheral T-Cell Lymphoma Project. Ann Oncol 20:715721, 2009.
Tan D, Horning SJ, Hoppe RT, et al: Improvements in observed and relative survival in follicular
grade 1-2 lymphoma during 4 decades: The Stanford University experience. Blood 122:981987,
2013.
Trappe R, Oertel S, Leblond V; German PTLD Study Group, European PTLD Network:
Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant
lymphoproliferative disorder (PTLD): The prospective international multicentre phase 2 PTLD-1 trial.
Lancet Oncol 13:196206, 2012.
Trautinger F, Knobler R, Willemze R, et al: EORTC consensus recommendations for the
treatment of mycosis fungoides/Szary syndrome. Eur J Cancer 42:10141030, 2006.
Treon SP, Xu L, Yang G, et al: MYD88 L265P somatic mutation in Waldenstrms
macroglobulinemia. N Engl J Med 367:826833, 2012.
Tsukasaki K, Hermine O, Bazarbachi A, et al: Definition, prognostic factors, treatment, and
response criteria of adult T-cell leukemia-lymphoma: A proposal from an international consensus
meeting. J Clin Oncol 27:453459, 2009.
Vegliante MC, Palomero J, Prez-Galn P, et al: SOX11 regulates PAX5 expression and blocks
terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood 121:21752185, 2013.
Vitolo U, Chiappella A, Ferreri AJ, et al: First-line treatment for primary testicular diffuse large
B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: Final
results of an international phase II trial. J Clin Oncol 29:27662772, 2011.
Wagner LI, Zhao F, Williams ME, et al: Quality of life results from Eastern Cooperative Oncology
Group Protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab
dosing strategies for indolent non Hodgkins-lymphoma. In: Proceedings from 54th American Society
of Hematology Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 235.
Wang M, Rule SA, Martin P, et al: Interim results of an international, multicenter, phase 2 study
of Brutons tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765) in relapsed or refractory mantle cell
lymphoma (MCL): Durable efficacy and tolerability with longer follow-up. Presented at: 54th ASH
Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 904.
Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory
mantle-cell lymphoma. N Engl J Med 369:507516, 2013.
Weisenburger DD, Savage KJ, Harris NL, et al: Peripheral T-cell lymphoma, not otherwise
specified: A report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood
117:34023408, 2011.
Westin JR, Chu F, Zhang M, et al: Safety and activity of PD1 blockade by pidilizumab in
combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label,
phase 2 trial. Lancet Oncol 15:6977, 2014.
Willemze R, Jaffe ES, Burg G: WHO-EORTC classification for cutaneous lymphomas. Blood
105:37683785, 2005.
Williams ME, Hong F, Kahl BS, et al: A subgroup analysis of small lymphocytic and marginal zone
lymphomas in the Eastern Cooperative Oncology Group protocol E4402 (RESORT): A randomized
phase III study comparing two different rituximab dosing strategies for low tumor burden indolent
non-Hodgkin lymphoma. J Clin Oncol 30:suppl; abstract 8007, 2012.
Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed
CD30-positive lymphomas. N Engl J Med 363:18121821, 2010.
Zhou Z, Sehn LH, Rademaker AW, et al: An enhanced International Prognostic Index (NCCN-IPI)
Page 41 of 42
for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123:837842,
2014.
Source URL: http://www.cancernetwork.com/cancer-management/non-hodgkin-lymphoma

Links:
[1] http://www.cancernetwork.com/cancer-management
[2] http://www.cancernetwork.com/authors/andrew-m-evens-do-ms
[3] http://www.cancernetwork.com/authors/jane-n-winter-md
[4] http://www.cancernetwork.com/authors/leo-i-gordon-md
[5] http://www.cancernetwork.com/authors/brian-c-h-chiu-phd
[6] http://www.cancernetwork.com/authors/richard-tsang-md
[7] http://www.cancernetwork.com/authors/steven-t-rosen-md
Page 42 of 42

Cancer Network - Non-Hodgkin Lymphoma - 2015-06-11

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Cancer Network - Non-Hodgkin Lymphoma - 2015-06-11

Uploaded by

Copyright:

Available Formats

Non-Hodgkin Lymphoma

Published on Cancer Network (http://www.cancernetwork.com)

Etiology, Pathogenesis, and Risk Factors

Signs and Symptoms

Screening and Diagnosis

TABLE 2: Immunophenotypic and

Staging and Prognosis

TABLE 5: Ann Arbor staging classification for NHL

TABLE 6: NCCNInternational Prognostic Index

TABLE 7: Follicular lymphoma International Prognostic Indices

TABLE 10: Commonly used salvage regimens for NHL

TABLE 11: Examples of monoclonal antibodies for lymphoid

The distinguishing genetic abnormality in Burkitt lymphoma is overexpression of the c-myc

TABLE 15: Stage classification for mycosis fungoides and Szary

TABLE 16: Treatment options for cutaneous T-cell lymphoma by stage

Primary cutaneous follicular center lymphoma (PCFCL) is defined as a proliferation of centrocytes

Follow-Up of Long-Term Survivors

Source URL: http://www.cancernetwork.com/cancer-management/non-hodgkin-lymphoma

You might also like