Lymphocyte-Rich Classical Hodgkin's Lymphoma: Clinical Presentation and Treatment Outcome in 100 Patients Treated Within German Hodgkin's St
http://www.100md.com
《临床肿瘤学》
the First Department of Internal Medicine I, University Hospital Cologne
German Hodgkin's Study Group
Department of Radiation Oncology, University of Cologne, Cologne
Evangelisches Krankenhaus, Innere Medizin, H?mato-Onkologie, Hamm
Kreiskrankenhaus, Innere Medizin, H?mato-Onkologie, Bad Hersfeld
Wald-Klinikum Gera gGmbH, II. Medizinische Klinik, Gera
Department of Pathology, University Hospital Benjamin Franklin, Berlin, Germany
ABSTRACT
PURPOSE: To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL).
PATIENTS AND METHODS: From a total of 2,715 patients with biopsy-proven HL treated within the trials HD7 to HD12 of the German Hodgkin's Study Group, 100 patients (4%) with LRCHL, 145 patients (5%) with lymphocyte-predominant HL (LPHL), 1,688 patients (62%) with nodular sclerosis, 731 patients (27%) with mixed cellularity, and 23 patients (1%) with lymphocyte depletion were identified. Patients with LRCHL had a median age of 38 years (range, 16 to 74 years).
RESULTS: Compared with other histologic subtypes, patients with LRCHL are, on average, older and usually present with early stages of disease (stage I, 34%; stage II, 46%). The median time of follow-up was 32.2 months (95% CI, 28.2 to 37.0 months). Complete and partial remission was achieved in 96 patients (96%) and four patients (4%), respectively, with LRCHL. The event-free and overall survival rates were 97% (95% CI, 96.7% to 96.9%) and 97% (95% CI, 96.8% to 97.0%), respectively, at 30 months. Only three patients died; all of the deaths were caused by treatment-related toxicities.
CONCLUSION: LRCHL is a distinct subtype of CHL, with features of CHL and LPHL, and is a rare entity accounting for only 4% of HLs. LRCHL has a different pattern of clinical presentation and age and sex distribution than other CHLs. It is associated with an excellent prognosis if treated with current treatment regimens. When treating patients with LRCHL, great attention should be paid to avoid acute toxicities.
INTRODUCTION
Lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) was introduced as a new provisional subtype of classical Hodgkin's lymphoma (CHL) in the Revised European-American Lymphoma (REAL) classification in 1994,1 which was subsequently taken over by the WHO classification.2 Histologically, LRCHL is characterized by infrequent Reed-Sternberg cells on a background dominated by small mature lymphocytes. It may show a nodular or a diffuse growth pattern. Morphologically, LRCHL may resemble either mixed cellularity (MC), nodular sclerosis (NS), or lymphocyte-predominant Hodgkin's lymphoma (LPHL). Exact diagnosis frequently requires immunohistochemical staining, which can aid in distinguishing between these subtypes.3 The immunophenotype of the malignant cells in LRCHL is identical to the immunophenotype of CHL; that is, LRCHL is CD15+ and CD30+, and this is contrary to LPHL, which is CD20+ but lacks expression of CD15 and CD30.
LRCHL comprises only approximately 3% to 5% of all Hodgkin's lymphomas (HL). Because of its rarity, little is known about the clinical characteristics, course, and treatment outcome of patients with LRCHL. The only larger study published to date was initiated by the European Task Force on Lymphoma and reported the clinical features of 115 patients with LRCHL.4 The purpose of this study was to assess the clinical features of LPHL. Of the 426 assessable patients originally diagnosed as having LPHL, review by a panel of expert hematopathologists revealed that only 219 patients (51%) were confirmed as having LPHL. Interestingly, 115 patients (27%) were reclassified as LRCHL. However, the results of this study were biased because only patients with LRCHL who were initially misdiagnosed as LPHL were included. Therefore, we retrospectively analyzed the data of 100 patients with LRCHL registered in the database of the German Hodgkin's Study Group (GHSG) with regard to clinical presentation, treatment course, and outcome and compared the data with data from patients with NS, MC, lymphocyte depletion (LD), or LPHL.
PATIENTS AND METHODS
Patient Selection
A total of 2,715 patients with HL diagnosed after introduction of the REAL classification and treated within the third and fourth trial generations (HD7 and HD10 for early stages, HD8 and HD11 for intermediate stages, and HD9 and HD12 for advanced stages) of the GHSG were included in this retrospective analysis. In addition, only patients who underwent central pathology review by an expert hematopathologist (88.3%) were included.
To be eligible for the GHSG trials, patients aged between 16 and 75 years (for HD9, between 16 and 60 years) had to have biopsy-proven disease at diagnosis and adequate organ function, as defined by a creatinine clearance of more than 60 mL/min, serum transaminases less than 3x normal, bilirubin less than 2 mg/dL, left ventricular ejection fraction of more than 0.45, forced expiratory volume in 1 second or diffusion capacity of carbon monoxide of more than 60% of predicted, WBCs 3,500/μL, hemoglobin level 8 g/dL, and platelets 100,000/μL. Patients were required to test negative for antibodies against HIV and to be free of active infections. All patients signed informed consent forms based on the institutional review board guidelines. Histologic diagnosis was made initially by local pathologists who were asked to send paraffin block biopsy samples for central pathology review by an expert hematopathologist.
Staging Procedures
All patients underwent uniform staging. The extent of disease was assessed by chest x-ray, abdominal ultrasound, computed tomography, bone scintigraphy, and bone marrow biopsy. After the end of therapy, all sites of initial disease were re-evaluated by adequate methods.
Response Definition
Complete response (CR) was defined as disappearance of all clinical and radiographic evidence of disease for at least 1 month. Partial response (PR) was defined as a greater than 50% reduction in the sum of the largest diameter and its perpendicular diameters of measurable disease lasting for at least 1 month. Any response less than PR was considered treatment failure.
Treatment
Patients had been recruited onto the GHSG trials for early-stage (HD7 and HD10), intermediate-stage (HD8 and HD11), and advanced-stage disease (HD9 and HD12). The chemotherapeutic regimens included doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); cyclophosphamide, vincristine, procarbazine, and prednisone alternating with ABVD; and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). All patients were treated according to the protocols of the respective trials. Table 1 gives an overview of the study design and treatment regimens of those trials.5-8 Patients with early- and intermediate-stage disease received extended-field radiotherapy with 30 Gy (HD7 and HD8) or involved-field radiotherapy with 20 or 30 Gy (HD10 and HD11). In addition to chemotherapy, patients with advanced-stage disease received local radiotherapy to all regions of initial bulky disease with 30 Gy or to residual disease more than 2 cm with 40 Gy. Radiation fields were restricted to the extent of initial bulky tumors or persisting tumor mass. There were no significant differences in primary treatment in an analysis stratified by disease stage (data not shown).
Statistics
Demographics and disease characteristics were summarized using descriptive statistics. Event-free survival (EFS) was measured from the date of entry onto the therapy protocol until progression, relapse, or death from any cause. Overall survival (OS) was measured from the date of entry onto the treatment protocol until death from any cause. OS and freedom from treatment failure rates were estimated using the Kaplan-Meier method.9 Removal and entry levels of significance were 0.1 and 0.05, respectively. No adjustment was made for multiple comparison; all P values are two sided. EFS was defined as ongoing survival without events including disease progression or relapse, death, or initiation of new alternative treatment. All statistical analyses were performed using SPSS 12.1 (SPSS Inc, Chicago, IL).
RESULTS
Patient Characteristics
Two thousand seven hundred fifteen patients with biopsy-proven HL were retrospectively analyzed. Of these patients, 100 patients (4%) had LRCHL, 1,688 patients (63%) had NS, 731 patients (27%) had MC, 23 patients (1%) had LD, and 145 patients (5%) had LPHL. The clinical features of assessable patients are listed in Table 2. The median age at diagnosis was 38 years (range, 16 to 74 years) in LRCHL patients, 40 years (range, 16 to 71 years) in LPHL patients, 32 years (range, 16 to 74 years) in NS patients, 38 years (range, 16 to 75 years) in MC patients, and 30 years (range, 16 to 72 years) in LD patients. Both LRCHL (P < .002) and LPHL (P < .0001) patients were significantly older than patients with CHL, but the difference between these two subtypes was not significant. In LRCHL there was a male predominance, with a male to female ratio of 2:1.
Patients with LRCHL tended to present with early stages of disease. Disease stage by Ann Arbor criteria was stage I in 34 patients (34%), stage II in 46 patients (46%), stage III in 14 patients (14%), and stage IV in five patients (5%). Constitutional symptoms were infrequent in LRCHL. Weight loss, fevers, and night sweats were noted in seven, six, and 14 patients, respectively. Of the risk factors used by the GHSG, elevated erythrocyte sedimentation rate (P < .0001), involvement of more than three lymph node areas (P < .0001), and large mediastinal tumor (P < .0001) were less frequent in patients with LRCHL compared with patients with CHL. The main site of organ involvement at the time of presentation in LRCHL patients was the lungs (four patients). Other sites of organ involvement included liver (two patients), skeleton (three patients), bone marrow (two patients), and miscellaneous other sites (two patients).
Response
Response rates by histologic subtype are listed in Table 3. Overall response rates were virtually identical for all groups. Treatment response in the LRCHL group was excellent. Two patients could not be evaluated for response because they died before completion of the treatment. The overall response rate was 100%. A total of 93 patients (96%) with LRCHL achieved a CR, and four patients (4%) achieved a PR. The overall response rates for the other subtypes were 99% for LPHL, 98% for NS, 99% for MC, and 95% for LD. Although no progressive disease occurred among patients with LRCHL during the follow-up period, one patient (2%) with LPHL, 30 patients (2%) with NS, nine patients (1%) with MC, and one patient (5%) with LD had early disease progression.
Treatment Outcome
The rates for EFS and OS are listed in Table 4. Figure 1 shows Kaplan-Meier curves for EFS of patients with LRCHL, LPHL, and CHL. The median follow-up time was not significantly different between groups. Patients with LRCHL had a significantly higher EFS rate (97%) than patients with other subtypes of CHL (P < .02). EFS rates did not differ significantly between patients with LRCHL (97%) and LPHL (94%). At 30 months, the EFS rate was 97% for patients with LRCHL. A strikingly worse EFS rate (P < .0001) than any other subtype was observed among patients with LD (55%).
Kaplan-Meier curves for OS by histologic subtype are shown in Figure 2. At 30 months, the overall EFS rate in LRCHL was 97%. Among the 100 patients with LRCHL, three have died during the follow-up period. Comparisons between the specific categories using the log-rank test failed to reveal any significant differences at P = .05 in the OS, although there was a trend for higher survival in patients with LRCHL and LPHL compared with CHL. No relapses were observed in the LRCHL group. In contract, there were nine relapses (6%) in the LPHL group, 161 relapses (10%) in the NS group, 65 relapses (9%) in the MC group, and six relapses (26%) in the LD group.
Three patients (3%) in the LRCHL group died before completion of the treatment. All of these patients died as a result of treatment-related toxicities. Patient 1 was a 46-year-old male and presented with stage IIIB disease. The patient died of a cardiovascular event after receiving four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline and 30 Gy of involved-field radiotherapy to bulky disease. Patient 2 was a 64-year-old male, had stage IVB disease, and died of acute chemotherapy-associated toxicity after receiving two cycles of BEACOPPescalated. The third patient, who had stage IIA disease, died of radiation pneumonitis at the age of 66 years. Before radiotherapy, she received two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone and ABVD as part of treatment arm A of the HD8 trial. Overall, HL and treatment-related toxicities were the most frequent causes of death. Although no patient with LRCHL died of HL, two patients (1%) with LPHL, 34 patients (2%) with NS, 15 patients (2%) with MC, and two patients (9%) with LD died of relapse or progression of disease. Treatment-related toxicities resulted in the deaths of one patient (1%) with LPHL, 24 patients (2%) with NS, and 22 patients (3%) with MC. None of the patients with LD died of treatment-related toxicities.
Secondary Malignancy
The number and frequency of secondary malignancies are listed in Table 5. Altogether, 45 secondary neoplasias were observed among the study population (one patient with acute lymphatic leukemia, 12 patients with acute myelogenous leukemia, 14 patients with lymphoma, and 18 patients with solid tumors). One patient with LRCHL developed a secondary malignancy (mucosa-associated lymphoid tissue lymphoma).
DISCUSSION
The following findings emerge from this analysis: patients with LRCHL are on average older than patients with CHL; patients with LRCHL usually present with early stages of disease; treatment outcome in LRCHL is excellent; and further studies should be aimed at reducing toxicity. The aim of this retrospective study was to gain a better understanding of the clinical features of LRCHL and to determine treatment outcome for this entity. Although the histologic and molecular features of LRCHL have been well characterized,3, 10 few data exist on the clinical characteristics of this subtype. Review of all patients with HL treated within the studies of the GHSG between 1996 and 2002 revealed 100 patients with a diagnosis of LRCHL. The clinical features of this group were compared with the features of patients with the other subtypes of HL, LPHL or CHL (NS, MC, and LD), treated during the same time period. The data presented here can be considered as population based and representative with regard to frequency and presentation because more than 70% of all patients older than 16 years of age with a diagnosis of HL in Germany were registered in the GHSG trials.
With a median age of 38 years, patients with LRCHL were significantly older (P < .002) than patients with the other subtypes of CHL, who had a median age of 33 years. This difference was mainly a result of a lower percentage of patients younger than 30 years. The median age of 40 years for LPHL patients in our study was higher than previously reported.4, 11 The majority of patients with LRCHL are male, which is reflected in a male to female ratio of more than 2:1. LRCHL patients usually presented with early stages of disease, and constitutional symptoms were rare. Only 19% of patients with LRCHL and 10% of patients with LPHL complained of B symptoms, whereas 38% of patients with CHL complained of B symptoms. The lower incidence of B symptoms could only partially be explained by the higher percentage of early disease stages in LRCHL compared with other subtypes of CHL (data not shown). Other risk factors with a lower incidence in LRCHL and LPHL were presence of a mediastinal mass and elevated erythrocyte sedimentation rate, even when balanced by disease stage. No difference in distribution was observed for extranodal involvement or affection of more than three lymph node areas. Not surprisingly, organ involvement was relatively rare. The most frequently involved extranodal sites in the LRCHL cohort were lungs (4%), skeleton (3%), bone marrow (2%), and liver (2%).
Although, on the basis of morphology and immunohistochemistry, LRCHL belongs to CHL, it clinically more closely resembles LPHL. In general, there were no major differences in the clinical characteristics of patients with LRCHL and LPHL except for the significantly lower frequency of an elevated erythrocyte sedimentation rate (P < .0001) and B symptoms (P < .04) in LPHL. LRCHL and LPHL are the two most highly curable subtypes of HL, with almost all patients responding to therapy and high long-term EFS rates. Primary treatment outcome of LRCHL and LPHL is excellent, with 30-month EFS rates of 97% and 94%, respectively; these rates were not significantly different. The superior outcome of these two entities is in line with earlier reports.4, 12-15 The better survival in LRCHL cannot simply be explained by the higher proportion of early disease stages because, even for early stages, there was still a significant difference (P < .04) between LRCHL and CHL. Contrary to the good results obtained for LRCHL and LPHL, the outcome of patients with LD was unsatisfactory. Of 23 patients, only 17 (81%) achieved a CR, three (14%) achieved a PR, and one (5%) had progressive disease. The EFS rate was only 55% at 30 months of follow-up. In addition, 26% of these patients experienced relapse. The relatively poor treatment outcome of patients with LD underlines the need for more effective primary treatment regimens capable of producing high response rates and low relapse rates in LD. However, the number of patients with LD was low (n = 23), and therefore, our results should be confirmed in a larger cohort.
The differences in clinical parameters of LRCHL that were noticed between the present and the European Task Force on Lymphoma study4, 16 can be easily explained by the different mechanisms of selection. In the European Task Force on Lymphoma study, only patients with LRCHL who were previously misclassified as having LRCHL were reviewed. However, our study analyzed a more representative series of LRCHL patients that also included patients who, in the past, would have been classified as NS or MC. Although the importance of histologic subtype as a prognostic marker for survival has basically disappeared with the development of more effective therapeutic regimens, our study demonstrates that histologic typing can still have a significant prognostic impact.
The observation that all deaths in the LRCHL group were a result of treatment-related toxicities underscores the importance of toxicities related to therapy in the care for patients with HL. With the high cure rates achieved with current therapeutic regimens, both the acute and long-term consequences of therapy have become a major concern.17 Because patients with LRCHL are generally older, they are at an increased risk of acute toxicities. In fact, two of the three patients who died were greater than 60 years old. Except for the patient with radiotherapy-induced pneumonitis, the two other patients received a more intensified BEACOPP regimen as part of their therapy.
What are the clinical implications of our study? One of the key questions raised by this analysis is whether patients with LRCHL should receive less intensive treatment. Unfortunately, the results of this study cannot conclusively answer this question. Because of the few events observed and a lack of longer follow-up, the data have to be interpreted with caution with regard to treatment decisions. The improvement in the EFS when compared with the previous study by Diehl et al4 also suggests that patients with LRCHL have benefited from an intensification of chemotherapeutic regimens. Therefore, current data do not suffice to justify a reduction in treatment intensity. With longer follow-up, this might change because the number of treatment-related deaths can be expected to increase with time. In future clinical trials, the reduction of treatment toxicity will play an important role because it was the sole cause of death in our LRCHL cohort. Elderly patients are at an especially increased risk of acute toxicities. The GHSG acknowledged this and has initiated two studies specifically designed for older patients.18 The future development of novel targeted therapies promises to reduce late sequelae, while maintaining or improving treatment outcome with low treatment-related toxicity.4, 19
In conclusion, this is the largest published series to date of uniformly treated patients with LRCHL using the definition set forth by the REAL and WHO classification schemes. Our data confirm the excellent prognosis of LRCHL in contrast to other subtypes of CHL. Additional larger, international, multicenter studies with longer follow-up are required to answer questions regarding the right standard treatment and the occurrence of late treatment-related sequelae, such as secondary malignancies and pulmonary and cardiac toxicity.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grants from the Deutsche Krebshilfe and the Kompetenznetz Maligne Lymphome.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Harris NL, Jaffe ES, Diebold J, et al: Lymphoma classification: From controversy to consensus—The R.E.A.L. and WHO Classification of lymphoid neoplasms. Ann Oncol 11:3-10, 2000 (suppl 1)
Anagnostopoulos I, Hansmann ML, Franssila K, et al: European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: Histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 96:1889-1899, 2000
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
Engert A, Schiller P, Josting A, et al: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: Results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21:3601-3608, 2003
Diehl V, Franklin J, Hasenclever D, et al: BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: Interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 16:3810-3821, 1998
Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348:2386-2395, 2003
Eich HT, Staar S, Gossmann A, et al: The HD12 panel of the German Hodgkin Lymphoma Study Group (GHSG): A quality assurance program based on a multidisciplinary panel reviewing all patients' imaging. Am J Clin Oncol 27:279-284, 2004
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Gough J: Hodgkin's disease: A correlation of histopathology with survival. Int J Cancer 5:273-281, 1970
Keller AR, Kaplan HS, Lukes RJ, et al: Correlation of histopathology with other prognostic indicators in Hodgkin's disease. Cancer 22:487-499, 1968
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
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 (suppl 4)
Linch DC, Gosden RG, Tulandi T, et al: Hodgkin's lymphoma: Choice of therapy and late complications. Hematology (Am Soc Hematol Educ Program) 205-221, 2000
Nogova L, Sienawski M, Nisters-Backes H, et al: A new BACOPP schedule is feasible and effective in elderly Hodgkin’s lymphoma patients: Interim results of a multicenter phase II trial of the German Hodgkin Study Group (GHSG). Ann Oncol 16:195, 2005
Borchmann P, Schnell R, Engert A: Immunotherapy of Hodgkin’s lymphoma. Eur J Haematol 75:159-165, 2005(Alexander Shimabukuro-Vor)
German Hodgkin's Study Group
Department of Radiation Oncology, University of Cologne, Cologne
Evangelisches Krankenhaus, Innere Medizin, H?mato-Onkologie, Hamm
Kreiskrankenhaus, Innere Medizin, H?mato-Onkologie, Bad Hersfeld
Wald-Klinikum Gera gGmbH, II. Medizinische Klinik, Gera
Department of Pathology, University Hospital Benjamin Franklin, Berlin, Germany
ABSTRACT
PURPOSE: To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL).
PATIENTS AND METHODS: From a total of 2,715 patients with biopsy-proven HL treated within the trials HD7 to HD12 of the German Hodgkin's Study Group, 100 patients (4%) with LRCHL, 145 patients (5%) with lymphocyte-predominant HL (LPHL), 1,688 patients (62%) with nodular sclerosis, 731 patients (27%) with mixed cellularity, and 23 patients (1%) with lymphocyte depletion were identified. Patients with LRCHL had a median age of 38 years (range, 16 to 74 years).
RESULTS: Compared with other histologic subtypes, patients with LRCHL are, on average, older and usually present with early stages of disease (stage I, 34%; stage II, 46%). The median time of follow-up was 32.2 months (95% CI, 28.2 to 37.0 months). Complete and partial remission was achieved in 96 patients (96%) and four patients (4%), respectively, with LRCHL. The event-free and overall survival rates were 97% (95% CI, 96.7% to 96.9%) and 97% (95% CI, 96.8% to 97.0%), respectively, at 30 months. Only three patients died; all of the deaths were caused by treatment-related toxicities.
CONCLUSION: LRCHL is a distinct subtype of CHL, with features of CHL and LPHL, and is a rare entity accounting for only 4% of HLs. LRCHL has a different pattern of clinical presentation and age and sex distribution than other CHLs. It is associated with an excellent prognosis if treated with current treatment regimens. When treating patients with LRCHL, great attention should be paid to avoid acute toxicities.
INTRODUCTION
Lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) was introduced as a new provisional subtype of classical Hodgkin's lymphoma (CHL) in the Revised European-American Lymphoma (REAL) classification in 1994,1 which was subsequently taken over by the WHO classification.2 Histologically, LRCHL is characterized by infrequent Reed-Sternberg cells on a background dominated by small mature lymphocytes. It may show a nodular or a diffuse growth pattern. Morphologically, LRCHL may resemble either mixed cellularity (MC), nodular sclerosis (NS), or lymphocyte-predominant Hodgkin's lymphoma (LPHL). Exact diagnosis frequently requires immunohistochemical staining, which can aid in distinguishing between these subtypes.3 The immunophenotype of the malignant cells in LRCHL is identical to the immunophenotype of CHL; that is, LRCHL is CD15+ and CD30+, and this is contrary to LPHL, which is CD20+ but lacks expression of CD15 and CD30.
LRCHL comprises only approximately 3% to 5% of all Hodgkin's lymphomas (HL). Because of its rarity, little is known about the clinical characteristics, course, and treatment outcome of patients with LRCHL. The only larger study published to date was initiated by the European Task Force on Lymphoma and reported the clinical features of 115 patients with LRCHL.4 The purpose of this study was to assess the clinical features of LPHL. Of the 426 assessable patients originally diagnosed as having LPHL, review by a panel of expert hematopathologists revealed that only 219 patients (51%) were confirmed as having LPHL. Interestingly, 115 patients (27%) were reclassified as LRCHL. However, the results of this study were biased because only patients with LRCHL who were initially misdiagnosed as LPHL were included. Therefore, we retrospectively analyzed the data of 100 patients with LRCHL registered in the database of the German Hodgkin's Study Group (GHSG) with regard to clinical presentation, treatment course, and outcome and compared the data with data from patients with NS, MC, lymphocyte depletion (LD), or LPHL.
PATIENTS AND METHODS
Patient Selection
A total of 2,715 patients with HL diagnosed after introduction of the REAL classification and treated within the third and fourth trial generations (HD7 and HD10 for early stages, HD8 and HD11 for intermediate stages, and HD9 and HD12 for advanced stages) of the GHSG were included in this retrospective analysis. In addition, only patients who underwent central pathology review by an expert hematopathologist (88.3%) were included.
To be eligible for the GHSG trials, patients aged between 16 and 75 years (for HD9, between 16 and 60 years) had to have biopsy-proven disease at diagnosis and adequate organ function, as defined by a creatinine clearance of more than 60 mL/min, serum transaminases less than 3x normal, bilirubin less than 2 mg/dL, left ventricular ejection fraction of more than 0.45, forced expiratory volume in 1 second or diffusion capacity of carbon monoxide of more than 60% of predicted, WBCs 3,500/μL, hemoglobin level 8 g/dL, and platelets 100,000/μL. Patients were required to test negative for antibodies against HIV and to be free of active infections. All patients signed informed consent forms based on the institutional review board guidelines. Histologic diagnosis was made initially by local pathologists who were asked to send paraffin block biopsy samples for central pathology review by an expert hematopathologist.
Staging Procedures
All patients underwent uniform staging. The extent of disease was assessed by chest x-ray, abdominal ultrasound, computed tomography, bone scintigraphy, and bone marrow biopsy. After the end of therapy, all sites of initial disease were re-evaluated by adequate methods.
Response Definition
Complete response (CR) was defined as disappearance of all clinical and radiographic evidence of disease for at least 1 month. Partial response (PR) was defined as a greater than 50% reduction in the sum of the largest diameter and its perpendicular diameters of measurable disease lasting for at least 1 month. Any response less than PR was considered treatment failure.
Treatment
Patients had been recruited onto the GHSG trials for early-stage (HD7 and HD10), intermediate-stage (HD8 and HD11), and advanced-stage disease (HD9 and HD12). The chemotherapeutic regimens included doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); cyclophosphamide, vincristine, procarbazine, and prednisone alternating with ABVD; and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). All patients were treated according to the protocols of the respective trials. Table 1 gives an overview of the study design and treatment regimens of those trials.5-8 Patients with early- and intermediate-stage disease received extended-field radiotherapy with 30 Gy (HD7 and HD8) or involved-field radiotherapy with 20 or 30 Gy (HD10 and HD11). In addition to chemotherapy, patients with advanced-stage disease received local radiotherapy to all regions of initial bulky disease with 30 Gy or to residual disease more than 2 cm with 40 Gy. Radiation fields were restricted to the extent of initial bulky tumors or persisting tumor mass. There were no significant differences in primary treatment in an analysis stratified by disease stage (data not shown).
Statistics
Demographics and disease characteristics were summarized using descriptive statistics. Event-free survival (EFS) was measured from the date of entry onto the therapy protocol until progression, relapse, or death from any cause. Overall survival (OS) was measured from the date of entry onto the treatment protocol until death from any cause. OS and freedom from treatment failure rates were estimated using the Kaplan-Meier method.9 Removal and entry levels of significance were 0.1 and 0.05, respectively. No adjustment was made for multiple comparison; all P values are two sided. EFS was defined as ongoing survival without events including disease progression or relapse, death, or initiation of new alternative treatment. All statistical analyses were performed using SPSS 12.1 (SPSS Inc, Chicago, IL).
RESULTS
Patient Characteristics
Two thousand seven hundred fifteen patients with biopsy-proven HL were retrospectively analyzed. Of these patients, 100 patients (4%) had LRCHL, 1,688 patients (63%) had NS, 731 patients (27%) had MC, 23 patients (1%) had LD, and 145 patients (5%) had LPHL. The clinical features of assessable patients are listed in Table 2. The median age at diagnosis was 38 years (range, 16 to 74 years) in LRCHL patients, 40 years (range, 16 to 71 years) in LPHL patients, 32 years (range, 16 to 74 years) in NS patients, 38 years (range, 16 to 75 years) in MC patients, and 30 years (range, 16 to 72 years) in LD patients. Both LRCHL (P < .002) and LPHL (P < .0001) patients were significantly older than patients with CHL, but the difference between these two subtypes was not significant. In LRCHL there was a male predominance, with a male to female ratio of 2:1.
Patients with LRCHL tended to present with early stages of disease. Disease stage by Ann Arbor criteria was stage I in 34 patients (34%), stage II in 46 patients (46%), stage III in 14 patients (14%), and stage IV in five patients (5%). Constitutional symptoms were infrequent in LRCHL. Weight loss, fevers, and night sweats were noted in seven, six, and 14 patients, respectively. Of the risk factors used by the GHSG, elevated erythrocyte sedimentation rate (P < .0001), involvement of more than three lymph node areas (P < .0001), and large mediastinal tumor (P < .0001) were less frequent in patients with LRCHL compared with patients with CHL. The main site of organ involvement at the time of presentation in LRCHL patients was the lungs (four patients). Other sites of organ involvement included liver (two patients), skeleton (three patients), bone marrow (two patients), and miscellaneous other sites (two patients).
Response
Response rates by histologic subtype are listed in Table 3. Overall response rates were virtually identical for all groups. Treatment response in the LRCHL group was excellent. Two patients could not be evaluated for response because they died before completion of the treatment. The overall response rate was 100%. A total of 93 patients (96%) with LRCHL achieved a CR, and four patients (4%) achieved a PR. The overall response rates for the other subtypes were 99% for LPHL, 98% for NS, 99% for MC, and 95% for LD. Although no progressive disease occurred among patients with LRCHL during the follow-up period, one patient (2%) with LPHL, 30 patients (2%) with NS, nine patients (1%) with MC, and one patient (5%) with LD had early disease progression.
Treatment Outcome
The rates for EFS and OS are listed in Table 4. Figure 1 shows Kaplan-Meier curves for EFS of patients with LRCHL, LPHL, and CHL. The median follow-up time was not significantly different between groups. Patients with LRCHL had a significantly higher EFS rate (97%) than patients with other subtypes of CHL (P < .02). EFS rates did not differ significantly between patients with LRCHL (97%) and LPHL (94%). At 30 months, the EFS rate was 97% for patients with LRCHL. A strikingly worse EFS rate (P < .0001) than any other subtype was observed among patients with LD (55%).
Kaplan-Meier curves for OS by histologic subtype are shown in Figure 2. At 30 months, the overall EFS rate in LRCHL was 97%. Among the 100 patients with LRCHL, three have died during the follow-up period. Comparisons between the specific categories using the log-rank test failed to reveal any significant differences at P = .05 in the OS, although there was a trend for higher survival in patients with LRCHL and LPHL compared with CHL. No relapses were observed in the LRCHL group. In contract, there were nine relapses (6%) in the LPHL group, 161 relapses (10%) in the NS group, 65 relapses (9%) in the MC group, and six relapses (26%) in the LD group.
Three patients (3%) in the LRCHL group died before completion of the treatment. All of these patients died as a result of treatment-related toxicities. Patient 1 was a 46-year-old male and presented with stage IIIB disease. The patient died of a cardiovascular event after receiving four cycles of BEACOPPescalated followed by four cycles of BEACOPPbaseline and 30 Gy of involved-field radiotherapy to bulky disease. Patient 2 was a 64-year-old male, had stage IVB disease, and died of acute chemotherapy-associated toxicity after receiving two cycles of BEACOPPescalated. The third patient, who had stage IIA disease, died of radiation pneumonitis at the age of 66 years. Before radiotherapy, she received two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone and ABVD as part of treatment arm A of the HD8 trial. Overall, HL and treatment-related toxicities were the most frequent causes of death. Although no patient with LRCHL died of HL, two patients (1%) with LPHL, 34 patients (2%) with NS, 15 patients (2%) with MC, and two patients (9%) with LD died of relapse or progression of disease. Treatment-related toxicities resulted in the deaths of one patient (1%) with LPHL, 24 patients (2%) with NS, and 22 patients (3%) with MC. None of the patients with LD died of treatment-related toxicities.
Secondary Malignancy
The number and frequency of secondary malignancies are listed in Table 5. Altogether, 45 secondary neoplasias were observed among the study population (one patient with acute lymphatic leukemia, 12 patients with acute myelogenous leukemia, 14 patients with lymphoma, and 18 patients with solid tumors). One patient with LRCHL developed a secondary malignancy (mucosa-associated lymphoid tissue lymphoma).
DISCUSSION
The following findings emerge from this analysis: patients with LRCHL are on average older than patients with CHL; patients with LRCHL usually present with early stages of disease; treatment outcome in LRCHL is excellent; and further studies should be aimed at reducing toxicity. The aim of this retrospective study was to gain a better understanding of the clinical features of LRCHL and to determine treatment outcome for this entity. Although the histologic and molecular features of LRCHL have been well characterized,3, 10 few data exist on the clinical characteristics of this subtype. Review of all patients with HL treated within the studies of the GHSG between 1996 and 2002 revealed 100 patients with a diagnosis of LRCHL. The clinical features of this group were compared with the features of patients with the other subtypes of HL, LPHL or CHL (NS, MC, and LD), treated during the same time period. The data presented here can be considered as population based and representative with regard to frequency and presentation because more than 70% of all patients older than 16 years of age with a diagnosis of HL in Germany were registered in the GHSG trials.
With a median age of 38 years, patients with LRCHL were significantly older (P < .002) than patients with the other subtypes of CHL, who had a median age of 33 years. This difference was mainly a result of a lower percentage of patients younger than 30 years. The median age of 40 years for LPHL patients in our study was higher than previously reported.4, 11 The majority of patients with LRCHL are male, which is reflected in a male to female ratio of more than 2:1. LRCHL patients usually presented with early stages of disease, and constitutional symptoms were rare. Only 19% of patients with LRCHL and 10% of patients with LPHL complained of B symptoms, whereas 38% of patients with CHL complained of B symptoms. The lower incidence of B symptoms could only partially be explained by the higher percentage of early disease stages in LRCHL compared with other subtypes of CHL (data not shown). Other risk factors with a lower incidence in LRCHL and LPHL were presence of a mediastinal mass and elevated erythrocyte sedimentation rate, even when balanced by disease stage. No difference in distribution was observed for extranodal involvement or affection of more than three lymph node areas. Not surprisingly, organ involvement was relatively rare. The most frequently involved extranodal sites in the LRCHL cohort were lungs (4%), skeleton (3%), bone marrow (2%), and liver (2%).
Although, on the basis of morphology and immunohistochemistry, LRCHL belongs to CHL, it clinically more closely resembles LPHL. In general, there were no major differences in the clinical characteristics of patients with LRCHL and LPHL except for the significantly lower frequency of an elevated erythrocyte sedimentation rate (P < .0001) and B symptoms (P < .04) in LPHL. LRCHL and LPHL are the two most highly curable subtypes of HL, with almost all patients responding to therapy and high long-term EFS rates. Primary treatment outcome of LRCHL and LPHL is excellent, with 30-month EFS rates of 97% and 94%, respectively; these rates were not significantly different. The superior outcome of these two entities is in line with earlier reports.4, 12-15 The better survival in LRCHL cannot simply be explained by the higher proportion of early disease stages because, even for early stages, there was still a significant difference (P < .04) between LRCHL and CHL. Contrary to the good results obtained for LRCHL and LPHL, the outcome of patients with LD was unsatisfactory. Of 23 patients, only 17 (81%) achieved a CR, three (14%) achieved a PR, and one (5%) had progressive disease. The EFS rate was only 55% at 30 months of follow-up. In addition, 26% of these patients experienced relapse. The relatively poor treatment outcome of patients with LD underlines the need for more effective primary treatment regimens capable of producing high response rates and low relapse rates in LD. However, the number of patients with LD was low (n = 23), and therefore, our results should be confirmed in a larger cohort.
The differences in clinical parameters of LRCHL that were noticed between the present and the European Task Force on Lymphoma study4, 16 can be easily explained by the different mechanisms of selection. In the European Task Force on Lymphoma study, only patients with LRCHL who were previously misclassified as having LRCHL were reviewed. However, our study analyzed a more representative series of LRCHL patients that also included patients who, in the past, would have been classified as NS or MC. Although the importance of histologic subtype as a prognostic marker for survival has basically disappeared with the development of more effective therapeutic regimens, our study demonstrates that histologic typing can still have a significant prognostic impact.
The observation that all deaths in the LRCHL group were a result of treatment-related toxicities underscores the importance of toxicities related to therapy in the care for patients with HL. With the high cure rates achieved with current therapeutic regimens, both the acute and long-term consequences of therapy have become a major concern.17 Because patients with LRCHL are generally older, they are at an increased risk of acute toxicities. In fact, two of the three patients who died were greater than 60 years old. Except for the patient with radiotherapy-induced pneumonitis, the two other patients received a more intensified BEACOPP regimen as part of their therapy.
What are the clinical implications of our study? One of the key questions raised by this analysis is whether patients with LRCHL should receive less intensive treatment. Unfortunately, the results of this study cannot conclusively answer this question. Because of the few events observed and a lack of longer follow-up, the data have to be interpreted with caution with regard to treatment decisions. The improvement in the EFS when compared with the previous study by Diehl et al4 also suggests that patients with LRCHL have benefited from an intensification of chemotherapeutic regimens. Therefore, current data do not suffice to justify a reduction in treatment intensity. With longer follow-up, this might change because the number of treatment-related deaths can be expected to increase with time. In future clinical trials, the reduction of treatment toxicity will play an important role because it was the sole cause of death in our LRCHL cohort. Elderly patients are at an especially increased risk of acute toxicities. The GHSG acknowledged this and has initiated two studies specifically designed for older patients.18 The future development of novel targeted therapies promises to reduce late sequelae, while maintaining or improving treatment outcome with low treatment-related toxicity.4, 19
In conclusion, this is the largest published series to date of uniformly treated patients with LRCHL using the definition set forth by the REAL and WHO classification schemes. Our data confirm the excellent prognosis of LRCHL in contrast to other subtypes of CHL. Additional larger, international, multicenter studies with longer follow-up are required to answer questions regarding the right standard treatment and the occurrence of late treatment-related sequelae, such as secondary malignancies and pulmonary and cardiac toxicity.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grants from the Deutsche Krebshilfe and the Kompetenznetz Maligne Lymphome.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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