(See also Overview of Lymphoma.)
Non-Hodgkin lymphoma is more common than Hodgkin lymphoma. It is the 6th most common cancer in the US and represents 4% of all new cancers in the US each year and 3% of all cancer deaths. Over 70,000 new cases are diagnosed annually in all age groups. Non-Hodgkin lymphoma is not one disease but rather a category of lymphocyte cancers with a number of subgroups largely divided into aggressive and indolent types. Incidence increases with age (median age, 67 years).
The cause of non-Hodgkin lymphoma is unknown, although, as with the leukemias, substantial evidence suggests a viral cause (eg, human T-cell leukemia-lymphoma virus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, HIV, human herpesvirus 8). Bacteria such as Helicobacter pylori also increase lymphoma risk.
Patients at increased risk of non-Hodgkin lymphoma include those with
Secondary immunodeficiency (eg, when induced by immunosuppressive drugs, such as those used in rheumatologic disorders and post-solid organ transplant)
Exposure to certain chemicals (eg, some herbicides and insecticides)
Chronic inflammation and reactive lymph node hyperplasia
Non-Hodgkin lymphoma is the 2nd most common cancer in HIV-infected patients, and some AIDS patients present with lymphoma. Indeed, patients with non-Hodgkin lymphoma should generally be screened for HIV and hepatitis viruses.
Genetic factors appear to play a role. Recent evidence shows that certain single nucleotide polymorphisms increase the risk of lymphoma. Also, patients with a first-degree relative with Hodgkin or non-Hodgkin lymphoma have an increased risk of non-Hodgkin lymphoma.
Most (80 to 85%) non-Hodgkin lymphomas arise from B lymphocytes; the remainder arise from T lymphocytes or natural killer cells. Either precursor or mature cells may be involved. The stage of lymphocyte differentiation at which the oncogenic event occurs determines the disease presentation and outcome.
Most lymphomas are nodal with variable involvement of the bone marrow and peripheral blood. A leukemia-like picture with peripheral lymphocytosis and bone marrow involvement may be present in up to 50% of children and about 20% of adults with some types of non-Hodgkin lymphoma.
Hypogammaglobulinemia caused by a progressive decrease in immunoglobulin production is present in 15% of patients at diagnosis. This increases the risk of serious bacterial infection and may require replacement with IV immune globulin.
Pathologic classification of non-Hodgkin lymphoma continues to evolve, reflecting new insights into the cells of origin and the biologic bases of these heterogeneous diseases. The 2016 WHO classification is valuable because it incorporates immunophenotype, genotype, and cytogenetics, but numerous other systems exist (eg, Lyon classification).
Non-Hodgkin lymphomas are commonly also categorized as indolent or aggressive:
In children, non-Hodgkin lymphoma is almost always aggressive. Follicular and other indolent lymphomas are unusual. The treatment of these aggressive lymphomas (Burkitt, diffuse large B cell, and lymphoblastic lymphoma) presents special concerns, including gastrointestinal tract involvement (particularly in the terminal ileum); meningeal spread (requiring cerebrospinal fluid prophylaxis or treatment); and other sanctuary sites of involvement (eg, testes, brain). In addition, with these potentially curable lymphomas, treatment of adverse effects as well as outcome must be considered, including late risks of secondary cancer, cardiorespiratory sequelae, fertility preservation, and developmental consequences. Current research is focused on these areas as well as on the molecular events and predictors of lymphoma in both children and adults.
Most patients present with
Enlarged lymph nodes can be rubbery and discrete and later coalesce into masses. Affected nodes are usually not painful, unlike the tender nodes that often occur with viral infections. Nodal involvement is localized in some patients, but most patients have several areas affected. The initial physical examination should carefully look for nodes in the cervical, axillary, inguinal, and femoral regions.
In some patients, enlarged mediastinal and retroperitoneal nodes produce pressure symptoms. The most important of these are
Compression of the superior vena cava (SVC): Shortness of breath and facial edema (SVC syndrome)
Compression of the external biliary tree: Jaundice
Compression of the ureters: Hydronephrosis
Bowel obstruction: Vomiting and obstipation
Interference with lymph drainage: Chylous pleural or peritoneal fluid or lymphedema of a lower extremity
The skin is involved in some non-Hodgkin lymphomas. B-cell non-Hodgkin lymphoma can affect the scalp (follicular non-Hodgkin lymphoma) or the legs (large cell non-Hodgkin lymphoma), typically causing slightly raised, erythematous nodules. In cutaneous T-cell non-Hodgkin lymphoma, skin lesions can be diffuse, nonpalpable erythema or discrete papules, plaques, or tumors.
Systemic symptoms (eg, fatigue, fevers, night sweats, weight loss) can be the first manifestations in some patients, most commonly in aggressive lymphomas. These patients may not have noticed lymphadenopathy or not have external, palpable disease; these patients require CT or positron emission tomography (PET) imaging to discover the lesion(s).
Anemia is initially present in about 33% of patients and eventually develops in many. It may be caused by bleeding due to gastrointestinal lymphoma, with or without low platelet levels; hemolysis due to hypersplenism or Coombs’-positive hemolytic anemia; bone marrow infiltration due to lymphoma; or marrow suppression due to chemotherapy or radiation therapy.
Adult T-cell leukemia-lymphoma, which is associated with human T-lymphotropic virus 1 (HTLV-1), has a fulminating clinical course with skin infiltrates, lymphadenopathy, hepatosplenomegaly, and leukemia. The leukemic cells are malignant T cells, many with convoluted nuclei. Hypercalcemia often develops, related to humoral factors rather than to direct bone invasion.
Anaplastic large cell lymphoma may cause rapidly progressive skin lesions, adenopathy, and visceral lesions. This disease may be mistaken for Hodgkin lymphoma or metastatic undifferentiated carcinoma.
As with Hodgkin lymphoma, non-Hodgkin lymphoma is usually suspected in patients with
Less commonly, patients present after a finding of peripheral lymphocytosis on a complete blood count (CBC) done for nonspecific symptoms. In such cases, the differential diagnosis includes leukemia, Epstein-Barr virus infection, and Duncan syndrome (X-linked lymphoproliferative syndrome).
Tests needed to make the diagnosis are followed by tests to complete staging and assess etiology and prognosis (1).
Enlarged lymph nodes are biopsied. If a node is palpable, no imaging is required initially, although CT or ultrasonography may be needed to properly plan subsequent tests.
If the lesion is easily palpable, an excisional biopsy is preferred. If the lesion is in the lung or abdomen, a core needle biopsy (18- to 20-gauge needle) done using CT or ultrasound guidance can often obtain an adequate specimen for diagnosis. A fine needle biopsy (percutaneous or bronchoscopic) frequently will not produce adequate tissue, especially for initial diagnosis; core biopsy is preferred if deemed safe.
Biopsies should be reviewed by a pathologist with expertise in lymphoma diagnosis. If this review is not available locally, the slides should be sent to a reference laboratory with hematopathology expertise. The proper classification of non-Hodgkin lymphoma is critical for treatment planning. Non-Hodgkin lymphomas are potentially curable, but without a precise diagnosis, optimal therapy may not be chosen.
Histologic criteria on biopsy include destruction of normal lymph node architecture and invasion of the capsule and adjacent fat by characteristic neoplastic cells. Immunophenotyping studies to determine the cell of origin are of great value in identifying specific subtypes and helping define prognosis and management; these studies also can be done on peripheral cells if they are present, but typically these stains are applied to formalin-fixed, paraffin-embedded tissue. Demonstration of the leukocyte common antigen CD45 by immunoperoxidase rules out metastatic cancer, which is often in the differential diagnosis of “undifferentiated” cancers. The test for leukocyte common antigen, most surface marker studies, and gene rearrangement (to document B-cell or T-cell clonality) can be done on fixed tissues. Cytogenetics and flow cytometry require fresh tissue.
Once the diagnosis of lymphoma is made, staging tests are done.
A combined fluorodeoxyglucose (FDG)-PET/CT scan of the chest, abdomen, and pelvis is recommended. PET/CT provides accurate location of lesions, their size (from CT) and tumor metabolism (from FDG-PET). If combined FDG-PET/CT is not available, a contrast-enhanced CT scan of the chest, abdomen, and pelvis is done.
Bone marrow aspiration and biopsy is often done in patients with non-Hodgkin lymphoma. Although bilateral posterior iliac crest biopsies can be done, unilateral biopsy is typically sufficient. Bone marrow biopsy may not be needed for staging large cell non-Hodgkin lymphoma if a PET scan has been done because FDG-PET is sensitive for bone marrow involvement. Bone marrow assessment in low-grade (indolent) non-Hodgkin lymphoma or T-cell non-Hodgkin lymphoma can also be limited to cases where findings will change management or are needed to assess cytopenias.
Blood tests typically include CBC with white blood cell differential, kidney function and liver tests (including serum creatinine, bilirubin, calcium, AST, albumin, alkaline phosphatase, and lactate dehydrogenase), uric acid, beta-2 microglobulin, and vitamin D levels. Serum protein electrophoresis with IgG, IgA, and IgM immunoglobulin levels are also done.
Other tests are done depending on findings (eg, MRI of brain and/or spinal cord for neurologic symptoms). If uric acid levels are high, serum glucose-6-phosphate dehydrogenase (G6PD) level is checked because G6PD deficiency precludes treatment with rasburicase (to prevent tumor lysis syndrome).
After diagnosis, stage is determined to guide therapy. The commonly used Lugano staging system (see table Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma) incorporates
Although stage I non-Hodgkin lymphoma does occur, the disease is typically disseminated when first recognized.
Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma
1. Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 32(27):3059-3068, 2014.
Prognosis varies by the type and stage of lymphoma and individual patient factors. In general, patients with peripheral T-cell or natural killer (NK)/T-cell lymphomas typically have a worse prognosis than those with B-cell non-Hodgkin lymphoma. Within each non-Hodgkin lymphoma variant, prognosis is related to differences in tumor cell biology.
The most commonly used prognostic scoring system is the International Prognostic Index (IPI) for diffuse large B-cell lymphoma). The IPI score is used only for diffuse large B-cell lymphoma (DLBCL). There are also scoring systems for follicular lymphoma (FLIPI) and mantle cell lymphoma (MIPI). Online calculators are available to estimate prognosis in other types of non-Hodgkin lymphoma as well.
The IPI considers 5 risk factors:
Age > 60 years
Poor performance status (can be measured using the Eastern Cooperative Oncology Group tool)
Elevated lactate dehydrogenase (LDH) level
> 1 extranodal site
Stage III or IV disease
Outcome is worse with an increasing number of risk factors. Patients in the highest risk groups (patients with 4 or 5 risk factors) now have a 50% 5-year survival. Patients without any of the risk factors have a very high cure rate. The original IPI score uses the 5 factors as discrete variables (ie, either age over 60 or under 60). A recent modification, the Diffuse Large B-cell Lymphoma Prognosis (IPI24), which calculates the chance of being disease free at 24 months from diagnosis, includes the above factors as continuous variables and also includes absolute lymphocyte count.
Watch and wait (for indolent, largely asymptomatic lymphomas)
Radiation therapy (most common in patients with limited-stage disease and sometimes in those with advanced-stage disease)
Immunotherapy (eg, monoclonal antibodies targeting CD20, CD19, or CD79, or chimeric antigen receptor T cells [CAR T cells])
Targeted drugs (eg, BTK [Bruton tyrosine kinase] inhibitors, PI3K [phosphoinositide 3-kinase] inhibitors, cereblon inhibitors)
Sometimes hematopoietic stem cell transplantation (autologous or allogeneic)
Treatment varies considerably with cell type, which are too numerous to permit detailed discussion. Generalizations can be made regarding limited vs advanced disease and aggressive vs indolent forms. Burkitt lymphoma and cutaneous T-cell lymphomas are discussed separately. For patients with indolent lymphomas and no significant signs or symptoms of lymphoma, a "watch and wait" approach (withholding treatment while closely monitoring) can be used.
For stage I indolent non-Hodgkin lymphoma (uncommon because most patients have stage II to IV when diagnosed), external beam radiation therapy can be the sole initial treatment. Regional radiation therapy may offer long-term control and possibly cure in about 40% of stage I patients. Stage II indolent non-Hodgkin lymphoma is most commonly treated as advanced-stage disease.
Limited-stage aggressive non-Hodgkin lymphomas can be managed with a combination of chemotherapy plus radiation therapy or with chemotherapy alone (plus anti-CD20 monoclonal antibodies for B-cell lymphomas).
Patients with stage I lymphoblastic lymphomas or Burkitt lymphoma are treated with intensive combination chemotherapy with meningeal prophylaxis.
Stage II non-Hodgkin lymphoma is managed as advanced stage disease in many circumstances. Most patients with all types of non-Hodgkin lymphoma who have stage II to IV disease are candidates for chemoimmunotherapy. In these cases, radiation therapy may be used to limit the number of cycles of chemoimmunotherapy or provide localized treatment for residual sites of bulk disease.
For indolent lymphomas, treatment varies considerably. Because these lymphomas are highly treatable but not reliably curable, treatment may not be recommended initially for asymptomatic patients, although with the advent of rituximab anti-CD20 immunotherapy, some of these patients may be given immunotherapy alone. This strategy can delay the need for myelosuppressive chemotherapy, but early immunotherapy alone has not been shown to impact overall survival. Patients with symptoms or bulky disease that puts vital organs at risk are treated with chemoimmunotherapy. In selected cases, radiolabeled anti-CD20 antibody can be used to target radiation to the tumor cell with potentially fewer effects on nearby normal organs.
In patients with aggressive B-cell lymphomas (eg, diffuse large B cell), the standard drug combination is rituximab plus cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine, and prednisone (R-CHOP). A complete response with disease regression is expected in 80% of cases, with an overall cure rate of about 60%. These results vary significantly by IPI score. Patients who are disease free at ≥ 24 months from diagnosis have a lifetime expectancy similar to that of the age- and sex-matched population. This key factor can guide follow-up strategies in this patient population.
Cure rates have improved with the use of R-CHOP, so autologous transplantation is not used as adjuvant therapy in patients who achieve complete metabolic response (ie, determined by PET) at the end of therapy.
The approach in peripheral T-cell non-Hodgkin lymphoma and primary central nervous system lymphoma is different. In these patients, autologous stem cell transplantation may be offered to initial responders before relapse occurs with the intention of improving the likelihood of cure. Similarly, in some younger patients with mantle cell lymphoma who have responded to initial therapy, autologous stem cell transplantation may be is done to prolong remission.
Patients with aggressive non-Hodgkin lymphoma not in remission at end of therapy or who relapse are treated with second-line chemotherapy regimens followed by autologous stem cell transplantation if they are relatively young and in good health. In autologous stem cell transplantation, stem cells are obtained from the patient by peripheral blood leukopheresis and are transfused back into the patient after high-dose chemotherapy. In some patients at very high risk of relapse as well as in those for whom autologous transplant is not feasible or has already failed, stem cells from a matched sibling or unrelated donor (allogeneic transplants) can be effective. In general, the older the patient, the less likely an allogeneic transplantation will be offered because they have higher rates of transplantation complications.
Patients with diffuse large B-cell lymphoma (DLBCL) who have persistent lymphoma despite at least 2 prior lines of therapy may be candidates for chimeric antigen receptor (CAR) T cells. CAR T cells are T cells (most commonly autologous T cells) that have been genetically engineered to recognize a tumor antigen (eg, CD19). After infusion, they undergo activation and expansion. About one third of patients achieve a durable response from this therapy.
Patients not eligible for the above therapies, or for whom they have failed, may receive treatment with various therapies, mostly for palliation. These therapies vary widely and are constantly changing as new agents are developed.
In indolent lymphomas, patients may be managed using a wide variety of strategies depending on lymphoma-related factors (eg, histopathology, stage, molecular and immunologic characteristics), patient-related factors (eg, age, comorbidities), and the type of and response to prior therapy. Many of the same agents used in for first-line treatment may be given. In some cases, the same treatment may be repeated if it was previously effective and well tolerated. High-dose chemotherapy with autologous stem cell transplantation is used occasionally in patients who have high-risk lymphoma biology (including a poor response to chemotherapy), and although cure remains unlikely, remission may be superior to that with secondary palliative therapy alone. Reduced intensity allogeneic transplantation is a potentially curative option in some patients with indolent lymphoma.
The mortality rate of patients undergoing myeloablative transplantation has decreased dramatically to 1 to 2% for most autologous procedures and to 15 to 20% for most allogeneic procedures (depending on age).
An immediate complication of most therapies is infection that occurs during periods of neutropenia. Although use of growth factors that stimulate white blood cell production has helped, infection continues to pose a problem.
The gastrointestinal adverse effects of chemotherapy can be largely relieved and prevented by antiemetics and bowel programs. Patients receiving anthracyclines are at risk of cardiomyopathy and/or arrhythmias.
After successful treatment, patients should be referred to a cancer survivorship clinic for a care plan that can be implemented by the patient's primary care team. This plan is tailored to the patient's comorbidities and risks specific to the treatment they received.
Drugs and radiation have late complications. In the first 10 years after treatment, there is a risk of myelodysplasia or acute leukemia due to bone marrow damage from certain chemotherapy agents. After 10 years, the risk of secondary cancers increases, especially in patients who received radiation to the chest.
Non-Hodgkin lymphomas are a group of related cancers involving lymphocytes; they vary significantly in their rate of growth and response to treatment.
The disease is usually already disseminated at the time of diagnosis.
Molecular and genetic tests are essential for diagnosis and management.
Limited indolent disease may be treated with radiation therapy.
Treat more advanced disease with immunotherapy, chemotherapy, hematopoietic stem cell transplantation, or a combination depending on the type and stage of non-Hodgkin lymphoma.
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