Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Non-Hodgkin Lymphomas
Definition
Lymphomas are solid tumors of the immune system. Increasing knowledge of the biology of the immune system has led to a corresponding increase in the understanding of these malignancies. In addition to better systems of classification and clinical evaluation, this new knowledge has led to the development of new therapies. Beneficial treatment is available for essentially every patient with non-Hodgkin lymphoma. The overall survival of lymphoma patients has increased steadily over the past 40 years, and many patients can be cured.
Epidemiology
In the United States, an estimated 80,000 or so new cases of non-Hodgkin lymphoma are diagnosed in annually, and about 20,000 patients to die of this disease each year. Non-Hodgkin lymphomas account for about 5% of new cancers in the United States and result in about 3% of cancer deaths. The U.S. lifetime risk for developing non-Hodgkin lymphoma is estimated to be 2.4% (1 in 42) for men and 1.9% (1 in 52) for women. The incidence rate increases dramatically with age and is higher in Whites than in other ethnic groups.
Geographic differences in the incidence of non-Hodgkin lymphomas vary as much as five-fold. The highest rates are seen in the United States, Europe, and Australia, whereas lower rates are seen in Asia. Even more striking are geographic differences in the incidence of certain types of non-Hodgkin lymphoma, such as Burkitt lymphoma, follicular lymphoma, extranodal natural killer (NK)/T-cell nasal lymphoma, and adult T-cell leukemia/lymphoma.
In the United States the incidence rate for non-Hodgkin lymphomas increased by about 3 to 4% yearly from 1950 and the beginning of the 21st century, likely related to increased longevity, to the acquired immunodeficiency syndrome (HIV/AIDS) epidemic ( Chapter 353 ), to occupational and environmental exposures (e.g., agricultural chemicals), to improvements in imaging techniques, and to improvements in the ability of pathologists to diagnose lymphoma. Since then, the incidence rate for non-Hodgkin lymphoma has reached a plateau, and the death rate from the disease has been declining.
Pathobiology
For most cases of non-Hodgkin lymphoma, the cause is unknown, although genetic, environmental, and infectious agents have been implicated ( Table 171-1 ).
TABLE 171-1
FACTORS ASSOCIATED WITH THE DEVELOPMENT OF NON-HODGKIN LYMPHOMA
Inherited immune disorders
Acquired immune disorders
Drug related
Infectious agents
Occupational and environmental exposure
|
Genetic Factors
Familial non-Hodgkin lymphoma clusters have been described, with a slightly higher risk for non-Hodgkin lymphoma among siblings and first-degree relatives of patients with lymphoma or other hematologic malignancies. The incidence of non-Hodgkin lymphoma has been associated with polymorphisms in a variety of genes related to immunity, including chemokines, tumor necrosis factor, interleukin-10 (IL-10), and lymphotoxin-α. Polymorphisms in other genes related to the cell cycle and apoptosis have also been associated with an increased risk for developing lymphoma.
Immune System Abnormalities
Several inherited disorders increase the risk for developing non-Hodgkin lymphoma as much as 250-fold (see Table 171-1 ). In some of these conditions, the lymphoma may be related to Epstein-Barr virus ( Chapter 348 ). For example, patients with X-linked lymphoproliferative disorder have mutations in the SH2D1A gene, which encodes proteins that regulate the host immune response against Epstein-Barr virus–infected cells; individuals with this disorder may develop fatal infectious mononucleosis or non-Hodgkin lymphoma after primary exposure to Epstein-Barr virus. Acquired immunodeficiency states are also associated with an increased risk for non-Hodgkin lymphoma. For example, post-transplantation lymphoproliferative disorders ( Chapter 348 ) occur in as many as 20% of solid organ transplant recipients, related to the proliferation of B lymphocytes that have been transformed during immunosuppressive therapy. The risk for non-Hodgkin lymphoma is also increased more than 100-fold in patients infected with the human immunodeficiency virus (HIV, Chapter 355 ). Almost all central nervous system (CNS) lymphomas and approximately 50% of other lymphomas in patients with the acquired immunodeficiency syndrome (AIDS) are related to Epstein-Barr virus. Some studies have shown a two-fold increase in the incidence of non-Hodgkin lymphomas among patients with rheumatoid arthritis ( Chapter 243 ), and the risk for marginal zone lymphomas is increased approximately 30- to 40-fold in patients with Sjögren syndrome ( Chapter 247 ). Increases in the incidence of thyroid lymphoma are seen in patients with Hashimoto thyroiditis ( Chapter 207 ). Enteropathy-type T-cell lymphomas are associated with celiac disease ( Chapter 126 ). Patients with the autoimmune lymphoproliferative syndrome, associated with mutations in the FAS gene, also appear to be at higher risk for developing lymphoma.
Infectious Agents
Epstein-Barr virus ( Chapter 348 ) is associated with the majority of post-transplantation lymphoproliferative disorders and many HIV/AIDS-associated lymphomas. This viral genome is detectable in more than 95% of cases of endemic Burkitt lymphoma and in approximately 15 to 35% of cases of sporadic Burkitt lymphoma and AIDS-associated lymphomas. This virus is also associated with Epstein-Barr virus-positive diffuse large B-cell lymphoma of elderly people, plasmablastic lymphoma, and extranodal NK/T-cell lymphoma.
The human T-lymphotropic virus type 1 (HTLV-1; Chapter 360 ) is detectable in virtually all cases of adult T-cell leukemia/lymphoma. The risk for lymphoma is approximately 3% in patients infected with HTLV-1. In endemic areas, up to 50% of all non-Hodgkin lymphomas may be related to HTLV-1.
Human herpesvirus-8 (HHV-8, Kaposi sarcoma–associated herpesvirus; Chapter 359 ), which is associated with expansion of the B-cell population, is also associated with primary effusion lymphoma (see later) in immunocompromised patients and with multicentric Castleman disease. Patients with primary effusion lymphoma are often coinfected with Epstein-Barr virus.
Epidemiologic evidence has linked hepatitis C virus ( Chapter 135 ) to lymphoplasmacytic lymphoma associated with type II cryoglobulinemia, nodal marginal zone lymphoma, and splenic marginal zone lymphoma. Chronic antigenic stimulation from this virus may lead to the emergence of malignant B-cell clones.
Helicobacter pylori is associated with gastric lymphoma ( Chapter 178 ) of extranodal marginal zone/mucosa-associated lymphoid tissue (MALT). Colonized patients develop gastritis from chronic antigenic stimulation mediated by T cells, which respond to H. pylori– specific antigens and emergence of malignant B-cell clones. Borrelia burgdorferi (associated with Lyme disease, Chapter 296 ) has been associated with marginal zone B-cell lymphoma of the skin. Evidence also links Chlamydia psittaci ( Chapter 294 ) with ocular adnexal lymphomas, Campylobacter jejuni with immunoproliferative small intestinal disease ( Chapter 279 ), and Coxiella burnetii with diffuse large B-cell and follicular lymphoma.
Environmental and Occupational Exposure
Agricultural chemicals have been associated with an increased risk for developing non-Hodgkin lymphomas, and the strongest associations involve phenoxy herbicides such as 2,4-dichlorophenoxyacetic acid (2,4-D), which was also a component of Agent Orange. An increased risk has also been associated with ionizing radiation ( Chapter 18 ), organic solvents, and nitrates in drinking water, although contradictory results have been reported. Some studies have also linked non-Hodgkin lymphomas to high-fat diets and ultraviolet radiation ( Chapter 18 ). The risk for non-Hodgkin lymphoma is increased approximately 20-fold after treatment for Hodgkin lymphoma ( Chapter 172 ). Heavy smokers ( Chapter 363 ) have an increased risk for developing follicular lymphoma. Low levels of vitamin D have been associated with increased risk for recurrent lymphoma, as well as poor outcome. Anti–tumor necrosis factor (anti-TNF) agents might be associated with an increased risk for developing lymphoma, particularly hepatosplenic T-cell lymphoma. Breast implants also are associated with the development of anaplastic large cell lymphoma.
Pathology
Non-Hodgkin lymphomas are derived from cells of the immune system at varying stages of differentiation. In some cases, the cell of origin is directly linked to the morphology, immunophenotype, and clinical behavior of the lymphoma ( E-Fig. 171-1 and Table 171-2 ).
TABLE 171-2
TYPICAL IMMUNOPHENOTYPES OF COMMON NON-HODGKIN LYMPHOMAS
| LYMPHOMA | CD20 | CD3 | CD10 | CD5 | CD23 | OTHER |
|---|---|---|---|---|---|---|
| Small lymphocytic | + | − | − | + | + | |
| Lymphoplasmacytic | + | − | − | − | − | Cytoplasmic immunoglobulin + |
| Extranodal marginal zone MALT | + | − | − | − | − | |
| Nodal marginal zone | + | − | − | − | − | |
| Follicular | + | − | + | − | ||
| Mantle cell | + | − | + | + | Cyclin D1 + | |
| Diffuse large B cell | + | − | ||||
| Mediastinal large B cell | + | − | ||||
| Burkitt | + | − | + | − | TdT − | |
| Precursor T lymphoblastic | − | +/− | TdT + , CD1a +/− , CD7 + | |||
| Anaplastic large T cell | − | +/− | CD30 + , CD15 − , EMA + , ALK +/− | |||
| Peripheral T cell | − | +/− | Other pan-T variable |
ALK = anaplastic lymphoma kinase; EMA = epithelial membrane antigen; MALT = mucosa-associated lymphoid tissue; TdT = terminal deoxynucleotidyl transferase.
The transformation of cells from the normal immune system into malignant lymphoma reflects the acquisition of specific genetic abnormalities. In many cases, cytogenetic studies can identify chromosomal translocations that underlie the development or progression of the lymphoma. In most cases of non-Hodgkin lymphoma, the activation of proto-oncogenes is the major abnormality, but occasionally chromosomal translocations can lead to fusion genes that code for chimeric proteins. In addition, some cases are associated with deletion of tumor suppressor genes. Specific genetic abnormalities are associated with some specific subtypes of non-Hodgkin lymphoma ( Table 171-3 ). It is becoming clear that the tumor microenvironment from cells of the host immune system is important in tumor cell survival and response to therapy.
TABLE 171-3
CHROMOSOMAL TRANSLOCATIONS CHARACTERISTIC OF NON-HODGKIN LYMPHOMA
| LYMPHOMA SUBTYPE | TRANSLOCATION | GENES INVOLVED | FREQUENCY (%) |
|---|---|---|---|
| Diffuse large B cell | t(3q27) t(14;18)(q32;q21) t(18;14)(q24;q32) |
BCL6 IgH, BCL2 MYC (c-Myc), IgH |
35 15-20 <5 |
| Burkitt | t(8;14)(q24;q32) t(8;22)(q24;q11) t(2;8)(p12;q24) |
MYC, IgH MYC, IgL IgK, MYC |
100% have one of these, most commonly t(8;14) |
| Follicular | t(14;18)(q32;q21) | IgH, BCL2 | ~90 |
| Mantle cell | t(11;14)(q13;q32) | BCL1, IgH | >90 |
| ALCL | t(2;5)(p23;q35) | ALK, NPM | >80 of ALK+ ALCLs |
| MALT | t(11;18)(q21;q21) t(14;18)(q21;q32) t(1;14)(p22;q32) |
API2, MALT1 IgH, MALT1 BCL10, IgH |
35 20 10 |
ALCL = anaplastic large cell lymphoma; ALK = anaplastic lymphoma kinase; MALT = mucosa-associated lymphoid tissue.
Classification
The updated 2016 World Health Organization (WHO) classification integrates genetic data into the clinicopathologic classification ( Table 171-4 ). This classification divides lymphomas on the basis of B-cell or T/NK-cell origin and whether they are derived from primitive precursor cells or from more mature “peripheral” cells. Specific clinical and pathologic entities are recognized within each of these groupings. In the United States and Europe, 85 to 90% of non-Hodgkin lymphomas are B cell in origin.
TABLE 171-4
2016 REVISION OF THE WHO CLASSIFICATION OF NON-HODGKIN LYMPHOMA
Modified from Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-2390.
| MATURE B-CELL NEOPLASMS |
| Chronic lymphocytic leukemia/small lymphocytic lymphoma Splenic marginal zone lymphoma Hairy cell leukemia/lymphoma Splenic B-cell lymphoma/leukemia, unclassifiable
Lymphoplasmacytic lymphoma
Large B-cell lymphoma with IRF4 rearrangement∗
Diffuse large B-cell lymphoma (DLBCL), NOS
T-cell/histiocyte-rich large B-cell lymphoma |
| MATURE T AND NK NEOPLASIA |
| Chronic lymphoproliferative disorder of NK cells Hydroa vacciniforme-like lymphoproliferative disorder∗ Adult T-cell leukemia/lymphoma Extranodal NK-/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Monomorphic epitheliotropic intestinal T-cell lymphoma∗ Indolent T-cell lymphoprolifeative disorder of the GI tract∗ Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30 + T-cell lymphoproliferative disorders
Primary cutaneous anaplastic large cell lymphoma |
| POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS (PTLD) |
| Plasmacytic hyperplasia PTLD Infectious mononucleosis PTLD Florid follicular hyperplasia PTLD∗ Polymorphic PTLD Monomorphic PTLD (B- and T-/NK-cell types) |
Provisional entities are listed in italics; ∗denotes changes from the 2008 classification (shown in Volume 25); ALK = anaplastic lymphoma kinase; EBV + = Epstein-Barr virus-positive; GI = gastrointestinal; HL = Hodgkin lymphoma; NK = natural killer; NOS = not otherwise specified; TFH = T follicular helper. This table does not include the lymphoid leukemias, plasma cell dyscrasia, and Hodgkin lymphoma (see Chapter 172 ).
The most frequent type is diffuse large B-cell lymphoma, which represents about 30% of all non-Hodgkin lymphomas worldwide. The next most frequent type is follicular lymphoma, which represents about 20% of cases. Follicular lymphoma is relatively more frequent in North America and Western Europe and less frequent in Asia. Less common types, each representing between 5 and 10% of all non-Hodgkin lymphomas, are extranodal marginal zone/MALT lymphomas, peripheral T-cell lymphomas, small lymphocytic lymphoma, and mantle cell lymphoma. Other types each represent less than 2% of non-Hodgkin lymphomas seen in the United States.
The non-Hodgkin lymphomas recognized in the WHO classification have clinically distinctive characteristics ( Table 171-5 ), such that an experienced hematopathologist can accurately classify 85% or more of patients by WHO criteria when adequate material is available. Some diagnoses, such as follicular lymphoma, can be made with a high degree of accuracy without immunologic or genetic studies. The diagnosis of T-cell lymphomas cannot be made accurately without immunophenotyping. Cytogenetic studies and molecular genetic studies (fluorescence in situ hybridization, or FISH) can help resolve difficult differential diagnoses. For example, the presence of a t(8;14) translocation supports the diagnosis of Burkitt lymphoma, whereas a t(11;14) with cyclin D1 overexpression can confirm the diagnosis of mantle cell lymphoma (see Tables 171-2 and 171-3 ).
TABLE 171-5
PRESENTING CLINICAL CHARACTERISTICS OF COMMON NON-HODGKIN LYMPHOMA SUBTYPES
Adapted from Armitage JO, Weisenburger DD, for the Non-Hodgkin Lymphoma Classification Project. New approach to classifying non-Hodgkin lymphomas: clinical features of the major histologic subtypes. J Clin Oncol . 1998;16:2780-2795.
| STAGE (%) | ||||||
|---|---|---|---|---|---|---|
| TYPE OF LYMPHOMA | MEDIAN AGE (yr) | MALE (%) | I | IV | B SYMPTOMS (%) | BONE MARROW INVOLVED (%) |
| B-CELL LYMPHOMAS | ||||||
| Small lymphocytic | 65 | 53 | 4 | 83 | 33 | 72 |
| Lymphoplasmacytic | 63 | 53 | 7 | 73 | 13 | 73 |
| Extranodal marginal zone MALT | 60 | 48 | 39 | 31 | 19 | 14 |
| Nodal marginal zone | 58 | 42 | 13 | 40 | 37 | 32 |
| Follicular | 59 | 42 | 18 | 51 | 28 | 42 |
| Mantle cell | 63 | 74 | 13 | 71 | 28 | 64 |
| Diffuse large B cell | 64 | 55 | 25 | 33 | 33 | 16 |
| Mediastinal large B cell | 37 | 34 | 10 | 31 | 38 | 3 |
| Burkitt | 31 | 89 | 37 | 38 | 22 | 33 |
| PRECURSOR B/T-CELL LYMPHOMAS | ||||||
| Precursor T lymphoblastic | 28 | 64 | 0 | 75 | 21 | 50 |
| T-CELL LYMPHOMAS | ||||||
| Anaplastic large T cell | 34 | 69 | 19 | 39 | 53 | 13 |
| Peripheral T cell, NOS | 61 | 55 | 8 | 65 | 50 | 36 |
B symptoms = fevers, night sweats, and weight loss; MALT = mucosa-associated lymphoid tissue; NOS = not otherwise specified.
Gene expression profiling has allowed the identification of distinct subsets of patients with diffuse large B-cell lymphoma (DLBCL). Patients with histologically identical lymphomas can be divided into those with gene expression patterns resembling normal germinal center B cells (GCBs), those whose tumors resemble activated post–germinal center B cells (ABCs), or those with patterns resembling that seen in Hodgkin lymphoma. The last pattern is most frequently found in young women who present with large mediastinal masses. Use of immunohistochemistry to subdivide diffuse large B-cell lymphoma into germinal center B cell subtype and activated post–germinal center B cell subtype is widely used but does not correlate perfectly with DNA microarray results. Using a combination of exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of selected genes, diffuse large B-cell lymphoma can be further subtyped based on shared genomic abnormalities.
Clinical Manifestations
The most common presentation of non-Hodgkin lymphoma is lymphadenopathy ( Fig. 171-1 ; Chapter 154 ). In many cases, patients notice cervical, axillary, or inguinal adenopathy and seek a physician’s advice. In general, lymph nodes containing lymphomas are firm, nontender, and not associated with a regional infection. In other patients, lymphadenopathy occurring in sites such as the mediastinum or retroperitoneum causes symptoms such as chest pain, cough, abdominal pain, and back pain. More extensive disease can also cause symptoms related to the superior vena cava syndrome, spinal cord compression, and renal insufficiency (associated with ureteral compression).
Non-Hodgkin lymphomas are often associated with systemic symptoms that may lead to the diagnosis. The most obvious symptoms, termed B symptoms, are fever, night sweats, and unexplained weight loss. Any of these symptoms without an obvious cause should lead a physician to consider the diagnosis of lymphoma. Other, less characteristic symptoms include fatigue, which is frequently present at the time of diagnosis if the patient is questioned carefully, and pruritus.
Non-Hodgkin lymphomas can involve essentially any organ in the body, and malfunction of that organ can cause symptoms that lead to the diagnosis. Examples include neurologic symptoms with primary brain lymphoma ( Chapter 175 ), shortness of breath with MALT lymphomas in the lung, epigastric pain and vomiting with gastric MALT lymphomas or diffuse large B-cell lymphomas ( Chapter 178 ), bowel obstruction with small bowel lymphomas ( Chapter 179 ), testicular masses with diffuse large B-cell lymphoma ( Chapter 185 ), and skin lesions with cutaneous lymphomas ( Chapter 407 ). Many lymphomas involve the bone marrow and occasionally cause extensive myelophthisis ( Chapter 151 ) and bone marrow failure. These patients may present with infections, bleeding, and anemia.
Non-Hodgkin lymphomas can also manifest with a variety of immunologic abnormalities. For example, autoimmune hemolytic anemia ( Chapter 146 ) and immune thrombocytopenia ( Chapter 158 ) can be the presenting manifestations of non-Hodgkin lymphoma, especially small lymphocytic lymphoma/chronic lymphocytic leukemia as well as other subtypes, including diffuse large B-cell lymphoma. Peripheral neuropathies ( Chapter 388 ), often associated with overproduction of a monoclonal protein, can be seen in a variety of subtypes but are most characteristic of lymphoplasmacytic lymphoma; sometimes they are also seen with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes; Chapter 173 ). Paraneoplastic neurologic complications of non-Hodgkin lymphoma include demyelinating polyneuropathy, Guillain-Barré syndrome, autonomic dysfunction, and peripheral neuropathy. Paraneoplastic syndromes ( Chapter 164 ) associated with non-Hodgkin lymphoma can affect the skin (e.g., pemphigus), kidney (e.g., glomerulonephritis), and miscellaneous organ systems (e.g., vasculitis, dermatomyositis, cholestatic jaundice).
Diagnosis
Each new patient with a non-Hodgkin lymphoma should be thoroughly evaluated in a systematic manner ( Table 171-6 ). The diagnosis of non-Hodgkin lymphoma must be considered in patients with compatible clinical presentations and then confirmed by an adequate biopsy read by an experienced hematopathologist. The diagnosis should never be inferred, and patients should not be treated until the diagnosis is confirmed by biopsy. Similarly, patients who achieve a complete remission with initial therapy should not be treated for presumed relapse on the basis of symptoms or abnormal images without a biopsy. Because subtle pathologic distinctions may alter therapy, the most important issue in managing non-Hodgkin lymphoma is to establish an accurate diagnosis.
TABLE 171-6
TYPICAL EVALUATION OF A PATIENT NEWLY DIAGNOSED WITH NON-HODGKIN LYMPHOMA
|
The differential diagnosis in patients with non-Hodgkin lymphoma is broad. Any cause of lymphadenopathy or splenomegaly can potentially be confused with non-Hodgkin lymphoma ( Chapter 154 ). However, this confusion is resolved by an appropriate biopsy. Core needle biopsies can occasionally be used for a primary diagnosis if the specimen is handled properly. Fine-needle aspirates should not be used to diagnose lymphoma, because they preclude an accurate diagnosis of the specific subtype of non-Hodgkin lymphoma. In most cases, an excisional biopsy is necessary (and is always preferred) for the initial diagnosis. A second biopsy should be performed if sufficient material is not obtained with the first attempt.
Staging and Prognostic Systems
After diagnosis, a meticulous staging evaluation is necessary to estimate prognosis and determine therapy. Staging requires a careful history and physical examination; complete blood count; renal and hepatic function tests; serum lactate dehydrogenase (LDH) level; either computed tomography (CT) of the chest, abdomen, and pelvis or positron emission tomography (PET), which can often replace CT scanning when done on a combined PET/CT machine; and bone marrow biopsy (might not be necessary in patients with diffuse large B-cell lymphoma if the PET/CT scan showed bone marrow involvement). PET can identify initial sites of involvement and, after treatment, can distinguish persisting lymphoma from residual fibrosis in masses seen on CT. The most common staging system is the Ann Arbor classification, which separates patients into four stages based on anatomic sites of disease ( Table 171-7 ). In addition, each stage is subdivided into A (no defined general symptoms) and B (unexplained weight loss >10% of body weight in the previous 6 months, unexplained temperature >38° C, or night sweats) categories. Known sites of disease can be re-evaluated after treatment to evaluate the response to therapy.
TABLE 171-7
STAGING OF NON-HODGKIN LYMPHOMA
Adapted from Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin Disease Staging Classification. Cancer Res . 1971;31:1860-1861.
| STAGE | DESCRIPTION |
|---|---|
| I | Involvement of a single lymph node region (I) or a single extralymphatic organ or site (I E ) |
| II | Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (II E ) |
| III | Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (III E ) or by involvement of the spleen (III S ) or both (III SE ) |
| IV | Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement |
| Subtypes A B |
No B symptoms B symptoms: unexplained weight loss ≥10% of body weight in prior 6 months, unexplained fever with temperature >38° C, or night sweats |
Although a wide variety of patient factors (e.g., age, symptoms, LDH level) and tumor factors (e.g., bulk, gene expression pattern, proliferation rate) can affect treatment outcomes, two prognostic systems can help in choosing therapy and determining an accurate prognosis. The International Prognostic Index ( Table 171-8 ) is the most widely used method to predict treatment outcome and survival. This index is based on five adverse factors (age >60 years, performance status ≤2, elevated serum LDH level, two or more extranodal sites of disease, Ann Arbor stage III or IV), which are summed to give the score. This index was developed for patients with diffuse aggressive lymphoma (predominantly diffuse large B-cell lymphoma), but it can be used to predict treatment outcome with any subtype. For patients younger than 60 years, an abbreviated index that uses only reduced performance status, elevated serum LDH level, and high stage can be applied. Because patients with follicular lymphoma rarely have a reduced performance status or a large number of extranodal sites, an alternative index termed the Follicular Lymphoma International Prognostic Index was developed. It substitutes more than four nodal areas of involvement and a hemoglobin value less than 12 g/dL as staging criteria and is better for predicting the outcome of treatment for follicular lymphoma.
TABLE 171-8
INTERNATIONAL PROGNOSTIC INDEX
Adapted from Shipp M, Harrington D, Anderson J, et al. A predictive model for aggressive non-Hodgkin lymphoma. N Engl J Med . 1993;329:987-994.
| CATEGORY | SCORE (NO. OF RISK FACTORS) |
|---|---|
| ALL PATIENTS ∗ | |
| Low | 0 or 1 |
| Low intermediate | 2 |
| High intermediate | 3 |
| High | 4 or 5 |
| AGE-ADJUSTED INDEX, PATIENTS ≤60 YEARS † | |
| Low | 0 |
| Low intermediate | 1 |
| High intermediate | 2 |
| High | 3 |
LDH = lactate dehydrogenase.
∗ Adverse factors for all patients: age >60 yr, ↑LDH, performance status 2-4, >1 extranodal site, Ann Arbor stage III or IV.
† Adverse factors for patients ≤60 yr: ↑LDH, performance status 2-4, Ann Arbor stage III or IV.
At the end of therapy, patients should undergo restaging, which involves repeating previously abnormal tests to prove the patient has achieved a complete remission. For most subtypes of lymphoma, the best definition of a complete remission is a PET/CT scan that has a score of Deauville 1, 2, or 3. The Deauville score uses the intensity of uptake in the mediastinum and liver as an internal control and is the most widely used system for documenting remission ( Table 171-9 ).
TABLE 171-9
THE DEAUVILLE SCORE FOR ASSESSING POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHIC SCANS TO MEASURE PATIENT RESPONSES TO THERAPY
| CRITERIA |
|
Treatment
Lymphomas may behave in an indolent or an aggressive manner. The behavior of many of these neoplasms is distinctive, but within each category, behavior is frequently influenced by disease site, tumor bulk, and performance status of the patient. Some lymphomas can be managed, at least initially, with observation, whereas other situations are medical emergencies, such as spinal cord compression. Three questions should be considered before starting therapy: (1) Does treatment have curative potential? (2) Can treatment prolong survival? (3) Will treatment alleviate symptoms? When treatment is appropriate, genomic profiling is typically recommended to guide therapy and inform prognosis.
Specific Types of Non-Hodgkin Lymphomas
Precursor T-Cell and B-Cell Lymphomas
Precursor T-cell and B-cell lymphomas are nodal or other solid tissue infiltrates of cells that are morphologically and immunophenotypically identical to the immature cells seen in B-cell or T-cell acute lymphoblastic leukemia ( Chapter 168 ). Patients who have predominantly nodal disease with minimal or no involvement of the bone marrow are frequently classified as having lymphoblastic lymphoma, whereas those with more than 25% neoplastic cells in the marrow are classified as having lymphoblastic leukemia . These distinctions are arbitrary and reflect the stage of disease rather than different diagnoses. These neoplasms are more common in children than in adults.
B-cell precursor lymphomas frequently manifest as solid tumors with involvement of the skin and bones, whereas T-cell neoplasms typically manifest as a mediastinal mass in young males. Involvement of the CNS is common in T-cell lymphomas. Approximately 90% of patients who present with lymphoblastic lymphoma have a T-cell phenotype, whereas about 85% of patients who present with acute lymphoblastic leukemia have a B-cell phenotype.
Treatment and Prognosis
Patients with either T-cell lymphoblastic lymphoma or precursor B-cell lymphoblastic lymphoma are typically treated with regimens modeled after those used for acute lymphoblastic leukemia ( Chapter 168 ). These regimens frequently contain cytarabine and high-dose methotrexate, and they often include maintenance therapy. CNS prophylaxis with intrathecal chemotherapy, high-dose methotrexate, or cranial irradiation is often a component of these regimens. Adverse prognostic characteristics include CNS involvement, stage IV disease, and an elevated LDH level.
Mature B-Cell Lymphomas
Small Lymphocytic Lymphoma and Chronic Lymphocytic Leukemia
Small lymphocytic lymphoma is defined as a lymph node or other tissue infiltrate that is morphologically and immunophenotypically identical to chronic lymphocytic leukemia ( Chapter 169 ). Patients frequently are symptom free, and the diagnosis is often made when blood counts are performed for other reasons. Patients frequently have lymphadenopathy or splenomegaly. Fatigue is common. Hypogammaglobulinemia can occur and may lead to an increased susceptibility to infection.
Treatment and Prognosis
The median survival time is more than 10 years for patients without adverse characteristics, and these patients often can be managed initially with observation. Therapy is necessary for patients who develop extreme fatigue or have systemic symptoms, for those with rapidly progressive or symptomatic lymphadenopathy or splenomegaly, and for those who develop cytopenias. Management ( Chapter 169 ) must be individualized because therapy is unlikely to be curative, and patients are often elderly. Allogeneic hematopoietic stem cell transplantation may be curative, but few patients are candidates for this approach. Patients may develop autoimmune thrombocytopenia ( Chapter 158 ), autoimmune neutropenia ( Chapter 153 ), and red blood cell aplasia ( Chapter 151 ). These disorders may respond to treatment with corticosteroids, intravenous immune globulin, anti-CD20 monoclonal antibodies such as rituximab or obinutuzumab, cyclosporine, or splenectomy, as used in patients without underlying lymphoma.
A poor prognosis is associated with advanced stage and systemic symptoms, unmutated immunoglobulin heavy chain genes, and genetic abnormalities such as del(17p) or TP53 mutation. As many as 10% of patients exhibit transformation to diffuse large B-cell lymphoma (Richter syndrome), which is associated with a poor prognosis.
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)
The WHO classification of lymphomas recognizes three groups of marginal zone lymphomas (MZL): (1) splenic MZL, (2) nodal MZL, and (3) extranodal MZL of the MALT type (MALT lymphoma). The marginal zone B cells in general are continuously exposed to exogenous antigens and have a physiologically reduced threshold for triggering proliferation, which may predispose them to malignant transformation. The first two types of marginal zone lymphomas are discussed later (section on “Rare Types of B-Cell Lymphoma”). They have different diagnostic criteria, behavior, and therapeutic implications.
MALT lymphomas are indolent lymphomas that originate in association with epithelial cells and are seen most commonly in the gastrointestinal tract, salivary glands, breast, thyroid, orbit, conjunctiva, skin, and lung. Gastric MALT lymphomas are frequently associated with infection by H. pylori ( Chapter 125 ). The majority of cases are stage I or II at diagnosis, although in some series as many as 30% disseminate to bone marrow or other sites. These lymphomas tend to remain localized for extended periods.
Treatment and Prognosis
Local treatment with surgery or radiation therapy cures a high proportion of localized neoplasms. Even in patients who have more than one extranodal site, locations can sometimes be successfully treated with local therapy. Patients without symptoms can be monitored closely without therapy until symptoms progress. Patients with symptoms can be treated with rituximab, single-agent chemotherapy, or combinations similar to the treatment of follicular lymphoma (see later).
About 75% of patients with gastric MALT lymphomas achieve remission after eradication of H. pylori (see Chapter 125 ), and more than 90% remain in remission for prolonged periods of time. Nonresponders are more likely to have submucosal invasion by endoscopic ultrasonography, lymph node metastases, or the t(11;18) chromosomal translocation. Approximately 25% of patients progress, of whom about 25% develop diffuse large B-cell lymphoma. Gastric MALT lymphoma that does not respond to antibiotics can be treated with radiation, rituximab as a single agent (similar to its use in follicular lymphoma), or several traditional combination chemotherapy regimens (see Table 171-10 ).
TABLE 171-10
COMBINATION CHEMOTHERAPY REGIMENS FOR NON-HODGKIN LYMPHOMA
bid = twice daily; IV = intravenous; PO = oral.
| REGIMEN | DOSE | DAYS OF ADMINISTRATION | FREQUENCY |
|---|---|---|---|
| R-CHOP | EVERY 21 DAYS | ||
| Cyclophosphamide | 750 mg/m 2 IV | 1 | |
| Doxorubicin | 50 mg/m 2 IV | 1 | |
| Vincristine | 1.4 mg/m 2 IV ∗ | 1 | |
| Prednisone, fixed dose | 100 mg daily PO | 1-5 | |
| Rituximab | 375 mg/m 2 IV | 1 | |
| R-EPOCH † | EVERY 21 DAYS | ||
| Etoposide | 50 mg/m 2 /day IV ‡ | 1-4 | |
| Doxorubicin | 10 mg/m 2 /day IV ‡ | 1-4 | |
| Vincristine | 0.4 mg/m 2 /day IV ‡ | 1-4 | |
| Cyclophosphamide | 750 mg/m 2 IV | 5 | |
| Prednisone | 60 mg/m 2 bid PO | 1-5 | |
| Rituximab | 375 mg/m 2 IV | 1 | |
| R-CVP | EVERY 21 DAYS | ||
| Cyclophosphamide | 1000 mg/m 2 IV | 1 | |
| Vincristine | 1.4 mg/m 2 IV ∗ | 1 | |
| Prednisone, fixed dose | 100 mg daily PO | 1-5 | |
| Rituximab | 375 mg/m 2 IV | 1 | |
| B-R | EVERY 28 DAYS | ||
| Bendamustine | 90 mg/m 2 /day IV | 1-2 | |
| Rituximab | 375 mg/m 2 IV | 1 |
∗ Vincristine dose is often capped at 2 mg total.
† Doses are adjusted based on myelosuppression with previous cycle.
Follicular Lymphoma
Follicular lymphoma is derived from germinal center B cells. The hallmark t(14;18)(q32;q21) translocation of follicular lymphomas occurs early in B-cell development, caused by an error in VDJ (“variable,” “diversity,” and “joining” gene segments) recombination. Follicular lymphoma is the most frequent of indolent or low-grade lymphomas in the United States. Follicular lymphoma is divided into three grades based on the proportion of large, transformed cells (centroblasts).
Patients with follicular lymphoma are frequently asymptomatic. The most common presenting complaint is painless lymphadenopathy. Some patients have cough or dyspnea related to pulmonary or mediastinal involvement or pleural effusions. Other patients have symptoms of abdominal pain or fullness related to subdiaphragmatic or splenic disease. A minority of patients have systemic symptoms of fevers, night sweats, or weight loss.
The clinical behavior and treatment of follicular lymphoma grades 1 and 2 are the same. Some grade 3 follicular lymphomas have a more aggressive clinical course and are treated similarly to diffuse large B-cell lymphoma (see later). This distinction between grade 3a (indolent behavior) and 3b (aggressive behavior) is based on the presence or absence of sheets of centroblasts, although this separation may not be reproducible among pathologists.
Treatment and Prognosis
Watch and Wait
A “watch and wait” approach is reasonable in asymptomatic elderly patients, patients with other medical illnesses, and in other selected patients who have low-grade follicular lymphoma and who are asymptomatic, have no disease involvement in sites that might be dangerous, and desire to avoid therapy as long as possible. Such patients can sometimes be observed for long periods before treatment is required. However, modern treatment options may improve the survival of a large proportion of patients with follicular lymphoma.
Localized Disease
Approximately 5 to 15% of patients have localized disease (stage I or minimal stage II disease) at diagnosis. These lymphomas are typically treated with involved-field radiation, preferably with 24 Gy in 12 equal fractions, and most series report 10-year disease-free survival rates of approximately 50% and overall survival rates of about 50% at 20 years.
Advanced Disease
Most patients with follicular lymphoma have extensive disease at diagnosis. The median survival time of these patients has improved after the addition of rituximab and is now 10 to 20 years. Spontaneous regression also has been described. However, as many as 30 to 50% of patients experience transformation to a more aggressive histology—usually diffuse large B-cell lymphoma. Transformation is frequently associated with new systemic symptoms, rapidly progressive lymphadenopathy, an aggressive clinical course, and a poor prognosis.
Most patients with follicular lymphoma eventually require treatment because of systemic symptoms, symptomatic or progressive lymphadenopathy, splenomegaly, effusions, or cytopenias. In elderly patients, patients who are poor candidates for intensive chemotherapy regimens, and patients who want to avoid the side effects of chemotherapy, single-agent rituximab (375 mg/m 2 intravenously, given weekly for 4 consecutive weeks) yields an objective response rate of well over 50%. The median duration of response is approximately 1 to 2 years for patients who receive no additional therapy, but the response can be extended with ongoing administration of rituximab once every 2 or 3 months or by repeating the initial four doses every 6 months. When rituximab is combined with standard chemotherapy regimens (see Table 171-10 ) or with lenalidomide, the response rate, duration of response, and survival are increased compared with the chemotherapy regimen alone. , Maintenance rituximab extends the duration of remission but not overall survival. An alternative is obinutuzumab, which can provide longer progression-free survival but at the expense of more side effects, without improving overall survival.
Salvage Therapy
Most patients respond to initial chemotherapy. However, follicular lymphoma recurs in the majority of patients with advanced-stage disease. Patients who relapse usually respond to additional therapy, sometimes with the same agents, although the duration of response becomes progressively shorter with repeated courses of therapy. For patients with disease that is refractory to rituximab, the combination of obinutuzumab plus bendamustine is preferable to bendamustine alone. Alternative therapies include lenalidomide with rituximab, or standard chemotherapies. Radiation therapy also may be useful for patients with a localized site of symptomatic disease.
Prolonged remissions have been observed after autologous hematopoietic stem cell transplantation, but autologous transplants are no more efficacious than radioimmunotherapy for relapsed or refractory follicular lymphoma. Allogeneic hematopoietic stem cell transplantation may cure some patients with relapsed follicular lymphoma but has more toxicity than autologous transplants. Chimeric antigen receptor (CAR) T-cell therapy ( Chapter 164 ) has shown promise as salvage therapy in patients with relapsed or refractory B-cell lymphomas and is now FDA approved for patients whose follicular lymphoma has failed two prior therapies.
Mantle Cell Lymphoma
Mantle cell lymphoma is a B-cell neoplasm composed of small lymphoid cells that may resemble small lymphocytic lymphoma or follicular lymphoma. It is most common in elderly patients and is usually at an advanced stage at the time of diagnosis. Males are more frequently affected, and extranodal disease, especially involvement of the bone marrow, Waldeyer ring, and the gastrointestinal tract, is common. Mantle cell lymphoma is the most common cause of multiple lymphomatous polyposis, and many oncologists recommend that the gastrointestinal tract be evaluated with endoscopy during the initial evaluation.
Some patients present with involvement of the peripheral blood as well as the bone marrow, a clinical picture that resembles chronic lymphocytic leukemia ( Chapter 169 ). The lymphocytes in both disorders are CD5 + , but the t(11;14) translocation and overexpression of cyclin D1 seen in mantle cell lymphoma usually allow an accurate diagnosis.
Treatment and Prognosis
Occasional patients, particularly patients with a leukemic presentation, may have an indolent course without initial therapy. However, the median survival of mantle cell lymphoma has significantly improved with new therapies. The combination of bendamustine plus rituximab and regimens that incorporate high-dose cytarabine are efficacious, as is the combination of lenalidomide plus rituximab. Ibrutinib added to rituximab plus bendamustine can significantly prolong remission-free survival and is commonly part of standard therapy. Substituting bortezomib (1.3 mg/m 2 on days 1, 4, 8, and 11) for vincristine (VR-CAP rather than R-CHOP) can improve the median progression-free survival seen with R-CHOP alone by about 40% (from 14 to about 25 months) in newly diagnosed patients. Maintenance rituximab seems to prolong the duration of remission.
Autologous hematopoietic stem cell transplantation is widely used for patients in their first remission. The Bruton tyrosine kinase inhibitors such as ibrutinib or acalabrutinib are very active and are part of standard therapy for relapsed disease. If such therapy is not successful, anti-CD19 CAR T-cell therapy may provide a complete response in about 60% of patients. Allogeneic transplantation can be curative but is associated with considerable morbidity and mortality.
The elderly comprise the majority of the patients with mantle cell lymphoma. For patients who are not too frail, 4-year overall survival of greater than 80% can be achieved with rituximab and moderate intensive chemotherapy such as R-CHOP followed by rituximab maintenance or R-bendamustine.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here