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© 2002 American Society for Clinical Oncology Primary Cutaneous Follicular Lymphoma: An Assessment of Clinical, Histopathologic, Immunophenotypic, and Molecular FeaturesByFrom the Cleveland Clinic Foundation, Cleveland, OH; British Columbia Cancer Agency, Victoria and Vancouver, British Columbia, Canada; and University of Michigan, Ann Arbor, MI. Address reprint requests to Eric Hsi, MD, Department of Clinical Pathology, L-1, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; email: ehsi{at}ccf.org
PURPOSE: Unlike nodal follicular lymphoma (NFL), Primary cutaneous follicular lymphomas (PCFLs) rarely express Bcl-2 protein or t(14;18)(q32;q21) (Bcl-2/IgH). The aim of this study was to further characterize PCFL in a large series from North America. PATIENTS AND METHODS: Clinical data and archival formalin-fixed, paraffin-embedded tissue were obtained from 32 patients. PCFL was defined as follicular lymphoma limited to the skin at the time of diagnosis and within the first 6 months after diagnosis. Specimens were analyzed for the expression of CD3, CD10, CD20, Bcl-2, and Bcl-6 proteins by immunohistochemistry as well as for the presence of t(14;18)(q32;q21) by polymerase chain reaction. RESULTS: The male-to-female ratio was 1.5:1, with a median age of 60 years. Twenty-four patients had lesions on the head and neck, five had lesions on the trunk, and three had lesions on both head and trunk. Follow-up data were available in all cases, with a mean length of 35.8 months. The majority of the patients were treated with radiation therapy. All patients were alive at last follow-up except one. Recurrence was noted in seven patients (22%), after a mean disease-free survival time of 17.7 months. CD10 and Bcl-6 expression were seen in 29 (91%) of 32 and 31 (97%) of 32 cases, respectively. Bcl-2 expression was noted in 13 (41%) of 32 cases. PCR results for t(14;18)(q32;q21) were positive in 11 (34%) of 32 patients and showed correlation with Bcl-2 protein expression. The sequencing of the t(14;18)(q32;q21) amplicons confirmed unique breakpoints in each of the seven tested cases. Comparison between the Bcl-2 and/or t(14;18)(q32;q21)-positive and t(14;18)(q32;q21)-negative cases revealed no significant difference in age, site, clinical course, or outcome. CONCLUSION: We demonstrated Bcl-2 protein expression and t(14;18)(q32;q21) in a significant minority of cases, suggesting a relationship with NFL. It remains to be seen whether, on longer follow-up, there is any clinical difference in cases with and without t(14;18)(q32;q21).
PRIMARY CUTANEOUS lymphomas (PCL) are the second most common extranodal lymphomas after gastrointestinal lymphomas.1-4 Approximately 40% of cutaneous lymphomas are primary cutaneous B-cell lymphomas (PCBCL).5 Although there are frequent cutaneous relapses, extracutaneous spread of these lymphomas is uncommon. When it does occur, the lymphoma most frequently spreads to lymph nodes and bone marrow.6-8 In general, the PCBCL are indolent lesions and have a good prognosis, with the 5-year survival rate ranging from 89% to 96%.5,6 Recently, the European Organization for Research and Treatment of Cancer (EORTC) has proposed a classification of primary cutaneous lymphomas.5 This classification has generated much debate on the applicability of this and other classification schemes, such as the Revised European-American Lymphoma (REAL) classification and the proposed World Health Organization (WHO) classification, as well as the necessity for organ-based classification schemes.9-19 There seem to be differences in the definition of primary cutaneous follicular lymphoma (PCFL) between the EORTC and REAL/WHO classifications. The term primary cutaneous follicle center cell lymphoma (PCFCcL) is used in the EORTC classification to describe a cutaneous lymphomatous lesion composed of a diffuse or nodular infiltrate of centrocytes and centroblasts, with rare formation of neoplastic follicles. The cells are CD20-positive and surface monotypic immunoglobulin–positive, but reportedly CD5-negative, CD10-negative, Bcl-2–negative, and t(14;18)(q32;q21) (Bcl-2/IgH)–negative.5 The REAL classification criteria require a follicular component as an essential element for the diagnosis of follicle center lymphoma, although diffuse areas may be present.9 PCFCcL, thus, seems to be a broader and less stringent entity because it might include not only PCFL but also other entities, such as extranodal marginal zone B-cell lymphoma and diffuse large B-cell lymphoma.18 Studies have demonstrated that the REAL classification can be effectively applied in categorizing various PCBCL cases.20,21 The results of our previous study also included findings in a small series of PCFL.21 We expand on this study by analyzing the clinical, histopathologic, immunophenotypic, and molecular characteristics of PCFL cases seen in three large tertiary care centers in North America. Our findings confirm the good prognosis of these lesions, demonstrate an immunophenotype consistent with follicular origin, and reveal that a significant minority of cases of PCFL indeed express Bcl-2 protein as well as harbor a t(14;18)(q32;q21).
Patients and Histopathology A retrospective review of clinical data of 32 patients with PCFL was conducted. All of these patients were seen in three large tertiary care centers in North America during a period of 10 years (1991 to 2000). Fourteen of these cases were included in our previous study.21 PCFL was defined as a B-cell lymphoma presenting in the skin, with follicular architecture, and no evidence of extracutaneous spread within 6 months after diagnosis. The medical records were reviewed for presentation, staging studies, treatment, recurrence, and status at last follow-up. All cases were histologically re-evaluated by two pathologists (I.M., E.D.H.) and graded using the criteria of Mann and Berard.22 An American Optical (Buffalo, NY) microscope with a non–wide field x10 eyepiece and x40 objective was used for grading.
Immunohistochemistry
Polymerase Chain Reaction Polymerase chain reactions (PCRs) for the presence of t(14;18)(q32;q21) (Bcl-2/IgH) and immunoglobulin heavy-chain (IgH) gene rearrangements were performed on genomic DNA extracted from formalin-fixed paraffin-embedded sections. After confirming the suitability of DNA extracts by PCR amplification of the beta-globin gene, all cases were tested for t(14;18)(q32;q21). A published primer set was used to detect the major breakpoint region (MBR) in all cases.23 Breakpoints that involved the minor cluster region (MCR) were analyzed in 22 cases. The PCR primer sequences were as follows: MBR primer: 5'-GAG TTG CTT TAC GTG GCC TG; MCR primer: 5'-GAC TTC TTT ACG TGC TGG TAC C; JH primer 5'-ACC TGA GGA GAC GGT GAC C. Two hundred nanograms of template DNA was amplified at an annealing temperature of 60°C for 43 cycles. A final 10-minute extension was performed at 72°C. DNA from previously positive nodal follicular lymphoma (NFL) cases was used as a positive control. A PCR reaction mixture without template DNA was included as a negative control. The PCR products were analyzed using 2% agarose gel electrophoresis stained with ethidium bromide and visualized under ultraviolet light. As previously reported, a seminested PCR technique was used to detect the immunoglobulin heavy chain VDJ gene rearrangement using published consensus primers (FRIIIA, LJH, VLJH).24 A case of B-cell chronic lymphocytic leukemia was used as a positive control.
Amplicon Sequencing
Statistical Analysis
Clinical Presentation and Follow-Up Thirty-two cases of PCFL were studied (Table 2). There were 19 males and 13 females (male:female, 1.5:1). The median age was 60 years (range, 35 to 85 years). All patients had the characteristic clinical features of PCFL and presented with solitary (53%) or multiple (47%) papular, nodular, or plaque-like lesions, ranging in size from less than 1 cm to more than 40 cm (Fig 1). All lesions were located on head, neck, or trunk. Reviews of clinical data revealed that history, complete physical examination, chest x-ray, and complete blood count were obtained in all cases. In 22 cases (69%), a staging bone marrow examination and computed tomographic (CT) studies of chest, abdomen, and pelvis were also performed. In seven cases, radiographic studies were performed, but the bone marrow status was not evaluated. One patient had received bone marrow examination, but no CT examination was performed. In two patients (nos. 11 and 16), neither radiographic nor bone marrow examination was performed. Patient no. 16 was diagnosed with metastatic colonic adenocarcinoma, and further work-up for his cutaneous lymphoma was felt to be unwarranted. The other patient has not shown any manifestations of extracutaneous disease 8 months after diagnosis after receiving only local therapy.
Follow-up data were available in all cases, with a mean length of 35.8 months (range, 7 to 124 months). All patients were alive at last follow-up except one (no. 16), who died of metastatic adenocarcinoma 11 months after the diagnosis of PCFL. Cutaneous recurrence was noted in seven (22%) of 32 cases after a mean disease-free survival of 17.7 months. Extracutaneous spread was not observed in any patient. Single-modality treatment with localized radiation therapy (RT) was administered in 18 (56%) of 32 cases, surgical excision was performed in five (16%) of 32 cases, and single-agent or multiagent chemotherapy was prescribed in three (9%) of 32 cases (Table 2). These regimens included chlorambucil only; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); or doxorubicin, cyclophosphamide, vincristine, and bleomycin (ACOB). Combination therapy that included two of the three modalities was used in six (19%) of 32 cases.
Histology and Immunophenotyping
Molecular Analysis Immunoglobulin heavy-chain gene rearrangement by VDJ PCR showed a monoclonal band in six (35%) of 17 cases tested (Table 3). The presence of t(14;18)(q32;q21) was detected in 11 (34%) of 32 PCFL cases by PCR analysis using MBR primers (Fig 4). Sequence analysis of amplicons in seven positive cases showed heterogeneous Bcl-2 gene breakpoints within a 115-base-pair region, extending from bp position 3052 to 3167 (Table 4). The IgH gene segments were noted to be either J4 or J6 joining segments, with a variable number of N-region or D-region nucleotides (Fig 5). Case no. 16 showed an IgH region homologous to a somatically hypermutated immunoglobulin gene segment (accession number, AF126264). PCR for the t(14;18)(q32;q21) using the MCR breakpoint primers was negative in all 22 cases tested.
Statistical Analysis Kaplan-Meier analysis showed an overall 5-year relapse-free survival rate of 64%. We found no difference in relapse rates between groups of patients on the basis of tumor grade (grades 1 and 2 v grade 3; Fisher’s exact test, P = .2). Similarly, when stratified by treatment modality (RT v other), no difference was observed (log-rank P = .43).
We also examined the association of Bcl-2 expression with the presence of t(14;18)(q32;q21) and the differences in the clinical features of cases with and without t(14;18)(q32;q21)/Bcl-2 expression. Fisher’s exact test showed an association between Bcl-2 expression and t(14;18)(q32;q21), as expected (P = .02). However, there seemed to be no statistical difference in age (< 60 years v
PCFL has been described as the most common PCBCL.25 The EORTC incorporated findings from a large series of PCFCcL (a histologically heterogeneous group) in their classification scheme.5,18 These lesions were reported to have a distinct clinicopathologic presentation and a favorable 5-year survival rate of 97%. Histologically, they were defined by the presence of centrocytes and centroblasts in various proportions, with rare formations of neoplastic follicles. Unlike NFL, they were described to be negative for CD10 and Bcl-2 protein expression, and the t(14;18)(q32;q21) commonly seen in NFL was not observed in these lesions. We have previously shown that the REAL classification can be used to classify these lesions and that PCFL may be closely related to NFL.21 Those observations are extended in the present report. Our patients were older adults with lesions limited to head and trunk, consistent with previously described age distribution and site predilection of these tumors.5,6,21,25 Because this represents a retrospective multi-institutional study, no consistent therapeutic modality was used to treat our patients. The chosen treatment modality in many cases resulted from consideration of age and general health of the patient, extent of the lesion, and the experience of the physician with the selected treatment option. Many of our patients (56%) were treated with RT alone. Notably, of the seven patients who experienced relapse, five had received RT only. Although the percentage of patients who received RT and subsequently experienced relapse is large (28%), we did not find a statistical correlation between relapse and RT (P = .43). Review of the studies that addressed the incidence of recurrence in patients treated with RT shows that, although PCBCL as a group are responsive to RT, a significant number of patients experience relapse with this modality. The report by Berti et al26 in 1988 showed complete remission in all 16 patients with PCBCL. However, 12 (75%) experienced relapse after initial response to RT. In the first comprehensive report examining the response of 31 cases of PCBCL to RT, Piccinno et al27 observed complete remission in all cases. However, relapse occurred in 65% of their cases, with a mean disease-free survival time of 6 months. The study of 45 cases of PCBCL by Santucci et al28 showed a relapse rate of 30% in patients treated with RT. The follow-up of most of their patients was less than 2 years, which may explain to some extent the lower relapse rate in comparison to the results from Piccinno et al.27 The above three studies included all PCBCL; Rijlaarsdam et al6 specifically studied 55 cases of PCFCcL, of which 40 patients underwent RT by electron beam. Thirty-four cases treated by RT were limited to head and trunk.6 Only three (9%) of these patients experienced cutaneous relapse after RT, and one patient developed extracutaneous relapse. The observed differences in recurrence rate after RT in all these studies, including ours, may reflect the variation in inclusion criteria, radiation technique, dose of radiation, tumor size, size of margin included in the radiation field, and importantly, the biologic behavior of the individual tumor. Prospective studies of distinct histopathologic entities are needed to examine the role and effectiveness of various therapies in the treatment of these lesions. Of significance is the fact that none of our patients has died of PCFL, and many are free of their disease. This attests to the excellent prognosis of these lymphomas, as highlighted by other reports.5,21,25 Previous studies have shown some similarities between the PCFL and NFL with regard to CD10, Bcl-6, and Bcl-2 expression.21,29 In this study, we show that CD10 and Bcl-6 protein expression are detectable in 91% and 97% of PCFL, respectively. These results are similar to those reported by Aguilera et al29 in abstract form, who studied 24 cases of PCFL and showed that 14 (78%) of 18 cases expressed CD10, and 16 (89%) of 18 expressed Bcl-6. Likewise, in a recent study of 15 cases of PCFL by Cerroni et al,30 all cases were positive for CD10. In regard to immunohistochemical detection of Bcl-2 protein in PCFL, various studies have generated conflicting data. Studies from Europe had shown an absence of Bcl-2 expression by PCFCcL.30,31 Cerroni et al30 reported a lack of Bcl-2 expression in their 15 PCFL cases. Of note, they also used REAL classification criteria for inclusion in the study. In contrast, 41% of our cases showed Bcl-2 immunostaining. Triscott et al32 reported Bcl-2 protein expression in three of four PCFL cases tested. Aguilera et al29 also described 14 (61%) of their 23 PCFL cases to be positive for Bcl-2. Other recent studies of PCFL have shown Bcl-2 expression ranging from 21% to 86%.33-35 However, some of the above-mentioned studies used antibodies from different sources. These technical issues and perhaps other factors, such as geographic variation, might help explain the variable Bcl-2 expression. Precedent exists for the geographic differences in lymphoma. For example, Burkitt’s lymphoma is known to have geographic differences in Epstein-Barr virus infection incidence.36 Analogously, many European studies have shown association of infection with Borrelia burgdorferi with some cases of PCBCL,37-40 a finding that has not been reproduced in North America.41,42 A significant minority (34%) of our cases were positive for t(14;18)(q32;q21) by PCR, similar to the 23% positivity suggested by Aguilera et al29 and to our previous data.21 Bergman et al33 reported 13%, and de Leval et al34 described 20% of PCFL to harbor t(14;18)(q32;q21). In contrast, none of the 15 cases of PCFL reported by Cerroni et al30 were positive for this translocation. Franco et al,35 in their recent series of 18 cases of PCFL, reported that, in the ten cases analyzed, t(14;18)(q32;q21) was not observed. We are uncertain of the reason for this difference in results. It is noteworthy that Cerroni et al35 used a laser beam microdissection technique for PCR analysis of their cases to increase the sensitivity of their assay, albeit with negative results. An extremely high sensitivity of our PCR assay can be effectively excluded as the reason for our results, because the sensitivity of our PCR assay was 0.1%.21 We also sequenced the PCR products in seven cases positive for t(14;18)(q32;q21) to exclude the possibility of false-positive results.43 All seven cases showed unique breaks within the MBR and alignment with published immunoglobulin heavy chain joining segments. We did not find PCFL cases with translocation that involved the MCR, in which 20% to 40% of breaks occur in NFL.44 The presence of either the t(14;18)(q32;q21) or Bcl-2 protein expression suggests that these cases of PCFL have a pathogenesis similar to NFL. The distribution of histologic grade is roughly similar to NFL.45 The great majority of cases were low grade. There may be a slight increase in high-grade lesions, but this may also be a result of the subjectivity of histologic grading. There was no definite association between grade and presence of the t(14;18)(q32;q21) but there was a trend for the lower grade cases to be Bcl-2 protein–positive. This is also the case in NFL.46 We noted a correlation between the expression of Bcl-2 protein and the presence of t(14;18)(q32;q21) (P = .02). Few of our cases showed only Bcl-2 immunoreactivity and lacked the t(14;18)(q32;q21) by PCR. It is known that Bcl-2 protein expression can occur in the absence of a t(14;18)(q32;q21).47,48 It is also possible that these cases may involve the translocation at sites other than MBR and MCR.44 Three cases showed t(14;18)(q32;q21) but were negative for Bcl-2 expression by immunohistochemical methods. This may be a consequence of disruption of Bcl-2 epitope as a result of somatic mutations subsequent to translocation in these cases, a phenomenon described to occur in NFL.49,50 Of clinical relevance, Sehn et al51 recently reported differences between t(14;18)(q32;q21)-positive and t(14;18)(q32;q21)-negative NFLs in tumor grade, stage at presentation, and patterns of extranodal involvement. They concluded that different patterns of cytogenetic evolution in these two groups may have a bearing on their distinct clinical presentation. We observed no difference in presentation, course, and outcome in our PCFL patients with or without Bcl-2 expression and/or t(14;18)(q32;q21). However, we cannot exclude the possibility that clinically significant differences may be revealed by extended follow-up of PCFL cases. In conclusion, in our series of PCFL from North America using the definition set forth by REAL and WHO classification schemes, we found morphologic, immunophenotypic, and molecular similarities to NFL in a proportion of cases. A substantial number of cases harbor the t(14;18)(q32;q21) and overexpress Bcl-2. Similar to previous studies, we confirm the distinct indolent clinical behavior of these lesions and their excellent prognosis. It remains to be seen whether, on longer follow-up, any significant clinical differences emerge between cases with and without t(14;18)(q32;q21)/Bcl-2 expression.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, unique breakpoints.
60 years; Fisher’s exact test, P = .73) or relapse-free survival (log-rank, P = .53) between the cases with or without t(14;18)(q32;q21). Similar comparative analyses for cases with and without Bcl-2 protein expression also revealed no difference in age (Fisher’s exact test, P = .73) or relapse-free survival (log-rank, P = .51). There was no association between histologic grade and presence of the t(14;18)(q32;q21) by Fisher’s exact test. In regard to Bcl-2 protein expression, a trend was observed for an association between low-histologic-grade cases (grades 1 and 2) and high-grade cases (grade 3) (Fisher’s exact test, P = .10). Low-grade cases seemed to express bcl-2 protein more frequently. 
