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Journal of Clinical Oncology, Vol 22, No 4 (February 15), 2004: pp. 634-639 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.044 Primary Cutaneous B-Cell Lymphoma Treated With Radiotherapy: A Comparison of the European Organization for Research and Treatment of Cancer and the WHO Classification SystemsFrom the Departments of Therapeutic Radiology, Dermatology, and Internal Medicine, Section of Oncology, Yale University School of Medicine, New Haven, CT Address reprint requests to Lynn D. Wilson, MD, MPH, Yale University School of Medicine, 333 Cedar St, PO Box 208040, New Haven, CT 06520; e-mail: lynn.wilson{at}yale.edu
PURPOSE: To determine the relationship between the WHO and European Organization for Research and Treatment of Cancer (EORTC) pathologic classifications for primary cutaneous B-cell lymphoma (CBCL) and the implication of this relationship on initial treatment. PATIENTS AND METHODS: Patients with primary CBCL treated with radiotherapy were identified retrospectively. Initial biopsy specimens were reviewed by two dermatopathologists and classified according to the EORTC and WHO systems. Primary outcomes were recurrence-free and overall survival. RESULTS: Thirty-four patients were identified; initial biopsy specimens were adequate for classification in 32 patients. Four different composite histopathologic subtypes of lymphoma were identified: 53% (17 of 32) follicle center cell by EORTC and diffuse large B-cell by WHO (FCC/DLB), 25% (eight of 32) follicle center cell by EORTC and follicular by WHO (FCC/Fol), 13% (four of 32) marginal zone by EORTC and WHO (MZ/MZ), and 9% (three of 32) large B-cell of the leg by EORTC and diffuse large B-cell by WHO (Leg/DLB). Five-year relapse-free survival ranged from 62% to 73% for FCC/DLB, FCC/Fol, and MZ/MZ but was 33% for Leg/DLB (P = .6). Five-year overall survival was 100% for FCC/DLB, FCC/Fol, and MZ/MZ but was 67% for Leg/DLB (P = .07). At 5 years, 21% of all patients had developed extracutaneous disease. CONCLUSION: Two-thirds of primary cutaneous FCC lymphomas by EORTC criteria satisfy WHO criteria for DLB lymphoma. Unlike DLB lymphoma presenting in nodal or noncutaneous sites, these lesions are associated with an indolent course and may be treated with local radiotherapy alone.
Primary cutaneous B-cell lymphoma (CBCL) is an uncommon form of extranodal non-Hodgkin's lymphoma characterized by malignant B-cells that are limited to the skin at initial diagnosis [1]. Two major pathologic classification systems for CBCL exist: the European Organization for Research and Treatment of Cancer (EORTC) system [2] and the WHO system [3]. The EORTC system applies exclusively to cutaneous lymphoma and classifies most CBCLs as indolent lymphomas, either follicle center cell (FCC) or marginal zone (MZ) or immunocytoma [4,5]. In contrast, the WHO system applies to all lymphoid neoplasms and classifies a significant proportion of primary CBCLs as diffuse large B-cell (DLB) lymphoma [6,7]. To date, direct comparisons of the EORTC and WHO classifications for primary CBCL have been limited [8]. Many lesions in the EORTC FCC category meet morphologic criteria for DLB in the WHO system [4,5]. As a result, at least four different composite pathologic categories may be created by combining the EORTC and WHO systems: FCC by EORTC but DLB by WHO (FCC/DLB); FCC by EORTC and follicular by WHO (FCC/Fol); MZ by both EORTC and WHO (MZ/MZ); and large B-cell of the leg (Leg) by EORTC with DLB by WHO (Leg/DLB). At present, there is general agreement that FCC/Fol and MZ/MZ are indolent processes [9,10], whereas Leg/DLB lesions are more aggressive [5]. However, the natural history and optimal treatment of FCC/DLB is controversial. Proponents of the EORTC system classify these lesions as indolent lymphoma and recommend radiotherapy alone [11,12]. In contrast, advocates of the WHO system suggest that these lesions are more aggressive, similar to nodal DLB, and therefore recommend combined-modality therapy [6,13]. The aim of this study, therefore, was to compare the natural history of FCC/DLB with other CBCL subtypes in a retrospective cohort of patients treated with radiotherapy. As a secondary hypothesis, we sought to analyze the relationship between radiotherapy dose and outcome.
After approval from our institution's Human Investigations Committee, we identified all patients recorded by tumor registry and billing data with a diagnosis of primary CBCL evaluated at our institution between 1990 and 2002. Of 44 patients identified, 34 met the following inclusion criteria: evaluated at our institution before definitive therapy; computed tomographic (CT) scan of chest, abdomen, and pelvis at the time of diagnosis negative for systemic disease, and primary treatment with radiotherapy. Two patients treated with radiotherapy were excluded because no CT scan was performed at diagnosis; the other eight patients were not treated with radiotherapy. Initial biopsy specimens from all patients were reviewed by two dermatopathologists (E.J.G. and J.M.M.) and categorized under both the EORTC and WHO classification systems [2,3]. All specimens were analyzed for expression of routine T- and B-cell markers by immunohistochemistry. The presence of B-cell clonality was not required if the clinical and morphologic data strongly suggested a diagnosis of CBCL. Adequate archival tissue was not available for two patients whose initial biopsies were obtained at outside institutions. However, both patients developed recurrent lymphoma with evidence of a monoclonal B-cell population, thus supporting the initial diagnosis of CBCL. These patients were therefore included in the study but were not assigned a specific subcategory of CBCL. Baseline covariates including age, sex, race, duration of symptoms, history of pseudolymphoma, number and location of lesions, size of largest lesion, identifiable monoclonal B-cell population, radiotherapy dose, and number of radiotherapy fields were abstracted from medical records. Main outcomes included recurrence and death. Local recurrence was defined as biopsy-proven evidence of recurrent cutaneous lymphoma either within or immediately adjacent to the initial radiotherapy portal. Follow-up time was calculated from date of completion of radiotherapy with data abstracted from the medical record and confirmed using tumor registry data. One patient presenting with numerous small cutaneous nodules and two larger cutaneous tumors received initial treatment with radiotherapy portals directed at the two tumors only. At the patient's last follow-up, both tumors remained in complete remission, but the numerous dermal nodules persisted. This patient was therefore classified as alive with disease at last follow-up and was included in time to local recurrence and survival analysis, but was excluded from relapse-free survival calculations.
EORTC-WHO composite categories were compared using the Kaplan-Meier log-rank test. Individual categories were then compared using dummy variables in Cox proportional hazards models. In the secondary analysis, radiotherapy dose was dichotomized at the median. The relationship between outcome and radiotherapy dose was compared using the Kaplan-Meier log-rank test and Cox proportional hazards model. To assess for possible confounders, the relationship between covariates and outcome was assessed using the Pearson
Baseline Parameters Baseline demographic and clinical variables are listed in Table 1. Median age was 60 years, 18 patients (53%) were male, and 32 patients were white (94%). Three patients (9%) presented with leg involvement.
CT of the chest, abdomen, and pelvis was negative for systemic lymphoma in all patients. A normal pretreatment CBC was documented in 30 patients; in four patients, the archival record did not contain a CBC. Bone marrow biopsy was performed on 14 patients and was negative in all patients. Peripheral-blood flow cytometry was normal in 22 of 23 evaluated patients. One patient was found to harbor a CD5 (dim), CD19+, CD 20+, CD25+, immunoglobulin M-kappa surface immunoglobulin–positive peripheral-blood lymphocyte population.
Pathologic Classification
Treatment Treatment parameters by composite histologic classification are listed in Table 3. All patients received radiotherapy and four patients (12%) received three to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Median radiotherapy dose was 40 Gy (range, 20 to 48 Gy). Twelve patients (35%) required more than one radiotherapy field because of multifocal lesions. Of these, three patients required a multiple-field electron setup typically employed for total skin radiation, although blocking was used so that only a portion of the body was treated, such as the back, head and neck, or legs. Appropriate bolus was used for all lesions treated with enface electrons and/or megavoltage. Because of the retrospective nature of this series, accurate determination of radiotherapy margins was not possible. However, the general policy at this institution has been to use a 2- to 3-cm margin around visible disease.
Outcome Median follow-up was 3.4 years (range, 5 months to 11 years) from completion of radiotherapy. All patients experienced a complete response to initial treatment. Five-year overall survival was 96%, relapse-free survival was 55%, local recurrence-free survival was 81%, and extracutaneous relapse-free survival was 79% (Table 4).
Of those patients who developed a recurrence, the median time to recurrence was 10 months (range, 2.3 months to 6 years). Median time to development of systemic disease was 1.9 years (range, 6 months to 6 years). The sites of initial failure are reported in Table 5. When including failure at all skin sites, a total of 62% (eight of 13) of initial relapses were confined to the skin.
Outcome As a Function of Composite Histologic Subtype Five-year overall survival, relapse-free survival, and extracutaneous recurrence-free survival for each composite histologic subtype are listed in Table 4. Overall survival was 100% for FCC/DLB, FCC/Fol, and MZ/MZ but was 67% for Leg/DLB (P = .07 by log-rank analysis). No significant differences between composite histologic groups were noted for relapse-free survival (P = .6 by log-rank analysis) or extracutaneous recurrence-free survival (P = .6 by log-rank analysis). Site of initial recurrence as a function of composite histologic subtype is presented in Table 5.
Kaplan-Meier curves for relapse-free survival by composite histologic subtype are presented in Figure 1. Comparisons between specific categories using Cox proportional hazards models failed to reveal any significant differences at P
Radiotherapy Dose and Outcome When dichotomized at 40 Gy, a borderline protective association existed between radiotherapy dose and risk for any recurrence, with a 5-year relapse-free survival of 41% in the group receiving less than 40 Gy and 67% in the group receiving  40 Gy (unadjusted hazards ratio [HR], 0.38; 95% CI, 0.12 to 1.2; P = .09). Total dose dichotomized at 40 Gy failed to correlate with risk for local recurrence (unadjusted HR, 0.45; 95% CI, 0.075 to 2.7; P = .4). However, patients who received less than 36 Gy were at increased risk of local recurrence, with a 5-year local recurrence-free survival of 50% in the group receiving less than 36 Gy compared with 90% in the group receiving 36 Gy (unadjusted HR, 0.163; 95% CI, 0.026 to 1.0; P = .05).
None of the baseline covariates including age, sex, race, duration of symptoms, history of pseudolymphoma, number and location of lesions, size of largest lesion, presence of documented B-cell clonality, number of radiotherapy fields, and administration of chemotherapy correlated with risk for any recurrence or local recurrence at P
In this retrospective study of 34 patients with primary CBCL treated with radiotherapy, 68% of lesions classified as FCC lymphoma by the EORTC system were classified as DLB by the WHO system. This group, abbreviated as FCC/DLB, experienced a 5-year overall survival of 100%, relapse-free survival of 62%, and systemic relapse-free survival of 81%. These results are similar to those observed in the FCC/Fol and MZ/MZ subgroups. In contrast, the small Leg/DLB subgroup experienced worse overall and relapse-free survival, although these differences were not statistically significant given the sample size. These results support the EORTC assertion that, for lesions classified as FCC lymphoma, the presence of DLB morphology does not convey an adverse prognosis. Furthermore, radiotherapy alone results in acceptable control of FCC/DLB lesions, given that systemic relapse and death are uncommon. The results of this study may help to address a matter of significant controversy regarding the treatment of CBCL. Advocates of the EORTC system have concluded that most CBCLs are indolent lymphomas with a low risk for systemic progression after treatment with radiotherapy. For example, a series of 102 patients with FCC lymphoma treated with radiotherapy alone to a median dose of 24 Gy showed a 5-year overall survival of 97% and 5-year systemic relapse-free survival of 91% [12]. Similar results have been reported in several other smaller retrospective cohorts [11,14,15]. In contrast, advocates of the WHO system have found that DLB is the most common subtype of primary CBCL. Given that nodal and noncutaneous DLB lymphomas are associated with intermediate to aggressive clinical behavior, combined-modality therapy for primary cutaneous DLB lymphoma has been recommended [13]. At present, the only clinical data to support this position is a retrospective study by Sarris et al [6] of 19 patients with primary cutaneous DLB lymphoma. Fifteen patients treated with chemotherapy with or without consolidative radiotherapy experienced long-term progression-free survival of 71%. In contrast, all four patients treated with radiotherapy alone developed recurrent disease and three ultimately died. The results of our study show that a majority of cutaneous FCC lymphomas actually meet morphologic criteria for DLB lymphoma. Nevertheless, they manifest an indolent clinical course, even when treated with radiotherapy alone. These results are consistent with the large number of studies published using the EORTC classification system and are at odds with the study by Sarris et al [6]. One potential bias in the study by Sarris et al [6] that may explain these discordant results is the relationship between year of diagnosis and treatment modality. All patients treated with radiotherapy alone were diagnosed before 1980, whereas all patients who received chemotherapy were diagnosed after 1980. These data are therefore subject to historical bias, particularly because of the evolution of imaging modalities that may have improved staging. In addition to the clinical data presented in this study, recent molecular data indicate a similarity between FCC/DLB and FCC/Fol. Storz et al [16] used a cDNA microarray to compare the gene expression of cutaneous lesions from five FCC/Fol, two FCC/DLB, two systemic follicular lymphomas with skin involvement, and two systemic DLB lymphomas with skin involvement. FCC/Fol, FCC/DLB, and systemic follicular lymphomas shared a similar gene expression profile, whereas the profile of systemic DLB lymphoma was significantly different. These results provide molecular justification for the similar clinical behavior of FCC/DLB and FCC/Fol reported in our study.
As a secondary hypothesis, the relationship between radiotherapy dose and outcome was analyzed. Patients in this series treated with doses Several limitations of this study deserve mention. First, the absolute number of patients, although comparable with other series in the literature, is small. Therefore, conclusions from this study should ideally be verified in larger series. Second, documented clonality was not an entry criterion. As a result, some patients with B-cell pseudolymphoma may have been included, thus biasing the cohort toward a more favorable outcome. However, many other studies have not required clonality as an entry criteria [5,6,8,12,14,15]. Furthermore, all patient cases in this study were reviewed by two dermatopathologists with expertise in cutaneous lymphoma and were believed to represent CBCL on histopathologic and cytologic grounds. Finally, the absence of definable clonality does not guarantee a benign diagnosis [19,20]. For example, nonclonal lesions in this study were not at lower risk for recurrence (33% recurrence rate in the nonclonal group and 41% in the clonal group). Furthermore, half of the recurrences in nonclonal patients were found to harbor an identifiable clonal B-cell population. In summary, two thirds of primary CBCLs classified as FCC lymphoma by EORTC criteria meet WHO criteria for DLB lymphoma. In contrast to nodal and noncutaneous DLB lymphoma, these lesions are not associated with rapid systemic dissemination and death. As a result, local radiotherapy alone is a reasonable treatment option for many of these patients. Other treatment options may include polychemotherapy alone, combined-modality therapy, and rituximab. For example, Rijlaarsdam et al [11] reported a 2-year disease-free survival of 100% in 11 patients with primary cutaneous FCC lymphoma treated with doxorubicin-based polychemotherapy. These authors therefore recommended primary radiation for localized FCC and polychemotherapy for widespread cutaneous disease. At present, no data exist to determine whether or not consolidative radiotherapy will improve outcome in patients who achieve a complete response to polychemotherapy. Finally, anecdotal reports suggest that rituximab monotherapy may produce impressive responses, although the long-term outcome of this approach remains unclear [21,22]. Clearly, additional prospective trials are required to determine whether or not combined-modality therapy will improve outcome compared with radiotherapy, chemotherapy, or rituximab alone. In the future, stratification of CBCL by gene expression profiling may improve prognostication and treatment selection.
The authors indicated no potential conflicts of interest.
No funding was required for this project. Presented at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 19-23, 2003, Salt Lake City, UT. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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2. Willemze R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: A proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354-371, 1997 3. Harris NL, Jaffe ES, Diebold J, et al: The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Histopathology 36:69-86, 2000[CrossRef][Medline]
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5. Grange F, Bekkenk MW, Wechsler J, et al: Prognostic factors in primary cutaneous large B-cell lymphomas: A European multicenter study. J Clin Oncol 19:3602-3610, 2001
6. Sarris AH, Braunschweig I, Medeiros LJ, et al: Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: Preferential cutaneous relapses but high cure rate with doxorubicin-based therapy. J Clin Oncol 19:398-405, 2001 7. Russell-Jones R: World Health Organization classification of hematopoietic and lymphoid tissues: Implications for dermatology. J Am Acad Dermatol 48:93-102, 2003[CrossRef][Medline] 8. Yap LM, Blum R, Foley P, et al: Clinical study of primary cutaneous B-cell lymphoma using both the European Organization for Research and Treatment of Cancer and World Health Organization classifications. Australas J Dermatol 44:110-115, 2003[CrossRef][Medline]
9. Mirza I, Macpherson N, Paproski S, et al: Primary cutaneous follicular lymphoma: An assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol 20:647-655, 2002 10. Servitje O, Gallardo F, Estrach T, et al: Primary cutaneous marginal zone B-cell lymphoma: A clinical, histopathological, immunophenotypic and molecular genetic study of 22 cases. Br J Dermatol 147:1147-1158, 2002[CrossRef][Medline]
11. Rijlaarsdam JU, Toonstra J, Meijer OW, et al: Treatment of primary cutaneous B-cell lymphomas of follicle center cell origin: A clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol 14:549-555, 1996 12. Piccinno R, Caccialanza M, Berti E: Dermatologic radiotherapy of primary cutaneous follicle center cell lymphoma. Eur J Dermatol 13:49-52, 2003[Medline] 13. Connors JM, Hsi ED, Foss FM: Lymphoma of the skin. Hematology (Am Soc Hematol Educ Program):263-282, 2002 14. Kirova YM, Piedbois Y, Le Bourgeois JP: Radiotherapy in the management of cutaneous B-cell lymphoma: Our experience in 25 cases. Radiother Oncol 52:15-18, 1999[CrossRef][Medline] 15. Eich HT, Eich D, Micke O, et al: Long-term efficacy, curative potential, and prognostic factors of radiotherapy in primary cutaneous B-cell lymphoma. Int J Radiat Oncol Biol Phys 55:899-906, 2003[CrossRef][Medline] 16. Storz MN, van de Rijn M, Kim YH, et al: Gene expression profiles of cutaneous B cell lymphoma. J Invest Dermatol 120:865-870, 2003[CrossRef][Medline]
17. Mac Manus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14:1282-1290, 1996 18. Lawrence TS, Urba WJ, Steinberg SM, et al: Retrospective analysis of stage I and II indolent lymphomas at the National Cancer Institute. Int J Radiat Oncol Biol Phys 14:417-424, 1988[Medline] 19. Kulow BF, Cualing H, Steele P, et al: Progression of cutaneous B-cell pseudolymphoma to cutaneous B-cell lymphoma. J Cutan Med Surg 6:519-528, 2002[Medline] 20. Prince HM, O'Keefe R, McCormack C, et al: Cutaneous lymphomas: Which pathological classification? Pathology 34:36-45, 2002[CrossRef][Medline] 21. Bonnekoh B, Schulz M, Franke I, et al: Complete remission of a primary cutaneous B-cell lymphoma of the lower leg by first-line monotherapy with the CD20-antibody rituximab. J Cancer Res Clin Oncol 128:161-166, 2002[CrossRef][Medline] 22. Aboulafia DM: Primary cutaneous large B-cell lymphoma of the legs: A distinct clinical pathologic entity treated with CD20 monoclonal antibody (rituximab). Am J Clin Oncol 24:237-240, 2001[CrossRef][Medline] Submitted August 6, 2003; accepted December 3, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, Fisher's exact test, or 
.05. All statistics were conducted using SAS Version 8 (SAS Institute, Cary, NC). 
