Pathology Update

Indolent Lymphomas: Classic Subtypes and Newer Entities

Serhan Alkan, MD, and Donald S. Karcher, MD
Department of Pathology
George Washington University Medical Center, Washington, DC.

Introduction

The incidence of low-grade lymphomas in the United States increased from 2.6 cases per 100,000 in 1978 to 3.3 cases per 100,000 in 1988, which is slightly higher than the overall increase in all lymphomas during the same period.[1] Our understanding of the biology of indolent lymphomas during the last decade has increased due to the availability of newer methods to study neoplastic disorders, including immunophenotyping, cytogenetics, and molecular biology.

Although the low-grade non-Hodgkin's lymphomas (NHLs) are considered to be indolent, they often are fatal diseases. Currently, the various subtypes of low-grade NHLs are treated similarly; however, they represent lymphoid neoplasms with heterogeneous cellular origin, pathogenesis, morphologic features, and clinical behavior.

Most of the indolent lymphomas seen in the United States and Europe are tumors of B-cell origin. The low-grade lymphomas in the Working Formulation (WF) classification system include small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), small lymphocytic lymphoma with plasmacytoid features (SLL/Pl), and follicular lymphoma, small cleaved-cell and mixed-cell types. In recent years, new low-grade B-cell lymphoma entities have been described. Examples of these disorders are mantle cell lymphoma (MCL), monocytoid B-cell lymphoma, lymphomas of mucosa-associated lymphoid tissues (MALT), and splenic lymphoma with villous lymphocytes. These entities are included in the recent lymphoma classification introduced by investigators mostly from Europe and the United States - the Revised European-American Lymphoma (REAL) Classification of lymphoid neoplasms (Table).[2]

Some of these newer lymphomas classified according to the WF encompass various morphologic entities under the same diagnostic category. For example, low-grade lymphoma of the stomach arising from MALT would be classified as SLL or diffuse, small cleaved-cell lymphoma. In view of recent findings demonstrating different prognosis and response to treatment of MALT lymphomas, it follows that the recognition of these entities will help to determine their etiology and the most effective treatment modalities. Similarly, MCL may be classified as either of the same two subtypes in the WF. Standard therapy for SLL is ineffective with MCL, and thus identifying their distinction has significant therapeutic and prognostic implications.

Understanding the clinical, morphologic, immunophenotypic, and genetic features of both the classic and the newer low-grade NHLs is assuming increasing importance for pathologists as well as clinicians.

Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

SLL/CLL is the most common indolent lymphoproliferative disorder in western Europe and North America. There has been a recent overall increase in the incidence rate of SLL/CLL.[3] One possible explanation for this phenomenon is the development of improved diagnostic criteria. There is a male predominance, and patients with nodal disease generally show bone marrow involvement. The histologic features of lymph node involvement in SLL and CLL are identical.[4] In general, the lymph node architecture is effaced by diffuse infiltration of small, round lymphocytes with clumped chromatin and scanty cytoplasm (Fig 1). Nodular growth is uncommon and should raise a suspicion of other diagnoses. Pseudoproliferation centers and paraimmunoblasts are good morphologic clues in support of SLL/CLL. The presence of a markedly increased number of paraimmunoblasts in clusters indicates more aggressive clinical behavior.[5]

The most common chromosomal abnormalities are trisomy 12 and structural abnormalities of the long arms of chromosomes 13 and 14.[6] Although trisomy 12 is a common finding in SLL/CLL (up to 54% by fluorescent in situ hybridization studies), it also occurs in other lymphomas.[7] The small lymphocytic lymphomas express CD19, CD20, CD22 (pan B-cell markers), CD23 (low-affinity Fc-IgE receptor), and surface immunoglobulin, most commonly IgM and IgD types.[8] These neoplasms are characterized by expression of CD5 normally found on most mature T lymphocytes.[9,10]

The majority of cases previously classified as SLL in extranodal sites are now thought to represent low-grade B-cell lymphomas of MALT. Although most SLLs show round to oval nuclei, occasional moderate nuclear irregularity can be seen and may raise a suspicion of MCL. Expression of CD23 is reported to be useful in distinguishing SLL/CLL from MCL.[11] Also, the level of expression of CD20 and surface immunoglobulin tends to be lower in SLL/CLL than MCL.[12]

The most common regimen for treating SLL/CLL is the combination of chlorambucil and prednisone. Nucleotide analogues, such as fludarabine and deoxycoformamycine,2-chlorodeoxyadenosine, and alpha-interferon have induced remission in some patients with drug-resistant disease.[13,14]

Lymphoplasmacytoid Lymphoma

Patients with this neoplasm usually present with clinical features of hyperviscosity (related to IgM hypergammaglobulinemia), organomegaly, and anemia.[15] The median age is older than 60 years.[15,16] Response rates to treatment are lower in this age group.[15] Involved lymph nodes typically show diffuse or partial effacement by a proliferation of small round to ovoid lymphocytes, with admixed plasmacytoid lymphocytes and plasma cells (Fig 2). Some neoplastic cells may show intranuclear inclusions (Dutcher bodies), and mast cells may be present. Immunophenotypic features include expression of the B-cell markers CD19, CD20, and CD22. These cases usually lack CD5 and CD10 expression.[2,17,18] There is no reported consistent specific chromosomal abnormality associated with this lymphoma.

Marginal-Zone B-Cell Lymphoma (Monocytoid B-Cell Lymphoma)

Marginal-zone lymphomas include lymphomas arising from lymph node and extranodal sites. The term marginal-zone B-cell lymphoma was proposed to clarify overlapping features of monocytoid B-cell lymphoma and low-grade lymphoma of MALT. The latter occurs at mucosal sites and may show monocytoid B-cell infiltrate; however, the diagnosis of MALT lymphoma does not require the identification of monocytoid B-cells. Node-based marginal-zone B-cell lymphoma is equivalent to monocytoid B-cell lymphoma.[2] Extranodal marginal-zone lymphomas frequently occur in patients with autoimmune diseases such as Sjögren syndrome.

The median age of patients with marginal-zone lymphomas is 65 years. Some of these neoplasms probably were previously classified as SLL/CLL or SLL/Pl in the WF. These lymphomas are characterized by the proliferation of small to medium sized lymphocytes with abundant cytoplasm and irregular nuclei. Plasmacytoid differentiation often is present. Most low-grade lymphomas arising from MALT share many histologic, immunophenotypic, and clinical features with monocytoid B-cell lymphomas and may represent an extranodal counterpart.[19,20] A recent study by the Southwest Oncology Group showed a better prognosis for the node-based marginal-zone lymphomas compared with the lymphomas of MALT.[21]

A characteristic finding in involved lymph nodes is the so-called "inverted follicular" appearance, due to the expansion of neoplastic monocytoid B cells; the lighter-staining neoplastic monocytoid B cells surround the darker-staining normal germinal centers (Fig 3). This is the inverse appearance of a normal lymph node in which the lighter-staining germinal center is surrounded by the darker-staining mantle zone.

Recent studies have shown an association between gastric low-grade MALT lymphomas and Helicobacter pylori infection.[22-24] H pylori is present in more than 90% of gastric MALT lymphomas. Reports of regression of gastric lymphomas following eradication of H pylori infection have been confirmed by two recent European studies showing complete remission in 60% to 70% of gastric lymphomas.[23,24]

Abnormalities of chromosome 3 and the t(11;18) translocation have been reported in MALT lymphomas.[25] These tumors show absence of the bcl-1 [t(11;14)] and bcl-2 [t(14;18)] gene translocations.[26] Marginal-zone lymphomas are positive for B-cell markers CD19, CD20, and CD22. They are CD5-, CD10-, and CD23-negative, which help to differentiate them from other low-grade lymphomas. Rare cases of CD5-positive extranodal marginal-zone B-cell lymphomas have been reported.

Splenic Marginal-Zone Lymphoma, With or Without Villous Lymphocytes

This is a proposed provisional entity in the REAL Classification.[2] Most of the clinical and pathologic features were described in the past as splenic lymphoma with villous lymphocytes.[27,28] The mean age is older than 60 years, and patients usually present with a markedly enlarged spleen and a low level of paraproteinemia. Most have circulating lymphocytes with villous cytoplasmic projections in the peripheral blood (Fig 4).

The diagnosis can be made by noting characteristic involvement of splenic white pulp. Bone marrow and peripheral blood involvement is usually present without lymph node involvement. The clinical course usually is indolent, and splenectomy without chemotherapy may be curative in some patients.[28]

Mantle Cell Lymphoma

MCL represents most of the lymphomas classified as diffuse, small cleaved-cell type in the WF.[21,29] Although some cases of tumors originating from follicular center cells may be included, most diffuse, small cleaved-cell lymphomas originate from cells normally found in the mantle zone surrounding germinal centers in lymph nodes.[2,29] The median age at presentation is in the late 50s to mid 60s. The survival of patients with MCL is much shorter than patients with other low-grade lymphomas.[21,30] Patients generally present with generalized lymphadenopathy, advanced-stage disease, and hepatosplenomegaly. Bone marrow involvement may be more common with MCL than with follicular lymphomas.

Accurate diagnosis of MCL may require a lymph node biopsy. Involved lymph nodes show diffuse to vaguely nodular infiltration by small- to medium-sized lymphoid cells, frequently with scattered uninvolved germinal centers (Fig 5).[30] Although most cases show irregular nuclei, there are some with rounder nuclei that could be difficult to differentiate from SLL/CLL. A diffuse small lymphoid infiltrate without pseudoproliferation centers and paraimmunoblasts should raise a suspicion of MCL. A blastic subtype of MCL characterized by cells with finer chromatin and brisk mitosis is important to recognize because of its reported aggressive clinical behavior.[31]

Treatment of MCL often is ineffective. High-dose chemotherapy and bone marrow transplantation may play a role in treatment of younger patients; however, the majority of patients would not be eligible because of advanced age.[32]

The t(11;14)(q13;q32) translocation is characteristic of MCL.[29] This translocation causes a cell cycle protein, cyclin D1, to be overexpressed.[33-35] The tumor cells are positive for B-cell markers CD19, CD20, as well as surface immunoglobulin (IgM and/or IgD types), and they express the CD5 antigen. The dual expression CD5 and CD19 is similar to SLL/CLL, but MCL usually lacks the CD23 antigen.[11] The intensity of CD20 and immunoglobulin light-chain expression usually is higher than that of SLL/CLL.[35]

Follicular Center Cell Lymphoma

The neoplastic cells in follicular center cell lymphoma (FCCL) originate from the germinal centers of lymph nodes. Involved lymph nodes characteristically show a follicular pattern consisting of small cleaved and/or large noncleaved cells (Fig 6). The relative number of large cells determines the grade.[2] The most reliable counting method for the determination of grade in FCCL classifies tumors as either follicular, small cleaved-cell type (if large noncleaved cells number fewer than five per high-power microscopic field) and follicular, mixed-type (if these cells number between five and 15 per field).[36,37]

The small cleaved-cell subtype is the most indolent subtype of follicular lymphomas. The majority of patients present with advanced-stage disease; however, they have relatively favorable prognosis, with long-term survival of up to nine years. The mixed cellularity subtype shows a more unstable and less favorable clinical course.

The neoplastic cells in FCCL are usually CD5-negative. The presence of CD10 expression is useful in confirming the follicular center cell origin of this lymphoma; however, it is present in only up to 70% of cases of follicular lymphomas. The t(14;18)(q32;q21) chromosome translocation, associated with a breakpoint involving the bcl-2 oncogene on chromosome 18, is reported to be present in 60% to 85% of cases.[38] The detection of bcl-2 translocation is a reliable marker for supporting the diagnosis of follicular lymphoma, since it is not detected in other low-grade lymphomas. This translocation causes overexpression of bcl-2 protein that prevents programmed cell death, known as apoptosis. Immunophenotypic demonstration of strong bcl-2 protein expression within follicles is helpful in differentiating follicular lymphoma from follicular hyperplasia.[39] However, this protein also is expressed in other low-grade lymphomas, and its expression cannot be used to differentiate FCCL from other types of lymphocytic neoplasms.

Polymerase chain reaction (PCR) amplification for the detection of bcl-2 translocation allows high sensitivity in detecting the presence of tumor cells.[40] One caveat to this sensitivity is that PCR positivity for bcl-2 translocation also can be detected in lymphocyte-rich tissues from normal individuals if a sensitive so-called "nested PCR" technique is used.[41] Therefore, it would be prudent for the clinician to communicate with the laboratory performing the PCR analysis for bcl-2 translocation. Determination of the use of PCR detection for clinical follow-up awaits further prospective, long-term studies to assess the risk of recurrence and potential influence on survival.

Conclusions

The evaluation of low-grade lymphomas requires a comprehensive analysis of the clinical, histologic, immunophenotypic, and genetic findings. The precise classification of these neoplasms is probably the first step in understanding their basic pathogenetic mechanisms and designing a rational approach toward effective therapy.

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