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Non-Hodgkin Lymphomas

(Non-Hodgkin's Lymphoma)

by Carol S. Portlock, MD

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the spleen, the liver, and the GI tract. Presenting symptoms usually include peripheral lymphadenopathy. However, some patients present without lymphadenopathy but with abnormal lymphocytes in circulation. Compared with Hodgkin lymphoma, there is a greater likelihood of disseminated disease at the time of diagnosis. Diagnosis is usually based on lymph node or bone marrow biopsy or both. Treatment involves radiation therapy, chemotherapy, or both. Stem cell transplantation is usually reserved for salvage therapy after incomplete remission or relapse.

NHL is more common than Hodgkin lymphoma. It is the 6th most common cancer in the US; about 70,000 new cases are diagnosed annually in all age groups. However, NHL is not one disease but rather a category of lymphocyte cancers. Incidence increases with age (median age, 50 yr).


The cause of NHL is unknown, although, as with the leukemias, substantial evidence suggests a viral cause (eg, human T-cell leukemia-lymphoma virus, Epstein-Barr virus, hepatitis C virus, HIV). Risk factors for NHL include immunodeficiency (secondary to posttransplant immunosuppression, AIDS, primary immune disorders, sicca syndrome, RA), Helicobacter pylori infection, certain chemical exposures, and previous treatment for Hodgkin lymphoma. NHL is the 2nd most common cancer in HIV-infected patients (see Non-Hodgkin lymphoma), and some AIDS patients present with lymphoma. C- myc gene rearrangements are characteristic of some AIDS-associated lymphomas.


Most (80 to 85%) NHL arise from B cells; the remainder arise from T cells or natural killer cells. Either precursor or mature cells may be involved. Overlap exists between leukemia and NHL because both involve proliferation of lymphocytes or their precursors. A leukemia-like picture with peripheral lymphocytosis and bone marrow involvement may be present in up to 50% of children and in about 20% of adults with some types of NHL. Differentiation can be difficult, but generally patients with more extensive nodal involvement (especially mediastinal), fewer circulating abnormal cells, and fewer blast forms in the marrow (< 25%) are considered to have lymphoma. A prominent leukemic phase is less common in aggressive lymphomas, except Burkitt (see Burkitt Lymphoma) and lymphoblastic lymphomas.

Hypogammaglobulinemia caused by a progressive decrease in immunoglobulin production occurs in 15% of patients, primarily those with histology that resembles chronic lymphocytic leukemia, and may predispose to serious bacterial infection.

Pearls & Pitfalls

  • There is considerable overlap between non-Hodgkin lymphoma and leukemia; both may have peripheral lymphocytosis and bone marrow involvement.


Pathologic classification of NHL continues to evolve, reflecting new insights into the cells of origin and the biologic bases of these heterogeneous diseases. The WHO classification (see Subtypes of Non-Hodgkin Lymphoma (WHO Classification)) is valuable because it incorporates immunophenotype, genotype, and cytogenetics, but numerous other systems exist (eg, Lyon classification). Among the most important lymphomas newly recognized by the WHO system are mucosa-associated lymphoid tumors (MALT—see Mucosa-associated lymphoid tissue (MALT) lymphoma), mantle cell lymphoma (previously diffuse small cleaved cell lymphoma), and anaplastic large cell lymphoma. Anaplastic large cell lymphoma is a heterogeneous disorder with 75% of cases of T-cell origin, 15% of B-cell origin, and 10% unclassified. However, despite the plethora of entities, treatment is often similar except in certain T-cell lymphomas.

Subtypes of Non-Hodgkin Lymphoma (WHO Classification)

Cell Origin


Precursor B-cell tumor

Precursor B-lymphoblastic leukemia/lymphoma*

Mature B-cell tumors

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma

Splenic marginal zone B-cell lymphoma (± villous lymphocytes)

Hairy cell leukemia

Plasma cell myeloma/plasmacytoma

Extranodal marginal zone B-cell lymphoma of the MALT type

Nodal marginal zone B-cell lymphoma (± monocytoid B cells)

Follicular lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphomas* (including mediastinal large B-cell lymphoma and primary effusion lymphoma)

Burkitt lymphoma*

Precursor T-cell tumor

Precursor T-lymphoblastic lymphoma/leukemia*

Mature T-cell tumors

T-cell prolymphocytic leukemia

T-cell granular lymphocytic leukemia*

Aggressive NK cell leukemia*

Adult T-cell lymphoma/leukemia* (HTLV 1-positive)

Extranodal NK/T-cell lymphoma, nasal type*

Enteropathy-type T-cell lymphoma*

Hepatosplenic γ-δ T-cell lymphoma*

Subcutaneous panniculitis-like T-cell lymphoma*

Mycosis fungoides/Sézary syndrome

Anaplastic large cell lymphoma, T/null cell, primary cutaneous type*

Anaplastic large cell lymphoma, T-/null-cell, primary systemic type*

Peripheral T-cell lymphoma, not otherwise characterized*

Angioimmunoblastic T-cell lymphoma*



Indolent but more rapidly progressive.

HTLV = human T-cell leukemia virus 1; MALT = mucosa-associated lymphoid tissue; NK = natural killer; ±= with or without.

Lymphomas are commonly also categorized as indolent or aggressive. Indolent lymphomas are slowly progressive and responsive to therapy but are not curable with standard approaches. Aggressive lymphomas are rapidly progressive but responsive to therapy and often curable.

In children, NHL is almost always aggressive. Follicular and other indolent lymphomas are very rare. The treatment of these aggressive lymphomas (Burkitt, diffuse large B cell, and lymphoblastic lymphoma) presents special concerns, including GI tract involvement (particularly in the terminal ileum); meningeal spread (requiring CSF prophylaxis or treatment); and other sanctuary sites of involvement (eg, testes, brain). In addition, with these potentially curable lymphomas, treatment 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 children.

Symptoms and Signs

Many patients present with asymptomatic peripheral lymphadenopathy. Enlarged lymph nodes are rubbery and discrete and later become matted. Disease is localized in some patients, but most patients have several areas of involvement. Mediastinal and retroperitoneal lymphadenopathy may cause pressure symptoms on various organs. Extranodal sites may dominate clinically (eg, gastric involvement can simulate GI carcinoma; intestinal lymphoma may cause a malabsorption syndrome; HIV patients who develop NHL often present with CNS involvement).

The skin and bones are initially involved in 15% of patients with aggressive lymphoma and in 7% of those with indolent lymphoma. Occasionally, patients with extensive abdominal or thoracic disease develop chylous ascites or pleural effusion because of lymphatic obstruction. Weight loss, fever, night sweats, and asthenia indicate disseminated disease. Patients may have hepatomegaly and splenomegaly as well.

Two problems are common in NHL but rare in Hodgkin lymphoma: Congestion and edema of the face and neck from pressure on the superior vena cava (superior vena cava or superior mediastinal syndrome) may occur. Also, ureters may be compressed by retroperitoneal or pelvic lymph nodes or both; this compression may interfere with urinary flow and cause secondary renal failure.

Pearls & Pitfalls

  • Superior vena cava syndrome and ureteral compression are common in non-Hodgkin lymphoma but rare in Hodgkin lymphoma.

Anemia is initially present in about 33% of patients and eventually develops in most. It may be caused by bleeding due to GI 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.

The acute illness of adult T-cell leukemia-lymphoma (ATLL, associated with human T-lymphotrophic 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.

Patients with anaplastic large cell lymphoma have rapidly progressive skin lesions, adenopathy, and visceral lesions. This disease may be mistaken for Hodgkin lymphoma or metastatic undifferentiated carcinoma.


  • Chest x-ray

  • CT of chest, abdomen, and pelvis and/or PET–CT

  • CBC, alkaline phosphatase, LDH, liver function tests, albumin, Ca, BUN, creatinine, electrolytes, and uric acid

  • HIV, hepatitis B virus, and hepatitis C virus testing; testing for HTLV-1 if ATLL is found

  • Lymph node and bone marrow biopsy

  • MRI of spine if neurologic symptoms are present

As with Hodgkin lymphoma, NHL is usually suspected in patients with painless lymphadenopathy or when mediastinal adenopathy is detected on routine chest x-ray. Painless lymphadenopathy can also result from infectious mononucleosis, toxoplasmosis, cytomegalovirus infection, primary HIV infection, or leukemia. Similar chest x-ray findings can result from lung carcinoma, sarcoidosis, or TB. Less commonly, patients present after a finding of peripheral lymphocytosis on CBC done for nonspecific symptoms. In such cases, the differential diagnosis includes leukemia, Epstein-Barr virus infection, and Duncan syndrome (X-linked lymphoproliferative syndrome).

A lymph node biopsy is done if lymphadenopathy is confirmed on chest x-ray, CT, or PET. If only mediastinal nodes are enlarged, patients require CT-guided needle biopsy or mediastinoscopy. Usually, tests should include CBC, alkaline phosphatase, kidney and liver function tests, LDH, and uric acid. Other tests are done depending on findings (eg, MRI for symptoms of spinal cord compression or CNS abnormalities).

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. 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.


Although localized NHL does occur, the disease is typically disseminated when first recognized. Staging procedures include CT of the chest, abdomen, and pelvis; PET; and bone marrow biopsy. The final staging of NHL (see Cotswold Modification of Ann Arbor Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma) is similar to that of Hodgkin lymphoma and is based on clinical and pathologic findings.


Patients with T-cell lymphomas generally have a worse prognosis than do those with B-cell types, although newer intensive treatment regimens may lessen this difference. Prognosis for each NHL variant is related to differences in tumor cell biology.

Survival also varies with other factors. The International Prognostic Index (IPI) is frequently used in aggressive lymphomas. It considers 5 risk factors:

  • Age > 60

  • Poor performance status (can be measured using the Eastern Cooperative Oncology Group tool)

  • Elevated LDH

  • > 1 extranodal site

  • Stage III or IV disease

Outcome is worse with an increasing number of risk factors. Survival, as determined by IPI factor, has improved with the addition of rituximab to the standard chemotherapeutic regimen. Patients in the highest risk groups (patients with 4 or 5 risk factors) now have a 50% 5-yr survival. Patients without any of the risk factors have a very high cure rate. A modified IPI (follicular lymphoma IPI [FLIPI]) is being used in follicular lymphomas and in diffuse large B-cell lymphoma (revised IPI [R-IPI]).


  • Chemotherapy, radiation therapy, or both

  • Anti-CD20 monoclonal antibody, with or without chemotherapy

  • Sometimes hematopoietic stem cell transplantation

Treatment varies considerably with cell type, which are too numerous to permit detailed discussion. Generalizations can be made regarding localized vs advanced disease and aggressive vs indolent forms. Burkitt lymphoma (see Burkitt Lymphoma) and mycosis fungoides (see Mycosis Fungoides) are discussed separately.

Localized disease (stages I and II)

Patients with indolent lymphomas rarely present with localized disease, but when they do, regional radiation therapy may offer long-term control. However, relapses may occur > 10 yr after radiation therapy.

About half of patients with aggressive lymphomas present with localized disease, for which combination chemotherapy, with or without regional radiation, is usually curative. Patients with lymphoblastic lymphomas or Burkitt lymphoma, even if apparently localized, must receive intensive combination chemotherapy with meningeal prophylaxis. Treatment may require maintenance chemotherapy, but cure is expected.

Advanced disease (stages III and IV)

For indolent lymphomas, treatment varies considerably. A watch-and-wait approach or treatment with the B-cell specific monoclonal anti-CD20 antibody rituximab alone or combined with chemotherapy (single drug or 2- or 3-drug regimens) may be used. Criteria considered in selecting management options include age, general health, distribution of disease, tumor bulk, histology, and anticipated benefits of therapy. Radiolabeled-antibody therapy is also sometimes used.

In patients with the aggressive B-cell lymphomas (eg, diffuse large B cell), the standard drug combination is rituximab plus cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine, and prednisone (R-CHOP). Complete disease regression is expected in 70% of patients, depending on the IPI category. More than 70% of complete responders are cured, and relapses > 2 yr after treatment ceases are rare.

Cure rates have improved with the use of R-CHOP, so autologous transplantation is reserved for patients with relapsed or refractory aggressive B-cell lymphomas, some younger patients with mantle cell lymphoma, and some patients with aggressive T-cell lymphomas.

Lymphoma relapse

The first relapse after initial chemotherapy is almost always treated with autologous stem cell transplantation. Patients usually should be 70 yr or in equivalent health and have responsive disease, good performance status, a source of uncontaminated stem cells, and an adequate number of CD34+ stem cells (harvested from peripheral blood or bone marrow). Consolidation myeloablative therapy may include chemotherapy with or without irradiation. Posttreatment immunotherapy (eg, rituximab, vaccination, IL-2) is being studied.

An allogeneic transplant is the donation of stem cells from a compatible donor (brother, sister, matched unrelated donor, or umbilical cord blood). The stem cells have a 2-fold effect: reconstituting normal blood counts and providing a possible graft-vs-tumor effect.

In aggressive lymphoma, a cure may be expected in 30 to 50% of eligible patients undergoing myeloablative therapy and transplantation.

In indolent lymphomas, cure with autologous stem cell transplantation remains uncertain, although remission may be superior to that with secondary palliative therapy alone. Reduced intensity allogenic transplantation is a potentially curative option in some patients with indolent lymphoma.

The mortality rate of patients undergoing myeloablative transplantation has decreased dramatically to 2 to 5% for most autologous procedures and to < 15% for most allogeneic procedures.

Complications of treatment

A late sequela of standard and high-dose chemotherapy is the occurrence of 2nd tumors, especially myelodysplasias and acute myelogenous leukemia. Chemotherapy combined with radiation therapy increases this risk, although its incidence is still only about 3%.

Key Points

  • Non-Hodgkin lymphomas are a group of related cancers involving lymphocytes; they vary significantly in their rate of growth and response to treatment.

  • Non-Hodgkin lymphomas overlap considerably with leukemias.

  • The disease is usually already disseminated at the time of diagnosis.

  • Molecular and genetic tests are essential for diagnosis and management.

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