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CHAPTER 97 and long-term survival exceeds 85 percent. Doxorubicin-containing chemo-

HODGKIN LYMPHOMA therapy plays a major role in treatment of all stages of the disease whereas
radiotherapy is used selectively because of concerns for late toxicities.
18-Fluorodeoxyglucose positron emission tomography is a valuable diagnostic
test for assessment of disease extent and response to treatment. High-dose
Oliver W. Press* therapy and autologous transplantation are effective in patients who have
relapsed, and several promising new biologic agents are available, including
brentuximab vedotin (an anti-CD30 antibody–drug conjugate) and nivolumab
SUMMARY (an anti-PD1 blocking antibody). Concerns regarding late treatment effects
guide therapy and followup decisions in Hodgkin lymphoma, which dispro-
Classical Hodgkin lymphoma is derived by malignant transformation of a portionately affects adolescents and young adults. Major treatment challenges
mature B cell at the germinal center stage of differentiation and is char- include the maintenance of high cure rates with fewer short-term and long-
acterized pathologically by multinucleated Hodgkin and Reed-Sternberg term complications, biomarker identification of the small refractory subgroup,
cells embedded in a mixed infiltrate of nonneoplastic cells. Hodgkin and and integration of biologic therapies into treatment paradigms.
Reed-Sternberg cells contain monoclonal immunoglobulin gene rear-
rangements, but have lost most of the B-cell–specific expression program.
Multiple signaling pathways and transcription factors are deregulated in
Hodgkin lymphoma and genetic lesions involving the JAK-STAT and nuclear DEFINITION AND HISTORY
factor-κB pathways are commonly identified. Epstein-Barr virus is an impor- Classical Hodgkin lymphoma (cHL) is a neoplasm of lymphoid tissue,
tant environmental factor in the pathogenesis of Hodgkin lymphoma, and also in most cases derived from a germinal center B cell, defined by the
leads to activation of the nuclear factor-κB pathway. The inflammatory micro- presence of the malignant Hodgkin and Reed-Sternberg cells with a
environment promotes survival and allows escape of Hodgkin and Reed-Stern- characteristic immunophenotype and appropriate cellular background.
berg cells from immune attack. Morphologic and immunophenotypic features cHL accounts for 95 percent of cases and contains four histologic sub-
distinguish the four subtypes of classical Hodgkin lymphoma (accounting for types distinguished on the basis of microscopic appearance and rela-
95 percent of cases) from nodular lymphocyte predominance Hodgkin lym- tive proportions of Hodgkin and Reed-Sternberg cells, lymphocytes,
phoma (accounting for 5 percent of cases). Hodgkin lymphoma spreads in and fibrosis (nodular sclerosis, mixed cellularity, lymphocyte-rich and
a predictable, contiguous manner and is classified into four stages, I to IV. lymphocyte-depleted; Table 97–1). Nodular lymphocyte-predominant
Hodgkin lymphoma is treated with the intent to cure the disease in all stages, Hodgkin lymphoma (NLPHL) represents the other major category,
which is distinguished by Hodgkin and Reed-Sternberg variants termed
lymphocytic and histiocytic cells that, unlike cHL, express typical
B-lineage markers.

Acronyms and Abbreviations: ABVD, Adriamycin (doxorubicin), bleomycin, vin-
blastine, dacarbazine; AP1, activator protein 1; BCMA, B-cell maturation antigen; HISTORICAL ASPECTS
BEACOPP, bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, vin- In his historic 1832 paper entitled On Some Morbid Appearances of the
cristine, procarbazine, prednisone; BEAM, bischloroethylnitrosourea (carmustine), Absorbent Glands and Spleen, Thomas Hodgkin described the clinical
etoposide, Ara C (cytarabine), melphalan; CBV, cyclophosphamide, bischloroethyl- histories and gross postmortem findings of seven cases of the disease
nitrosourea (carmustine), etoposide; cHL, classical Hodgkin lymphoma; COPP, cyclo- that was later to bear his name. In 1856, Samuel Wilks independently
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phosphamide, vincristine, procarbazine, prednisone; CT, computed tomography; described 10 cases of “a peculiar enlargement of the lymphatic glands
DHAP, dexamethasone, cytarabine, cisplatin; EBV, Epstein-Barr virus; EBVP, epirubicin, frequently associated with disease of the spleen,” including four of
bleomycin, vinblastine, prednisone; EORTC, European Organization for the Research Hodgkin’s original cases. Upon discovering Hodgkin’s original report,
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and Treatment of Cancer; ERK, extracellular signal-regulated kinase; ESR, erythrocyte he used the appellation “Hodgkin’s Disease” in a subsequent series
sedimentation rate; FDG, 18-fluorodeoxyglucose; FIL, Fondazione Italiana Linfomi; of 15 cases published in 1865. Thirteen years after Hodgkin’s original
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GELA, Groupe d’Etude des Lymphomes de l’Adulte; GHSG, German Hodgkin Study paper, the first cases of leukemia were described. Cases in which the neo-
Group; GVD, gemcitabine, vinorelbine, liposomal doxorubicin; HLA, human leu- plastic cells remained confined to the lymphatic system were described
kocyte antigen; ICE, ifosfamide, carboplatin, etoposide; IL, interleukin; JAK, Janus by Dreschfield (1892) and Kundrat (1893) ; Kundrat gave the name
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kinase; LMP, latent membrane protein; LySA, Lymphoma Study Association; MOPP, lymphosarcoma to these cases. The description of additional members
mechlorethamine (nitrogen mustard), Oncovin (vincristine), procarbazine, predni- of the lymphoma–leukemia complex continued up to the present time.
sone; NF-κB, nuclear factor-κB; NLPHL, nodular lymphocyte-predominant Hodgkin Carl Sternberg (1898) and Dorothy Reed (1902) are credited
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lymphoma; OS, overall survival; PD1, cell death protein 1; PET, positron emission with the first definitive and thorough descriptions of the pathology
tomography; PI3K, phosphoinositide 3′-kinase; RANK, receptor activator of nuclear of cHL, although a number of investigators from England, Germany,
factor-κB; R-CHOP, rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine and France had previously recognized the characteristic multinucle-
(Oncovin), prednisone; STAT, signal transducer and activator of transcription; TACI, ated giant cells. In 1926, Fox examined microscopic sections from the
transmembrane activator, calcium modulator, and cyclophilin ligand interactor.
gross specimens preserved in the Gordon Museum of Guy’s Hospital in
London of three of Hodgkin’s original cases. It is remarkable that the
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preserved microanatomy allowed him to confirm the histopathologic
* Sandra J. Horning, MD, was the author of this chapter for the 8th edition of diagnosis in two of these cases. Jackson and Parker made the first seri-
Williams Hematology and significant portions of that chapter have been retained. ous effort at the histopathologic classification of cHL, correlating their

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