Cortex

The lymph node is surrounded by a capsule of fibrous tissue. Immediately below the capsule is the cortex, the most superficial portion of the lymph node consisting of primary and secondary follicles. Primary follicles are microscopic aggregates of small, round naive B lymphocytes. These lymphocytes express pan–B-cell markers, including CD19 and CD20, and are frequently CD5⁺ (Figure 37-3). The formation of secondary follicles, including germinal centers, starts with antigen presentation by follicular dendritic cells.^2,3 On antigen encounter, naive B lymphocytes undergo transformation, proliferation, and differentiation into precursors of antibody-producing plasma cells and memory B cells (see Figure 37-3). The remaining naive B cells are displaced into the periphery of the germinal center and form the mantle zone.

Germinal center B cells have a specific immunophenotype. In addition to pan–B-cell markers, they express germinal center cell antigens CD10 and BCL-6, and, in contrast to circulating B cells, they lack antiapoptotic BCL-2 protein. The functional compartments of the germinal center include the dark zone occupied by centroblasts, large B cells with round vesicular nuclei, small nucleoli adjacent to nuclear membrane, and basophilic cytoplasm (Figure 37-4). The dark zone is a site of high proliferative activity and somatic mutations of B-cell immunoglobulin variable regions. The latter process allows for the production of immunoglobulins with the best affinity for a particular antigen.

After completing somatic mutations, centroblasts differentiate into centrocytes, smaller cells with dense chromatin and irregular nuclear outlines, which form the light zone (see Figure 37-4). Subsequently, centrocytes with low-affinity (“unfit”) surface immunoglobulins undergo apoptosis and are phagocytized by germinal center macrophages (tingible body macrophages). The presence of numerous macrophages with apoptotic debris contributes to the characteristic “starry sky” pattern of the germinal center. Centrocytes with immunoglobulins with high affinity for a particular antigen lose their germinal center antigens (CD10 and BCL-6) and differentiate into memory B cells that form a marginal zone at the periphery of the mantle zone. Marginal zone lymphocytes are medium-sized with abundant clear cytoplasm and indented nuclei.

The final step of B-cell differentiation is plasma cells that are present in the medullary cords of the lymph nodes and migrate to the bone marrow. Plasma cells are negative for pan–B-cell antigens and surface immunoglobulins; however, they express CD138, CD38, and cytoplasmic immunoglobulins.

Paracortex

The paracortex occupies the area separating the follicles and extends toward the medullary cords. This compartment generates immunocompetent T cells and is occupied predominantly by T cells, interdigitating dendritic cells (antigen-presenting cells), and high endothelial venules. The latter are specialized vessels serving as a gate of entry for lymphocytes from peripheral blood into the lymph node. T cells express pan–T-cell antigens CD3, CD5, CD2, and CD7. Both CD4⁺ and CD8⁺ T lymphocytes are seen in the paracortex. Similar to B cells, T cells transform in response to antigen stimulation. In this process, small lymphocytes become immunoblasts: large lymphoid cells with vesicular nuclei; prominent nucleoli, often single; and abundant basophilic cytoplasm. The paracortex also contains numerous B immunoblasts.

Medulla

The medulla represents the innermost portion of the lymph node surrounding the hilum. This area is composed of medullary cords with plasma cells and medullary sinuses.

Sinuses

The filtration of lymphatic fluid through the lymph node is accomplished through afferent lymphatics communicating with the subcapsular sinus, which is situated immediately beneath the capsule (see Figure 37-2). The subcapsular sinus drains to cortical sinuses, which run through the cortex and empty to medullary sinuses. The latter converge into the efferent lymphatic vessel at the hilum. The sinuses are filled with macrophages or sinus histiocytes. These cells play an important role in antigen capture and processing.

Follicular Pattern

Follicular hyperplasia is the most common of the reactive lymphadenopathies. It is seen frequently in lymph nodes and tonsils of children and adolescents as a reaction to infections. In adults, it occurs in association with autoimmune disorders (rheumatoid arthritis, systemic lupus erythematosus), syphilis, and early human immunodeficiency virus (HIV) infection. Microscopically, the expansion of reactive follicles can be prominent and extend beyond the cortex into the medulla (Figure 37-5). The follicles retain all the hallmarks of reactive germinal centers, including distinct polarization, presence of tingible body macrophages, abundant mitotic figures, and a preserved mantle zone (see Figure 37-4).

Paracortical Pattern

Paracortical expansion is associated with viral infections (e.g., infectious mononucleosis) and drug reactions and is also seen in patients with chronic skin diseases (dermatopathic lymphadenopathy). In addition to small lymphocytes, the paracortex shows numerous immunoblasts, increased mitotic activity, and vascular proliferation (Figure 37-6). Focal areas of necrosis may also be seen. In dermatopathic lymphadenopathy, the paracortex has a characteristic mottled appearance as a result of an increased number of large cells with abundant clear cytoplasm scattered among small lymphoid cells (Figure 37-7). These cells include histiocytes, often carrying melanin pigment, and Langerhans cells (Figure 37-8). Scattered immunoblasts, plasma cells, eosinophils, and vascular proliferation are also encountered.

Sinusoidal Pattern

Expanded subcapsular, cortical, and medullary sinuses are often seen in lymph nodes draining limbs, abdominal organs, various inflammatory lesions, and malignancies. In advanced cases, the prominent sinuses compress the nodal parenchyma. They may be completely filled with histiocytes showing abundant cytoplasm, a small oval nucleus with inconspicuous nucleolus, and delicate chromatin. Monocytoid B cells with abundant cytoplasm and oval indented nuclei that may mimic histiocytes are seen in nodal sinuses in HIV-associated lymphadenopathy and Toxoplasma lymphadenitis (Figure 37-9, A). Numerous malignant lesions show a predilection for sinuses, such as Langerhans cell histiocytosis, B-cell and T-cell lymphomas, and carcinomas; a high-power microscopic evaluation of expanded sinuses is always necessary.

Mixed Pattern

A classic example of mixed-pattern hyperplasia is seen in Toxoplasma gondii infection, a common protozoal infection typically seen after ingestion of raw meat or contamination by cat feces. Histologically, the expansion of all lymph node compartments is seen (see Figure 37-9). Florid follicular hyperplasia is accompanied by paracortical expansion, aggregates of histiocytes encroaching on germinal centers, and expanded sinuses. Sinuses are focally filled with a specific subset of B cells, so-called monocytoid B cells.

Mature B-Cell Lymphomas

Mature B-cell lymphomas are neoplasms derived from various stages of B-cell differentiation. Although they show significant morphologic and immunophenotypic heterogeneity, all B-cell lymphomas produce monoclonal light chain immunoglobulins, clonal immunoglobulin gene rearrangements, or both. Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common subtypes of B-cell lymphoma.⁹ Most cases are lymph node based and occur in elderly individuals. However, leukemic involvement (peripheral blood and bone marrow) can occur with any lymphoma subtype. The most common mature B-cell neoplasms are discussed in the following paragraphs and are summarized in Table 37-2.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Definition

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by the accumulation of small lymphoid cells in the peripheral blood, bone marrow, and lymphoid organs. They are derived from recirculating B cells expressing CD5, immunoglobulin M (IgM), and IgD that are normally present in the peripheral blood. The World Health Organization (WHO) classification considers CLL and SLL as one entity with different clinical presentations. The diagnosis is based on the predominant site of involvement. CLL, by definition, has involvement of the peripheral blood (monoclonal B-lymphocytes greater than 5 × 10⁹ cells/L) and bone marrow. SLL primarily involves lymph nodes and other lymphoid organs.

Morphology and Immunophenotype

Bone marrow and peripheral blood films shows small lymphoid cells with a coarse chromatin pattern, inconspicuous nucleoli, and scant cytoplasm¹⁰ (Figure 37-10). Larger lymphoid cells with less condensed chromatin and distinct nucleoli (prolymphocytes) are rare. Smudge cells, representing disintegrated lymphoid cells, are present on the peripheral blood film. These cells are helpful in the diagnosis because they are not often seen in other subtypes of malignant lymphoma. The bone marrow biopsy specimen shows nodular, diffuse, or interstitial infiltrates of small lymphoid cells (Figure 37-11).

Lymph nodes involved by SLL show an effacement of normal nodal architecture (Figure 37-12, A) by a diffuse proliferation of small round lymphoid cells with coarse chromatin, indistinct nucleoli, and scant cytoplasm. In addition, scattered nodules (so-called pseudofollicles, growth centers, or proliferation centers) composed of medium-sized and large lymphoid cells with dispersed chromatin and distinct nucleoli are observed (see Figure 37-12, B). The diffuse proliferation of small lymphoid cells with pseudofollicles is pathognomonic for SLL.

As noted earlier, CLL/SLL is derived from circulating CD5⁺IgM⁺IgD⁺ B cells. Currently, two groups of CLL/SLL are recognized.¹¹ The first corresponds to the pre–germinal center phenotype with naive B cells showing no mutations in the variable region of the immunoglobulin heavy chain (V_H) gene. The second form is derived from memory B cells (the post–germinal center stage), with mutated V_H genes. Both types are positive for pan–B-cell antigens, including CD19 and weakly expressed CD20. In addition, the expression of CD5, CD23, and weak surface monoclonal κ or λ light chains is seen. The presence of CD23 and absence of FMC7 and cyclin D1 distinguish CLL/SLL from mantle cell lymphoma. The presence of monoclonal B cells with an immunophenotype similar to that of CLL/SLL has been described in a small proportion of healthy individuals; thus the demonstration of these cells by flow cytometry must always to be interpreted in the context of other clinical and laboratory features.¹²

Clinical Features and Prognosis

Overall, CLL/SLL is regarded as an indolent lymphoproliferative disorder of the elderly (median age at diagnosis is 65 years). Although this disease is incurable by current therapeutic approaches, the median survival is 10 years.¹³

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