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© 1999 American Society for Clinical Oncology Treatment of Multifocal Primary Cutaneous B-Cell Lymphoma: A Clinical Follow-Up Study of 29 PatientsFrom the Departments of Dermatology and Pathology, Free University Hospital, Amsterdam; Department of Radiation Oncology, Leiden University Medical Center, Leiden; Department of Dermatology, University of Rotterdam, Rotterdam; Department of Dermatology, University of Groningen, Groningen; Department of Dermatology, University of Utrecht, Utrecht, the Netherlands; and Department of Dermatology, University of Ghent, Ghent, Belgium. Address reprint requests to Rein Willemze, MD, Department of Dermatology, Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; email r.willemze{at}azvu.nl
PURPOSE: Although patients with primary cutaneous B-cell lymphoma (CBCL) and localized skin lesions are generally treated with radiotherapy and have an excellent prognosis, the clinical behavior and optimal treatment of CBCL presenting with multifocal skin lesions are less well defined. In this study, we evaluated the clinical behavior of and results of treatment for multifocal CBCL in 29 patients, and we formulated therapeutic guidelines. PATIENTS AND METHODS: The study group included 16 patients with primary cutaneous follicular center-cell lymphoma (PCFCCL), eight with primary cutaneous immunocytoma (PCI), and five with primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL of the leg). RESULTS: Only one of the 24 patients with multifocal PCFCCL or PCI developed extracutaneous disease, and no patient died from lymphoma (median follow-up, 54 months). In patients with PCFCCL, treatment with either multiagent chemotherapy (nine patients) or radiotherapy directed toward all skin lesions (five patients) proved equally effective in terms of complete remission, relapse, and survival. In contrast, all five patients with PCLBCL of the leg developed extracutaneous disease, and four of the five died from systemic lymphoma, 8 to 36 months (median, 21 months) after diagnosis. CONCLUSION: The results of these preliminary studies suggest that patients with PCFCCL or PCI presenting with multifocal skin lesions have the same excellent prognosis that patients with localized PCFCCL or PCI have and that radiotherapy directed toward all skin lesions is as effective as multiagent chemotherapy. Patients with PCLBCL of the leg have a more unfavorable prognosis, particularly patients presenting with multifocal skin lesions. This last group should always be treated with multiagent chemotherapy.
PRIMARY CUTANEOUS B-cell lymphomas (CBCLs) constitute approximately 20% to 25% of all cutaneous lymphomas.1,2 The European Organization for Research and Treatment of Cancer (EORTC) divides primary CBCLs into primary cutaneous follicular center-cell lymphoma (PCFCCL), primary cutaneous immunocytoma (PCI), and primary cutaneous large B-cell lymphoma (PCLBCL) of the leg.2 PCFCCLs, which comprise malignant B-cell lymphomas classified as centroblastic/centrocytic or centroblastic lymphoma in the updated Kiel classification,3 represent the most common type of CBCL. These lymphomas generally present with localized skin lesions (usually localized on the head or trunk), rarely disseminate to extracutaneous sites, and are associated with an excellent prognosis, with a 5-year survival rate of more than 95%.4-7 PCI more often presents with skin lesions on the arms and legs and is also associated with an excellent prognosis.8,9 Disease-related deaths have not been reported thus far. In the Revised European-American Lymphoma classification,10 similar lymphomas are designated primary cutaneous marginal zone B-cell lymphomas or mucosa-associated lymphoid tissue–type lymphomas.11-13 PCLBCLs of the leg, which histologically resemble centroblastic lymphomas in most cases and immunoblastic lymphomas less commonly, have recently been delineated as a separate group. This type of CBCL predominantly affects elderly patients, more often disseminates to extracutaneous sites, and is associated with a more unfavorable prognosis (5-year survival rate, 58%) compared with the other two groups.14 In patients with CBCL presenting with solitary or localized skin lesions, radiotherapy is the preferred treatment.15,16 However, the optimal treatment for patients presenting with multifocal skin lesions, which is more uncommon, has not yet been well defined. Because patients with such lymphomas are considered to have a higher risk for developing extracutaneous disease, some studies suggest that these patients should be treated with aggressive multiagent chemotherapy.17 In the present study, we evaluated the clinical and histologic data from 29 patients with primary CBCL and multifocal skin lesions who registered with the Dutch Cutaneous Lymphoma Group between 1985 and 1997. The main goals of this study were, first, to determine whether the clinical behavior of multifocal CBCL differs from that of the more common localized CBCL and, second, to formulate guidelines for the management and treatment of patients with multifocal CBCL.
All patients with primary CBCL with multifocal skin lesions at presentation who were registered with the Dutch Cutaneous Lymphoma Group were selected for this study. Multifocal skin disease was defined as skin involvement of at least two nonadjacent skin areas. Patients presenting with multiple skin lesions that did not fit into one radiation field were considered to have multifocal skin disease. Of the 149 patients with primary CBCL registered between 1985 and 1997, 29 (14%) had multifocal lesions at the time of diagnosis, a proportion similar to those in other large series.7,18 In all cases, adequate staging procedures—including physical examination, complete blood cell counts, hepatic and renal function tests, chest radiography, abdominal computed tomography, and bone marrow cytology and histology—had been performed and extracutaneous disease had not been demonstrated. According to the EORTC classification for primary cutaneous lymphomas, this study group included 16 patients with PCFCCL (patients no. 1 through 16), eight with PCI (patients no. 17 through 24), and five with PCLBCL of the leg (patients no. 25 through 29) (Table 1). This latter group included patients presenting with skin lesions on both lower legs, and three of these patients had skin lesions at other sites as well. Follow-up data had been collected each year from referring dermatologists or oncologists and were available for all cases in the registry of the Dutch Cutaneous Lymphoma Group.
The main clinical characteristics of the three patient groups are presented in Tables 1 and 2. The total group of 29 patients included 17 men and 12 women. The median age at the time of diagnosis was 56 years (range, 26 to 92 years). The length of time before diagnosis that patients had had skin lesions varied between 2 and 480 months (median, 24 months). In eight of the 29 patients, a diagnosis of pseudo–B-cell lymphoma had been made on viewing the same lesions (patient no. 17) or other lesions (patients no. 9, 10, 16, 20, 22, 23, and 24) 24 to 192 months (median, 60 months) before a definite diagnosis of CBCL was made.
The group of patients with PCFCCL was composed of 16 patients, 11 men and five women. The median age at the time of diagnosis was 56 years (range, 27 to 84 years). Clinically, these multifocal PCFCCLs usually involved the trunk (Fig 1). These 16 patients presented with multiple tumors, nodules, and/or plaques on the back (n = 16), the chest or abdomen (n = 10), the arms (n = 7), and/or the head and neck region (n = 2). Initial therapy consisted of six cycles of multiagent chemotherapy—including courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (in eight patients: patients no. 6 through 13) and courses of cyclophosphamide, vincristine, and prednisone therapy (patient no. 14)—or radiotherapy directed toward all visible skin lesions (in five patients: patients no. 1 through 5) (Table 1). Radiotherapy consisted of electron beam irradiation (4 to 10 million electron volts) with a radiation dose of 40 Gy. Of the two remaining patients, one patient (patient no. 15) refused any aggressive treatment and was therefore treated with topical corticosteroids only, and the other patient (patient no. 16) did not receive any treatment, because the skin lesions showed the tendency to regress spontaneously.
Initial treatment in the PCFCCL group resulted in complete remission in 15 of 16 patients, including patient no. 16, all of whose skin lesions disappeared without any therapy. The disease-free survival time for these 15 patients varied between 11 and 72 months (median, 38 months). Cutaneous relapse was noted in four of 16 patients (patients no. 11, 14, 15, and 16). Only one patient (patient no. 12) developed positive cervical lymph nodes, but these lesions regressed spontaneously and the patient did not require additional treatment. It is interesting to note that cutaneous or extracutaneous relapse occurred in three of the nine patients treated with multiagent chemotherapy but in none of the five patients in whom all initial skin lesions had been treated with radiotherapy. Follow-up data indicated that none of these 16 patients died from lymphoma, after a median follow-up of 52 months (range, 20 to 179 months). The group of patients with PCI consisted of five men and three women. The median age at the time of diagnosis was 43 years (range, 26 to 80 years). Consistent with findings of previous studies, these lymphomas usually involved the arms and/or legs (seven of eight cases), whereas the head and trunk were involved in one and four cases, respectively. Initial treatment was more varied than that in the PCFCCL group and consisted of multiagent chemotherapy (patients no. 17 and 21), single-agent chemotherapy (patient no. 22), radiotherapy or surgical excision of only some of the skin lesions (patients no. 18, 19, and 20), or treatment with topical corticosteroids (patients no. 23 and 24) (Table 1). Only the patient who was treated with CHOP therapy achieved complete remission. Cutaneous relapse occurred in all eight patients, including the patient treated with CHOP therapy. However, none of these eight patients developed extracutaneous disease or died from lymphoma, after a median follow-up of 65 months (range, 14 to 149 months). Partial spontaneous regression occurred in 50% of cases; complete spontaneous regression of all lesions did not occur. The group of patients with PCLBCL of the leg included four women and one man. The median age at diagnosis was 76 years (range, 35 to 92 years). Clinically, these patients presented with plaques and tumors on both lower legs (patients no. 25 and 26) or on the leg or legs and other sites as well (Fig 2). Initial therapy, which was often suboptimal because of the age and general condition of the patients, consisted of single-agent or multiagent chemotherapy (patients no. 26 through 29) or radiotherapy directed toward all skin lesions (patient no. 25).
Only two patients with PCLBCL of the leg achieved complete remission, which was, however, short-lived (6 and 7 months). All five patients developed extracutaneous disease, 7 to 36 months (median, 18 months) after diagnosis. Two patients (patients no. 25 and 27) died rapidly, before further treatment could be initiated. In two patients (patients no. 26 and 29), treatment with more aggressive chemotherapy (CHOP or CHOP-like therapy) resulted in only partial remission. One patient (patient no. 28), a 35-year-old man who only partially responded to cyclophosphamide, etoposide, and vincristine therapy, received an autologous bone marrow transplant, which resulted in sustained complete remission. Follow-up data indicated that four (80%) of the five patients in this group died from systemic lymphoma, 8 to 36 months after diagnosis; only one patient remained alive and well. The median survival time for this group was 31 months (range, 8 to 85 months).
Although there is general consensus among cutaneous lymphoma centers that primary CBCL presenting with solitary or localized skin lesions, irrespective of clinical or histologic subtype, should be treated with optimal doses of radiotherapy (40 Gy), the optimal treatment for the rare CBCL presenting with skin lesions at multiple sites has not been well defined. Some anecdotal reports suggest that patients with multifocal CBCL have a more unfavorable prognosis and should therefore be treated with aggressive multiagent chemotherapy.17 The guidelines of the Dutch Cutaneous Lymphoma Group, most recently revised in 1990, also indicate that patients with PCFCCL and PCLBCL of the leg presenting with multifocal skin lesions are best treated with systemic chemotherapy. Patients with multifocal PCI are treated less aggressively because they rarely develop extracutaneous disease, and lymphoma-related deaths in this group have not yet been reported.8,9 These therapeutic guidelines, however, are mainly based on clinical experience and are not supported by published studies. In fact, follow-up data from large groups of patients with multifocal CBCL have never been published. In recent years, in view of the favorable prognosis for most patients with CBCL, there has been increasing reluctance to treat these patients with multifocal CBCL with multiagent chemotherapy, particularly when they present with only two or three skin lesions at different sites. In such patients, radiotherapy directed toward all visible skin lesions is considered an attractive alternative. In an attempt to create new guidelines for the treatment of patients with multifocal CBCL, we first evaluated clinical, histologic, and follow-up data from 29 patients with multifocal CBCL who were registered with the Dutch Cutaneous Lymphoma Group between 1985 and 1997. We first wanted to determine whether the clinical behavior of multifocal primary CBCL differs from that of CBCL presenting with localized skin lesions. Only six of the 29 patients in our study developed extracutaneous disease, and only four died from systemic lymphoma. However, analysis of the data for the separate groups of CBCL recognized in the EORTC classification for primary cutaneous lymphomas showed that only one of the 24 patients with PCFCCL or PCI developed extracutaneous disease and that none of these patients died from lymphoma, after a median follow-up of 54 months (range, 14 to 179 months). These data clearly indicate that patients with multifocal PCFCCL and those with multifocal PCI have the same low tendency to develop extracutaneous disease, and the same excellent prognosis, as do patients with the more common CBCLs presenting with localized skin lesions. Similar results can be found in the report of a study by Santucci et al,7 in which 11 of 83 patients presented with multifocal skin lesions. In contrast, in our group of patients with PCLBCL of the leg, all five patients developed extracutaneous disease, and four of the patients died from systemic lymphoma. These findings confirm the results of recent studies indicating that PCLBCLs of the leg represent a separate group, with a higher tendency to disseminate to extracutaneous sites and associated with a more unfavorable prognosis.14,19 Most recently, it was found that PCLBCLs of the leg consistently express bcl-2 protein as well as Fas (CD95) ligand, whereas expression of Fas (CD95) is variable (Zoi-Toli et al, manuscript submitted for publication).20 In contrast, PCFCCLs do not or rarely express bcl-2 protein and Fas ligand, whereas Fas is always strongly expressed. The differing expression of these apoptosis-related molecules may explain, at least in part, the different clinical behavior of these two types of primary CBCL. Compared with our previous study of PCLBCL of the leg (18 patients),14 in the present study the rates of extracutaneous relapse (38% v 100%) and lymphoma-related death (28% v 80%) were considerably higher. This increase may be related to the small sample size in the current study. However, recent evaluation of 21 patients with PCLBCL of the leg who were registered with the Dutch Cutaneous Lymphoma Group, including the 18 patients described previously,14 shows that only one of six patients presenting with a single tumor on one leg died from lymphoma, after a median follow-up of 40 months (range, 18 to 120 months) (unpublished data). It is therefore possible that in this particular group, patients presenting with multifocal skin lesions (eg, skin lesions on both legs) have a worse prognosis than do patients presenting with a skin lesion or lesions limited to one leg. A European multicenter study of more than 150 primary cutaneous large B-cell lymphomas has recently been started and will address this issue. The ultimate goal of the present study was to create new guidelines for the treatment of patients with multifocal CBCL. The central issue to be addressed was which patients should be treated with aggressive multiagent chemotherapy (CHOP or CHOP-like therapy). The guidelines of the Dutch Cutaneous Lymphoma Group, formulated in 1990, indicated that all patients with multifocal CBCL, except for patients with PCI, should be treated with CHOP or CHOP-like therapy. However, the results of the present study indicate that in patients with multifocal PCFCCL, irradiation of all visible sites may be equally effective. Such an approach was taken in five patients (patients no. 1 through 5) and resulted in sustained complete remission, with a median disease-free survival time of almost 5 years. Relapse was not noted in these patients. In contrast, two of eight patients with multifocal PCFCCL treated with CHOP therapy had multiple cutaneous relapses (patient no. 11) or an extracutaneous relapse (patient no. 12). The other patients treated with CHOP achieved sustained complete remission, varying in length between 20 and 59 months. No major differences were found between the patients treated with radiotherapy and those treated with CHOP in terms of histologic subtype (centrocytic/centroblastic or centroblastic lymphoma), the number of affected skin sites, or total tumor burden. Taken together, these preliminary findings suggest that in patients with multifocal PCFCCL, irrespective of histologic appearance, radiotherapy directed toward all skin lesions is an effective and safe alternative. Only in exceptional cases—involving numerous or extremely thick tumors—should CHOP therapy still be considered. In cases of cutaneous relapse with only one or a few skin lesions, radiotherapy is again the preferred treatment. The prolonged complete remissions (up to 6 years or more) achieved in these patients with multifocal PCFCCL after irradiation of all visible skin lesions are intriguing. In particular, in such multifocal cases, one would expect low levels of circulating clonal B cells and—given that these cells are unlikely to be affected by radiotherapy—recurring disease. However, the presence of circulating clonal B cells in patients with CBCL has not been investigated thus far. These prolonged remissions are reminiscent of the results of total-skin electron beam irradiation in patients with early (patch/plaque)-stage mycosis fungoides (MF), namely 5-year relapse-free survival rates of 25% to 50%, depending on the extent of skin involvement.21,22 Muche et al23 demonstrated circulating clonal T cells in more than 50% of patients with early MF but considered a relationship between the presence of circulating clonal T cells and poor prognosis unlikely. Nevertheless, studies on the relationship between the presence of circulating clonal T cells (in MF) or clonal B cells (in CBCL) and disease-free survival would be of interest because they may provide a rationale for the optimal treatment in these conditions. PCIs show the characteristic clinical behavior of low-grade malignant (small-cell) B-cell lymphomas.24 Spontaneous regression of (part of the) skin lesions is frequently noted, and prognosis is excellent, as it is in patients with multifocal skin lesions. In addition, most patients have recurrent or persistent disease, and sustained complete remission or cure is rarely achieved. Therefore, these multifocal PCIs are best treated with radiotherapy or excision of individual skin lesions. When excision or radiation is no longer an option, because patients have too many lesions, nonaggressive chemotherapy—such as chlorambucil and/or prednisone therapy or perhaps even courses of cyclophosphamide, vincristine, and prednisone therapy—may be considered. Intralesional administration of recombinant interferon alfa has been suggested as an effective alternative in the treatment of both PCI and PCFCCL and could be a useful addition to the nonaggressive therapeutic options for these lymphomas, but the number of patients so treated who have reported on thus far is still small.25-27 Moreover, the advantage of interferon alfa over radiotherapy is uncertain and further study is needed. In cases of small recurrent skin lesions, topical or intralesional administration of corticosteroids may be considered. Borrelia burgdorferi infections have been implicated in the pathogenesis of both pseudo–B-cell lymphomas and CBCLs, including PCI and PCFCCL.28,29 In patients with serologic, bacteriologic, or molecular evidence of B. burgdorferi infection, treatment with antibiotics may result in complete remission and should therefore be attempted first.28,29 In accordance with previous findings by our group,14 patients with PCLBCL of the leg with or without involvement of other cutaneous sites have a more unfavorable prognosis. In this type of CBCL, multifocal skin lesions (eg, on both lower legs) might be an additional risk factor. With the exception of patients presenting with one solitary tumor, patients with PCLBCL of the leg should be treated with CHOP or CHOP-like therapy whenever possible. Less aggressive therapies, sometimes necessary because of the age of these patients, are unlikely to result in sustained complete remission. Finally, the results of the present study are also important for patients suspected of having CBCL and in whom a definite diagnosis cannot or cannot yet be made. The clinical consequences of not making a final diagnosis are generally minor, particularly in patients presenting with a solitary lesion. In such cases, radiotherapy or surgical excision may be a simple solution. However, in rare cases of suspected but not definite CBCL presenting with multifocal skin lesions, it is often difficult to decide whether aggressive chemotherapy should be given. The results of the present study clearly indicate that in such patients a conservative approach may be taken. This recommendation is supported by follow-up data from 14 patients with suspected CBCL, which is considered a separate type in the Dutch registry. Treatment for these patients consisted of topical and/or intralesional administration of corticosteroids, low-dose radiotherapy, or excision. In none of the patients was there progression to genuine CBCL, after a median follow-up of 36 months. In conclusion, the results of this and other studies suggest that not only in CBCL patients with solitary or localized skin lesions but also in CBCL patients presenting with skin lesions at multiple sites, irradiation of all visible skin lesions is equally effective and may be preferable because of less systemic toxicity (Fig 3). Only in patients with PCLBCL of the leg (with the exception of those presenting with one solitary tumor) and patients with PCFCCL and numerous or extremely thick skin lesions is CHOP or CHOP-like therapy indicated. However, it must be noted that although this study, compared with other studies to date, involves by far the largest group of patients with multifocal primary CBCL, these guidelines are based on findings for relatively small groups of patients and therefore require additional confirmation.
We are grateful to Professor Dr P.C. Huijgens for helpful discussions during the preparation of the manuscript.
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Muche JM, Lukowsky A, Asadullah K, et al: Demonstration of frequent occurrence of clonal T cells in the peripheral blood of patients with primary cutaneous T-cell lymphoma. Blood90:1636-1642, 1997 25. Horning SJ: Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin Oncol20:75-88, 1993[Medline] 26. Peris K, Caracciolo E, Weirich G, et al: Primary centroblastic/centrocytic lymphoma of the skin: Detection of B-cell monoclonality by polymerase chain reaction. Am J Dermatopathol17:506-510, 1995[Medline] 27. Kutting B, Bonsmann G, Metze D, et al: Borrelia burgdorferi-associated primary cutaneous B cell lymphoma: Complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a. J Am Acad Dermatol36:311-314, 1997[Medline] 28. Parodi A, Micallizi C, Rebora A: Intralesional natural interferon alpha in the treatment of Crosti's lymphoma (primary cutaneous B follicular center-cell lymphoma): Report of four cases. J Dermatol Treat7:105-107, 1996 29. Garbe C, Stein H, Dienemann D, et al: Borrelia burgdorferi-associated cutaneous B cell lymphoma: Clinical and immunohistologic characterization of four cases. J Am Acad Dermatol24:584-590, 1991[Medline] 30. Cerroni L, Zochling N, Putz B, et al: Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol24:457-461, 1997[Medline] Submitted November 5, 1998; accepted April 14, 1999.
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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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ABSTRACT
INTRODUCTION
