CHAPTER 23: Hodgkin Lymphoma

Hodgkin lymphoma bears the name of Thomas Hodgkin, who described the disease in 1832. It affects about 8500 patients each year in the United States and is distinguished from all other forms of lymphoma (the non-Hodgkin lymphomas) by several unique pathologic and biologic features.

• The presence of Reed-Sternberg cells or variants and peculiar tumor giant cells within an exuberant tissue response consisting of reactive lymphocytes, granulocytes, macrophages, and plasma cells. Unlike virtually all other forms of cancer, in Hodgkin lymphoma the tumor cells make up a small fraction (often <1%) of the overall tumor mass.

• A strong tendency to arise within a single lymph node group and to spread in a predictable, stepwise fashion from one lymph node group to the next. As a result, staging has a greater influence on the treatment of Hodgkin lymphoma than on non-Hodgkin lymphomas.

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.

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.

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.

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).

The diagnosis requires a biopsy of involved tissues, usually a lymph node, and is primarily based on the identification of typical Reed-Sternberg cells and variants within the appropriate cellular background. Cells resembling Reed-Sternberg cells can be found on occasion in non-Hodgkin lymphomas and even in some solid tumors, and immunohistochemical studies are typically carried out to confirm suspected cases of Hodgkin lymphoma. In the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted subtypes (sometimes referred to together as classical Hodgkin lymphoma), the tumor cells are usually positive for CD15 (an adhesion molecule often expressed on myeloid cells), always positive for CD30 (a member of the tumor necrosis factor receptor family), and negative for CD45 (leukocyte common antigen). In classical Hodgkin lymphoma, the tumor cells are also positive for PAX-5, a transcription factor that is a master regulator of B-cell development, but the tumor cells of classical Hodgkin lymphoma usually are negative for other B-cell markers (eg, CD20). A significant proportion of classical Hodgkin lymphomas (particularly the mixed cellularity and uncommon lymphocyte-depleted subtypes) is positive for EBV. In contrast, the L&H variants of nodular lymphocyte-predominant Hodgkin lymphoma are uniformly positive for B-cell markers such as CD20 and negative for CD15, CD30, and EBV, further distinguishing this subtype.

The overall prognosis for patients with Hodgkin lymphoma is excellent, even in those with advanced disease. As mentioned previously, staging plays a key role in guiding the selection of therapy. Patients with localized, low-stage disease without B symptoms (stages IA and IIA) are currently treated with involved field radiation and limited chemotherapy, whereas those with high-stage disease are treated with combination chemotherapy, sometimes with radiotherapy if bulky masses are present. Responses to both are excellent, and, overall, 60% to 90% of patients are now cured.

The treatment of Hodgkin lymphoma represents a major success in oncology but has come with a price. More patients now die of complications of therapy than from Hodgkin lymphoma itself. These iatrogenic complications take the form of accelerated cardiovascular disease, valvular heart disease, and a wide variety of secondary malignancies (including melanoma, sarcoma, and breast cancer), all of which appear to be related mainly to radiation exposure 15 to 20 years prior to the development of these adverse events. Earlier chemotherapy regimens were also culpable, because they contained alkylating agents that were potent inducers of myelodysplastic syndromes and secondary acute myeloid leukemias. Newer chemotherapy regimens do not appear to be leukemogenic, and clinical research is now being conducted to evaluate treatment with chemotherapy alone, in hope of developing safe, curative treatment regimens that minimize or completely avoid complications associated with radiotherapy.