Updated REAL/WHO Classification
PDQ Modification of REAL Classification of Lymphoproliferative Diseases
Indolent NHL
Aggressive NHL

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

A pathologist should be consulted prior to a biopsy because some studies require special preparation of tissue (e.g., frozen tissue). Knowledge of cell surface markers and immunoglobulin and T-cell receptor gene rearrangements may help with diagnostic and therapeutic decisions. The clonal excess of light chain immunoglobulin may differentiate malignant from reactive cells. Since the prognosis and the approach to treatment are influenced by histopathology, outside biopsy specimens should be carefully reviewed by a hematopathologist who is experienced in diagnosing lymphomas. Although lymph node biopsies are recommended whenever possible, sometimes immunophenotypic data are sufficient to allow diagnosis of lymphoma when fine-needle aspiration cytology is preferred.[1,2]

Historically, uniform treatment of patients with non-Hodgkin lymphoma (NHL) has been hampered by the lack of a uniform classification system. In 1982, results of a consensus study were published as the Working Formulation.[3] The Working Formulation combined results from six major classification systems into one classification. This allowed comparison of studies from different institutions and countries. The Rappaport Classification, which also follows, is no longer in common use.

As the understanding of NHL has improved and as the histopathologic diagnosis of NHL has become more sophisticated with the use of immunologic and genetic techniques, a number of new pathologic entities have been described.[4] In addition, the understanding and treatment of many of the previously described pathologic subtypes have changed. As a result, the Working Formulation has become outdated and less useful to clinicians and pathologists. Thus, European and American pathologists have proposed a new classification, the Revised European American Lymphoma (REAL) Classification.[5-8] Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification, which represents an updated version of the REAL system.[9-11]

The WHO modification of the REAL classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)–cell neoplasms, and Hodgkin lymphoma. Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For example, B-cell chronic lymphocytic leukemia and B-cell small lymphocytic lymphoma are simply different manifestations of the same neoplasm, as are lymphoblastic lymphomas and acute lymphocytic leukemias. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.[9-11]

B-cell neoplasms

1. Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).
2. Peripheral B-cell neoplasms.
   1. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.
   2. B-cell prolymphocytic leukemia.
   3. Lymphoplasmacytic lymphoma/immunocytoma.
   4. Mantle cell lymphoma.
   5. Follicular lymphoma.
   6. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type.
   7. Nodal marginal zone B-cell lymphoma (± monocytoid B-cells).
   8. Splenic marginal zone lymphoma (± villous lymphocytes).
   9. Hairy cell leukemia.
   10. Plasmacytoma/plasma cell myeloma.
   11. Diffuse large B-cell lymphoma.
   12. Burkitt lymphoma.

T-cell and putative NK-cell neoplasms

1. Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL.
2. Peripheral T-cell and NK-cell neoplasms.
   1. T-cell chronic lymphocytic leukemia/prolymphocytic leukemia.
   2. T-cell granular lymphocytic leukemia.
   3. Mycosis fungoides/Sézary syndrome.
   4. Peripheral T-cell lymphoma, not otherwise characterized.
   5. Hepatosplenic gamma/delta T-cell lymphoma.
   6. Subcutaneous panniculitis-like T-cell lymphoma.
   7. Angioimmunoblastic T-cell lymphoma.
   8. Extranodal T-/NK-cell lymphoma, nasal type.
   9. Enteropathy-type intestinal T-cell lymphoma.
   10. Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).
   11. Anaplastic large cell lymphoma, primary systemic type.
   12. Anaplastic large cell lymphoma, primary cutaneous type.
   13. Aggressive NK-cell leukemia.

Hodgkin lymphoma

1. Nodular lymphocyte–predominant Hodgkin lymphoma.
2. Classical Hodgkin lymphoma.
   1. Nodular sclerosis Hodgkin lymphoma.
   2. Lymphocyte-rich classical Hodgkin lymphoma.
   3. Mixed-cellularity Hodgkin lymphoma.
   4. Lymphocyte-depleted Hodgkin lymphoma.

The REAL classification encompasses all the lymphoproliferative neoplasms. Refer to the following PDQ summaries for more information:

• Adult Acute Lymphoblastic Leukemia Treatment
• Adult Hodgkin Lymphoma Treatment
• AIDS-Related Lymphoma Treatment
• Chronic Lymphocytic Leukemia Treatment
• Hairy Cell Leukemia Treatment
• Multiple Myeloma and Other Plasma Cell Neoplasms Treatment
• Mycosis Fungoides/Sézary Syndrome Treatment
• Primary Central Nervous System Lymphoma Treatment

The more than 20 clinicopathologic entities described here can be divided into the more clinically useful indolent or aggressive lymphomas as follows:

1. Plasma cell disorders. (Refer to the PDQ summary on Multiple Myeloma and Other Plasma Cell Neoplasms Treatment for more information.)
   1. Bone.
   2. Extramedullary.
      1. Monoclonal gammopathy of undetermined significance.
      2. Plasmacytoma.
      3. Multiple myeloma.
      4. Amyloidosis.
2. Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
   1. Nodular sclerosis Hodgkin lymphoma.
   2. Lymphocyte-rich classical Hodgkin lymphoma.
   3. Mixed-cellularity Hodgkin lymphoma.
   4. Lymphocyte-depleted Hodgkin lymphoma.
3. Indolent lymphoma/leukemia.
   1. Follicular lymphoma (follicular small-cleaved cell [grade 1], follicular mixed small-cleaved, and large cell [grade 2], and diffuse small-cleaved cell).
   2. Chronic lymphocytic leukemia/small lymphocytic lymphoma. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
   3. Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
   4. Extranodal marginal zone B-cell lymphoma (MALT lymphoma).
   5. Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma).
   6. Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes).
   7. Hairy cell leukemia. (Refer to the PDQ summary on Hairy Cell Leukemia Treatment for more information.)
   8. Mycosis fungoides/Sézary syndrome. (Refer to the PDQ summary on Mycosis Fungoides/Sézary Syndrome Treatment for more information.)
   9. T-cell granular lymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
   10. Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+).
   11. Nodular lymphocyte–predominant Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
4. Aggressive lymphoma/leukemia.
   1. Diffuse large cell lymphoma (includes diffuse mixed-cell, diffuse large cell, immunoblastic, and T-cell rich large B-cell lymphoma).

      Distinguish:

      1. Mediastinal large B-cell lymphoma.
      2. Follicular large cell lymphoma (grade 3).
      3. Anaplastic large cell lymphoma (CD30+).
      4. Extranodal NK-/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphoma.
      5. Lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma).
      6. Angioimmunoblastic T-cell lymphoma.
      7. Peripheral T-cell lymphoma, unspecified.
         1. Subcutaneous panniculitis-like T-cell lymphoma.
         2. Hepatosplenic T-cell lymphoma.
      8. Enteropathy-type T-cell lymphoma.
      9. Intravascular large B-cell lymphoma.
   2. Burkitt lymphoma/Burkitt cell leukemia/Burkitt-like lymphoma.
   3. Precursor B-cell or T-cell lymphoblastic lymphoma/leukemia. (Refer the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
   4. Primary central nervous system (CNS) lymphoma. (Refer to the PDQ summary on Primary Central Nervous System Lymphoma Treatment for more information.)
   5. Adult T-cell leukemia/lymphoma (HTLV 1+).
   6. Mantle cell lymphoma.
   7. Polymorphic posttransplantation lymphoproliferative disorder (PTLD).
   8. AIDS-related lymphoma. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
   9. True histiocytic lymphoma.
   10. Primary effusion lymphoma.
   11. B-cell or T-cell prolymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)

Follicular lymphoma

Follicular lymphoma comprises 20% of all non-Hodgkin lymphomas and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[7,8,11] Most patients with follicular lymphoma are 50 years and older and present with widespread disease at diagnosis. Nodal involvement is most common and is often accompanied by splenic and bone marrow disease. Rearrangement of the bcl-2 gene is present in more than 90% of patients with follicular lymphoma; overexpression of the bcl-2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis.[12]

Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent.[13-15] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options.[16] The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment.[17] Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[18] An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI])[19-21] identified five significant risk factors prognostic of overall survival (OS):

1. Age (≤60 years vs. >60 years).
2. Serum lactate dehydrogenase (normal vs. elevated).
3. Stage (stage I or stage II vs. stage III or stage IV).
4. Hemoglobin level (≥120 g/L vs. <120 g/L).
5. Number of nodal areas (≤4 vs. >4).

Patients with 0 to 1 risk factors have an 85% 10-year survival rate, while three or more risk factors confer a 40% 10-year survival rate.[19] Gene expression profiles of tumor biopsy specimens suggest that follicular lymphoma that is surrounded by infiltrating T-lymphocytes has a much longer median survival (13.6 years) than follicular lymphoma that is surrounded by dendritic and monocytic cells (3.9 years) (P < .001).[22] These infiltrating nonmalignant cells may be valuable therapeutic targets.[23]

Follicular small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.[10] Therapeutic options include watchful waiting; rituximab, an anti-CD20 monoclonal antibody, alone or with purine nucleoside analogs; oral alkylating agents; and combination chemotherapy.[24] Radiolabeled monoclonal antibodies, vaccines, and autologous or allogeneic bone marrow or peripheral stem cell transplantation are also under clinical evaluation.[24] Currently, no randomized trials guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options. On a comparative basis, it is difficult to prove benefit when relapsing disease is followed with watchful waiting, or when the median survival is more than 10 years.

Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type.[25] Rapid growth or discordant growth between various disease sites may indicate a histologic conversion. The risk of histologic transformation was 30% by 10 years in a retrospective review of 325 patients from diagnosis between 1972 and 1999.[26] In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index (FLIPI), and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after retreatment.[27] Histologic conversions should be treated with the regimens described in the Aggressive, Recurrent Adult Non-Hodgkin's Lymphoma section of this summary. The durability of the second remission may be short, and clinical trials should be considered.[27-29]

Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[30-32] Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Other lymphomas may also be associated with serum paraproteins.

The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia.[31-35] If the viscosity relative to water is greater than four, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and CNS dysfunction) but should be combined with chemotherapy for prolonged control of the disease. Symptomatic patients with a serum viscosity of not more than four are usually started directly on chemotherapy. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; chlorambucil, with or without prednisone, is the mainstay. Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.

Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.[18] First-line regimens include rituximab, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[36,37] Rituximab shows 60% to 80% response rates in previously untreated patients, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[36,38,39][Level of evidence: 3iiiDiv] The nucleoside analogues 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[40-42][Level of evidence: 3iiiDiv] Single-agent alkylators and combination chemotherapy also show similar response rates.[43][Level of evidence: 3iiiDiv] Currently, no randomized trials guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, or combinations of these options.[31,32,36]

Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma.[44] Myeloablative therapy with autologous hematopoietic stem cell support is under clinical evaluation.[45,46] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells.[36] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomized to fludarabine versus cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration 19 months vs. 3 months, P < .01), no difference was observed in OS.[47][Level of evidence: 1iiDii] Among patients with concomitant hepatitis C virus (HCV) infection, some will attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[48][Level of evidence: 3iiiDiv]

Marginal zone lymphoma

Marginal zone lymphomas were previously included among the diffuse small lymphocytic lymphomas. When marginal zone lymphomas involve the nodes, they are called monocytoid B-cell lymphomas or nodal marginal zone B-cell lymphomas, and when they involve extranodal sites (e.g., gastrointestinal tract, thyroid, lung, breast, orbit, and skin), they are called MALT lymphomas.[4,49-57]

Many patients have a history of autoimmune disease, such as Hashimoto thyroiditis or Sjögren syndrome, or of Helicobacter gastritis. Most patients present with stage I or stage II extranodal disease, which is most often in the stomach. Treatment of Helicobacter pylori infection may resolve many cases of localized gastric involvement.[56,58-62] After standard antibiotic regimens, 50% of patients show resolution of gastric MALT by endoscopy after 3 months. Other patients may show resolution after 12 to 18 months of observation. Of the patients who attain complete remission, 30% demonstrate monoclonality by immunoglobulin heavy chain rearrangement on stomach biopsies with a 5-year median follow-up.[63] The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts for poor response to antibiotic therapy, for Helicobacter pylori–negative testing, and for poor response to oral alkylator chemotherapy.[64-66] Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression.[61,62] Patients who progress are treated with radiation therapy,[67-70] rituximab,[71] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[72] chemotherapy,[54] or combined modality therapy.[73] The use of endoscopic ultrasonography may help clinicians to follow responses in these patients.[74] Three small case series (two retrospective and one prospective) reported durable complete remissions after treatment of Helicobacter pylori in patients with aggressive lymphoma (complete remission rate of 35%–88% and a median duration of 21–60 months).[75-77]

Localized involvement of other sites can be treated with radiation or surgery.[68-70,78] Patients with extragastric MALT lymphoma have a higher relapse rate than patients with gastric MALT lymphoma in some series, with relapses many years and even decades later.[79] Many of these recurrences involve different MALT sites than the original location. When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[55,80] For patients with ocular adnexal MALT, antibiotic therapy using doxycycline targeting Chlamydia psittaci resulted in durable remissions for half of the patients in a small series of 27 patients.[81][Level of evidence: 3iiiDiv] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[82]

Patients with nodal marginal zone lymphoma (monocytoid B-cell lymphoma) are treated with the same paradigm of watchful waiting or therapies as described for follicular lymphoma. Among patients with concomitant HCV infection, the majority attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[48][Level of evidence: 3iiiDiv]

The disease variously known as Mediterranean abdominal lymphoma, heavy chain disease, or immunoproliferative small intestinal disease (IPSID), which occurs in young adults in eastern Mediterranean countries, is another version of MALT lymphoma, which responds to antibiotics in its early stages.[83] Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.[84]

Splenic marginal zone lymphoma

Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy.[85-87] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[57,88] Management is similar to that of other low-grade lymphomas and usually involves rituximab alone or rituximab in combination with purine analogs or alkylating agent chemotherapy.[89] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[86,87,89] Among small numbers of patients with splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes) and infection with HCV, the majority attained a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[48,90,91][Level of evidence: 3iiiDiv] In contrast, no responses to interferon were seen in six HCV-negative patients.

Primary cutaneous anaplastic large cell lymphoma

Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no pre-existing lymphoproliferative disease and no extracutaneous sites of involvement.[92,93] Patients with this type of lymphoma encompass a spectrum ranging from clinically benign lymphomatoid papulosis, marked by localized nodules that may regress spontaneously, to a progressive and systemic disease requiring aggressive doxorubicin-based combination chemotherapy. This spectrum has been called the primary cutaneous CD30-positive T-cell lymphoproliferative disorder. Patients with localized disease usually undergo radiation therapy. With more disseminated involvement, watchful waiting or doxorubicin-based combination chemotherapy is applied.[92,93]

(Refer to the PDQ summaries on Chronic Lymphocytic Leukemia Treatment; Mycosis Fungoides/Sézary Syndrome Treatment; Hairy Cell Leukemia Treatment; and Adult Hodgkin Lymphoma Treatment for more information.)

Diffuse large cell lymphoma

Diffuse large B-cell lymphoma is the most common of the non-Hodgkin lymphomas and comprises 30% of newly diagnosed cases.[7] Most patients present with rapidly enlarging masses, often with symptoms both locally and systemically (designated B symptoms with fever, recurrent night sweats, or weight loss). (Refer to the PDQ summary on Fever, Sweats, and Hot Flashes and for more information on weight loss, refer to the Nutrition in Cancer Care summary.) The vast majority of patients with localized disease are curable with combined modality therapy or combination chemotherapy alone.[94] For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.[95-97]

An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[98]

1. Age (≤60 years of age vs. >60 years of age).
2. Serum lactate dehydrogenase (LDH) (normal vs. elevated).
3. Performance status (0 or 1 vs. 2–4).
4. Stage (stage I or stage II vs. stage III or stage IV).
5. Extranodal site involvement (0 or 1 vs. 2–4).

Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, CNS, liver, lung, and spleen. Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[99] Patients at high risk of relapse may be considered for clinical trials.[100] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[101-104]

CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved, and patient morbidity is decreased.[105] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not.[106] A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence. Patients with both risk factors have a 17% probability of CNS recurrence at 1 year after diagnosis (95% confidence interval [CI], 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[107][Level of evidence: 3iiiDiii] Some cases of large B-cell lymphoma have a prominent background of reactive T-cells and often of histiocytes, so-called T-cell/histocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has frequent liver, spleen, and bone marrow involvement; however, the outcome is equivalent to that of similarly staged patients with diffuse large B-cell lymphoma.[108-110] Some patients with diffuse large B-cell lymphoma at diagnosis have a concomitant indolent small B-cell component; while OS appears similar after multidrug chemotherapy, there is a higher risk of indolent relapses.[111]

Mediastinal large B-cell lymphoma (primary mediastinal large B-cell lymphoma)

Primary mediastinal (thymic) large B-cell lymphoma is a subset of diffuse large cell lymphoma characterized by significant fibrosis on histology.[112-118] Patients are usually female and young (median age 30–40 years). Patients present with a locally invasive anterior mediastinal mass that may cause respiratory symptoms or superior vena cava syndrome. Therapy and prognosis are the same as for other comparably staged patients with diffuse large cell lymphoma, except for advanced-stage patients with a pleural effusion, who have an extremely poor prognoses (progression-free survival is less than 20%) whether the effusion is cytologically positive or negative. (For information on superior vena cava syndrome and pleural effusion, refer to the Cardiopulmonary Syndromes summary.) High-dose chemotherapy with hematopoietic stem cell rescue has been applied to these poor prognosis patients. Evidence for this approach is anecdotal.[118]

Follicular large cell lymphoma

The natural history of follicular large cell lymphoma remains controversial.[119] While there is agreement about the significant number of long-term disease-free survivors with early stage disease, the curability of patients with advanced disease (stage III or stage IV) remains uncertain. Some groups report a continuous relapse rate similar to the other follicular lymphomas (a pattern of indolent lymphoma).[120] Other investigators report a plateau in freedom-from-progression at levels expected for an aggressive lymphoma (40% at 10 years).[121,122] This discrepancy may be caused by variations in histologic classification between institutions and the rarity of patients with follicular large cell lymphoma. A retrospective review of 252 patients, all treated with anthracycline-containing combination chemotherapy, showed that patients with more than 50% diffuse components on biopsy had a worse OS than other patients with follicular large cell lymphoma.[123] Treatment of these patients is more similar to treatment of aggressive NHL than it is to the treatment of indolent NHL. In support of this approach, treatment with high-dose chemotherapy and autologous hematopoietic peripheral stem cell transplantation shows the same curative potential in patients with follicular large cell lymphoma who relapse as it does in patients with diffuse large cell lymphoma who relapse.[124][Level of evidence: 3iiiA]

Anaplastic large cell lymphoma

Anaplastic large cell lymphomas (ALCL) may be confused with carcinomas and are associated with the Ki-1 (CD30) antigen. These lymphomas are usually of T-cell origin, often present with extranodal disease, and are found especially in the skin. The translocation of chromosomes 2 and 5 creates a unique fusion protein with a nucleophosmin-ALK.[125] Patients whose lymphomas express ALK (immunohistochemistry) are usually younger and may have systemic symptoms, extranodal disease, and advanced stage disease; however, they have a more favorable survival rate than that of ALK-negative patients.[126] Patients with these types of lymphomas are generally treated the same as patients with diffuse large cell lymphomas and have as good a prognosis as comparably staged patients, as evidenced in the NHL-BFM-90 trial. Anaplastic large cell lymphoma in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy.[127]

Extranodal NK-/T-cell lymphoma

Extranodal NK-/T-cell lymphoma (nasal type) is an aggressive lymphoma marked by extensive necrosis and angioinvasion, most often presenting in extranodal sites, in particular the nasal or paranasal sinus region.[128-133] Other extranodal sites include the palate, trachea, skin, and gastrointestinal tract. Hemophagocytic syndrome may occur; historically these tumors were considered part of lethal midline granuloma.[134] In most cases, Epstein-Barr virus (EBV) genomes are detectable in the tumor cells and immunophenotyping shows CD56 positivity. Cases with blood and marrow involvement are considered NK-cell leukemia. In addition to doxorubicin-based combination chemotherapy, the increased risk of CNS involvement and of local recurrence has led to recommendations for radiation therapy locally, often prior to the start of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy.[129,133,135-138] The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced stage disease, has led some investigators to recommend bone marrow or peripheral stem cell transplantation consolidation.[130-132] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.[139]

Lymphomatoid granulomatosis

Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[140,141] The histology shows association with angioinvasion and vasculitis, usually manifesting as pulmonary lesions or paranasal sinus involvement. Patients are managed like others with diffuse large cell lymphoma and require doxorubicin-based combination chemotherapy.

Angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma.[142-144] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coomb test, and polyclonal hypergammaglobulinemia.[134] (For information on night sweats, weight loss, and skin rash, refer to the PDQ summaries on Fever, Sweats, and Hot Flashes, Nutrition in Cancer Care, and Pruritus, respectively.) Opportunistic infections are frequent because of an underlying immune deficiency. Doxorubicin-based combination chemotherapy is recommended as it is for other aggressive lymphomas.[142] Myeloablative chemotherapy and radiation therapy with autologous peripheral stem cell support has been described in anecdotal reports.[145] Occasional spontaneous remissions and protracted responses to steroids only have been reported. B-cell EBV genomes are detected in most affected patients.[146]

Peripheral T-cell lymphoma

Patients with peripheral T-cell lymphoma have diffuse large cell or diffuse mixed lymphoma that expresses a cell surface phenotype of a postthymic (or peripheral) T-cell expressing CD4 or CD8 but not both together.[147] Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[134] This includes the so-called Lennert lymphoma, a T-cell lymphoma admixed with a preponderance of lymphoepithelioid cells. Most investigators report worse response and survival rates for patients with peripheral T-cell lymphomas than for patients with comparably staged B-cell aggressive lymphomas.[148-150] Therapy involves doxorubicin-based combination chemotherapy, which is also used for B-cell diffuse large cell lymphoma. Most patients present with multiple adverse prognostic factors (i.e., older age, stage IV, multiple extranodal sites, and elevated LDH), and these patients have a low (<20%) failure-free survival and OS at 5 years.[150] High-dose chemotherapy with hematopoietic stem cell support has been applied to patients with advanced-stage peripheral T-cell lymphoma. Evidence for this approach is anecdotal.[145,151] Anecdotal responses have also been seen with alemtuzumab, an anti-CD52 monoclonal antibody, or denileukin difitox, a toxin-antibody ligand, after relapse from previous chemotherapy.[152,153] An unusual type of peripheral T-cell lymphoma occurring mostly in young men, hepatosplenic T-cell lymphoma, appears to be localized to the hepatic and splenic sinusoids, with cell surface expression of the T-cell receptor gamma/delta.[154-158] Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome.[159-162] These patients have cells that express alpha/beta phenotype. Those with gamma-delta phenotype have a more aggressive clinical course and are classified as cutaneous gamma-delta T-cell lymphoma.[163-165] These patients may manifest involvement of the epidermis, dermis, subcutaneous region, or mucosa. These entities have extremely poor prognoses with an extremely aggressive clinical course and are treated with the same paradigm as for the highest-risk groups with diffuse large B-cell lymphoma.

Enteropathy-type intestinal T-cell lymphoma

Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[134,166,167] Since a gluten-free diet prevents the development of lymphoma, patients diagnosed with celiac sprue in childhood rarely develop lymphoma. The diagnosis of celiac disease is usually made by finding villous atrophy in the resected intestine. Surgery is often required for diagnosis and to avoid perforation during therapy. Therapy is with doxorubicin-based combination chemotherapy, but relapse rates appear higher than for comparably staged diffuse large cell lymphoma.[167,168] Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae; patients often require parenteral nutrition. (For information on parenteral nutrition, refer to the Gastrointestinal Complications summary and the Nutrition in Cancer Care summary.) Multifocal intestinal perforations and visceral abdominal involvement are seen at the time of relapse. High-dose therapy with hematopoietic stem cell rescue has been applied in first remission or at relapse.[167] Evidence for this approach is anecdotal.

Intravascular large B-cell lymphoma (intravascular lymphomatosis)

Intravascular lymphomatosis is characterized by large cell lymphoma confined to the intravascular lumen; with the use of aggressive combination chemotherapy, the prognosis is similar to more conventional presentations.[169,170] The brain, kidneys, lungs, and skin are the organs most likely affected by intravascular lymphomatosis.

Burkitt lymphoma/diffuse small noncleaved-cell lymphoma

Burkitt lymphoma/diffuse small noncleaved-cell lymphoma typically involves younger patients and represents the most common type of pediatric non-Hodgkin lymphoma.[171] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-myc gene on chromosome 8.[172] A subgroup of patients with dual translocation of C-myc and bcl-2 appear to have an extremely poor outcome despite aggressive therapy (5-month OS).[173][Level of evidence: 3iiiA] In some patients with larger B cells, there is morphologic overlap with diffuse large B-cell lymphoma. These Burkitt-like large cell lymphomas show C-myc deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma.[10,174,175] Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing EBV genomes. Sporadic cases usually involve the gastrointestinal system, ovaries, or kidneys. Patients present with rapidly growing masses and a very high lactate dehydrogenase but are potentially curable with intensive doxorubicin-based combination chemotherapy. Treatment of Burkitt lymphoma/diffuse small noncleaved-cell lymphoma involves aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (diffuse large cell).[176-178] Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been described in CALGB-9251, for example, and has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[179-184] Adverse prognostic factors include bulky abdominal disease and high serum LDH. In some institutions, treatment includes the use of consolidative bone marrow transplantation (BMT).[185,186] Patients with Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. Prophylaxis with intrathecal chemotherapy is required as part of induction therapy.[187] (Refer to the PDQ summaries on Primary Central Nervous System Lymphoma Treatment and AIDS-Related Lymphoma Treatment for more information.)

Lymphoblastic lymphoma

Lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It often occurs in young patients but not exclusively.[188] It is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and to the CNS. Treatment is usually patterned after that for acute lymphoblastic leukemia. Intensive combination chemotherapy with or without BMT is the standard treatment of this aggressive histologic type of NHL.[189-191] Radiation therapy is sometimes given to areas of bulky tumor masses. Since these forms of NHL tend to progress so quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

Adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma is caused by infection with the retrovirus human T-cell lymphotropic virus type I and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to chemotherapy.[192,193] (Refer to the PDQ summary on Hypercalcemia for more information.) Using combination chemotherapy, only 10% to 20% of patients survived even 3 years in a trial of 118 patients.[194] The combination of zidovudine and interferon-alpha has activity against adult T-cell leukemia/lymphoma, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in 66% of presenting patients with this combination, but long-term disease-free survival rates are not yet available.[195-197]

Mantle cell lymphoma

Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis).[4,198,199] Mantle cell lymphoma is characterized by CD5-positive follicular mantle B cells, a translocation of chromosomes 11 and 14, and an overexpression of the cyclin D1 protein.[200] Like the low-grade lymphomas, mantle cell lymphoma appears incurable with anthracycline-based chemotherapy and occurs in older patients with generally asymptomatic advanced-stage disease.[201] The median survival, however, is significantly shorter (3–5 years) than that of other lymphomas, and this histology is now considered to be an aggressive lymphoma.[202] A diffuse pattern and the blastoid variant have an aggressive course with shorter survival, while the mantle zone type may have a more indolent course.[49,203] A high cell proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[200,204] It is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity; refractoriness to chemotherapy is a usual feature.[202,205-210] Many investigators are exploring high-dose therapy with stem cell/marrow support or the use of interferon or anti-CD20 antibodies after CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.[207-209,211-218] Thus far, randomized trials have not shown OS benefits from these newer approaches.[218] Bortezomib shows response rates close to 50% in relapsed patients, prompting clinical trials combining this proteasome inhibitor with rituximab and cytotoxic agents in first-line therapy.[219-221][Level of evidence: 3iiiDiv]

Polymorphic posttransplantation lymphoproliferative disorder (PTLD)

Patients who undergo transplantation of the heart, lung, liver, kidney, or pancreas usually require life-long immunosuppression. This may result in PTLD in 1% to 3% of recipients, which appears as an aggressive lymphoma.[222] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[223] Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[224,225] In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[226] When this is unsuccessful or not feasible, a trial of rituximab may be considered, because it has shown durable remissions in approximately 60% of patients and a favorable toxicity profile.[227] Sometimes, a combination of acyclovir and interferon-alpha has been used.[222,228] If these measures fail, doxorubicin-based combination chemotherapy is recommended, though most patients can avoid cytotoxic therapy.[229] Localized presentations can be controlled with surgery or radiation therapy alone. These localized mass lesions, which may grow over a period of months, are often phenotypically polyclonal and tend to occur within weeks or a few months after transplantation.[223] Multifocal, rapidly progressive disease occurs late after transplantation (>1 year) and is usually phenotypically monoclonal and associated with EBV.[230] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[230-232] Instances of EBV-negative PTLD occur late (median, 5 years posttransplant) and have particularly poor prognoses.[233] A sustained clinical response after failure from chemotherapy was attained using an immunotoxin (anti-CD22 B-cell surface antigen antibody linked with ricin, a plant toxin).[234] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[235]

True histiocytic lymphoma

True histiocytic lymphomas are very rare tumors that show histiocytic differentiation and express histiocytic markers in the absence of B-cell or T-cell lineage-specific immunologic markers.[236,237] Care must be taken with immunophenotypic tests to exclude anaplastic large cell lymphoma or hemophagocytic syndromes caused by viral infections, especially EBV. Therapy is modeled after the treatment of comparably staged diffuse large cell lymphomas, but the optimal approach remains to be defined.

Primary effusion lymphoma

Primary effusion lymphoma presents exclusively or mainly in the pleural, pericardial, or abdominal cavities in the absence of an identifiable tumor mass.[238] Patients are usually HIV-seropositive, and the tumor usually contains Kaposi sarcoma-associated herpes virus/human herpes virus 8. Therapy is usually modeled after the treatment of comparably staged diffuse large cell lymphomas, but the prognosis is extremely poor.

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