Hodgkin lymphoma is divided into five major pathologic subtypes based on differences in the appearance of the Reed-Sternberg cells and variants as well as the composition of the reactive cellular response:
Nodular sclerosis. This form is most common in young adults and sometimes occurs in adolescents and even children. It is characterized by two pathologic findings: 1) the presence of a particular type of Reed-Sternberg cell variant, the lacunar cell (Fig. 23-1A), and 2) the presence of large bands of collagen that are deposited by reactive fibroblasts. The reactive background consists of a variable mixture of lymphocytes (mainly T cells), granulocytes (particularly eosinophils), macrophages, and plasma cells. The nodular sclerosis subtype is only rarely associated with Epstein-Barr virus (EBV).
Mixed cellularity. This subtype is most common in older males in the United States but also occurs in young adults and children, particularly in parts of the developing world such as Peru. Lymph nodes are diffusely effaced by a polymorphous infiltrate composed of a mixture of inflammatory cells, scattered classic Reed-Sternberg cells (Fig. 23-1C), and relatively frequent mononuclear Reed-Sternberg variants (Fig. 23-1B). About 70% of cases are associated with EBV (Fig. 23-2).
Lymphocyte rich. This is an uncommon subtype in which the predominant cellular response consists of lymphocytes. About 40% of cases are associated with EBV.
Lymphocyte depleted. This is a rare subtype except in human immunodeficiency virus (HIV)-positive patients. Frequent Reed-Sternberg cells are seen in involved tissue sections, whereas the host response to these cells is relatively sparse. It is almost always associated with EBV, particularly in those who are HIV positive.
Nodular lymphocyte predominant. This uncommon subtype (5% of cases) most often arises in young to middle-aged males within axillary or cervical lymph nodes. The tumor cells have nuclei that are lobulated or popcorn kernel–like (Fig. 23-1D); classic Reed-Sternberg cells are rare or absent. For historic reasons, the tumor cells in this subtype are referred to as lymphocytic and histiocytic variants, or L&H cells. L&H cells are typically present within nodular aggregates of B lymphocytes, which represent expanded B-cell follicles. This form of Hodgkin lymphoma is not associated with EBV.
Reed-Sternberg cells. A) Lacunar variants are seen within spaces created by tearing away of the wispy cytoplasm during tissue sectioning. B) Mononuclear variant. A large mononuclear variant with a single, enormous, eosinophilic nucleolus is present in the middle of the field. C) Diagnostic Reed-Sternberg cell. A classic Reed-Sternberg cell with two nuclei, each with a large nucleolus, and abundant cytoplasm is shown. D) L&H variants. Two typical lymphocytic and histiocytic variants with polypoid, folded nuclei are denoted with asterisks.
Until relatively recently, the nature of the malignant Reed-Sternberg cells in Hodgkin lymphoma was obscure, in part because their paucity in tissues made them very difficult to study. This long-standing mystery was finally solved by elegant studies using individual Reed-Sternberg cells isolated from tissues. These revealed that in all forms of Hodgkin lymphoma the Reed-Sternberg cells have clonal rearranged immunoglobulin heavy chain genes that have undergone somatic hypermutation, proving that these cells are derived from germinal center B cells. Nevertheless, except in the nodular lymphocyte predominant subtype, Reed-Sternberg cells fail to express most B-cell markers and often instead express markers of other cell types, such as granulocytes, macrophages, or even hematopoietic stem cells. This wholesale reprogramming of gene expression contributed mightily to difficulties in determining the origin of Reed-Sternberg cells. The mechanisms underlying this phenomenon are largely unknown.
The characteristic tissue reaction in Hodgkin lymphoma is elicited by a variety of chemokines and cytokines produced by Reed-Sternberg cells, which include chemoattractants and growth factors for T cells, granulocytes, and macrophages (Fig. 23-3). Various subtypes elaborate different combinations of factors, some of the most important of which include the following:
Interleukin (IL)-4, IL-10, and IL-13, which act together to promote humoral immunity and suppress cellular immunity.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), which can lead to hyperplasia of marrow granulocytic and monocytic progenitors, leukocytosis, and infiltration of lymphomatous tissues by neutrophils and macrophages.
CCL28 and IL-5, which increase marrow production of eosinophils and provoke peripheral blood and tissue eosinophilia.
Tumor necrosis factor (TNF)-beta (lymphotoxin) and basic fibroblast growth factor, which activate fibroblasts and stimulate fibrosis, particularly in the nodular sclerosis subtype.
Detection of Epstein-Barr virus (EBV) in Reed-Sternberg cells. EBV small nuclear ribonucleic acids were detected with a chromogenic in situ staining method that produces a brown color. In this field, the nuclei of multiple Reed-Sternberg cells stain positively.
Although the etiology of Hodgkin lymphoma is incompletely understood, some of the molecular events that lead to its development have been discovered. In cases associated with EBV, the tumor cells express latent membrane protein-1, an EBV protein that acts like a constitutively active version of the TNF receptor. Latent membrane protein-1 turns on nuclear factor-kappa B (NF-κB), a transcription factor that promotes the growth and survival of B cells. It was subsequently determined that EBV-negative cases are often associated with mutations that disrupt the function of IκB and A20, two negative regulators of NF-κB. Thus, activation of NF-κB is believed to be a central event in the pathogenesis of Hodgkin lymphoma.
Cross-talk between Reed-Sternberg cells and inflammatory cells. Some of the more important receptors and factors that contribute to the brisk inflammatory response around Reed-Sternberg cells in tissues are shown. (Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus. In: Kumar V, Abbas A, Fausto N, and Aster JC, eds. Robbins Pathologic Basis of Disease. 8th ed. Philadelphia, United States: Elsevier; 2010: p.621.)
Regardless of the subtype, most patients with Hodgkin lymphoma present with painless lymphadenopathy, most commonly in the cervical or supraclavicular region.1 The nodular sclerosis type usually also involves the mediastinum (Fig. 23-4), often inducing chest discomfort, cough, or dyspnea. On occasion, lymphomatous masses in the mediastinum impinge on blood return to the heart and produce superior vena cava syndrome, associated with plethora (redness) and swelling of the face and upper extremities. About one-third of patients have so-called B symptoms such as weight loss and night sweats, and many also complain of pruritus. Laboratory studies often show leukocytosis and eosinophilia, sometimes accompanied by anemia related to the systemic inflammatory state induced by the tumor (anemia of chronic inflammation).
Mediastinal involvement by Hodgkin lymphoma, nodular sclerosis subtype. The upper image is a normal chest computed tomography (CT) scan. The lower image is the chest CT scan of a patient with a large mediastinal mass that proved on biopsy to be nodular sclerosis Hodgkin lymphoma.