Diffuse large B-cell lymphoma - Clinical review

An overview for GPs of the diagnosis, management and prognosis of this type of non-Hodgkin lymphoma.

Most patients will be treated with R-CHOP chemotherapy first line
Most patients will be treated with R-CHOP chemotherapy first line

Section 1: Epidemiology and aetiology

Diffuse large B-cell lymphoma (DLBCL) is the most common type of high-grade non-Hodgkin lymphoma (NHL). About 5,000 cases are diagnosed every year in the UK.1

DLBCL is slightly more common in males than in females and much more frequent in older patients.

Haematological Malignancy Research Network data show that 63% of cases are patients aged over 65 years.

Risk factors
For most patients with DLBCL, the aetiology is unclear. However, certain risk factors are associated with the development of NHL, including increasing age and immunosuppression. HIV infection increases the risk of NHL more than 100-fold. For patients receiving immunosuppressive drugs after solid organ transplantation, the risk of NHL increases 30- to 50-fold.

Lymphoma is classified as Hodgkin or non-Hodgkin type. NHL encompasses a heterogenous group of lymphoid malignancies, subclassified according to whether they exhibit an aggressive or an indolent clinical course and whether they have originated in Tor B-lymphocytes.2

DLBCL is the most common type of NHL, accounting for about one-third of cases in the UK.3 DLBCL is classified as high-grade or aggressive, but more than 60% of patients will be cured following first-line chemotherapy.

This is in contrast to low-grade or indolent NHLs, which are usually incurable but nevertheless associated with a good prognosis.

The key advance in understanding the biology of DLBCL has been molecular classification according to the malignant B-cell of origin, by gene expression profiling.4-6

There are three main types: activated B-cell (ABC), germinal centre B-cell (GCB) and type III.

GCB-type DLBCL expresses genes characteristic of normal germinal centre B-cells, whereas ABC-type DLBCL expresses a subset of genes that are characteristic of post germinal centre B-cells blocked during plasmacytic differentiation.

Type III is a default category where neither gene set is expressed at a high level.

Section 2: Making the diagnosis

Most patients present with lymphadenopathy +/hepatosplenomegaly, but almost any other organ can be involved. Systemic or 'B' symptoms may be present.

Primary mediastinal B-cell lymphoma, a rare subtype of DLBCL, classically presents with an isolated mediastinal mass in the absence of disease elsewhere.

This very aggressive subtype may be associated with superior vena cava obstruction (SVCO), a medical emergency. Possible symptoms of SVCO include dyspnoea, cough, chest pain or dysphagia. Signs include facial/arm oedema or venous distension in the neck or chest wall.

Initial investigations should include routine bloods, such as FBC, renal and liver profiles, lactate dehydrogenase (LDH) level and a chest X-ray for any mediastinal masses.

Staging and biopsy
Initial staging consists of a contrast enhanced CT scan of thorax, abdomen and pelvis. An FDG-PET scan is routinely performed at baseline.

All patients undergo a bone marrow aspirate and biopsy, to look for bone marrow involvement.

Patients are staged according to the Ann Arbor staging system (see table 1). Once the stage has been determined, note is made of any 'B' symptoms. For example, if a patient has lymphoma on both sides of the diaphragm and 'B' symptoms are present, they are classified as stage IIIB.

A biopsy is essential for the diagnosis of lymphoma. An excisional lymph node biopsy is preferred where possible. However, if the lymph node is not easily accessible, a core biopsy of a lymph node mass or involved organ is used to make the diagnosis.

Section 3: Managing the condition

Management of DLBCL depends on the stage of disease at diagnosis.

In addition, comorbidities, especially cardiac dysfunction, need to be taken into consideration.

Older patients or those with a history of cardiac disease should undergo an echocardiogram to assess left ventricular function.

Most patients will be treated with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) chemotherapy as the first line, but the number of cycles administered depends on the extent of disease.

Stage I (non-bulky)

For patients with stage I non-bulky disease, the standard of care is three cycles of R-CHOP followed by involved field radiotherapy.

Stage I (bulky)-IV

For patients with stage I (bulky)-IV disease, the standard of care is six cycles of R-CHOP administered every 21 days.

In the pre-rituximab era, the results of the NHL-B2 trial showed that CHOP-14 (administered every 14 days) was superior to CHOP-21 in elderly patients with DLBCL.7 Concurrently it was found that the addition of the anti-CD20 monoclonal antibody rituximab improved cure rates by 10-15%.8-10

A phase III randomised trial investigated whether the survival benefit from dose intensification with R-CHOP-14 (administered every 14 days) versus R-CHOP-21 (administered every 21 days) persisted in the presence of rituximab in patients of all age groups with untreated DLBCL.11

In this study, R-CHOP-14 was not superior to R-CHOP-21, which remains the standard of care.

New developments

Most patients (approximately 60%) will be cured following first-line R-CHOP, but the remainder will relapse or have refractory disease.

Improved understanding of disease biology in terms of malignant B-cell of origin has partly explained why some patients are not cured following initial chemotherapy.

In the Lymphoma/Leukaemia Molecular Profiling Project (2002), the ABC subtype, which makes up approximately 30% of DLBCL, was associated with much poorer outcomes compared to either GCB-type or type III DLBCL6 and this holds true in the rituximab era.4

ABC-type DLBCL is associated with constitutive overactivation of the NF-kappaB pathway,12 which appears to suppress the apoptotic effect of cytotoxic chemotherapy13 and may contribute to the observed differences in outcome between DLBCL subtypes.

Bortezomib is a proteosome inhibitor, which acts by inhibiting the NF-kappaB pathway.14 A current trial is investigating the benefit of the addition of bortezomib to R-CHOP in first-line treatment across all molecular subtypes of DLBCL.

Section 4: Prognosis

The International Prognostic Index (IPI)15 is the most commonly used prognostication tool in patients with DLBCL.

The IPI combines five high-risk features (age >60 years, elevated LDH, performance status 2 or higher, stage III/IV and more than one site of extranodal disease), which can be used to risk-stratify patients.

Although more than 60% of patients with DLBCL will be cured following R-CHOP, a significant proportion will have relapsed or refractory disease. Unfortunately, for those patients undergoing second-line treatment, the outcome is much poorer, with three-year overall survival rates of <50% quoted in the landmark CORAL study.16

If the patient is in remission on completion of first-line R-CHOP, regular outpatient follow-up is recommended for five years.

Section 5: Case study

A 61-year-old, previously healthy woman presented with a four-month history of severe back pain, but no history of weight loss, sweats or fever.

An MRI of the spine showed a paravertebral mass. A core biopsy of the paravertebral mass was consistent with NHL, diffuse large B-cell subtype.

A staging CT of the thorax, abdomen and pelvis showed mesenteric and external iliac lymphadenopathy. A bone marrow biopsy was negative for involvement by lymphoma and baseline FDG-PET confirmed stage II disease.

In the absence of 'B' symptoms, the patient was classified as stage IIA and commenced treatment with six cycles of R-CHOP chemotherapy administered every 21 days.

Restaging CT scans were performed after every two cycles of R-CHOP and the patient had an initial partial response.

Restaging CT at the end of treatment showed persistence of the paravertebral mass and external iliac lymphadenopathy, however, and this was FDG-avid on PET.

The patient commenced second-line chemotherapy with rituximab, gemcitabine, cisplatin and methylprednisolone (R-GEM-P), to which she had a complete response after two cycles. She underwent stem cell harvesting and will proceed to an autologous stem cell transplant following a third cycle of salvage chemotherapy.

Section 6: Evidence base

Clinical trials

  • Pfreundschuh M, Trumper L, Kloess M et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634-41.
  • Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 2002; 346:235-42.
  • Coiffier B, Thieblemont C, van den Neste E et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010; 116: 2040-5.
  • Habermann TM, Weller EA, Morrison VA et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006; 24: 3121-7.
  • Cunningham D, Hawkes EA, Jacks A et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 2013; 381(9880): 1817-26.
  • Gisselbrecht C, Glass B, Mounier M et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. JCO 2010; 28(27): 4184-90.



These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Review patients with HIV and ensure six-monthly FBC, renal profile and LDH levels are undertaken to pick up lymphoma early.
  • Discuss the diagnosis of lymphoma and agree a protocol for investigating patients with night sweats and rapid weight loss.
  • Raise awareness of lymphoma by designing a poster summarising its symptoms, to increase early presentation to the GP.

Click here to take a test on this article and claim a certificate on MIMS Learning


1. Cancer Research UK.

2. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 2008.

3. Armitage JO, Weisenburger DD. J Clin Oncol 1998; 16: 2780-95.

4. Lenz G, Wright GW, Emre NC et al. Proc Natl Acad Sci USA 2008; 105: 13520-5.

5. Barrans SL, Crouch S, Care MA et al. Br J Haematol 2012; 159: 441-53.

6. Rosenwald A, Wright G, Chan WC et al. N Engl J Med 2002; 346: 1937-47.

7. Pfreundschuh M, Trumper L, Kloess M et al. Blood 2004; 104: 634-41.

8. Coiffier B, Lepage E, Briere J et al. N Engl J Med 2002; 346: 235-42.

9. Coiffier B, Thieblemont C, van den Neste E et al. Blood 2010; 116: 2040-5.

10. Habermann TM, Weller EA, Morrison VA et al. J Clin Oncol 2006; 24: 3121-7.

11. Cunningham D, Hawkes EA, Jacks A et al. Lancet 2013; 381: 1817-26.

12. Davis RE, Brown KD, Siebenlist U et al. J Exp Med 2001; 194: 1861-74.

13. Packham G. Br J Haematol 2008; 143: 3-15.

14. Nencioni A, Grunebach F, Patrone F et al. Leukemia 2007; 21: 30-36.

15. N Engl J Med 1993; 329: 987-94.

16. Gisselbrecht C, Glass B, Mounier M et al. JCO 2010; 28(27): 4184-90.

  • Contributed by Dr Mary Gleeson, clinical research fellow, and Professor David Cunningham, consultant medical oncologist, The Royal Marsden Hospital (NHS and Private), London

Have you registered with us yet?

Register now to enjoy more articles and free email bulletins


Already registered?

Sign in