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 lymphomas^2,5. Age range is broad, including children, but with a peak in the 7^th 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

CD5	10% of cases0, 9/209 (by tissue microarray)5, 0/2513
CD10	27%2 to 41%1 of cases, 68/213 (by tissue microarray)5, 14/34 (cut off of 10% of cells positive)11, 5/2513
CD19†	positive0
CD20	positive0, 202/208 (by tissue microarray)5, 25/2513
CD22	positive0
CD23	22/213 (by tissue microarray)5
CD30	almost all anaplastic cases and some others0, 17/213 (by tissue microarray)5
CD44s	63/80 (by tissue microarray)5
CD44 6v	26/80 (by tissue microarray)5
CD44 9v	18/80 (by tissue microarray)5
CD45	usually positive, negative in 30% of anaplastic and immunoblastic variants5
CD79a	positive0 , 73/110 (by tissue microarray)5, 25/2513
CD138	minority of cases0
surface Ig	50-75% of cases (IgM > IgG > IgA)0
cytoplasmic Ig	in cases showing plasmacytic differentiation0
bcl-2	20-50% of cases (bcl-2 expression is less frequent in gastric than in nodal and non-gastric extranodal high-grade B-cell lymphoma.)6, 126/213 (by tissue microarray)5, 24/34 (cut off of 10% of cells positive)11, 19/2513
bcl-6	20-40% of cases, 95/212 (by tissue microarray)5, 29/34 (cut off of 10% of cells positive)11, 24/2513
bcl-10	positive in 50% of extranodal cases5
cyclin D1	negative0
MUM-1	17/2513
p53	minority of cases0, 12/34 (cut off of 10% of cells positive)11
Ki67	proliferation fraction usually high (>40% and may be >90%)0
ALK	2/123 (by tissue microarray)5

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

		germinal centre type	non-germinal centre type
	Mum-1	0/813	17/1713
	CD10	5/813	0/1713

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 controversial^5,8,9,10, 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.

• 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.

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

This page last revised 19.11.2005.

©SMUHT/PW Bishop