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© 2001 American Society for Clinical Oncology Prognostic Factors in Primary Cutaneous Large B-Cell Lymphomas: A European Multicenter StudyByFrom the Department of Dermatology, Hôpital Pasteur, Colmar; Departments of Pathology and Dermatology, Hôpital Henri-Mondor, Créteil; Department of Pathology, Institut Gustave Roussy, Villejuif; Department of Epidemiology and Public Health, University Louis Pasteur, Strasbourg; Department of Dermatology, Hôpital Charles Nicolle, Rouen, France; Department of Dermatology, Leiden University Medical Centre, Leiden; Departments of Pathology and Dermatology, Free University Hospital, Amsterdam, the Netherlands; Department of Dermatology, University of Graz, Graz, Austria; and Department of Dermatology, University of Turin, Italy. Address correspondence to Florent Grange, MD, Service de Dermatologie, Hôpital Pasteur, 39 Ave de la Liberté, 68024 Colmar Cedex, France; email: florent.grange{at}ch-colmar.rss.fr
PURPOSE: Most primary cutaneous B-cell lymphomas have an excellent prognosis. However, primary cutaneous large B-cell lymphomas (PCLBCLs) of the leg have been recognized as a distinct entity with a poorer prognosis in the European Organization for Research and Treatment of Cancer (EORTC) classification. This distinction on the basis of site has been debated. Our aim was to identify independent prognostic factors in a large European multicenter series of PCLBCL. PATIENTS AND METHODS: The clinical and histologic data of 145 patients with PCLBCL were evaluated. According to the EORTC classification, 48 patients had a PCLBCL of the leg and 97 had a primary cutaneous follicle center-cell lymphoma (PCFCCL). Data from both groups were compared. Univariate and multivariate analyses of specific survival were performed using a Cox proportional hazards model. RESULTS: Compared with PCFCCL, PCLBCL-leg were characterized by an older age of onset, a more recent history of skin lesions, a more frequent predominance of tumor cells with round nuclei and positive bcl-2 staining, and a poorer 5-year disease-specific survival rate (52% v 94%; P < .0001). Univariate survival analysis in the entire study group showed that older age, a more recent onset of skin lesions, the location on the leg, multiple skin lesions, and the round-cell morphology were significantly related to death. In multivariate analysis, the round-cell morphology (P < .0001), the location on the leg (P = .002), and multiple skin lesions (P = .01) remained independent prognostic factors. The round-cell morphology was an adverse prognostic factor both in PCLBCL-leg and in PCFCCL, whereas multiple skin lesions were associated with a poor prognosis only in patients with PCLBCL-leg. CONCLUSION: With site, morphology, and number of tumors taken into account, guidelines for the management of PCLBCL are presented.
PRIMARY CUTANEOUS B-cell lymphomas represent a heterogeneous group of B-cell neoplasms, which present in the skin without evidence of extracutaneous disease.1-8 The majority of these primary cutaneous B-cell lymphomas are large-cell lymphomas (primary cutaneous large B-cell lymphomas [PCLBCLs]).9 In the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas, two main groups of PCLBCL are distinguished.6 Most cases are included in the group of primary cutaneous follicle center-cell lymphomas (PCFCCLs). This term was introduced in 19875 as an encompassing term for cutaneous lymphomas that were composed of centroblasts and centrocytes of various sizes and that were classified as either centroblastic/centrocytic or centroblastic lymphomas according to the criteria of the Kiel classification.10 These PCFCCLs appeared as a well-defined group of primary cutaneous B-cell lymphomas which often presented with skin lesions confined to a limited skin area on the head or the trunk; they had an excellent prognosis, irrespective of the proportion of large cells and the histologic subclassification.5-8 However, it was noted from the first publications regarding these PCFCCLs that patients presenting with skin tumors on the leg had a different clinical behavior.5 Since these tumors of the leg were consistently composed of a majority of large B-cells, the term primary cutaneous large B-cell lymphoma of the leg (PCLBCL-leg) was used.11 Recent studies have demonstrated that patients with PCLBCL-leg differed from patients with PCFCCLs arising at other sites by a higher age of onset, a poorer prognosis, and the almost constant expression of bcl-2 protein.6,8,11,12 For these reasons, PCLBCL-leg was included as a separate entity in the EORTC classification.6 Although recent studies have confirmed that these PCLBCL-leg are a distinct group with an intermediate prognosis,8 the subdivision of primary cutaneous B-cell lymphomas into two main categories (PCLBCL-leg and PCFCCL) primarily based on site of presentation (leg v other sites) has been much disputed.13-17 Indeed, it remained unknown to what extent site, age, morphology, bcl-2 expression, or other parameters contribute to the difference in survival between these two groups. This prompted us to perform a large European study of primary cutaneous B-cell lymphomas, including both PCLBCL-leg and PCFCCL with a predominance of large cells (nonleg PCLBCLs). The main goals of this study were (1) to identify independent prognostic factors in the total group of PCLBCLs, (2) to find out whether PCLBCL-leg have indeed a different clinical behavior, and (3) to define additional prognostic parameters within pertinent subgroups of PCLBCL. The ultimate goal of this study was to provide practical guidelines to both pathologists and clinicians that may contribute to appropriate management and treatment of these PCLBCLs.
The Dutch Cutaneous Lymphoma Working Group, the French Study Group on Cutaneous Lymphomas, and two departments of dermatology from other countries (Graz, Austria, and Turin, Italy) participated in the study.
Inclusion Criteria
Histologic Review
Reproducibility Study Since in the course of the study the distinction between cleaved-cell and round-cell PCLBCL appeared as a major independent prognostic parameter, we studied the reproducibility of this simple histologic subclassification in a sample of 38 randomly selected cases. Fourteen cases were reviewed by a panel of six pathologists from the Dutch group and 24 cases were reviewed by a panel of six pathologists from the French group. Participants had not taken part in the previous histologic review. They were asked to classify each tumor into one of the two main categories: cleaved-cell PCLBCL and round-cell PCLBCL. Results were compared with the final histologic classification obtained on the basis of consensus during the histologic review (Table 1)
Data Collection
Follow-Up Data
Statistical Analysis Prognostic factors in the entire study group and in different subgroups of patients were evaluated by specific survival (disease-related) univariate and multivariate analyses using a Cox proportional hazards model.23 Factors significant at the .2 level in univariate analysis were included in a stepwise regression multivariate analysis.
Clinical Characteristics of the Total Group of 145 PCLBCL Patients The clinical characteristics and follow-up data of the 145 patients included in the study are summarized in Table 2. The ratio of men to women was 1 (72:73). The age at diagnosis ranged between 23 and 92 years (mean, 64 years; median, 68 years). None had any history of noncutaneous lymphoma or leukemia. Fifteen patients (10%) had a history of cutaneous pseudolymphoma. Only one patient had been diagnosed as having a small-cell primary cutaneous B-cell lymphoma before it evolved into a large B-cell lymphoma. Clinically, patients presented with cutaneous nodules or tumors (94%) or deeply infiltrated plaques (6%). Therapy resulted in a complete remission in 131 (90%) of 145 patients. Thirty-five (24%) of 145 patients developed extracutaneous disease. The mean time until extracutaneous dissemination was 22 months. The extracutaneous progression was restricted to the lymph nodes in 12 cases, whereas 23 patients developed a visceral disease either associated with lymph node involvement (nine cases) or not (14 cases). Anatomic sites of visceral dissemination included the CNS (four cases), the bone marrow (four cases), the bones (four cases), the lung (three cases), the small intestine (two cases), the spleen (two cases), the testis (two cases), the kidney (two cases), the heart (two cases), the breast (one case), the thyroid (one case), and the brachial plexus (one case). Twenty-six (18%) of 145 patients died of lymphoma, whereas 13 patients (9%) died of unrelated disease. Death from lymphoma occurred in 19 of 26 patients within 3 years after diagnosis. Disease-related death was extremely rare in younger patients: no patient younger than 63 and only five patients younger than 70 at the time of diagnosis died of lymphoma. The overall and disease-specific 5-year survival rates were 72% and 81%, respectively.
Prognostic Factors in the Total Group of PCLBCL Patients Univariate and multivariate analyses of disease-specific survival were performed on the total group of 145 patients to identify independent prognostic factors. Univariate analysis showed that the following variables were related to death from lymphoma: older age (> 75 years; P < .0001); short duration of skin lesions before diagnosis (< 10 months; P = .0013); location on the leg (PCLBCL-leg v PCFCCL, P < .0001); presence of more than one skin lesion at diagnosis (P = .03); disseminated skin lesions (P = .036); increased LDH level (P = .05); and round-cell morphology (P < .0001). Sex, diameter of the largest skin lesion and occurrence of spontaneous regression had no significant effect on death from lymphoma. When multivariate analysis was performed, the round-cell morphology (P < .0001), location on the leg (P = .002), and presence of more than one skin lesion at diagnosis (P = .01) remained significant independent factors associated with a poor prognosis (Table 3). In view of these results, the main features at diagnosis and follow-up data were studied within the four subgroups of patients determined by location and morphology, as well as within the two major EORTC groups (Table 2). Kaplan and Meier disease-specific survival curves of these different subgroups of patients are shown in Fig. 2.
Comparison Between PCFCCL and PCLBCL-Leg On the basis of the criteria of the EORTC classification,6 97 patients were assigned to the PCFCCL group and 48 patients were assigned to the PCLBCL-leg group according to site of presentation. In the PCFCCL group, the skin lesions were confined to the head and the neck (40 cases), a localized area on the trunk (45 cases), or the arm (one case), or they involved several anatomic sites excluding the leg (11 cases). The other clinical findings at diagnosis and follow-up data are listed in Table 2. In the PCFCCL group, 11 (11%) of 97 patients developed extracutaneous disease, six (6%) of 97 patients died of lymphoma, and the estimated overall and disease-specific 5-year survival rates were 85% and 94%, respectively. In the PCLBCL-leg group, the skin lesions were confined to one leg (34 patients) or both legs (eight patients) in 42 of 48 patients. The other six patients had tumors on one or both legs associated with skin lesions at other sites. Follow-up data in this group indicate that 24 (50%) of 48 patients developed extracutaneous disease, and 20 (42%) of 48 died of lymphoma. The estimated overall and disease-specific 5-year survival rates were 42% and 52%, respectively. A comparison between the two EORTC groups demonstrated that patients with PCLBCL-leg were older than patients with PCFCCLs (mean age, 73 v 60 years, P < .0001) and had more frequently disseminated skin lesions (P = .01), short duration of lesions before diagnosis (P < .0001), elevated LDH levels (P = .04), round-cell morphology (75% v 17.5%, P < .0001), and positive bcl-2 staining (P < .0001). Moreover, they were at increased risk of developing extracutaneous disease (50% v 11%; P < .0001) and had a poorer 5-year disease-specific survival rate (52% v 94%; P < .0001) (Table 2 and Fig 2A).
Prognostic Parameters Within the PCFCCL and PCLBCL-Leg Groups Within the PCLBCL-leg group, multivariate analysis of disease-specific survival showed that multiple skin lesions at diagnosis (P = .001) and round-cell morphology (P = .003)—but not age, duration of skin lesions before diagnosis, or size and extent of skin lesions—were independent adverse prognostic factors. Further analysis of the relation between number and extent of skin lesions and survival showed that only one (9%) of 11 patients with a solitary tumor, compared with 12 (52%) of 23 patients with multiple tumors on one leg, and seven (50%) of 14 patients with generalized skin lesions including one or both legs died of lymphoma (P = .01).
Reproducibility Study
Previous studies demonstrated that PCLBCL-leg differs from PCFCCL that arises at other sites by several characteristics, including age at presentation and bcl-2 protein expression, and by a more unfavorable prognosis.5,6,8,11,12,24 For these reasons, PCLBCL-leg was included as a separate group in the EORTC classification.6 However, delineation of this subgroup of PCLBCL patients on the basis of site has been much disputed.13-17 Indeed, the respective role of site and other potential clinical or histologic prognostic factors had to be evaluated in a large multivariate study. Such multivariate analyses were rarely performed in primary cutaneous lymphomas. In a recent evaluation of 158 patients with a primary cutaneous lymphoma other than mycosis fungoides and the Sézary syndrome,8 we found that the prognostic group according to the EORTC classification and the distribution of skin lesions were independent prognostic factors. However, this previous study included only a minority of patients with a PCLBCL and was unable to identify specific prognostic factors in these lymphomas which represent the most controversial group of the EORTC classification. In particular, the delineation of PCLBCL-leg as an independent subgroup had to be validated in a large international study restricted to PCLBCL. In this European multicenter study of 145 patients with PCLBCL, we found that round-cell morphology, the location on the leg, and multiple skin lesions at diagnosis were independent adverse prognostic factors. Other characteristics, including age, had no significant effect on death from lymphoma after morphology, site, and number of skin lesions were taken into account. This study shows that location is an independent prognostic factor in PCLBCL and provides further evidence that major differences exist between PCLBCL presenting on the leg and PCLBCL presenting at other sites. Patients from this latter group, included in the PCFCCL group in the EORTC classification for primary cutaneous lymphomas, presented with skin lesions on the head or trunk in most cases, rarely developed extracutaneous disease, and had an excellent prognosis with overall and disease-specific 5-year survival rates of 85% and 94%, respectively. In contrast, patients with PCLBCL-leg were older, developed extracutaneous disease more often, and had a significantly poorer prognosis, with overall and disease-specific 5-year survival rates of 42% and 52%, respectively. In addition, the duration of skin lesions before diagnosis was much shorter in this group. In contrast to 14 (14%) of 97 patients with PCFCCL, only one (2%) of 48 patients with PCLBCL-leg had a history of a pseudo-B-cell lymphoma. Histologically, PCLBCL-leg much more frequently showed a predominance of round blast cells (75% v 17.5%; P < .0001) and much more often expressed bcl-2 protein (Table 2). Expression of bcl-2 protein was not included in the multivariate prognostic analysis, since bcl-2–stained sections were only available in approximately 35% of cases. Therefore, additional studies are required to determine whether bcl-2 protein expression is primarily related to site or to a round-cell morphology and whether it represents an independent prognostic parameter in PCLBCL. In the present study, tumors were not investigated for the presence of the 14;18 translocation. However, a previous study demonstrated that the increased bcl-2 expression in PCLBCL-leg was not associated with the 14;18 translocation.12 The most discriminating prognostic parameter in the total group of 145 patients with PCLBCL was a predominance (> 50%) of large B cells with round nuclei. Although there was an important overlap between location and morphology, this parameter remained an independent prognostic factor both in the PCFCCL group and the PCLBCL-leg group. This observation has not been reported previously. Therefore, the question arises of whether PCLBCL should be subdivided primarily on the basis of morphology rather than site, as suggested in the EORTC classification. However, histologic subclassification of diffuse large B-cell lymphomas in a reproducible way is notoriously difficult (Revised European-American Lymphoma classification).18 Because of these difficulties, we preferred a simple subdivision on the basis of more or less than 50% blast cells with round nuclei. The reproducibility of this subdivision was evaluated in a small sample because it was not anticipated that multivariate analysis would indicate morphology as the most discriminating parameter. We found that 28 (74%) of 38 cases were classified consistently as either round-cell or cleaved-cell PCLBCL by all or all but one of six pathologists. This demonstrates that distinction on the basis of morphology may be difficult in some cases and that a primary subdivision of PCLBCL on this basis would probably have a lower reproducibility than the more simple classification according to location (EORTC).6 However, morphology constitutes an independent additional prognostic factor that should be taken into account for a more accurate management and treatment of PCLBCL (Fig 3).
The presence of multiple skin lesions at diagnosis was the last independent prognostic factor associated with death from lymphoma in the total group of 145 PCLBCL patients. This result has to be interpreted in view of prognostic analyses in subgroups before being translated into guidelines for practical management of PCLBCL. Within the PCFCCL group, only round-cell morphology was associated with a poor prognosis. Neither the number of skin lesions nor the presence of multifocal as opposed to solitary or localized skin lesions was significantly related to survival, which is consistent with the results of previous studies.5,6,25 In contrast, both round-cell morphology and the presence of multiple skin lesions at diagnosis were significant adverse prognostic factors within the PCLBCL-leg group. Furthermore, the number of skin lesions was indeed the most important prognostic parameter in these patients. The 5-year survival rate was100% in patients with a single skin tumor on one leg versus 45% and 36% in patients with multiple tumors on one or both legs, respectively. Therefore, we suggest that only patients with a single tumor should be treated with radiotherapy. All other patients with PCLBCL-leg can probably best be treated with systemic chemotherapy. In view of the results of this prognostic analysis in 145 patients with PCLBCL, practical guidelines for appropriate management and treatment can be provided (Fig. 3). Four subgroups can be distinguished. PCFCCL with a cleaved-cell morphology is the most common subgroup. The disease-related 5-year survival rate in this group was 99% (Fig 2C), and the 5-year relative survival rate was 100%. This indicates that mortality in these patients does not exceed mortality in a similar cohort matched by age and sex in the general population. Radiotherapy is the preferred mode of treatment in this group, probably even in patients presenting with multifocal skin lesions.25 PCFCCLs with a round-cell morphology are uncommon and have a more unfavorable prognosis. Although definite conclusions cannot be drawn from this small group, we suggest that patients presenting with a single lesion or few clustered lesions can best be treated with radiotherapy, whereas in case of multifocal skin lesions, systemic chemotherapy is required. Most patients with PCLBCL-leg have a round-cell morphology. Cases of PCLBCL-leg with a cleaved-cell morphology are less common and have a somewhat better prognosis. However, irrespective of the histologic subtype, patients with PCLBCL-leg should be treated with systemic chemotherapy whenever possible.6,8,11,26 Only in patients presenting with a single tumor may radiotherapy be preferred. However, no definite conclusions can yet be drawn only on the basis of retrospective studies. Appropriate clinical trials are necessary to validate these therapeutic guidelines.
Supported in part by a grant from the Comité Départemental de Seine-Maritime de la Ligue Contre le Cancer. We thank the following clinicians and pathologists who actively participated in the study: B. Audhuy, M.F. Avril, P. Bernard, M. Beylot-Barry, C. Bodemer, A. Carlotti, A. Colson, P. Courville, S. Dalac, P. Dechelotte, M. Delaunay, A. Durlach, E. Esteve, S. Fraitag, N. Franck, M.L. Geerts, J.C. Guillaume, F. Heule, H. Hollema, F. Husseini, M. D’Incan, P.M. Kluin, L. Laroche, F. Maître, C. Michel, A. de Muret, S. Pals, T. Petrella, M. de Rie, B. Schubert, P. Souteyrand, E. Thomine, M.C. Tortel, L. Vaillant, B. Vergier, and P.C. van Voorst Vader.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 years (range, 10 to 59 months). 
2 test or Fisher’s exact test for categorical variables and Student’s t test or Mann-Whitney test for continuous variables. Survival duration was calculated from diagnosis to date of death or censoring. Observed survival, specific (disease-related) survival, and relative survival rates were estimated in the entire study group and in different subgroups of patients according to location and histology of skin lesions. Observed survival and specific survival rates were estimated using the method of Kaplan and Meier.
