AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

In 1956, Rappaport initially described a subset of non-Hodgkin lymphoma (NHL) that was characterized by a mixed population of diffusely infiltrating malignant histiocytes and lymphocytes and referred to them as mixed histiocytic-lymphocytic malignant lymphomas. These malignant histiocytes were later identified as lymphocytes; thus, the term malignant lymphoma, mixed small and large cell, was adopted. Histologically, these lymphomas contain an equal number of small and large cells (30-70%).

In the Working Formulation classification system proposed by a National Cancer Institute working group in 1982, these lymphomas were classified as an intermediate-grade NHL, representing 3-11% of all NHLs.

With the development of immunophenotypic and molecular diagnostics, the Revised European-American Lymphoma (REAL) classification was subsequently proposed and then modified by the World Health Organization (WHO) in 2001. Diffuse mixed lymphoma is now classified as diffuse large B-cell lymphoma. Clinically, patients with this type of lymphoma usually present with advanced and, often, extranodal disease.

Pathophysiology

Diffuse mixed lymphomas are more or less composed of equal numbers of small and large cells. The small cells are usually slightly larger than normal lymphocytes and have a cleaved or indented nucleus and coarse chromatin. The large cells can be cleaved or noncleaved. The cytoplasm of these cells is pale, and the cells have an irregular, central, indented nucleus with inconspicuous nucleoli. A subset of the large cells has rounded nuclei with one or more nucleoli; these are the noncleaved large cells and are somewhat larger compared to the cleaved cells.

Similar to all other intermediate-grade lymphomas, the mixed small and large cell NHLs most often manifest as primary nodal disease, although involvement of the spleen and other organs is common.

Frequency

International

Diffuse large B-cell lymphomas comprise approximately 30% of all NHLs.

Mortality/Morbidity

Based on the International Prognostic Index (IPI), patients can be grouped into the prognostic categories of low risk (category 0 or 1), low-intermediate risk (category 2), high-intermediate risk (category 3), and high risk (category 4 or 5). The 5 factors rated in the IPI are age, lactate dehydrogenase (LDH), stage, performance status, and number of extranodal sites.

• For intermediate and aggressive lymphomas, the complete remission (CR) rate for low-risk patients is 87% and the 5-year overall survival (OS) rate is 73%.
• The CR rate for high-risk patients is 44% and the 5-year OS rate is 26%

Sex

This condition affects females more often than males.

Age

Most patients are diagnosed during the seventh or eighth decade of life, with a median age of 63 years.

CLINICAL

Section 3 of 11  

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• Follow-up
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History

Patients usually present with lymphadenopathy, most commonly affecting either the cervical or inguinal region. Other common complaints from the history findings may include the following:

• B symptoms (eg, fever, night sweats, >10% weight loss)
• Anorexia
• Pedal edema (caused by pelvic lymphadenopathy)
• Fatigue
• Chest discomfort or shortness of breath (caused by mediastinal lymphadenopathy)

Physical

Common findings upon physical examination are as follows:

• Lymphadenopathy (ie, cervical, axillary, inguinal)
• Splenomegaly
• Low-grade fever
• Pedal edema, resulting from extensive pelvic lymphadenopathy

Causes

A number of risk factors have been associated with NHLs in general. These include Epstein-Barr virus, HIV, pesticides, hair dyes, primary and transplant-related immunodeficiency, and rheumatoid arthritis and other autoimmune disorders. Occupational factors have a weak or an inconsistent risk.

DIFFERENTIALS

Section 4 of 11  

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WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• CBC: Involvement of the bone marrow may result in anemia, thrombocytopenia, and/or leukopenia.
• Serum electrolyte levels: Electrolyte abnormalities may occur from renal involvement with lymphoma. Abnormal renal function may require a chemotherapy dose adjustment.
• Lactate dehydrogenase: An elevated level of LDH corresponds with the tumor burden and the extent of disease. The LDH value is also a useful indicator of the response to treatment and can be used as an early nonspecific indicator of disease relapse and is part of the IPI.
• Uric acid: An elevated level signifies a high tumor burden and an increased likelihood of tumor lysis syndrome with chemotherapy.
• Flow cytometry: Expression of different immunophenotypes helps in determining a clonal cell population and in differentiating between B- or T-cell origins.
• Cytogenetic or fluorescent in situ hybridization (FISH) studies may reveal common chromosomal translocations:
• • t(3q27) (bcl-6) - Occurs in 35% of patients
  • t(14;18)(q32;q21) (bcl-2) - Occurs in 15-20% of patients
  • t(8;14)(q24;q32) - Occurs in fewer than 5% of patients
• Gene expression profiling may be able to distinguish 2 separate subtypes of diffuse B-cell lymphoma with different prognoses (normal germinal center B-cell pattern vs activated B-cell–like).
• Results from gene rearrangement studies can be used to establish clonality.

Imaging Studies

• CT scans (neck, chest, abdomen, pelvis)
• • These studies are used to help identify the degree of lymphadenopathy, the presence or absence of extranodal disease, and/or the presence of visceral involvement. CT scans are also part of the complete staging workup.
  • Baseline CT scan findings aid in disease follow-up care after chemotherapy to assess the degree of response to therapy, as well as an aid in planning consolidating radiation therapy, if used.
• Findings from gallium scans provide an estimate of the extent of disease and are sometimes used as a means of assessing sites of relapse.
• Findings from positron emission tomography (PET) scanning for glucose uptake can indicate areas of increased metabolic activity and can be useful to help determine whether residual masses represent scars or persistent lymphoma, in addition to their frequent use in initial disease staging. PET scan findings are being investigated as prognostic indicators during treatment (after 2-4 cycles), but the clinical utility of this is still unclear.

Other Tests

• Findings from multiple gated acquisition (MUGA) scans are used to evaluate the ejection fraction before chemotherapy because anthracyclines have a potential cardiotoxic effect.

Procedures

• Perform bone marrow aspiration and biopsy as part of the staging process to help rule out involvement with lymphoma.
• Lymph node biopsy is required to establish a definitive diagnosis of NHL. This should be an excisional biopsy rather than a needle biopsy because nodal architecture is often difficult to assess using small amounts of tissue.

Staging

These lymphomas are staged according to the commonly used Ann Arbor staging system.

• Stage I - Involvement of a single lymph node region or lymphoid structure (ie, spleen, thymus, Waldeyer ring) or involvement of a single extralymphatic site (IE)
• Stage II - Involvement of 2 or more lymph node regions on the same side of the diaphragm; localized contiguous involvement of only 1 extranodal site and 1 lymph node region on the same side of the diaphragm
• Stage III - Involvement of lymph node regions on both sides of the diaphragm
• Stage IV - Diffuse or disseminated involvement of 1 or more extranodal organs or tissues, with or without associated lymph node involvement.

TREATMENT

Section 6 of 11  

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Medical Care

• Diagnosis is usually confirmed after obtaining positive findings from a lymph node biopsy specimen. Pathology findings should be reviewed by an expert hematopathologist because lymphomas can be difficult to classify.
• Most patients are treated in an outpatient setting.
• Patients with a high tumor burden may need to be admitted to the hospital for prevention of tumor lysis syndrome to receive prophylaxis with allopurinol and alkaline hydration.
• Combination chemoimmunotherapy is the standard of care for all stages of diffuse, mixed-cell NHL, with abbreviated chemotherapy and local irradiation as an option for early-stage disease.

Surgical Care

• Because multiple chemotherapy cycles are usually administered, an implanted venous access device is helpful for chemotherapy infusions and for the repeated blood samples required to monitor treatment toxicity.

Consultations

• Consult a surgeon to obtain a lymph node or tissue biopsy sample and for subcutaneous venous access.
• Consultation with a radiation oncologist may be sought in early-stage disease.

Diet

• A regular diet is recommended; however, a neutropenic diet is suggested during periods of neutropenia.

Activity

• No activity limitations are recommended; however, the lymphoma, its treatment, or both may result in substantial fatigue.

MEDICATION

Section 7 of 11  

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For early-stage disease (I and II nonbulky), combined-modality therapy, usually incorporating 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (CHOP/R) with involved-field radiation, has been used. The addition of rituximab, an anti-CD20 antibody, has proved very beneficial in lymphoma treatment. Recent studies have suggested that 4 cycles of CHOP may be at least as good as CHOP plus radiotherapy (RT) in patients older than 60 years. For advanced-stage disease (II bulky, III, and IV), systemic chemotherapy with the CHOP/R regimen is the standard of care. This combination has been shown to be superior to CHOP alone.

The CHOP/R regimen is administered every 21 days and consists of 750 mg/m²L IV of cyclophosphamide (Cytoxan) on day 1, 50 mg/m² IV of doxorubicin (Adriamycin) on day 1, 2 mg IV of vincristine on day 1, 375 mg/m² IV of rituximab on day 1, and 100 mg PO of prednisone on days 1-5. This combination is moderately emetogenic and should be accompanied by aggressive antiemetics.

The following regimens have also been used for the treatment of intermediate-grade NHL and may be used as salvage therapy in cases of relapse.

• The DHAP chemotherapy regimen
  • Dexamethasone (40 mg PO/IV on days 1-4)
  • Cisplatin (100 mg/m²/d via continuous infusion on day 1)
  • Cytarabine (2000 mg/m² IV q12h for 2 doses on day 2)
• The ESHAP chemotherapy regimen
  • Etoposide (40 mg/m² IV on days 1-4)
  • Methylprednisolone (500 mg IV on days 1-4)
  • Cisplatin (25 mg/m² via continuous infusion on days 1-4)
  • Cytarabine (2000 mg/m² IV on day 5)
  • ICE (ifosfamide, carboplatin, etoposide)

Other regimens are now only considered for patients who relapse and are not candidates for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT).

• ICE - Ifosfamide, carboplatin, etoposide
• ProMACE-MOPP - Prednisone, methotrexate, leucovorin calcium, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone
• MACOP-B - Methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone, leucovorin calcium, trimethoprim/sulfamethoxazole DS, ketoconazole
• ProMACE-CytaBOM - Prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin calcium, concomitant trimethoprim/sulfamethoxazole DS

Patients who relapse and who have chemoresponsive disease, as evaluated after salvage therapy, should be considered for HDC followed by stem cell rescue. The Parma trial unequivocally established the superiority of HDC and ASCT over conventional salvage treatments. In this trial, patients younger than 60 years with NHL ranging from intermediate grade to high grade who were in first or second relapse were given 2 doses of the DHAP chemotherapy regimen. Those patients with responsive disease were then randomly selected to receive either 4 courses of conventional chemotherapy or HDC plus ASCT. At 8-year follow-up, the reported OS rate was 47% versus 27% (P=.042) and the event-free survival rate was 36% compared with 11% (P=.002) in the HDC and DHAP arms, respectively. How these results can be applied in the current era, where initial treatment almost always incorporates rituximab, is unclear.

The Groupe d' Etudes des Lymphomes de l' Adults studied the role of HDC and ASCT in early or late intensification. The OS rate in the late intensification arm was 44% versus 22% in the early intensification group, thus suggesting that HDC plus ASCT should not be considered in patients with untested relapse.

Current recommendations are to consider HDC and ASCT for patients in their first relapse, after chemoresponsiveness is established with a second-line salvage therapy. The role of HDC plus ASCT in first CR for patients who have a slow initial response to first-line chemotherapy, those with poor initial prognostic factors, or as upfront therapy has not been clearly defined and remains controversial. Recently, a German trial explored the safety and feasibility of dose-escalated CHOP-etoposide with 3 autologous stem cell transplants as aggressive up-front therapy in young patients with high LDH. They found it safe and feasible, but its role is unclear. Rituximab was not used, and whether these intensive regimens are better than less intense chemotherapy plus rituximab is currently under investigation.

Antisense therapy, ie, Bcl-2 antisense therapy, has now entered clinical trials. It is currently under investigation and has shown promising results; however, its role outside a clinical trial is not yet established.

The addition of bortezomib, a protease inhibitor approved for treatment of myeloma, to CHOP/R is also being investigated in phase I and II trials.

Multicenter trials of radioimmunotherapy with ibritumomab tiuxetan (Yttrium-90 Zevalin) and I-131 tositumomab (Bexxar), CD20-targeting radiolabeled antibodies approved for use in follicular lymphomas, are also ongoing.

Drug Category: Antineoplastic agents

Chemotherapy remains the mainstay of treatment. Many different regimens are used, but, to date, no single regimen has been shown to be superior to the standard CHOP/R regimen.

Drug Category: Antiemetic agents

Used as supportive medication for prevention of chemotherapy-induced nausea and vomiting.

Palonosetron (Aloxi) is a selective 5-HT3 receptor antagonist with a long half-life (40 h). The adult dose is 0.25 mg IV once (30 min before chemotherapy). Administer IV over 30 seconds, and do not repeat dose within 7 days. May cause headache, constipation, diarrhea, or dizziness.

Drug Category: Growth factors

Stimulate blood cell production. Endogenous erythropoietin stimulates red blood cell hematopoiesis. Recombinant human erythropoietin (epoetin alfa) stimulated erythropoiesis in anemic conditions. Colony-stimulating factors act on hematopoietic cells to stimulate hematopoietic progenitor cells proliferation and differentiation. Interleukins stimulate stem cell proliferation.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Hospitalization may be necessary for patients with the following disease- or therapy-associated complications:
• • Neutropenic fever: Patients are usually expected to be neutropenic approximately 10-14 days after a dose of chemotherapy and are most susceptible to infections at this point. If febrile, they should be admitted to the hospital and treated with intravenous antibiotics.
  • Anemia and thrombocytopenia: Transfusions (red blood cells or platelets) should be administered as clinically indicated for anemia and thrombocytopenia.

Further Outpatient Care

• Growth factor support: Patients with a previous episode of febrile neutropenia should be treated with growth factor (ie, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor) during subsequent cycles.
• Anemia: Patients with persistently low hemoglobin values due to disease or chemotherapy may require red blood cell transfusions or erythropoietin or darbepoetin alfa (Aranesp) injections.

In/Out Patient Meds

• Antiemetics are administered as required for control of nausea and vomiting.
• • The 5-HT3 antagonists such as granisetron (1 mg PO q12h) or ondansetron (8 mg PO q8h) for severe chemotherapy-induced nausea and vomiting
  • Lorazepam (1 mg PO/SL q4-6h)
  • Metoclopramide (0.5-2 mg/kg PO q3-4h)
  • Prochlorperazine (10 mg PO q4-6h)
• For patients with anemia, consider erythropoietin or epoetin alfa (Procrit) at 40,000-60,000 U subcutaneously once per week, or darbepoetin alfa 300 mcg SC weekly.

Transfer

• Patients who relapse after multiple regimens or who have poor performance status are thus not candidates for further chemotherapy and should be considered for palliative management and hospice care. The following services can be sought in appropriate clinical situations:
• • Pain management service
  • Nursing home
  • Terminal care facility (hospice)
  • Home care with specialized nursing support for pain management
  • Rehabilitative centers

Deterrence/Prevention

• Patients who administer growth factors to themselves should be carefully advised on sterile techniques.
• Fevers during periods of neutropenia should be immediately brought to the attention of the treating physician.

Complications

• Chemotherapy-associated complications
• • Cardiomyopathy (related to anthracycline)
  • Infections (during neutropenia, postchemotherapy)
  • Gonadal dysfunction (sterility related to chemotherapy)
  • Secondary leukemias (exposure to alkylating agents)
  • Alopecia
  • Neuropathy
  • Related to bone marrow transplant

Prognosis

• The 5-year relapse-free survival rate for low-risk patients is 70%, and the 5-year OS rate is 73%. For the high-risk group, the 5-year relapse-free survival rate is 40% and the 5-year OS rate is 26%.
• The IPI uses 5 pretreatment characteristics to identify the various risk groups, which are as follows:
• • Age ( <60 y vs >60 y)
  • Number of extranodal sites of involvement ( <1 vs >1)
  • Tumor stage I or II (localized) versus III or IV (advanced)
  • Patient performance status (0 or 1 vs >2)
  • Serum LDH level (normal vs abnormal)
• Based on the 5 IPI characteristics, patients are classified into 4 categories:
• • High risk: Four or 5 adverse factors
  • High-intermediate risk: Three adverse factors
  • Low-intermediate risk: Two adverse factors
  • Low risk: No or 1 adverse factor

Patient Education

• Patients should be educated about the following:
• • Febrile neutropenia
  • Postchemotherapy thrombocytopenia and the tendency to bleed with minimal trauma
  • Chemotherapy-associated alopecia
  • Avoidance of pregnancy in reproductive-aged women
  • Chemotherapy-induced nausea and vomiting
  • Chemotherapy-associated menstrual dysregulation (females) and the possibility of sexual dysfunction
  • Fatigue
  • Sperm banking and risk of sterility for males
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

MISCELLANEOUS

Section 9 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
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Medical/Legal Pitfalls

• Failure to inform patients about the long-term sequelae of chemotherapeutic agents, which include the following:
• • Infertility
  • Secondary leukemias
  • Myelodysplastic syndrome
  • Possible anaphylactic reactions
  • Serious and potentially fatal infections
• Failure to clearly explain transfusions (both red blood cells and platelets) and associated complications
• Failure to inform patients who require HDC and ASCT that long-term complications of higher doses of chemoradiotherapy and mortality rates as high as 3-5% from the conditioning regimen are possible
• Cardiomyopathy

Special Concerns

• The pathology findings in patients with possible diffuse, mixed cell NHL should be reviewed by an experienced hematopathologist.
• Patients with induction-failure NHL (ie, those with chemosensitive disease who do not achieve CR with primary therapy) or recurrent NHL should be carefully selected for bone marrow transplantation. Only patients with chemosensitive disease should be considered for HDC and ASCT.

MULTIMEDIA

Section 10 of 11  

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• Miscellaneous
• Multimedia
• References

Media file 1:  Diffuse, mixed lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost with a diffuse pattern of involvement.
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Media type:  Photo

Media file 2:  Patient with diffuse mixed cell non-Hodgkin lymphoma with extranodal involvement. Picture shows an enlarged spleen and liver as a result of lymphomatous involvement.
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Media type:  CT

Media file 3:  Patient with diffuse mixed cell non-Hodgkin lymphoma with extranodal involvement. The patient has an enlarged spleen and liver as a result of lymphomatous involvement. Picture shows extensive retroperitoneal lymphadenopathy (same patient as in Image 2).
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Media type:  CT

Media file 4:  Gallium scans performed as part of a staging workup for a patient with diffuse mixed cell non-Hodgkin lymphoma, showing extensive hepatosplenic and multiple sites of nodal involvement with gallium-avid tumor.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Fillet G, Bonnet C, Mounier N. No role for chemoradiotherapy when compared with chemotherapy alone in elderly patients with localized low risk aggressive lymphoma: final results of the LNH93--4 GELA study. Blood. 2005;106:9a.
• Glass B, Kloess M, Bentz M, et al. Dose-escalated CHOP plus etoposide (MegaCHOEP) followed by repeated stem cell transplantation for primary treatment of aggressive high-risk non-Hodgkin lymphoma. Blood. Apr 15 2006;107(8):3058-64.
• International Non-Hodgkin''s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin''s lymphoma. N Engl J Med. Sep 30 1993;329(14):987-94. [Medline].
• Kunkel L, Wong A, Maneatis T, et al. Optimizing the use of rituximab for treatment of B-cell non-Hodgkin''s lymphoma: a benefit-risk update. Semin Oncol. Dec 2000;27(6 Suppl 12):53-61. [Medline].
• Leonard JP, Furman RR, Cheung YK. Phase I/II trial of bortezomib + CHOP-Rituximab in diffuse large B-cell (DLBCL)and mantle cell lymphoma (MCL): Phase I results. Blood. 2005;106:491a.
• Link MP, Donaldson SS, Berard CW, et al. Results of treatment of childhood localized non-Hodgkin''s lymphoma with combination chemotherapy with or without radiotherapy. N Engl J Med. Apr 26 1990;322(17):1169-74. [Medline].
• Pfreundschuch M, Truemper LGD, Gill D. First analysis of the completed Mabthera International (MInT) trial in young patients with low risk diffuse large B-cell lymphoma: Addition of rituximab to a CHOP-like regimen significantly improves outcome of all patients of a very favorable subgroup. Blood. 2004;104:48a.
• Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin''s lymphoma. N Engl J Med. Dec 7 1995;333(23):1540-5. [Medline].
• Philip T, Chauvin F, Armitage J, et al. Parma international protocol: pilot study of DHAP followed by involved- field radiotherapy and BEAC with autologous bone marrow transplantation. Blood. Apr 1 1991;77(7):1587-92. [Medline].
• Rodriguez MA, Cabanillas FC, Velasquez W, et al. Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol. Jul 1995;13(7):1734-41. [Medline].
• Sehn LH, Donaldson J, Chhanabhai M. Introduction of combined CHOP-rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma (DLBC) in British Columbia (BC). Blood. 2003;102:29a.
• Sweetenham JW. Diffuse large B-cell lymphoma: risk stratification and management of relapsed disease. Hematology (Am Soc Hematol Educ Program). 2005;252-9.
• Tondini C, Zanini M, Lombardi F, et al. Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non- Hodgkin''s lymphomas. J Clin Oncol. Apr 1993;11(4):720-5. [Medline].
• Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin''s lymphoma. J Clin Oncol. Jan 15 2001;19(2):389-97. [Medline].
• Vose JM, Zhang MJ, Rowlings PA, et al. Autologous transplantation for diffuse aggressive non-Hodgkin''s lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol. Jan 15 2001;19(2):406-13. [Medline].

Article Last Updated: Aug 16, 2006