dpc-arcive

Dermatopathology: Practical & Conceptual

October – December 2010 | Volume 16, No. 4

Nodal diffuse large B-cell lymphoma

Raweily, Essam

Introduction

In parts one to seven in this series we discussed the basic features of lymphoid histology and basic principles of lymphoid pathology. Subsequently we described some of the nodal lymphomas that have a cutaneous counterpart. Despite often identical morphologies, it was demonstrated that the cutaneous counterparts have a different prognosis and often express distinct phenotypic and/or genotypic features. In this contribution, we will discuss principally nodal diffuse large B-cell lymphoma (DLBCL) with few notes about its cutaneous counterpart.

Diffuse large B-cell lymphoma

This term refers to a group of malignant lymphomas characterized by B-cell phenotype, large nuclear size (equal or exceeding the normal macrophage size or double the size of a normal lymphocyte), and a diffuse growth pattern. Usually the growth rate is higher than in indolent lymphomas with a proliferation rate that can vary from 40% to above 90%. Half of the patient present at an early stage of disease (stage I or II).

The term diffuse large B-cell lymphoma appeared as a practical entity lumping a multitude of morphological entities described in previous classifications when it was believed that, provisionally and for practical purposes, such distinction was not necessary for therapeutic and prognostic purposes. It was first used in its current meaning in the REAL and the WHO Classification of Lymphoma 2001. The term large was employed in previous classifications to designate most of the lymphomas included in the term DLBCL, but it also included other entities, e.g., the blastic variant of mantle cell lymphoma, which was later classified separately in the WHO classification.

DLBCL constitute a quarter to a third of non-Hodgkin’s lymphomas with incidence in the elderly, males, and developing countries. [1] Approximately 60% of the cases present in lymph nodes. Extranodal tissue can be involved with the gastrointestinal tract being the most common extranodal site. The bone marrow is involved in 10-30% of cases depending on the method of detection for minimal disease. The cause is mainly unknown but immunodeficiency states are clearly predisposing factors. Most of the latter are associated with EBV infection with a smaller percentage of EBV association in the sporadic cases (10%).

DLBCL may be diagnosed de novo (primary) but also may be seen in a variable period after the diagnosis of an indolent lymphoma (secondary DLBCL or so called blastic or large cell transformation). The latter event can follow a diagnosis of small lymphocytic lymphoma, nodular lymphocyte predominant Hodgkin’s disease, follicular lymphoma, and marginal zone lymphoma.

The typical morphology (centroblastic type) is characterised by a medium to large sized cell with vesicular chromatin pattern and peripheral multiple nucleoli (Fig. 1). The cytoplasm is scant and amphophilic or basophilic. Most cases show a monotonous morphology with a smaller number of reactive T-cells and macrophages. Less commonly, the morphology is polymorphous with a mixture of centroblastic, immunoblastic, and polylobated forms. The two other common morphological variants are the immunoblastic (Fig. 2) and the anaplastic variant which can be morphologically similar to anaplastic large T-cell lymphoma but which is biologically and clinically unrelated to it. Rare morphologic subtypes occur with no current prognostic or therapeutic significance.

Fig 1

DLBCL with the most common morphological pattern (centroblastic morphology). Note the presence of a round to ovoid morphology and multiple nucleoli.

Fig 2

DLBCL with immunoblastic morphology. Note the central location of single nucleolus.

Tumour cells express typical pan B-cell markers such as CD20, CD22, CD79a and CD19. Co-expression of B-cell markers and CD30 can be seen but is of uncertain significance. Co-expression of CD5 characterises one of the immunophenotypic variants without necessarily implying a transformation from a small lymphocytic lymphoma or a mantle cell lymphoma. It is important to differentiate these cases from the blastic variant of mantle cell lymphoma. This could be achieved by demonstrating a positive reaction of Cyclin-D1 in the latter. In some cases, distinction from Burkitt’s lymphoma can be difficult, therefore in some cases the designation of borderline DLBCL/ Burkitt’s lymphoma is used.

Genotypic profiling shows two distinctive gene signatures. One is a germinal centre B-cell like (GBC) pattern which predicts a good prognosis. The second is an activated B-cell like (ABC) pattern which predicts a poor prognosis. Immunohistochemical demonstration of germinal centre markers such as Bcl-6, IRF4/MUM1, and CD10 correlates only partially with the above distinction making it an unreliable feature of classification. However, enlarging the battery of immunohistochemical markers by including additional markers such as Bcl-2 and Cyclin-D2 is getting closer to separate those two groups more accurately.

Primary cutaneous diffuse large B-cell lymphoma (leg type)

This entity characterises patients presenting usually with unilateral or bilateral lower leg mass/masses, although 10-15% of cases present at other sites. The morphology is mainly round centroblastic/immunoblastic and very similar to systemic DLBCL, although an admixture with reactive small T-cells is less often seen (Fig. 3). [2]

Fig 3

Primary cutaneous DLBCL. Notice the absence of epidermotropism and the centroblastic/ immunoblastic morphology, an aggressive form of cutaneous lymphoma.

Using the term leg type B-cell lymphoma was initially met with scepticism, however, as we accept using the term nasal type NK/T-cell lymphoma, there is no reason why a tumor with characteristic clinicopathologic and genetypic features may not be named according to its prototypic site of presentation. It is a tumor with an ABC gene expression profile. It represents 4% of primary cutaneous lymphomas and 20% of primary B-cell lymphomas. Contrary to the trend of having a good prognosis for most primary cutaneous lymphomas, this is an aggressive tumour with propensity for systemic spread and a 50% 5-year survival.

Summary

In this part of a series on lymph node pathology nodal diffuse large B-cell lymphoma is discussed. This term refers to a group of malignant lymphomas characterized by B-cell phenotype, large nuclear size (equal or exceeding the normal macrophage size or double the size of a normal lymphocyte), and a diffuse growth pattern. Tumour cells express typical pan B-cell markers such as CD20, CD22, CD79a and CD19. Co-expression of CD5 characterises one of the immunophenotypic variants. Genotypic profiling shows two distinctive gene signatures. One is a germinal centre B-cell like (GBC) pattern, which predicts a good prognosis. The second is an activated B-cell like (ABC) pattern, which predicts a poor prognosis.

A few notes about the cutaneous counterpart, primary cutaneous diffuse large B-cell lymphoma (leg type) are added.

Essam Raweily, M.D., is a pathologist at the Department of Pathology, Epsom & St Helier NHS Trust in England. This article is an invited contribution and was reviewed solely by the Editor-in-Chief. Contact corresponding author via e-mail: essam.raweily@gmail.com .

References

1. Jaffe E et al Ed. Pathology and genetics of tumours of the haemaopoietic and lymphoid tissue (IARC WHO Classification of Tumours). IARC press, 2008.

2. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification of for cutaneous lymphomas. Blood. 2005;105: 3768-3785.