Diffuse large B cell lymphoma, DLBCL

Definition

A diffuse proliferation of large neoplastic B lymphoid cells, with nuclear size at least twice that of a small lymphocyte (>20 mm5). This is a heterogeneous group of tumours. Some are of follicle centre cell origin. It is unclear which combination of positivity for CD10, bcl-2, bcl-6 and t(14;18) may indicate derivation from a follicle centre cell, either de novo or by transformation11.

Synonyms

Epidemiology

Constitutes 30-40% of all adult non-Hodgkin lymphomas2,5. Age range is broad, including children, but with a peak in the 7th decade.

Clinical features

At presentation, 40% of cases are extranodal, most commonly involving the gastrointestinal tract but also lung, skin, central nervous system, salivary gland, Waldeyer's ring, bone, testis, soft tissue, female genital tract, kidney or spleen. Many patients have disseminated disease at presentation.

The majority of cases are primary, but DLBCL may also arise by transformation of B-CLL/SLL, lymphoplasmacytic lymphoma, follicular lymphoma, MALT lymphoma, lymphomatoid granulomatosis or NLPHL5. Immunodeficiency is a risk factor.

Macroscopic appearance

At extranodal sites, DLBCL usually forms a distinct tumour mass.

Histopathology

There is diffuse replacement of the nodal architecture, completely, partially or in an interfollicular or (rarely) sinusoidal pattern. Bands of sclerosis may be seen. The tumour cells are large. Mitotic figures are always numerous5.

Variants

• centroblastic is most common. Most commonly, nuclei are oval to round, vesicular and have two to four peripheral nucleoli. Up to 90% of nuclei may be of immunoblastic type. Both the monomorphic and the polymorphic forms under the Kiel classification are included. Some cases have multilobated nuclei.

• immunoblastic; more than 90% of nuclei are of immunoblastic type with a single large central nucleolus and an appreciable amount of appreciable basophilic cytoplasm. The differential includes extramedullary deposition of the plasmablastic variant of plasma cell myeloma. This variant is particularly common in DLBCL secondary to primary immune disorders.

• anaplastic - unrelated to anaplastic large cell lymphoma of cytotoxic T-cell derivation.

• plasmablastic; typically presents in the oral cavity in association with HIV infection. It may also occur as a PTLD in patients who have undergone solid organ transplantation5. VS38c but not CD20 or CD45.

• Multilobated

• diffuse large B-cell lymphoma with expression of full-length ALK This variant may also be plasmablastic5.

• T cell rich B cell lymphoma

• Primary mediastinal (thymic) B cell lymphoma

• Intravascular large B-cell lymphoma

• epithelioid

• with spindle cell features

• with cytoplasmic projections: these may form rosettes resembling a neuroblastoma5.

Immunohistochemistry

DLBCL can be classified as of germinal centre orgin or non-germinal centre type:

The CD5+ DLBCLs appear to be a subset with a uniform phenotype, CD5+/CD10-/CD19+/CD20+/CD21+/CD23-/cyclinD1-, usually of centroblastic morphology and may be more aggressive5.

Cytogenetics

• There is frequently a translocation involving 3q27 and one of the immunoglobulin genes. 3q27 is the site of the bcl-6 gene, although how over-expression of bcl-6 leads to transformation is uncertain7.

• t(14;18) is found in 10% to 40% of DLBCL11. Since overexpression of bcl-2 is found in 24%-66% of DLBCL, amplification of bcl-2 has been suggested as an alternative mechanism.

Differential diagnosis

• CD5+ DLBCL is negative for cyclin D1, differentiating it from the blastoid variant of mantle cell lymphoma, which is cyclin D1 positive.

• plasmablastic variant shows a higher growth fraction and lacks mature monoclonal plasma cells, differentiating it from plasma cell myeloma.

• Kikuchi's lymphadenitis may be mimicked if the number of apoptotic bodies is large. DLBCL is positive for B-cell markers, while Kikuchi's expresses myeloperoxidase and CD68.

• anaplastic variant: anaplastic large cell lymphoma of cytotoxic T-cell derivation At times, the only B-cell marker positive in the anaplastic variant of DLBCL is BSAP5. VHIg and TCR gene analysis may also be needed5.

†: fresh frozen tissue only

Prognosis

DLBCL accounts for about 40% of all lymphomas and prognosis is very variable. It is generally aggressive but potentially curable. About 40% of adult DLBCL patients respond well to therapy and have prolonged survival, the remainder die of the disease12.

 Adverse prognostic indicators include:

• a poor International Prognostic Index based on clinical factors

• a high proliferation rate

• p53 overexpression

• bcl-2 expression

• In general, no distinct prognostic significance has been correlated with any of the histomorphologic variants: in some series, the immunoblastic variant has a worse prognosis than the centroblastic5.

• There is a suggestion that CD5+ cases may be associated with an older age, female predominance, more frequent bone marrow involvement and shorter survival3.

• The association of CD10 positivity with behavior is controversial5,8,9,10, as is the relative prognosis of DLBCL lymphoma of follicle centre cell origin. Markers of germinal centre derivation combined with absence of activation markers may indicate a good prognosis. DLBCL of germinal centre type that shows negativity for both cyclin-D2 and bcl-2 is said to have a good prognosis15.

• Expression of cyclin D3 by more than 50% of the neoplastic cells appears to be an adverse indicator5.

• KIP1 over-expression. This may occur by complexing with cyclin D3, rendering the KIP1 unavailable for complexing with cyclin E - CDK27.

• Disruption of the INK4a regulatory pathway7.

• Gene expression profiling by DNA microarray analysis may be useful: those with a germinal centre gene profile have a better survival. Refractory DLBCL arising from follicular lymphoma has an activated B-cell profile4.

• Expression of BMI1, one of the genes present in the signature of the activated B-cell-like phenotype (ABC) is associated with unfavourable clinical outcome14.

References

0World Health Organization Classification of Tumours, Tumours of the haematopoietic and lymphoid tissues, IARC Press 2001.

1 Kaufmann, O. Flath, B. Spath-Schwalbe, E. Possinger, K. Dietel, M. Immunohistochemical detection of CD10 with monoclonal antibody 56C6 on paraffin sections. Am J Clin Pathol 1999;111:117-22.

2 de Leval, L., Ferry, J. A., Falini, B., Shipp, M., Harris, N. L. Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells? Am J Surg Path 2001;25:1277-1282.

3 Gascoyne, RD. CD5-positive diffuse large B-cell lymphoma: a distinct entity? Advances in Anatomic Pathology 2002;9:269-270.

4 Large B-cell lymphomas can be stratified and outcome predicted by gene expression profiling. Advances in Anatomic Pathology 2002;9:323-4.

5 Pileri, S.A., Dirnhofer, S., Went, P., Ascani, S., Sabattini, E., Marafioti, T., Tzankov, A., Leoncini, L., Falini, B. and Zinzani, P.L. Diffuse large B-cell lymphoma: one or more entities? Present controversies and possible tools for its subclassification. Histopathology 2002;41:482-509.

6 Cogliatti, S.B., Griesser, H., Peng, H., Du, M.Q., Isaacson, P.G., Zimmermann, D.R., Maibach, R.C. and Schmid, U. Significantly different bcl-2 expression profiles in gastric and non- gastric primary extranodal high-grade B-cell lymphomas. J Pathol 2000;192:470-8.

7 Leoncini, L., Lazzi, S., Bellan, C. and Tosi, P. Cell kinetics and cell cycle regulation in lymphomas. J Clin Pathol 2002;55:648-55.

8 Ohshima, K., C. Kawasaki, et al. (2001). "CD10 and Bcl10 expression in diffuse large B-cell lymphoma: CD10 is a marker of improved prognosis." Histopathology 39(2): 156-62.

9 Uherova, P., C. W. Ross, et al. (2001). "The clinical significance of CD10 antigen expression in diffuse large B-cell lymphoma." Am J Clin Pathol 115(4): 582-8.

10 Xu, Y., R. W. McKenna, et al. (2001). "Clinicopathologic analysis of CD10+ and CD10- diffuse large B-cell lymphoma. Identification of a high-risk subset with coexpression of CD10 and bcl-2." Am J Clin Pathol 116(2): 183-90.

11 McCluggage, W. G., M. Catherwood, et al. (2002). "Immunohistochemical expression of CD10 and t(14;18) chromosomal translocation may be indicators of follicle centre cell origin in nodal diffuse large B-cell lymphoma." Histopathology 41(5): 414-20.

12 Alizadeh, A. A., M. B. Eisen, et al. (2000). "Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling." Nature 403(6769): 503-11.

13 Kusumoto S, Kobayashi Y, Sekiguchi N, et al. Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a "non-germinal center phenotype". Am J Surg Pathol 2005; 29:1067-73

14 van Galen JC, Muris JJ, Oudejans JJ, et al. Expression of the polycomb-group gene BMI1 is related to an unfavourable prognosis in primary nodal DLBCL. J Clin Pathol 2007; 60:167-72

15 Amen F, Horncastle D, Elderfield K, et al. Absence of cyclin-D2 and Bcl-2 expression within the germinal centre type of diffuse large B-cell lymphoma identifies a very good prognostic subgroup of patients. Histopathology 2007; 51:70-9

This page last revised 10.8.2007.

©SMUHT/PW Bishop