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© 1999 American Society for Clinical Oncology
Lymphocyte-Predominant Hodgkin's Disease: How Little Therapy Is Enough?Brigham and Women's Hospital, Boston, MA THE RETROSPECTIVE REPORT from the multicenter European Task Force on Lymphoma (ETFL) project appearing in this edition of the Journal of Clinical Oncology1 compares the clinical features and outcomes of two uncommon forms of Hodgkin's disease (HD), lymphocyte-predominant Hodgkin's disease (LPHD) and the lymphocyte-rich variant of classical HD. It has been recognized for some time that LPHD is distinct from the better-characterized forms of classical HD (mixed cellularity, nodular sclerosis, and lymphocyte-depletion types), and the series from Diehl et al1 are entirely consistent with tendencies noted in other large series. LPHD usually presents in young males without B symptoms as early-stage disease at cervical or inguinal nodal sites, rarely involves the mediastinum, and has a good to excellent prognosis with therapy that is standard for classical forms of HD. Prognosis is primarily related to stage and patient age at diagnosis. It is interesting to note that patients with the lymphocyte-rich subtype of classical HD share many of these features; they are also predominantly male, usually present with stage I or II disease without B symptoms or mediastinal involvement, and have a good prognosis. These entities may also be mistaken for one another by less experienced pathologists, as about 25% of cases originally classified as LPHD in the ETFL series were reclassified as lymphocyte-rich classical HD after examination by an expert panel of hematopathologists. The superficial resemblance of LPHD and the lymphocyte-rich variant of classical HD breaks down, however, when the pathologic features of the two entities are carefully compared. With the advent of immunohistochemical analysis in the 1980s, it was shown that the characteristic lymphohistiocytic cells (L & H variants) of LPHD are B lymphocytes that fail to express markers, such as CD15, CD30, and fascin, usually found on Reed-Sternberg cells in classical HD.2-4 In contrast, the Reed-Sternberg cells in the lymphocyte-rich variant are morphologically and immunophenotypically identical to the diagnostic and mononuclear Reed-Sternberg cells seen in mixed cellularity HD.5 L & H variants are typically found within nodules containing reactive polyclonal B cells, macrophages, and mantle zone–like dendritic cells, which indicates that they usually arise within and home to B-cell follicles. This is in contrast to classical forms of HD, including the lymphocyte-rich variant, in which background lymphocytes are predominantly mature T cells. These pathologic differences suggest that the lymphocyte-rich variant is rightly considered an unusual variant of classical HD. Its histology presumably reflects the failure of Reed-Sternberg cells and reactive T cells in the lymphocyte-rich variant to produce cytokines, such as interleukin-56 and interleukin-6,7 involved in the recruitment and maintenance of the reactive granulocytes, macrophages, and plasma cells that are the hallmark of other forms of classical HD. Little is currently known about the pathogenesis of LPHD, but one clue is its inconstant association with a reactive condition called progressive transformation of germinal centers, which also preferentially occurs in young males and shows the same pattern of lymph node involvement as LPHD. Progressive transformation of germinal centers differs histologically from LPHD only in that L & H variants are absent, and it may be found in lymph node biopsies before, at the time of, or after the diagnosis of LPHD. This association has led to the suggestion that progressive transformation of germinal centers constitutes a precursor lesion, albeit one that only infrequently gives rise to LPHD.8 Of note, progressive transformation of germinal centers has not been associated with classical forms of HD. A second, more important, issue raised by the ETFL experience concerns the fact that low-stage patients with LPHD or lymphocyte-rich classical HD were found to be more likely to die of secondary neoplasms and cardiovascular disease than their primary neoplasm. This finding is a particularly troublesome recurrent theme in low-stage LPHD, as most,9-11 but not all,12,13 prior series have also found iatrogenic complications to be the major cause of death. These findings make it likely that many LPHD patients are currently being overtreated. On the basis of these outcomes and those compiled by others, Diehl et al1 provocatively propose a prospective clinical trial with a "watch-and-wait" arm. Placing this proposal in context requires consideration of the biologic basis and natural history of LPHD as well as the current data pertaining to the risks and efficacy of less intensive therapy. As in other forms of HD, the relative paucity of L & H cells in LPHD has made biologic studies daunting. After much initial controversy, possibly stemming from the technical difficulties, recent polymerase chain reaction–based studies of multiple microdissected L & H cells from individual patients have demonstrated the presence of monoclonal immunoglobulin (Ig) gene rearrangements.14-16 The rearranged gene segments were also noted to have undergone somatic hypermutation, a process normally confined to follicular-center B cells. These data strongly support the contention that LPHD is a B-cell neoplasm of follicular origin. The genetic or epigenetic events necessary for outgrowth of LPHD are completely unknown. The observation from Diehl et al1 that the absence of detectable J-chain, a polypeptide essential for oligomerization of IgA and IgM, correlates with a worse prognosis is potentially important but needs to be confirmed by other workers in the field. Although outcomes in LPHD are generally excellent, it must be remembered that the natural history of LPHD is extremely prolonged, particularly in low-stage patients. In fact, a case can be made for LPHD being the most indolent of lymphomas. A look back at studies published in the pretreatment era is rendered difficult by the differences in nomenclature and histologic criteria. One series that is unimpeachable (to use the vernacular of the times) on pathologic grounds is the study of Lukes et al17 of 377 United States army recruits diagnosed with HD during World War II. Based on essentially the same histologic criteria used today, this cohort contained 23 cases of nodular LPHD, the form least likely to be confused with the lymphocyte-rich variant of classical HD or T-cell–rich, large B-cell lymphoma. Although some of these patients must have been understaged, the median survival of "stage I" untreated patients in this group was 16 years. In 1983, Miettinen et al18 observed 80% survival at 10 years in Finnish LPHD patients who went untreated because of misdiagnosis and made the prescient statement that "because of its good natural prognosis, the value of therapy against its potential hazards may be difficult to assess in LPHD." Indeed, from time to time, all hematopathologists come across misdiagnosed cases of LPHD where patients have remained well, sometimes for many years, without treatment. So, is a watch-and-wait approach a good idea? Diehl et al1 suggest that low-stage LPHD may be analogous to stage I follicular lymphoma, and indeed it could be argued that the occurrence of multiple late recurrences in LPHD is consistent with the expected behavior of a low-grade non-Hodgkin's lymphoma.10,19 However, this pattern of multiple relapses has not been observed in other large series,11,13,20 and the incidence of relapse in LPHD seems to fall off beyond 12 years.11 Hence, unlike the case with indolent non-Hodgkin's lymphomas, relapse in LPHD is probably not inevitable and some patients are likely truly cured. Further, although the course of untreated LPHD is prolonged, it can eventually prove lethal. As the authors note, early treatment may prevent progression to more difficult to treat higher-stage disease and development of large B-cell lymphoma, an event occurring in approximately 3% of LPHD patients that is probably part of the natural history of the disease rather than a consequence of therapy.18 Some data suggest that large-cell lymphomas arising in LPHD patients are highly responsive to therapy, but the number of such cases is too small for one feel confident that this will be generally true. The watch-and-wait approach would be more attractive if nothing could be done to limit therapeutic complications, but there is reason to believe this is not the case. With the recognition that most fatal complications can be attributed to radiotherapy,21 efforts have been made to narrow fields and reduce radiation dose to the breast and mediastinal structures, which should decrease the incidence of secondary malignancies and cardiovascular, and pulmonary complications. Because of the low incidence of mediastinal disease in LPHD, a number of these complications should be particularly avoidable in this subtype. Most patients in the ETFL series who received chemotherapy were treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or MOPP-like regimens, which are more leukemogenic than current regimens that avoid alkylating drugs. Unfortunately, it will be many years before we know with certainty whether these alterations maintain efficacy while limiting late complications, particularly given the prolonged natural history and rarity of LPHD. If a prospective multi-institutional watch-and-wait trial is to be conducted in the interim, rigorous staging and careful follow-up will be essential. REFERENCES
1.
Diehl V, Sextro M, Franklin J, et al: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: Report from the European Task Force on Lymphoma project on lymphocyte-predominant Hodgkin's disease. J Clin Oncol 17:776-783, 1999 2. Poppema S, Timens W, Visser L: Nodular lymphocyte predominance type of Hodgkin's disease is a B cell lymphoma. Adv Exp Med Biol 186:963-969, 1985[Medline] 3. Pinkus GS, Said JW: Hodgkin's disease, lymphocyte predominance type, nodular: A distinct entity? Unique staining profile for L & H variants of Reed-Sternberg cells defined by monoclonal antibodies to leukocyte common antigen, granulocyte-specific antigen, and B-cell-specific antigen. Am J Pathol 118:1-6, 1985[Abstract] 4. Pinkus GS, Pinkus JL, Langhoff E, et al: Fascin, a sensitive new marker for Reed-Sternberg cells of Hodgkin's disease: Evidence for a dendritic or B cell derivation? Am J Pathol 150:543-562, 1997[Abstract] 5. Sextro M, Diehl V, Franklin J, et al: Lymphocyte predominant Hodgkin's disease: A workshop report—European Task Force on Lymphoma. Ann Oncol 7:61-65, 1996
6.
Samoszuk M, Nansen L: Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin's disease with eosinophilia. Blood 75:13-16, 1990
7.
Jucker M, Abts H, Li Wet al: Expression of interleukin-6 and interleukin-6 receptor in Hodgkin's disease. Blood 77:2413-2418, 1991 8. Poppema S: Lymphocyte-predominance Hodgkin's disease. Semin Diagn Pathol 9:257-264, 1992[Medline] 9. Trudel MA, Krikorian JG, Neiman RS: Lymphocyte predominance Hodgkin's disease: A clinicopathologic reassessment. Cancer 59:99-106, 1987[Medline] 10. Regula DP Jr Hoppe RT, Weiss LM: Nodular and diffuse types of lymphocyte predominance Hodgkin's disease. N Engl J Med 318:214-219, 1988[Abstract] 11. Bodis S, Kraus MD, Pinkus G, et al: Clinical presentation and outcome in lymphocyte-predominant Hodgkin's disease. J Clin Oncol 15:3060-3066, 1997[Abstract] 12. Borg-Grech A, Radford JA, Crowther D, et al: A comparative study of the nodular and diffuse variants of lymphocyte-predominant Hodgkin's disease. J Clin Oncol 7:1303-1309, 1989[Abstract] 13. Tefferi A, Zellers RA, Banks PM, et al: Clinical correlates of distinct immunophenotypic and histologic subcategories of lymphocyte-predominance Hodgkin's disease. J Clin Oncol 8:1959-1965, 1990[Abstract]
14.
Ohno T, Stribley JA, Wu Get al: Clonality in nodular lymphocyte-predominant Hodgkin's disease [see comments]. N Engl J Med 337:459-465, 1997
15.
Marafioti T, Hummel M, Anagnostopoulos I, et al: Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells [see comments]. N Engl J Med 337:453-458, 1997
16.
Braeuninger A, Kuppers R, Strickler JG, et al: Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells[published erratum appears in Proc Natl Acad Sci USA]. 94:14211, 1997 Proc Natl Acad Sci USA94:9337-9342, 1997 17. Lukes RJ, Butler JJ, Hicks EB: Natural history of Hodgkin's disease as related to its pathologic picture. Cancer 19:317-344, 1966 18. Miettinen M, Franssila KO, Saxen E: Hodgkin's disease, lymphocytic predominance nodular: Increased risk for subsequent non-Hodgkin's lymphomas. Cancer 51:2293-2300, 1983[Medline] 19. Orlandi E, Lazzarino M, Brusamolino E, et al: Nodular lymphocyte predominance Hodgkin's disease: Long-term observation reveals a continuous pattern of recurrence. Leuk Lymphoma 26:359-368, 1997[Medline]
20.
Pappa VI, Norton AJ, Gupta RK, et al: Nodular type of lymphocyte predominant Hodgkin's disease. A clinical study of 50 cases. Ann Oncol 6:559-565, 1995 21. DeVita VT Jr: Late sequelae of treatment of Hodgkin's disease. Curr Opin Oncol 9:428-431, 1997[Medline] This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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