CHAPTER 102 HODGKIN LYMPHOMA
CHAPTER 102 HODGKIN LYMPHOMA
SANDRA J. HORNING
Definition and History
Etiology and Pathogenesis
Origin of the Reed-Sternberg Cell
Association with EBV
Association with the Non-Hodgkin Lymphomas
Therapy, Course, and Prognosis
Treatment of Recurrent Disease
Complications of Treatment
Hodgkin lymphoma is a neoplasm of lymphoid tissue defined by the presence of the malignant Reed-Sternberg and Hodgkin cells (RS-H) with an appropriate cellular background. Four histologic types (lymphocyte predominance, nodular sclerosis, mixed cellularity, and lymphocyte depletion) are distinguished on the basis of the appearance and relative proportions of RS-H cells, lymphocytes, and fibrosis. The anatomic extent of disease and, to a lesser degree, the histologic subtype are the primary factors determining the presenting features, prognosis, and optimal therapy of Hodgkin lymphoma.
The goal of treatment is to cure the greatest number of patients with minimal complications. Outstanding results have been achieved by combining radiotherapy and chemotherapy, each of which are independently effective in Hodgkin lymphoma, with ongoing efforts to minimize cumulative exposure to each modality. This chapter discusses both modalities and their application to presentations of Hodgkin lymphoma at diagnosis and upon relapse, as well as the complications of treatment.
Acronyms and abbreviations that appear in this chapter include: ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; BEAM, carmustine, etoposide, cytosine arabinoside, melphalan; CT, computed tomography; EBV, Epstein-Barré virus; EBVP, epirubicin, bleomycin, vinblastine, and prednisone; HIV, human immunodeficiency virus; HLA, human lymphocyte antigen; ICAM-1, intercellular adhesion molecule 1; IL-2R, IL-2 receptor; L&H, lymphocyte and histiocyte variants; LMP, latent-membrane protein; LPHD, lymphocyte predominant Hodgkin disease; MOPP, nitrogen mustard, vincristine, procarbazine, and prednisone; NLPHD, nodular lymphocyte predominant Hodgkin disease; PET, positron emission tomography; PCR, polymerase chain reaction; PS, laparotomy-stage; RS-H, Reed-Sternberg and Hodgkin cells; SPECT, single photon-emitted computed tomography; TGF-b, transforming growth factor beta; VAPEC-B, vinblastine, doxorubicin, prednisone, etoposide, cyclophosphamide, and bleomycin chemotherapy; VBM, vinblastine, bleomycin, and methotrexate.
DEFINITION AND HISTORY
In his historic 1832 paper entitled “On Some Morbid Appearances of the Absorbent Glands and Spleen,” Thomas Hodgkin described the clinical histories and gross postmortem findings of seven cases of the disease that was later to bear his name.1 In 1856 Samuel Wilks independently described 10 cases of “a peculiar enlargement of the lymphatic glands frequently associated with disease of the spleen,” including four of Hodgkin’s original cases.2 Upon discovering Hodgkin’s original report, he used the appellation “Hodgkin’s Disease” in a subsequent series of 15 cases published in 1865.3
Thirteen years after Hodgkin’s original paper, Craigie,4 Bennett,5 and Virchow6 described the first cases of leukemia. Cases in which the neoplastic cells remained confined to the lymphatic system were described by Dreschfield (1892)7 and Kundrat (1893)8; the latter gave the name lymphosarcoma to these cases. The description of additional members of the lymphoma-leukemia complex has continued throughout the twentieth century up to the present time.
Carl Sternberg (1898)9 and Dorothy Reed (1902)10 are credited with the first definitive and thorough descriptions of Hodgkin lymphoma, although a number of investigators from England, Germany, and France had previously recognized the characteristic multinucleated giant cells. In 1926 Fox examined microscopic sections from the gross specimens preserved in the Gordon Museum of Guy’s Hospital in London of three of Hodgkin’s original cases.11 It is remarkable that the preserved microanatomy allowed him to confirm the histopathologic diagnosis in two of these cases. Jackson and Parker made the first serious effort at histopathologic classification, correlating their findings with prognosis.12 A second advance was made in 1966 when Lukes, Butler, and Hicks proposed a classification that related well to clinical presentation and course.13 Their proposal was slightly modified into the Rye classification, in which four histopathologic subtypes were described: lymphocyte predominance, nodular sclerosis, mixed cellularity, and lymphocyte depletion. The new proposed World Health Organization classification of lymphoid neoplasms (1999) specifically recognizes Hodgkin lymphoma as a lymphoma and clearly delineates the nodular lymphocyte predominance subtype from classical Hodgkin lymphoma. A new category of “lymphocyte-rich” classical Hodgkin lymphoma is introduced (Table 102-1).
TABLE 102-1 WORLD HEALTH ORGANIZATION CLASSIFICATION OF HODGKIN LYMPHOMA
Peters described a clinical staging system in 1950, emphasizing the diagnostic evaluation of the anatomic extent of disease.14,15 In 1952 Kinmouth introduced lower-extremity lymphangiography, which allowed roentgenologic visualization of the pelvic and retroperitoneal lymph nodes and was found to be far more sensitive than palpation or other radiographic methods.16 The frequency of unsuspected splenic involvement was revealed in a group of 65 patients subjected to laparotomy and splenectomy with biopsy of splenic hilar, para-aortic and mesenteric nodes, and liver at Stanford University.17 These diagnostic procedures led to improved understanding of the mode of dissemination of disease and correlated well with prognosis, culminating in the modern concepts of staging codified at the Rye, New York conference in 196518 and further refined at the workshop on the staging of Hodgkin disease in Ann Arbor, Michigan, in 1971.19
Pusey (1902)20 and Senn (1903)21 were the first to report dramatic regressions of lymphadenopathy with the x-rays newly discovered by Roentgen in 1896. Based upon the nearly inevitable appearance of recurrences in untreated areas, Gilbert proposed the systematic treatment of both involved and uninvolved areas in 1939.22 Peters (1950) is given credit for the first demonstration of the curative potential of radiotherapy in her classic paper.14 The development of megavoltage radiotherapy (doses >4000 cGy), as reported by Kaplan in 1962,23 permitted the delivery of tumoricidal doses to virtually all lymphoid regions in the body within acceptable limits of normal tissue tolerance.
The chemotherapy of Hodgkin lymphoma originated as a by-product of the wartime work on the mustard gases.24,25 Following the initial work with the nitrogen mustards, antimetabolites were synthesized, and a number of alkaloids and antibiotics extracted from various plant, fungus, and microbial sources became available for clinical use. DeVita and colleagues introduced the first highly effective combination chemotherapy, “MOPP” (nitrogen mustard, vincristine, procarbazine, prednisone), based on experimental studies indicating the desirability of combining agents with nonoverlapping toxicities.26 Combination chemotherapy extended the curative potential to advanced disease.
ETIOLOGY AND PATHOGENESIS
Difficulty in the characterization of the neoplastic cells, which account for only about 1 to 2 percent of the cellular composition, led to controversy regarding the etiology and pathogenesis of Hodgkin lymphoma for more than 150 years. New techniques affording molecular analyses of single cells have facilitated the study.
ORIGIN OF THE REED-STERNBERG CELL
The histologic diagnosis is based on the recognition of the Reed-Sternberg cell in an appropriate cellular background. The classic Reed-Sternberg cell has a bilobed nucleus with prominent eosinophilic nucleoli separated by a clear space from the thickened nuclear membrane (Fig. 102-1). Mononuclear variants (Hodgkin cells) have similar nuclear characteristics and may represent Reed-Sternberg cells cut in a plane that shows only one lobe of the nucleus. Reed-Sternberg cells are not pathognomonic for Hodgkin lymphoma; they may be seen in reactive and other neoplastic conditions. Study of the Reed-Sternberg cell has been complicated by the fact that the neoplastic cells are sparsely interspersed among a reactive mixed cell population of lymphocytes, eosinophils, histiocytes, plasma cells, and neutrophils.
FIGURE 102-1 (a) Characteristic Reed-Sternberg cell of Hodgkin disease and surrounding mononuclear variants. (b) Lymphocyte and histiocyte (L&H) variant of the nodular form of lymphocyte predominance. (The “histiocyte” may actually be a lymphocyte.) Note the multilobulated “popcorn” nucleus and surrounding small lymphocytes. (c) Immunoperoxidase staining of the L & H variant of the nodular form of lymphocyte predominance with the L26 antibody directed against a pan-B-cell antigen (CD20) outlines the large atypical cells. (d) Low-power view of nodular sclerosis, demonstrating broad bands of collagen partitioning the lymph node into nodules.
Reed-Sternberg cells and their mononuclear variants (RS-H) demonstrate inconsistent lineage-specific antigen expression. Approximately 85 percent of cases of nodular sclerosis and mixed cellularity express the CD30 antigen (Ki-1), which was identified by Stein and colleagues.27 This antigen is a marker of lymphocyte activation and is expressed by both reactive and neoplastic lymphoid cells, including a number of non-Hodgkin lymphomas.28,29 The majority of RS-H cells in classic Hodgkin lymphoma express the CD15 antigen, which is characteristically expressed in the late stages of granulopoiesis.30,31 However, CD15 expression is not limited to granulocytes and monocytes; it has been identified in activated T cells and cytomegalovirus-infected cells as well as nonlymphoid cells.32,33 and 34 Most RS-H cells express the interleukin 2 receptor, (CD25 or Tac), characteristic of activated T cells.35 The B-cell antigens CD19 and CD20 are expressed by RS-H cells in about 35 to 40 percent of nodular sclerosis and mixed cellularity cases.36,37,38 and 39
Immunohistochemical analysis of Hodgkin lymphoma provides evidence that nodular lymphocyte predominance (LPHD) is a distinctive subtype. The RS-H cells in this subtype, known as lymphocyte and histiocyte (L&H) variants, have a unique polylobated, “popcorn” appearance, and they consistently express B-cell markers such as CD20 and CD45 (leukocyte common antigen)40 (Figure 102-1). They lack expression of CD15 and have variable expression of CD30.41 The synthesis of cytoplasmic J chain and immunoglobulin also indicates the B-cell origin of this subtype.42 Although most investigators describe polyclonal staining for light chains, others have reported light-chain restriction.43,44
The new category of lymphocyte-rich Hodgkin lymphoma requires immunohistochemistry for diagnosis. As in nodular lymphocyte predominance, the majority of cells are small B lymphocytes, and a nodular or follicular pattern may be seen. The RS-H cells express CD15 and CD30, lack CD45, and may or may not express CD20. Thus, although the morphologic features of the lymphocyte-rich subtype may be confused with lymphocyte predominance, the immunophenotype of the RS-H cells is that of classical Hodgkin lymphoma.
Historically, a macrophage origin of RS-H cells was postulated by the presence of polyclonal immunoglobulins in the cytoplasm, the expression of HLA-DR (Ia), and the presence of natural sugar receptors detected by lectins such as peanut agglutinin (PNA-binding).45,46 The interdigitating reticulum cell or T-zone macrophage was proposed as the cell of origin because, like RS-H cells, this cell expresses CD15, HLA-DR, the transferrin receptor, intercellular adhesion molecule-1 (ICAM-1), or CD54, and forms spontaneous T-cell rosettes.47,48 Molecular analyses of single cells indicate that RS-H cells largely represent clonal populations, as discussed below.
LYMPHOCYTE ANTIGEN RECEPTOR GENE STUDIES
Because the configuration of antigen receptor genes is a reliable clonal marker of the B-cell lymphomas, these genes were studied for clues to the etiology of Hodgkin lymphoma. However, it was more challenging to detect clonal populations in Hodgkin lymphoma, since RS-H cells comprise less than 1 to 2 percent of the total cell population, the limit of detection for the DNA hybridization methods used in most studies. The majority of studies in unselected cases demonstrated a germline configuration of antigen receptor genes.49,50,51,52 and 53 Clonal immunoglobulin heavy-chain and light-chain rearrangements were reported in cases selected for a larger proportion of RS-H cells or enrichment for these cells in vitro, but clonality was not confirmed by others.51,53,54
In 1994, RS-H cells were isolated by micromanipulation of histologic sections of three cases of Hodgkin lymphoma and individual cells analyzed for immunoglobulin variable gene rearrangements by polymerase chain reaction (PCR).55 In each case a single variable gene rearrangement was amplified, indicative of a single clone. In 1997 evidence was found for clonal gene rearrangements in 13 of 14 cases.56 The rearranged VH genes carried extensive somatic mutations, indicating a germinal center origin. The presence of stop codons in some RS-H cells has led to the hypothesis that these cells have acquired crippling mutations that prevent antigen selection but escape apoptosis through some transforming event.57 Of considerable interest with regard to possible mechanisms of escape, constitutive expression of the nuclear transcription factor NFkB has been found in R-SH cells, and inactivation of NFkB in cell lines restored sensitivity to apoptosis.58 The lost capacity to express functional antigen receptor may be due to mutations in the untranslated regions as well as the coding region of the immunoglobulin gene.59
Single-cell analyses in lymphocyte predominant Hodgkin lymphoma demonstrated identical rearranged variable genes, but sequencing studies demonstrated that they were highly mutated.60,61 and 62 The monoclonal expansion of cells with intraclonal diversity suggests that the L&H cells are of germinal center origin.
Immunoglobulin variable gene rearrangements have also served as clonal markers when multiple sites were examined and at primary diagnosis and upon relapse.63,64 This observation of an identical clone at diagnosis and upon relapse after intensive treatment defines the malignant nature of RS-H cells. A common B-cell precursor has also been reported for two cases of classic Hodgkin lymphoma and non-Hodgkin lymphoma.65
In sum, the RS-H cell in most cases of Hodgkin lymphoma represent monoclonal outgrowths of germinal center B cells that have lost the ability to express antigen receptor through crippling mutations, which in turn, escape apoptosis through mechanisms such as viruses or regulator genes.66
The demonstration that transforming proteins related to Epstein-Barr virus (EBV) are capable of upregulating BCL-2 in cultured cells created further interest in a relationship between BCL-2 expression and Hodgkin lymphoma. However, correlation between BCL-2 expression, seen in about 35 to 40 percent of cases, and EBV detection or expression of EBV-related transforming protein has not been found.37,67,68 Whereas BCL-2 expression does not appear to correlate with EBV-infection or the t(14;18) translocation, several reports suggest that BCL-2 expression may be related to prognosis, as has been established in the non-Hodgkin lymphomas.69,70
The tumor suppressor gene p53 has been found in most cases of classical Hodgkin lymphoma with nuclear accumulation.71,72 and 73 The significance of this finding remains uncertain as mutations in the p53 gene have been rarely detected.72,74 Overexpression of MDM2 gene product, an antagonist of p53, has been described in RS-H cells.75 Preservation of p53 function is suggested by expression of p21 in a proportion of RS-H cells.76 To date, no characteristic patterns of genomic alteration or deregulated expression of oncogenes have been detected but clinical correlative data are just emerging.
Karyotypes are usually hyperdiploid with structural abnormalities but without pathognomonic chromosomal aberration or specific defects. Relatively few cases have been well documented by banding techniques due to the paucity of RS-H cells and the difficulty of growing the cells in culture. However, clonal populations with numeric or structural chromosome abnormalities have been demonstrated by cytogenetic studies in over half of the cases that have been well-studied.77,78 and 79
In one large series, the most common breakpoints identified (11q23, 14q32, 6q11–21, and 8q22–24) are shared with the non-Hodgkin lymphomas, and this has been used as further support of a lymphoid origin.77 Deletions or translocation of the short arm of chromosomes 12 and 13 have also been described.77 The most commonly observed aberrations in a genetic analysis of sorted RS-H cells using comparative genomic hybridization were a loss on 16q11–21, a gain on 1p13, and a gain on 7q35–36.80 The large number of chromosomal alterations, gains, and losses in each studied case, suggests that genetic stability plays a role in the etiology of Hodgkin lymphoma.
The t(14;18) (q32,q21) translocation in which BCL-2 on chromosome 18 is juxtaposed to the joining region of the immunoglobulin heavy-chain gene has been the subject of several investigations in Hodgkin tissues. Although rearranged BCL-2 was found in about a third of the cases in one report, using PCR technique, subsequent studies failed to confirm this finding.81,82 and 83 Using micromanipulation, it has been established that the translocation is found in bystander B cells.84 However, identical clonal rearrangements were identified in a composite follicular and Hodgkin lymphoma.65
ASSOCIATION WITH EBV
Although long suspected on the basis of epidemiological and serologic data, the presence of EBV genomes in Hodgkin lymphoma was not confirmed until 1987.85 With highly sensitive in situ hybridization methods, there is agreement that about 50 percent of Hodgkin cases are EBV-associated and associated with a monoclonal population of cells. An active role for EBV in pathogenesis is further supported by the demonstration that EBV-positive malignant cells express the viral latent-membrane protein (LMP).86,87 This protein has transforming potential in transfection assays and upregulates a number of cellular genes. However, EBV cannot be implicated as the transforming factor in all cases because it is detectable in only half the cases. As discussed below, detection of EBV genomes is positively associated with mixed cellularity histology, very young and old age, low socioeconomic status, and human immunodeficiency virus (HIV) infection.
ASSOCIATION WITH THE NON-HODGKIN LYMPHOMAS
There are numerous reports of the coexistence of Hodgkin lymphoma with a non-Hodgkin lymphoma, either occurring as sequential events or in the same site, where they are referred to as composite. The most common association is between lymphocyte predominance and large cell lymphoma.86,88,89 The association of other subtypes of Hodgkin lymphoma is common with follicular lymphoma.90 In a series of cases with coexisting CLL and RS-H cells, several patients subsequently developed disseminated Hodgkin lymphoma.91,92 While these findings are consistent with a B-lineage origin of RS-H cells, rare association with mycosis fungoides, a T-lineage neoplasm, has been reported.93,94
With microdissection techniques, the clonal relationship between the non-Hodgkin lymphomas/leukemia and Hodgkin lymphoma can be addressed. Such studies confirmed a clonal relationship in Hodgkin lymphoma and CLL.95 Amplification and sequencing of genomic DNA from the rearranged immunoglobulin variable chain genes from two patients with both Hodgkin lymphoma and non-Hodgkin lymphoma (one follicular and one T-cell rich) demonstrated clonal identity.65 In contrast, a small non-cleaved-cell lymphoma was found to be derived from the same clone of B cells as that accounting for a preceding Hodgkin lymphoma.96
The relative amounts of collagen sclerosis and inflammatory cells, and the cytology of the malignant RS-H cells, define the histologic subtypes of Hodgkin lymphoma. It is hypothesized that these subtypes result from the cytokines elaborated by RS-H cells or the “bystander” cells. The autocrine or paracrine interactions between RS-H and bystander cells are complex. Observations have been made on primary tissues and several well-characterized Hodgkin-lymphoma cell lines. CD40 ligand (CD154), IL-4, IL-6, and IL-9 appear to stimulate the growth of RS-H cells.97,98,99,100,101 and 102 RS-H cells secrete a variety of cytokines that may be responsible for the presence and characteristics of the nonmalignant cells surrounding them. In turn, these reactive cells produce cytokines that can affect RS-H cells and further influence the surrounding cellular milieu. For example, secretion of IL-5 by RS-H cells attracts eosinophils, which then express CD30-ligand (CD30L) and transforming growth factor beta (TGF-b). Another example is IL-8 release by RS-H cells which attracts neutrophils that express CD30L. Cytokines can also influence the expression of RS-H cell surface adhesion molecules such as CD54 (ICAM-1), LDFA-3, CD40, and the integrin family including CD15 and others. RS-H cells have receptors for interleukin-2, CD30L, and CD154.103 Human IL-10 expression has been associated with EBV infection in Hodgkin lymphoma. Because of its potential inhibitory effects on cell-mediated immunity, expression of IL-10 may inhibit development of cytotoxic responses directed at this antigen.104 An IL-9-mediated autocrine loop has been suggested for Hodgkin lymphoma; of interest, in vivo overexpression of IL-9 results in the development of thymic lymphomas.105 Elevated levels of IL-13 were identified in RS-H cells by gene expression pattern analyses.106 Treatment of a Hodgkin lymphoma-derived cell line with a neutralizing antibody resulted in inhibition, suggesting that modulation of the IL-13 signaling pathway might be a target for future therapeutic strategies. The expression of selected cytokines and factors—IL-2 receptor (IL-2R), IL-6, IL-10, and CD30—in tissues and secretion into the serum have been found to correlate with constitutional symptoms and advanced disease.107,108,109,110 and 111
The different types of Hodgkin lymphoma have different quantities of cytokines, and these appear to relate to the distinctive histopathologic features. Adhesion molecules, modulated by cytokines, affect the interaction of RS-H cells with surrounding T cells and probably affect the spread of disease.
Hodgkin lymphoma is associated with abnormal cellular immunity. Abnormalities include impaired delayed cutaneous hypersensitivity, decreased natural killer cytotoxicity, enhanced suppressor T-cell and suppressor monocyte activity, high levels of circulating immune complexes with increased immunoglobulin production, production of antilymphocyte and anti-Ia antibodies, and an impaired proliferative response to T-cell mitogen stimulation and lymphokine production.112,113,114 and 115 Some of these defects persist for several years following successful treatment. Patients observed to be free of disease for several years continued to have suppressed hypersensitivity to neoantigens, although anergy to recall antigens was reversible.116,117 and 118 Responses to concanavalin-A and phytohemagglutinin were significantly less than in normal controls.119 Lymphopenia is common in advanced Hodgkin lymphoma and is also seen as a consequence of radiotherapy. This treatment primarily decreases the CD4+ T-cell population that slowly regenerates after treatment is completed.120 Profound defects in naive CD4 and CD8 T cells persist up to 30 years in patients treated with mediastinal irradiation.121
The immunophenotype and cytokine production of the T cells surrounding RS-H cells are consistent with a Th2-type response, which is characterized by IL-4 and interferon gamma (IFN-g) production, but not IL-2. Absence of IL-2 production is also characteristic of anergic cells. The cytokine TGF-b produced by RS-H cells has potent immunosuppressive effects. The immune response may also be modulated toward a Th2 type by IL-10. Production of the chemokine TARC by RS-H cells provides a possible explanation for the attraction of a Th2-subset in Hodgkin lymphoma.122 The expression of cytokines described above on RS-H cells and their natural ligands by surrounding lymphocytes may also play a role. For instance, expression of the FAS ligand (CD95L) may induce apoptosis of activated, FAS-expressing, CD8+ T cells and NK cells. A range of factors appears to contribute to the apparent paradox of a rich inflammatory infiltrate, ineffective host response, and generalized immune deficiency.
The incidence of Hodgkin lymphoma in the United States has been stable over the past several decades with an incidence of 3.2 per 100,000 population.123 It is higher among men than women and higher among Americans of European than of African descent.
Unlike most malignancies, Hodgkin lymphoma has a bimodal age-incidence curve: rates rise through early life, peaking in the third decade and declining until age 45, after which the incidence increases steadily.124,125 and 126 The clinical presentation tends to be different in childhood (ages 0 to 14), young adult (15 to 34 years), and older adults. The nodular sclerosis subtype predominates in young adults while the mixed cellularity subtype is more common in the pediatric population and at older ages. There is a male predominance at all ages, but this is most marked in childhood cases (85 percent).
An increased risk of Hodgkin lymphoma in the young adult population has been associated with high socioeconomic status in multiple studies.124,127,128 High intelligence, small family size, single-family dwelling, and high educational attainment of patients and their immediate families have all been associated with increased risk.
The geographic patterns vary for the three major age groups: the incidence of Hodgkin lymphoma is greater in childhood, and there is a predominance of mixed cellularity histology in less developed countries, while the incidence peaks in young adulthood and is associated with more favorable histologic subtypes in developed countries.129 An intermediate picture may be seen in rural areas of developing countries. Together these data suggest a remarkable association between socioeconomic and environmental factors in the incidence of Hodgkin lymphoma.
POSSIBLE INFECTIOUS ETIOLOGY
The demographic features have long supported the concept that one or more subtypes of Hodgkin lymphoma have an infectious etiology. In 1966 MacMahon proposed that the first age peak in young adults was infectious in nature while that seen in the second peak resulted from causes similar to other lymphomas.124
Several reports of clustering of Hodgkin lymphoma at the time of diagnosis suggested the possibility of infectious transmission.130,131 The weaknesses of the retrospective methodology in these studies have been critically assessed, and further statistical analyses indicate that these likely occurred by chance alone.129 Some population-based studies have found significant case aggregation (shared exposure) in schools, but these results have been seriously questioned on the basis of the methods used.132,133,134 and 135
Several large studies have demonstrated that a prior history of serologically confirmed infectious mononucleosis confers about a threefold increased risk of young adult Hodgkin lymphoma.136,137 and 138 Elevations in titers of EBV, the etiologic agent of infectious mononucleosis, have been reported in people diagnosed with Hodgkin lymphoma. A large population study showed that people who developed Hodgkin lymphoma had abnormally high titers of some anti-EBV antibodies in prediagnostic sera.139 The demonstration of EBV viral genomes in RS-H cells discussed above further supports a relationship between EBV and Hodgkin lymphoma.
The epidemiological features of Hodgkin lymphoma appear to fit a polio model where delayed age at infection leads to an increased risk of young adult disease. In less developed countries where early infection is probable, childhood Hodgkin lymphoma is more common than young adult disease while the reverse is true in developed countries. A similar pattern of geographic occurrence and age at initial infection also occurs for EBV infection. However, the presence of EBV in tumor tissue presents some unexpected results.
Whereas it is the young-adult, nodular sclerosis type that is associated with the epidemiological factors that suggest an association with EBV, the highest proportion of EBV-positive cases are in the mixed cellularity category.140,141 Several studies report a high incidence of EBV association, 85 to 100 percent in pediatric Hodgkin lymphoma.142,143,144 and 145 Geographic, ethnic, and racial factors have been implicated in the association of EBV with pediatric Hodgkin lymphoma.143 A high frequency of EBV within RS-H cells is reported in HIV-infected individuals with Hodgkin lymphoma.146
Evidence that supports a genetic basis for increased susceptibility to Hodgkin lymphoma includes the increased risk among siblings and close relatives and an association with other tumor types in a familial setting. Hodgkin-lymphoma-prone families, with or without other forms of cancer, have been described.147,148,149 and 150 Hodgkin lymphoma has also been described in monozygotic twins.151,152 and 153 Examples of consanguinity have been reported as well.127,154 The fact that the time interval between diagnoses in affected siblings is shorter than their age differences supports an environmental influence in Hodgkin-lymphoma-prone families.155 The increased incidence in same sex siblings (ninefold) versus opposite sex siblings (fivefold) also supports an environmental influence.156 However, connubial occurrence in Hodgkin lymphoma is rare.157 Lack of concordance of EBV association in tissues and serology does not indicate a viral role in the pathogenesis in familial Hodgkin lymphoma.158
In addition to the presentation of both Hodgkin lymphoma and a non-Hodgkin lymphoma in the same individual, both diagnoses have been noted in lymphoma-prone families, favoring a common mechanism of lymphomagenesis.149,159,160
Immunoregulatory genes within or near the major histocompatibility complex that may govern susceptibility to viral infections have been postulated to influence susceptibility to Hodgkin lymphoma.161 This hypothesis is supported by the data that demonstrate that patients have lifelong, depressed cellular immunity that also has been noted in their healthy relatives.162 Studies have implicated specific human lymphocyte antigen (HLA) regions in the etiology of Hodgkin lymphoma, and there is increased HLA haplotype sharing among relatives in multiple-case families.161,163,164 Epidemiological and prognostic associations between HLA-DP alleles and Hodgkin lymphoma have been made in several studies using molecular techniques.165,166 and 167
HISTORY AND PHYSICAL EXAMINATION
Constitutional symptoms, some of which confer a less favorable prognosis, may accompany the diagnosis. Patients with fever in excess of 38°C, drenching night sweats, and weight loss exceeding 10 percent of baseline body weight during the 6 months preceding diagnosis are designated as having “B” disease. Fevers, present in 27 percent of patients at diagnosis, are usually of low grade and irregular.168 Rarely, a cyclic pattern of high fevers for 1 to 2 weeks alternating with afebrile periods of similar duration is present at diagnosis. This classic Pel-Ebstein fever is virtually diagnostic.169,170 Generalized pruritus, often accompanied by marked excoriation, may be present at diagnosis, but is not of prognostic significance.171 Pain in involved lymph nodes immediately after the ingestion of alcohol is a curious complaint that is nearly specific to Hodgkin lymphoma. It occurs in fewer than 10 percent of patients and has no prognostic significance.172 The etiology of these symptoms has been the subject of speculation but remains unexplained. Patients with extensive intrathoracic disease may present with cough, chest pain, dyspnea, and, rarely, hemoptysis. Infrequently, patients present with bone pain, including the constellation of back pain accompanied by signs and symptoms of spinal cord compression.
Detection of an unusual mass or swelling in the superficial lymph nodes is the most common presentation. Lymphadenopathy is usually nontender and has a rubbery consistency. A diffuse, puffy swelling rather than a discrete mass may be apparent in the supraclavicular, infraclavicular, or anterior chest wall regions. Infrequently, compression of the superior vena cava will result in facial swelling and engorgement of the veins in the neck and upper chest. Auscultation of the chest may reveal a pleural effusion. Palpation is an insensitive method for the detection of intraabdominal adenopathy or organ enlargement, but examination should be oriented toward the liver, spleen, and upper retroperitoneal area. While parenchymal or meningeal involvement of the central nervous system is rare, paraneoplastic syndromes of several varieties have been described. Patients have presented with signs of progressive multifocal leukoencephalopathy,173 subacute cerebellar degeneration,174,175 necrotizing myelopathy,176 subacute sensory or motor neuropathy,177 episodic neurologic dysfunction,178 memory loss,179 the Guillain-Barré syndrome,180 and granulomatous angiitis of the central nervous system.181
Intrathoracic disease is present at diagnosis in two-thirds of patients. Mediastinal adenopathy is common, particularly in young women with nodular sclerosis.182 Hilar adenopathy, pulmonary parenchymal involvement, pleural effusions, pericardial effusions, and chest wall masses may be appreciated by computed tomography of the chest; these are more common in the presence of extensive mediastinal disease.
Bipedal lymphography is accomplished by cannulation of the lymphatics on the dorsum of each foot, followed by the injection of a radiopaque contrast material. When the lymphangiographic interpretation was correlated with histologic findings in surgically removed lymph nodes in 197 consecutive patients, the overall predictive accuracy was 92 percent, with no false negatives and a 25 percent false positive rate.183 Extensive experience with lymphography has demonstrated that about 30 to 60 percent of patients with clinical disease limited to the supradiaphragmatic regions had involvement of the abdominal or pelvic lymph nodes.184 A significant advantage of this technique is that contrast material may remain for months to years and can be used to assess the response to treatment and in follow-up.
Computerized tomography (CT) of the chest, abdomen, and pelvis is routinely employed in diagnostic evaluation. Although technologic advances have greatly increased the resolution of this technique, the correlation with histologic involvement of the spleen has been disappointing. CT has been valuable in detecting lymph nodes such as celiac, portal, splenic hilar, and mesenteric which are not appreciated by lymphography. Although lymphography is more sensitive than CT because it can detect filling defects in normal-size lymph nodes, it is becoming less and less available except at specialized treatment centers.185,186 and 187
Gallium-67 scintigraphy is useful in evaluating the mediastinum or areas that appear abnormal on bone scan and in the evaluation of residual masses following treatment. Single photon-emitted computed tomography (SPECT) increases the accuracy of the gallium scan. Whole-body positron emission tomography (PET) correlates well with CT evaluation and may demonstrate additional areas of disease, although this information results in few changes in stage or therapy.188,189 Magnetic resonance imaging has been disappointing in the evaluation of abdominal disease or residual mediastinal masses in treated patients.190,191
CLINICAL AND PATHOLOGIC CORRELATION
There is a strong correlation among age at onset, the anatomic extent of disease, and histologic subtype of Hodgkin lymphoma (see Table 102-1). About 10 percent of patients present with nodular lymphocyte predominance (NLPHD) which, as stated above, is considered to be a special subtype. Progressive transformation of germinal centers may precede or follow NLPHD in other sites.44,192 The cellular composition is predominantly benign B lymphocytes, with or without histiocytes. Patients most commonly present with stage I disease (70 percent), particularly in the axillae, and there is a 4:1 male predominance.193 This subtype has been associated with large-cell non-Hodgkin lymphoma as a composite tumor, or the large cell lymphoma may occur at a later date.88,89
Nodular sclerosis is noted for its distinctive histologic features and frequent involvement of the lower cervical, supraclavicular, and mediastinal lymph nodes in adolescents and young adults, particularly females. About 70 percent of patients present with limited-stage disease. Nodular sclerosis constitutes the majority of cases, ranging from 40 to 70 percent. One of the distinguishing histologic features is the lacunar cell, an RS variant that results from retraction of the cytoplasm of RS cells during formalin fixation. Another feature is the thickened capsule and fibrous bands which divide the lymphoid tissue into cellular nodules (Fig. 102-1). Nodular sclerosis has been subclassified as type I or II based on the frequency of malignant cells and normal lymphocytes. The malignant cells are numerous in the lymphocyte-depleted type (II), also referred to as the syncytial variant. The clinical and prognostic significance of nodular sclerosis subtypes is controversial.194,195
Mixed cellularity Hodgkin lymphoma involves both pediatric and older age groups and is more commonly associated with advanced-stage disease, constitutional symptoms, and immunodeficiency. About 30 to 50 percent of patients have this histology. Classic RS-H cells are easily found amid a cellular background composed of lymphocytes, eosinophils, plasma cells, and histiocytes (Fig. 102-1). A worse prognosis has been characteristic of this subtype in the historical literature, but these differences have been largely blurred by modern therapy.
The incidence of lymphocyte-depletion Hodgkin lymphoma is much lower than originally reported, as many cases have been reclassified as non-Hodgkin lymphoma.196 Two subtypes have been described: reticular and diffuse fibrosis. The reticular variant contains abundant pleomorphic neoplastic cells. The more common diffuse fibrosis variant, as the name implies, has a prominent fibroblastic proliferation with few normal lymphocytes. RS-H cells are sparse. The disease presents in the older age group with symptomatic, extensive disease. Peripheral and mediastinal adenopathy is much less common than in other cases of Hodgkin lymphoma.197 Presentation with fever of unknown origin, jaundice, hepatosplenomegaly, or pancytopenia is not uncommon. This subtype is also associated with the acquired immunodeficiency syndrome.
The 1999 World Health Organization classification of lymphoma introduces a new subtype for the first time in 25 years. Lymphocyte-rich Hodgkin lymphoma was discovered during an expert pathology review of cases of lymphocyte predominance.198 As noted above, the two subtypes differ subtly on morphologic grounds, but the major difference is that the RS-H cells in lymphocyte-rich have a classic immunophenotype. The presenting features are very similar, although patients with the lymphocyte-rich subtype tend to be older.
ANATOMIC DISTRIBUTION OF DISEASE
About 60 to 80 percent of clinical presentations are in the cervical nodes, 6 to 20 percent are in axillary nodes and 6 to 12 percent in the inguinal nodes.168 A minority of patients presents with exclusive subdiaphragmatic disease. Figure 102-2 illustrates the anatomic distribution of sites of involvement in 285 consecutive, unselected, and untreated patients. Involvement of abdominal lymph nodes and spleen was documented in 272 of these patients at staging laparotomy, a surgical diagnostic procedure in which the intraabdominal and pelvic lymph nodes are sampled, the spleen is removed and examined pathologically in thin slices, the liver is biopsied by needle and wedge technique, and the bone marrow is biopsied. The frequency of splenic involvement at laparotomy in untreated patients averages 37 percent in 17 published series.168 Involvement is strongly dependent on histologic subtype; it is present in 60 percent of mixed cellularity and lymphocyte depletion cases compared with 34 percent of lymphocyte predominance or nodular sclerosis. Hepatic and marrow diseases are invariably associated with splenic involvement.
FIGURE 102-2 Anatomical distribution of sites of involvement in 285 consecutive, previously untreated patients with Hodgkin disease, 272 of whom were submitted to staging laparotomy with splenectomy. (Reprinted with permission from Kaplan et al.206)
Two different theories, the contiguity theory of Kaplan and Rosenberg199 and the susceptibility theory of Smithers,200 have been proposed to account for the mode of spread of Hodgkin lymphoma. In support of the former, most cases of Hodgkin lymphoma appear to spread via lymphatic channels to contiguous lymphatic structures in a predictable, nonrandom pattern. Controversy has surrounded the mode of spread to the spleen, which lacks afferent lymphatics. When four or more lymph node regions are involved, the possibility of spread by hematogenous distribution appears more likely.201 Disseminated disease is more common in mixed cellularity and lymphocyte depletion, consistent with the presence of vascular invasion reported in these subtypes.201 While vascular invasion is controversial, it has been reported to be more common in the spleen compared to lymph nodes and to connote a poor prognosis.202,203 Even when involvement beyond the lymphatic system occurs, patterns of association are evident as described by Kaplan and Rosenberg.
The extent of Hodgkin lymphoma is classified using the four-stage Ann Arbor classification, as indicated in Table 102-2.19 Clinical stage refers to the results of physical, radiographic, and laboratory examination, while pathologic stage refers to the use of additional biopsy procedures. The presence or absence of constitutional symptoms further characterizes the classification. Extranodal disease, representing extracapsular extension of lymph node disease that can be treated with a curative dose of radiotherapy, is distinguished from disseminated, stage IV disease. The correlation of this staging classification system with prognosis has been extensively verified. Prognostic information such as mediastinal bulk, other bulky nodal masses, and the extent of subdiaphragmatic nodal disease is included in a modification of the Ann Arbor system, known as the Cotswold classification.204
TABLE 102-2 ANN ARBOR STAGING CLASSIFICATION*
Recommended staging procedures for untreated patients have evolved with changes in therapy. Exploratory laparotomy and splenectomy are reserved for a small subset of patients who are candidates for management with limited radiotherapy only. Historically, staging laparotomy advanced about one-third of clinical stage I and II patients to pathologic stage III and IV while reducing fewer than one-fourth of clinical stage III patients to pathologic stage I or II.205,206,207 and 208 Prognostic indicators of laparotomy findings have been described.209,210 For instance, clinical stage I women, patients with intrathoracic-only disease or high neck disease of favorable histology, and men with lymphocyte predominance have less than a 5 to 10 percent risk of subdiaphragmatic disease. In Europe and Canada, where most patients were clinically staged without laparotomy, a number of prognostic factors for the risk of relapse were identified as discussed below.
Marrow involvement occurs in 5 to 20 percent of new patients and is more common in patients of older age, advanced stage, less favorable histology, or those with constitutional symptoms or immunodeficiency. Because the marrow is almost never involved in young, asymptomatic patients with favorable clinical stage I or II presentations, marrow biopsy may be omitted in their staging. Bone scans are indicated in patients with bone pain; skeletal x-rays may demonstrate osteolytic, osteoblastic, or mixed lesions.
There are no diagnostic laboratory features of Hodgkin lymphoma. A complete blood count may reveal granulocytosis,211 eosinophilia,212 lymphocytopenia,213 thrombocytosis,214 or anemia.215 The anemia is usually due to chronic disease but rarely may be due to hemolysis secondary to high fever216 or associated with a positive direct antiglobulin test (Coombs’ test).217 Thrombocytopenia may occur as a result of marrow involvement, hypersplenism, or an autoimmune mechanism.218,219 and 220 Autoimmune neutropenia has been reported.221 Cytopenias are particularly common in advanced-stage disease and lymphocyte depletion histology. Elevation of the erythrocyte sedimentation rate is most common in advanced disease and correlates with constitutional symptoms.222,223 The degree of elevation has been correlated with prognosis, particularly in limited-stage disease.224 Although nonspecific, it may be useful in follow-up, heralding recurrent disease. Serum lactate dehydrogenase levels are elevated in 30 to 40 percent of patients at diagnosis.225,226 The alkaline phosphatase may be elevated, nonspecifically in limited disease or in association with involvement of liver, bone, or bone marrow in advanced disease.227 Hypercalcemia is unusual but when it occurs may be secondary to synthesis of increased levels of 1,25-dihydroxyvitamin D by Hodgkin lymphoma tissue.228 A variety of other abnormalities have been reported, including hypoglycemia229,230 due to an autoantibody to insulin receptors and inappropriate secretion of antidiuretic hormone.231
Anemia, granulocytosis, lymphopenia, and low serum albumin constitute four of seven adverse prognostic factors identified in advanced Hodgkin lymphoma by an international consortium.232 As in the non-Hodgkin lymphomas, serum beta 2 microglobulin levels correlate with tumor burden and prognosis.233 Serum levels of cytokines including soluble CD30, IL-6, IL-10, and the IL-2 receptor have been reported to correlate with constitutional symptoms and advanced disease.107,108,109,110 and 111
Examination of pleural fluid may reveal transudative, exudative, or chylous properties. Because cytology rarely yields diagnostic RS-H cells, the etiology is most often considered to be one of central lymphatic obstruction. Laboratory abnormalities may be prominent in rare presentations of Hodgkin lymphoma. These include abnormal liver function tests associated with marked enlargement of porta hepatis nodes and biliary obstruction or intrahepatic cholestasis.234 The nephrotic syndrome is a rare presentation.235,236
Clinically enlarged lymph nodes may be associated with a variety of infectious, inflammatory, autoimmune, or neoplastic disorders. Biopsies of suspicious adenopathy should be reviewed by a competent hematopathologist. The differential diagnosis is usually between Hodgkin lymphoma and a non-Hodgkin lymphoma. The syncytial variant of nodular sclerosis may be particularly troublesome. Mixed cellularity Hodgkin lymphoma may demonstrate a spectrum of pattern and cellular and stromal composition and should be distinguished from peripheral T-cell lymphoma and T-cell-rich, B-cell lymphoma. In these cases and those of lymphocyte depletion histology, immune markers as described above have proved invaluable. Nonneoplastic conditions that may simulate Hodgkin lymphoma include viral infections, particularly infectious mononucleosis. Depleted nodes of any histology may resemble the diffuse fibrosis variant of lymphocyte depletion, including the depleted phase of lymph nodes from HIV-infected patients. The diagnosis in an extranodal site depends upon the organ involved and whether there is a known diagnosis of Hodgkin lymphoma. Diagnostic RS cells are not required in liver and bone marrow because the foci of involvement are so small. Of course, the rare presentations of Hodgkin lymphoma, such as those in the CNS, liver, or as a fever of unknown origin, may have an extensive differential diagnosis.
THERAPY, COURSE, AND PROGNOSIS
The goal of treatment is to cure the greatest number of patients with minimal complications. Figure 102-3 illustrates the freedom from progression and overall survival in 363 patients managed at Stanford University from January 1989 through December 1998. At 5 years 98 percent of patients are estimated to be alive and 85 percent are continuously free of disease. These encouraging results have been achieved by combining radiotherapy and chemotherapy, each of which is independently effective in Hodgkin lymphoma, with ongoing efforts to minimize cumulative exposure to each modality.
FIGURE 102-3 Survival data for 363 patients treated at Stanford University from 1989–1998. Overall survival (solid line) was estimated at 98%, and freedom from progression (dashed line) was estimated at 85% at 10 years.
The pioneering work of Vera Peters in Toronto14,15 and of Henry S. Kaplan and his colleagues at Stanford University provided the basis for modern radiotherapy. Hodgkin lymphoma first became a curable neoplasm through the systematic study of the spread of the disease and the use of supervoltage radiotherapy techniques.
Kaplan and others237,238 provided evidence for a tumoricidal dose level. This important concept led to the incorporation of high doses that could permanently ablate Hodgkin lymphoma. Modern supervoltage techniques allow high doses of radiation to be given in large volumes with acceptable normal tissue tolerance. This method has the advantage of increased depth of dose that spares the skin and sharp beam edges that reduce scatter. The modern linear accelerator provides x-rays in the 4- to 8-MeV range. When radiotherapy is used alone, involved fields usually receive doses of 3500 to 4400 cGy with prophylactic doses of 3000 to 3500 cGy to uninvolved tissues, but 3000 cGy may be adequate.239 Tumor doses of 150 to 200 cGy are given daily five times per week.
The classic regions of radiotherapy employed in Hodgkin lymphoma include the mantle, paraaortic region, and pelvis. The mantle region encompassed the cervical, supraclavicular, infraclavicular, axillary, mediastinal, and hilar nodes. The paraaortic region included the splenic pedicle or the spleen, if still intact. Together, these regions were referred to as subtotal lymphoid irradiation. The combination of the paraaortic region and the pelvic region was called an inverted Y, and total lymphoid irradiation referred to the combined mantle and inverted Y regions. In the current management of Hodgkin lymphoma, wide-field irradiation is infrequently used. When used, match lines between fields must not overlap to ensure that the spinal cord does not receive excessive radiation that can result in myelopathy. Pelvic irradiation requires careful shielding of the testes in men and consideration for oophoropexy plus shielding in premenopausal women.240,241
In the setting of combined chemotherapy and radiotherapy treatment, modifications of the mantle field have been made to address adverse consequences of treatment. Figure 102-4 illustrates a typical simulated chest film for a modified mantle. The axillae and the upper neck are not included in the field. Lung blocks are shaped to ensure adequate irradiation of the tumor volume. The whole heart is not treated unless there is evidence of pericardial involvement. A pericardial block is placed at 1500 cGy, and a subcarinal block is placed at 3000 cGy. The technical aspects of radiotherapy are extremely important. These include use of simulators, individually constructed blocks, detailed patient positioning, careful beam definition, and verification of dose with dosimetry.
FIGURE 102-4 Simulated film for radiation treatment of mediastinal Hodgkin disease. The contours of the lung-shielding blocks are outlined. Note that a small portion of the left lung block is cut separately and omitted when mediastinal adenopathy is present. In this case, a dose of 1,500 cGy is given to the heart, and then the block is inserted for the remaining treatment. The subcarinal block is placed after a dose of 3,000 cGy is delivered.
From 1942 through 1963 a number of chemotherapy drugs became available for clinical use.24,25 Nitrogen mustard, other alkylating agents, the antifols, corticosteroids, the vinca alkaloids, and a new agent with exciting activity in Hodgkin lymphoma, procarbazine, were all studied as single agents in advanced disease. While responses were observed, there was no evidence of cure. The first modern combination chemotherapy program was devised by DeVita and colleagues.26 The MOPP program differed from previous attempts in its curative intent, longer (6-month) treatment program, and the introduction of a sliding scale for dose adjustment based upon hematologic toxicity. The national mortality figures for Hodgkin lymphoma decreased by more than 60 percent in the decade that followed the introduction of MOPP chemotherapy.242 In the 20-year follow-up of the original series of 188 advanced-stage patients treated with MOPP, 54 percent were continuously free of disease.243
A number of modifications were made to the original MOPP regimen by others with the intent to reduce acute toxicity, particularly the neuropathy and nausea and vomiting.244 Of the MOPP-like regimens, the MVPP regimen that substitutes vinblastine for vincristine, and the ChlVPP regimen, which substitutes chlorambucil for nitrogen mustard and vinblastine for vincristine, had comparable efficacy with somewhat improved tolerance.245,246,247 and 248 Neither the use of maintenance therapy nor the addition of bleomycin resulted in improved outcome when compared with the original MOPP program administered in full doses.244,249,250 and 251
An important alternative regimen, ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) was effective in the treatment of patients who had failed MOPP.252,253 In addition, as discussed below, this regimen has a different toxicity profile than MOPP. ABVD was subsequently employed alone, in combination with radiotherapy, and used together with MOPP in alternating or “hybrid” programs.254,255,256,257,258,259 and 260
Multiple alternative chemotherapy regimens have been introduced for the treatment of Hodgkin lymphoma. An abbreviated 12-week combination, Stanford V (doxorubicin, vinblastine, vincristine, bleomycin, nitrogen mustard, etoposide, prednisone), has been developed.263,264 Table 102-3 describes the drugs, doses, and schedules of combination chemotherapy programs effective in the management of Hodgkin lymphoma.
TABLE 102-3 COMBINATION CHEMOTHERAPY REGIMENS FOR HODGKIN LYMPHOMA
FAVORABLE, LIMITED-STAGE DISEASE
Favorable, limited-stage disease may be defined as asymptomatic stage I or II supradiaphragmatic disease with no bulky sites and no or only one extranodal site. As defined above, staging may or may not include exploratory laparotomy. Extended field (subtotal lymphoid) radiotherapy, usually administered after staging laparotomy, was the treatment of choice for these patients in the United States for many years. This treatment was based on a pivotal clinical trial in which patients with stage I-IIA disease were randomized to involved field or extended field radiotherapy.265 With more than 15 years follow-up, extended field radiotherapy yielded a highly significant advantage in freedom from relapse, 80 percent, compared with 32 percent for involved field. The overall survival was no different in the two groups due to effective treatment at relapse. Subsequent reports from multiple institutions have confirmed the high rate of cures in stage I and II with extended field radiotherapy. A metaanalysis concluded that more extensive radiotherapy increased the chance of cure by more than 30 percent, although no survival benefit was seen at 10 years.266
A very favorable group of patients (40 years old or younger with nodular sclerosis or lymphocyte predominance, laparotomy-stage I and IIA with mediastinal disease, and ESR less than 70) was studied to determine the role of prophylactic abdominal radiotherapy.267,268 A 1997 update of this randomized trial showed no difference between mantle radiotherapy or subtotal lymphoid radiotherapy either for treatment failure or overall survival.269 These results with mantle irradiation alone in selected laparotomy-stage (PS) patients have been corroborated in other retrospective studies.270,271 and 272
The description of prognostic factors for the probability of occult disease, improvements in radiographic imaging, and the desire to eliminate staging laparotomy have resulted in the more routine use of clinical staging for favorable, limited Hodgkin lymphoma. However, mantle radiotherapy alone is not sufficient for clinical stage patients, even those selected for very favorable prognostic features. Mature follow-up of a clinical trial resulted in a 6-year event-free survival of 66 percent, an unacceptably high rate of relapse among this very favorable group of clinical stage IA women aged 40 or younger with lymphocyte predominance or nodular sclerosis histology.273
The treatment of early-stage disease has become so successful that at 15 to 20 years, the overall mortality rate from other causes exceeds deaths due to Hodgkin lymphoma.274 As detailed below, the largest cause of mortality is second cancers, and these seem to be related to the extent of radiotherapy treatment. Thus, there is interest in reducing the volume and dose of radiotherapy in limited Hodgkin lymphoma without compromising the therapeutic results.
Stanford University first demonstrated that chemotherapy could substitute for extended field radiotherapy in stage I and II patients. In sequential clinical trials, MOPP and VBM (vinblastine, bleomycin, and methotrexate) were given as adjuvants to involved field radiotherapy with equivalent or superior results.265,275 In a subsequent trial, clinical stage I and II patients were randomized to subtotal lymphoid radiotherapy or a combination of limited radiotherapy and VBM, with excellent results in both treatment arms.276 Six cycles of EBVP (epirubicin, bleomycin, vinblastine, and prednisone) plus involved field radiotherapy or subtotal radiotherapy were randomly assigned selected clinical stage I-IIA patients with favorable prognostic features. At 6 years, the event-free survival on the combined modality arm was 90 percent, significantly higher than radiotherapy alone.273
In recent years, clinical trials have been designed to test the optimal number of cycles of chemotherapy and the volume and dose of radiotherapy when both modalities are used in limited Hodgkin lymphoma. Greater than 95 percent disease control was achieved with four cycles of ABVD and radiotherapy. No advantage of extended field over involved field treatment was found.277 Preliminary data in favorable I-II patients indicate that two cycles of ABVD followed by subtotal radiotherapy are superior to subtotal radiotherapy alone.278 Excellent preliminary results, 91 percent progression-free survival at 3 years, have also been published with just 4 weeks of VAPEC-B (vinblastine, doxorubicin, prednisone, etoposide, cyclophosphamide, and bleomycin) chemotherapy and limited radiotherapy.279 An 8-week course of Stanford V and limited field and dose radiotherapy appear to yield comparable results in favorable CS I-IIA patients as 95 percent event-free survival at 3 years has been reported.280 Although these outstanding results with modest therapy are encouraging, the strategy of short-course chemotherapy and involved field radiotherapy allows omission of mediastinal radiotherapy, a source of considerable morbidity, in just 20 percent of patients. Thus there is considerable interest in chemotherapy alone in limited-stage Hodgkin lymphoma.
MOPP and ChlVPP have been studied in pediatric Hodgkin lymphoma.281,282 Excellent results have been achieved with both, with cures above 75 to 80 percent. Similarly, an excellent outcome for chemotherapy alone was reported for CVPP (cyclophosphamide substituted for mustard) alone compared with combined chemotherapy and radiotherapy.283 MOPP chemotherapy alone and subtotal lymphoid irradiation have been compared in pathologically staged patients in two prospective randomized trials. In a study of stage I-IIA or B and selected IIIA patients,284 freedom from progression at 10 years significantly favored chemotherapy; however, when the subset of patients with massive mediastinal or stage III disease was excluded, the difference was no longer significant. In a study of similar design,285 no difference was seen in relapse-free survival among stage I and IIA patients, but the overall survival significantly favored the radiotherapy group (93 percent versus 56 percent at 8 years) due to the limited ability to cure patients who failed MOPP. It was speculated that the chemotherapy arm might induce chemoresistant clones. Because MOPP chemotherapy has an undesirable toxicity profile, clinical trials in Europe and North America are exploring the use of ABVD in limited Hodgkin lymphoma. Ongoing studies in North America and Europe test the efficacy of ABVD alone, the number of cycles of chemotherapy (two versus four) and the optimal dose of radiotherapy (2000 cGy versus 3000 cGy).
Several subsets of limited patients deserve further mention. CS I patients presenting with inguinofemoral disease may be treated with inverted Y (paraaortic and pelvic) radiation only. Other subdiaphragmatic presentations of Hodgkin lymphoma are best managed with combined modality therapy or chemotherapy alone. A number of reports indicate that patients with extensive mediastinal disease have a much less favorable outcome with radiotherapy alone.286,287 About half of patients with masses greater than one-third of the chest diameter relapsed. Although selected patients have been managed with radiation therapy incorporating careful CT planning, most are managed with combined treatment as in the following section.288 Similarly, IIB patients are generally managed with chemotherapy or combined modality. Although a series of PS IIB patients with extended field radiotherapy enjoyed an excellent outcome, the requirement for laparotomy and the development of less toxic chemotherapy led to abandoning this approach for most IIB patients.289
LOCALLY EXTENSIVE, LIMITED-STAGE HODGKIN LYMPHOMA
Extensive mediastinal Hodgkin lymphoma is frequently accompanied by extranodal extension to lung, pericardium, and chest wall. Pleural effusions may also be seen. The use of combined chemotherapy and radiation (combined modality therapy) results in freedom from relapse in 80 percent or more of such patients compared with only 40 to 55 percent following radiation alone.287 Significant numbers of patients can be effectively treated with chemotherapy after radiation failure, and their ultimate survival is similar to patients treated with combined modality. However, in addition to the psychological trauma of recurrent disease, patients managed with radiotherapy alone are subject to the potential morbidity of extensive radiation to normal heart and lung tissue. In question are the optimal chemotherapy regimen and its duration, the radiation dose, and the sequence of therapy for combined treatment. Two hundred thirty-two patients were randomized to six courses of MOPP or ABVD combined with subtotal lymphoid irradiation.256,290 Many of these patients had extensive mediastinal disease. The ABVD/RT combination was significantly superior to MOPP/RT as measured by both freedom from progression and survival. The major concerns in choice of chemotherapy relate to late effects, specifically the concern for sterility and acute leukemia ascribed to alkylating agents and the potential for enhanced cardiopulmonary toxicity with ABVD, especially when combined with radiotherapy. Subsequently, the efficacy of four cycles of ABVD and involved field radiotherapy in stage I-II patients, many of whom had massive mediastinal disease, was reported.277 The 12-week Stanford V program together with modified mantle radiotherapy was very effective in these patients also.263 As described below, an Intergroup randomized clinical trial testing ABVD with radiotherapy versus Stanford V with radiotherapy is in progress. There are relatively few data regarding the use of chemotherapy alone for bulky mediastinal Hodgkin lymphoma. A retrospective report of the results with MOPP alone or MOPP with adjuvant radiotherapy in this subset described cure of less than half of these patients with MOPP alone, leading to the recommendation of combined treatment for massive mediastinal Hodgkin lymphoma.291
Historically, there was controversy regarding the treatment of stage IIIA Hodgkin lymphoma. Because the most favorable presentations (involvement of the spleen, celiac, splenic hilar, or porta hepatis nodes only) required total nodal irradiation, there is general agreement that IIIA patients should be managed with chemotherapy alone or with combined modality treatment if bulky mediastinal or other sites are observed. Patients with IIIA disease fared superbly in the original NCI MOPP trial, and multiple studies have corroborated a 90 percent disease-free survival in this group.
As noted above, 20-year follow-up of the original MOPP series demonstrated that the actuarial freedom from progression was 54 percent, and 48 percent were alive.243 Constitutional symptoms, male sex, advanced-stage disease, and administration of vincristine lower than the projected rate were prognostic for complete response. Bonadonna and colleagues tested a program of MOPP alternating with ABVD for 12 monthly cycles in a randomized trial in stage IV patients.255 The control arm received 12 courses of MOPP. The 8-year freedom-from-progression rates were significantly different: 65 percent versus 36 percent for the MOPP/ABVD and MOPP groups respectively. Although overall survival rates were superior for MOPP/ABVD (84 percent) compared with MOPP (64 percent), these differences did not achieve statistical significance because of the relatively small number of patients in the trial. A large multi-institutional comparison of MOPP for 8 cycles, ABVD for 8 cycles, or MOPP alternating with ABVD for 12 monthly cycles was undertaken in patients with stages IIIA, IIIB, and IV disease.257 The ABVD and MOPP/ABVD results were superior to MOPP as described in Table 102-4. The failure-free survival rates were similar for ABVD (61 percent) and MOPP/ABVD (65 percent), and both were significantly better than those achieved with MOPP (50 percent). Two groups combined MOPP and ABVD in a slightly different hybrid regimen as detailed in Table 102-3.259,260 Both of these hybrid strategies have been compared with MOPP alternating with ABVD in randomized trials. In one study equivalent outcome for the two study arms was seen, but the hybrid regimen was more toxic, particularly in older patients.259 Similarly, freedom from progression and overall survival were not different in the alternating and hybrid arms in the other study.260
TABLE 102-4 RESULTS OF COMBINATION CHEMOTHERAPY FOR ADVANCED HODGKIN LYMPHOMA
In a subsequent study patients were randomized to ABVD alone versus a hybrid regimen. The study was stopped early due to excess deaths and second cancers in the hybrid arm. At the time the study was reported, there were no differences in efficacy with 65 percent of ABVD patients and 67 percent of hybrid patients failure-free.292 These results were achieved with 8 to 10 monthly cycles of chemotherapy. In aggregate the constellation of clinical trials indicate that 60 to 70 percent of patients with advanced Hodgkin lymphoma are cured with ABVD, hybrid, or alternating combinations. ABVD alone has emerged as the preferred treatment because it has a more favorable toxicity profile.
In an attempt to further improve outcomes in advanced Hodgkin lymphoma, the BEACOPP regimen was developed.261,262 This treatment program is delivered every 3 weeks and features relatively dose-intense etoposide and cyclophosphamide. An escalated version incorporates very high doses of these drugs facilitated by granulocyte colony-stimulating factor. Patients with initial tumor bulk or residual radiographic disease received radiotherapy after chemotherapy. Several interim analyses showed superior outcomes for BEACOPP compared with the standard alternating chemotherapy arm. The results achieved, cure rates in excess of 80 percent, are the best recorded for a large phase III trial in advanced Hodgkin lymphoma. Multiple second cancers were reported in these early reports, and long-term follow-up is required to determine the combined efficacy and toxicity of this approach. Investigators tested an alternate approach to locally extensive and advanced Hodgkin lymphoma, abbreviating the duration of therapy and reduction of the cumulative drug doses. The Stanford V regimen was administered over 12 weeks and given in combination with radiotherapy for patients with bulky (5 cm or larger) nodal or macroscopic splenic disease. Freedom from progression in excess of 85 percent and overall survival in excess of 95 percent were reported with this approach in single-arm studies.263,264,293 ABVD versus Stanford V is being tested in locally extensive and advanced Hodgkin lymphoma with zero to two adverse international prognostic factors as defined below (Table 102-5).232
TABLE 102-5 INTERNATIONAL PROGNOSTIC FACTORS FOR ADVANCED HODGKIN LYMPHOMA
Low-dose irradiation as a consolidation to combination chemotherapy was reported as a successful strategy in adults and children in single-arm experiences.294,295 However, when compared with chemotherapy alone in randomized trials, low-dose consolidative radiotherapy provided no significant advantage.296,297,298 and 299
A number of complex prognostic factor schemes have been developed for limited Hodgkin lymphoma treated with radiotherapy alone. Massive mediastinal disease and constitutional symptoms were consistently identified as independent predictors of relapse, whereas only older age was predictive of inferior survival. Investigators incorporated gender, age, ESR, number of Ann Arbor disease sites, stage, and histology into stratifications for favorable, very favorable, and unfavorable disease categories.268,302 The significance of these factors when newer combined modality treatments are used for limited disease is unknown, but it is important to be aware of the variable eligibility criteria when interpreting the literature. An international consortium pooled patient data and identified a prognostic score for advanced Hodgkin lymphoma based on seven factors (Table 102-5).232 These include male sex, age greater than or equal to 45 years, stage IV, white blood count greater than or equal to 15,000/µl, lymphocyte count less than 6 percent or less than 800/µl, hemoglobin less than 10.5 g/dl, and albumin less than 4 g/dl. The presence of each factor reduced the freedom from progression by about 7 percent. Only 7 percent of patients were in the worst prognostic group (five to seven factors), and the freedom from progression in this subset was 42 percent at 5 years. Consensus with regard to prognostic factors promotes uniformity in clinical trial design and provides a rationale for new approaches such as dose intensification and autologous bone marrow transplantation in high-risk subsets.303 As noted, the influence of age in Hodgkin lymphoma is consistent regardless of tumor burden. Reports in the older age groups indicate that dose reductions may explain inferior results in a subset of patients, but results in older patients are worse, even when therapy is controlled.304,305
These clinical prognostic factors are surrogates for the underlying biology of Hodgkin lymphoma. Prognostic significance has been ascribed to a variety of biologic parameters including histopathologic grading of nodular sclerosis, immunophenotype, oncogene expression, and characteristics of the T-cell infiltrate.38,70,194,306 As noted earlier, serum levels of cytokines including soluble CD30, Il-6, IL-10, and the IL-2 receptor have been reported to correlate with constitutional symptoms and advanced disease.107,108,109,110 and 111
TREATMENT OF RECURRENT DISEASE
Patients who relapse after radiotherapy alone have an excellent rate of cure with chemotherapy.307,308 Most of the accumulated experience is with MOPP. Patients with extensive disease at recurrence and those with constitutional symptoms have a less favorable prognosis.309 The outlook is significantly less favorable for patients who relapse after chemotherapy alone or chemotherapy given in combination with radiotherapy. The length of prior remission, greater or less than 1 year, has a significant effect on the ability of patients to respond to subsequent treatment and maintain their response.310 The relapse-free survival for long initial remissions was 24 percent at 11 years compared with 11 percent for those with short initial remissions in the updated MOPP experience.311 About half of the deaths in the group with longer remissions were due to second cancers and other treatment complications, indicative of the cumulative effects of cancer treatment. The importance of initial remission duration following primary chemotherapy has been confirmed.312,313 Among those with long initial remissions, treatment results were quite good with 45 percent free of disease at 5 years. The results were equivalent whether the same regimen, a non-cross-resistant regimen, or an alternating approach was used.313
The availability of chemotherapy and autologous stem cell transplantation has markedly increased the options for treatment of recurrent Hodgkin lymphoma because these approaches allow dose intensification of drugs with dose-limiting myelotoxicity, such as cyclophosphamide, carmustine, etoposide, cytosine arabinoside, or melphalan. Initially, these strategies were tested in unfavorable patients resistant to standard chemotherapy; despite this, complete responses were seen in up to half. In the last several years high-dose therapy and stem cell rescue has been offered to patients in first relapse with encouraging results.314,315,316 and 317 Disease-free survival rates of 50 to 60 percent are reported at 4 to 5 years, and, in addition, transplant-related mortality has reduced from 10 to 25 percent to less than 5 percent. Although these data reflect selection bias, two randomized clinical trials provide compelling evidence for the superiority of transplantation in relapsed Hodgkin lymphoma. Patients were randomized to conventional or high-dose BEAM (carmustine, etoposide, cytosine arabinoside, melphalan), the latter with autologous stem cell transplantation.318 This study was stopped because the 3-year event-free survival was markedly superior in the high-dose arm compared with standard BEAM, 53 percent versus 10 percent, respectively. The largest multicenter trial was conducted in Europe, where patients with relapsed Hodgkin lymphoma were randomly assigned to four cycles of dexa-BEAM (dexamethasone and BEAM) or two cycles of dexa-BEAM followed by autologous stem cell transplantation.319 Interim analysis of this trial demonstrated superior freedom from treatment failure in the transplant group, 53 percent, versus 39 percent for patients receiving dexa-BEAM alone, P = 0.025. No survival advantage was seen. Similarly, no survival advantage was seen in retrospective analysis of patients treated with conventional or high-dose therapy.320 Seven to eight years of follow-up are required for the survival curve to plateau, and early and late treatment-related mortality must be considered in the final analysis.
Prognostic factors for the success of autologous transplantation have been described by several groups.316,321,322 Among patients transplanted earlier in their disease course, sensitivity to chemotherapy, disease in extranodal sites at relapse, and constitutional symptoms at relapse have emerged as consistent prognostic features. Primary treatment induction failures present a special challenge to clinicians. Single-institution and registry data indicate that a subset of refractory patients, as many as 38 to 49 percent, were alive and disease-free after high-dose therapy and transplantation with follow-up of 3 to 4 years.323,324 and 325 These results have encouraged investigators to consider treatment of adverse-risk patients with high-dose therapy and transplantation in the primary management; randomized clinical trials utilizing this strategy are in progress.
COMPLICATIONS OF TREATMENT
The treatment of Hodgkin lymphoma is associated with a wide array of acute and chronic side effects. While the acute complications of chemotherapy and radiotherapy may be troublesome, they are relatively easily managed. Late treatment effects in the form of sterility, cardiopulmonary disease, and second malignancy are more serious.
Acute leukemia and myelodysplasia were the initial second malignancies to be observed after successful treatment for Hodgkin lymphoma with MOPP chemotherapy.326,327 and 328 The risk was proportional to the cumulative dose of alkylating agents, which in some cases included maintenance therapy, prolonged treatment, or salvage therapy.329,330 Actuarial risks of 1 to 10 percent with relative risks in excess of 100 have been reported over a 7- to 10-year period. It is unclear if the risk plateaus at 10 years or this finding is an artifact of inadequate follow-up.331,332 In a multi-institutional, case-control study of 29,552 Hodgkin lymphoma patients, the relative risk of acute leukemia was increased in patients receiving more than six cycles of MOPP chemotherapy, but no increased risk was found with combined radiation and chemotherapy.329 Several studies have suggested that prior splenectomy increases the risk about twofold.329,333 The risk of acute leukemia is significantly less after ABVD chemotherapy, although it is not zero.
There is an increased relative risk of non-Hodgkin lymphomas after treatment for Hodgkin lymphoma.332,333 These are diffuse, aggressive B-cell lymphomas that may occur early or late after treatment. There is no clear relationship to the type of primary treatment. Some have considered the non-Hodgkin lymphomas to be a result of the ongoing immunodeficiency while others have suggested a common cell of origin.
An increased risk of solid cancers after treatment for Hodgkin lymphoma has been identified by several authors.332,334,335 The risk is related to radiotherapy exposure, with tumors occurring infield or at the edges of the radiotherapy field. The overall actuarial risk of second solid cancer malignancy at 15 years was about 18 percent in the Stanford series.332 Cancers of the lung, stomach, bone, and soft tissue were observed in a temporal pattern consistent with radiation-induced neoplasms. The latency for developing second cancers is an important consideration. For instance, an increased risk of breast cancer and thyroid cancer was only appreciated when mean follow-up was 10 or more years.336,337 and 338 Breast cancer is increased in women treated before age 30 and is markedly increased in children and adolescents.336,338,339
Mediastinal radiotherapy is associated with an increased risk of cardiac disease. An increased risk of death from coronary artery disease and acute myocardial infarction has been identified in adults and children.274,340,341 Other types of cardiac disease following chest radiotherapy include valvular disease, constrictive pericarditis, and cardiomyopathy. The risks of radiation-related heart disease do not appear to be influenced significantly by the addition of chemotherapy. The onset of increased risk is within 5 to 10 years. The incidence of radiation pneumonitis depends on the volume of lung irradiated and the total dose. Symptoms include cough, dyspnea, and fever. Although prospective assessment of pulmonary function demonstrates reduction of lung volumes following mantle radiotherapy, recovery is seen in 12 to 24 months, and symptomatic radiation pneumonitis is unusual.349,350
About 90 percent of males are permanently sterilized by six cycles of MOPP chemotherapy.342 The risk is related to the cumulative dose of alkylating agents such that two to three cycles of MOPP result in azoospermia in about 50 percent of patients.343 Female fertility after MOPP is related to age at treatment as well as cumulative alkylating agent dose.344,345 Women over 25 at treatment have an 80 percent probability of sterility following six courses of MOPP. The ABVD combination is associated with temporary amenorrhea or azoospermia with full recovery noted in 50 to 90 percent of patients.346,347 Pregnancy has been a possible outcome following treatment for Hodgkin lymphoma. No increases in birth defects or complications of pregnancy have been seen.345
Lhermitte’s sign, or the induction of a sharp or lancinating sensation or pain down the spine produced by flexion, is a common complication of mantle radiotherapy.348 An elevated thyroid-stimulating hormone level, with or without a low T3 or T4, is seen in about 30 percent of patients following mantle radiotherapy.337 Rarely, hyperthyroidism, Grave’s ophthalmopathy, or thyroid neoplasms occur after neck radiotherapy.337
Full-dose radiation therapy interferes with normal growth and development in children. Current therapy programs use low-dose or no radiotherapy for all stages of disease. Overwhelming sepsis is a rare event in patients who have had their spleen removed and been treated for Hodgkin lymphoma and occurs particularly in children.351,352 Vaccination against encapsulated organisms 10 to 14 days prior to the onset of treatment is advised. However, neither vaccines nor antibiotic prophylaxis can provide certain protection.
Psychosocial sequelae of treatment for Hodgkin lymphoma deserve further study.353 With the high rates of cure currently attained in the management of Hodgkin lymphoma (see Fig. 102-3), reduction in late effects and quality of life assume even greater importance.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn