—  SYMPOSIUM #07  —

Cutaneous Lymphomas: Pathology, Biology, and Clinical Correlations
Moderators: Elaine S. Jaffe and Christopher Meijer

Section 2 - Low Grade Cutaneous B-cell Lymphomas: Similarities and Differences with Nodal Counterparts

Steven H. Swerdlow


The WHO-EORTC classification of cutaneous lymphomas includes two primary indolent B-cell lymphomas: cutaneous marginal zone B-cell lymphoma (MALT-type) and cutaneous follicle centre lymphoma. [1]

Cutaneous Marginal Zone B-cell Lymphoma (MALT-type)
The criteria for cutaneous marginal zone B-cell lymphoma (MALT-type) (CMZL) were only perhaps minimally altered in the WHO-EORTC classification so that this entity now clearly includes cases previously diagnosed as "immunocytoma" & non-myelomatous "plasmacytomas" of skin. [2] Our question for today is how the CMZL compare to other MALT lymphomas – their similarities and differences. Morphologically, CMZL fulfill the criteria for MALT lymphomas at other sites. They do appear to have more frequent plasmacytic differentiation found in 89% of the cases in our series. [3] Cytogenetic studies, particularly fluorescence in situ hybridization (FISH) investigations, and genotypic studies demonstrate that CMZL share many of the chromosomal abnormalities seen in other MALT lymphomas; however, the frequency of the individual abnormalities is different than what is found for MALT lymphomas from many other sites. [4, 5] Some have found even more striking differences with an absence of t(11;18) and any 14q32 translocations in the CMZL. [3, 6] Some of these discrepant findings in the literature raise the possibility of geographic differences, a recurring theme when it comes to trying to explain the cutaneous lymphoma literature. It has been reported mostly in European studies that a significant subset of CMZL are related to Borrelia burgdorferi infection (an agent not implicated in other MALT lymphomas) with some antibiotic-induced responses. [7, 8, 9, 10] However, studies from the U.S. and Japan have failed to identify any such cases. [3, 10, 11] One American study has reported B. burgdorferi seropositivity in many patients with CMZL with 2 patients with B.burdorferi and H. pylori seropositivity who responded to antibiotics alone. [12]

Although we will not have time to discuss our study of immunoglobulin VH gene analysis of CMZL , our data suggests that, CMZL are distinct from at least some other types of MALT lymphomas, based on their VH gene usage. [13] In addition, the non-random features of the VH genes which are expressed suggest antigenic selection, as seen in other MALT lymphomas, and also suggest that some of these cases may bind the same or similar antigen. The antigen, however, remains to be discovered.

Primary Cutaneous Follicle Center Lymphoma – the Real Problem Child!
Primary cutaneous follicle center lymphoma (PCFCL) is defined as a "tumor of neoplastic follicle center cells [FCC], usually a mixture of centrocytes…and variable numbers of centroblasts [CB]…with a follicular, follicular and diffuse or diffuse growth pattern…" "Lymphomas with a diffuse growth pattern and a monotonous proliferation of centroblasts and immunoblasts are…classified as PCLBCL." [14, 15] Many 1º cutaneous lymphomas that would fulfill the basic criteria for a diffuse large B-cell lymphoma (DLBCL) at any other site are therefore now grouped with PCFCL. because of a presumed similar "cell of origin" and a similar indolent behavior.

How different are PCFCL from their "nodal" (and other extranodal) counterparts?
Firstly, it must be recognized that there are some definitional differences derived solely from the way that PCFCL are defined compared to their "nodal counterparts". PCFCL include cases that would fulfill the criteria for both nodal FL and a significant subset of nodal DLBCL so that comparisons with either of these groups will be found by definition. Furthermore, there is a definitional bias to cases that do not have a propensity to disseminate to extracutaneous sites since any case that had disseminated at diagnosis (and in the past disseminated during the first 6 months following diagnosis) will be excluded from the PCFCL category.

Are PCFCL clinically distinct?
PCFCL have a disease specific 5 year survival of 95% independent of their growth pattern or proportion of large cells. [14] Cutaneous recurrences reported in ~20% but extra-cutaneous dissemination is rare. This indolent behavior is seen even in the cases growing diffusely and with many large cells. Some have compared the PCFCL to limited stage nodal follicular lymphoma (FL). [16] Anghel, et al found that these two entities had similar excellent survivals and similar relapse free survivals even though there was an increased proportion of grade 3 and diffuse 1º cutaneous lymphomas compared to the nodal lymphomas. Goodlad, et al, in a study of PCFL and stage I nodal FL also found similar survivals and freedom from progression curves but, there was a trend for better survival among PCFL and the PCFL were more likely to be disease free at last follow-up. [17] Others might suggest that these are the wrong comparisons since localized nodal FL are an atypical subset of FL or because so many PCFCL are completely diffuse. Although comparing survival curves from one study to another is a very dangerous exercise, it does appear that the survival for patients with PCFCL is better than for FL in general and certainly for DLBCL, even of germinal center type. [18, 19] Another clinical feature of 1º cutaneous FL or FCL is that they tend to relapse in the skin. A review of four series shows that 41-46.5% of cases had cutaneous relapses with up to about 11% also including extracutaneous sites. [20, 21, 22, 23] Only one series reported 6% lymph node only relapses. [22] In contrast, while 2º FL also relapse in the skin with a frequency similar to that seen for the 1º cases, in about half there is an associated extracutaneous relapse. [21] Furthermore, about 25% of our cases had extracutaneous relapses without further skin involvement.

Are PCFCL morphologically distinct?
Many PCFCL are diffuse and include many large centrocytes. [15] In addition, we found a floral-like growth pattern to be more common in 1º (32%) comparted to 2º (5%) cutaneous FL. [21]

Are PCFCL phenotypically and genotypically distinct from other lymphomas of FCC origin?
There is a large body of literature that says that PCFCL are less likely to be CD10+ than at least other follicular lymphomas and that they are most unique because they have little or no bcl-2 expression and completely lack BCL-2 translocations. [15] Hoefnagel, et al, reported CD10+ in only 1/24 PCFCL and Bcl-2+ in only 2/24 cases. [24] They do note, however, that, as in many similar series, all but two of their cases would be categorized as DLBCL in the WHO classification. In a series of 1º cutaneous FL with a follicular growth pattern all of which were CD10+, Cerroni, et al, still report no bcl-2 expression and no t(14;18). [25] However, there are also a reasonable number of series that report definite bcl-2 staining and often even BCL2 translocations in 1° cutaneous FL. Bcl-2 protein expression is reported in up to 86% 1° cutaneous FL, and BCL2/IGH translocations are reported in 10 - 41% 1° cutaneous FL, with both findings more often in cases with fewer CB. [21, 22, 26, 27, 28] Although it has been suggested that the positive PCR studies for BCL-2/IGH rearrangements in PCFCL represent an overly sensitive test that may be picking up normal BCL-2/IGH rearrangements present in contaminating peripheral blood [29] , cytogenetic FISH studies have also documented the translocation. [21, 30] In a FISH-based study, however, direct comparison does demonstrate that while bcl-2 expression and BCL2/IGH rearrangements are seen in PCFL, they are less frequent than in 2º cutaneous FL (and less frequent than in reported nodal FL). [21] The 1º cutaneous FL or PCFCL that are most unlike the 2º cases or nodal FL are those that have more numerous CB/large cells and those that would have been called DLBCL in the past. [21, 31] CD10 is also less common in 1º cutaneous FL and PCFCL especially those with more transformed cells and those that are diffuse. [21, 31, 32] This topic, however, remains full of confusion. A recent European report of PCFCL that were at least minimally follicular and which showed a phenotype similar to that in many U.S. studies with 78% CD10+ and 37% Bcl-2+, found 41% BCL2/IGH positive cases by FISH with a higher proportion among the grade 1 cases, but their PCR studies were all negative! [30] In contrast, Mirza, et al, found 34% of PCFL to have a BCL2/IGH by PCR which correlated with bcl-2 protein expression (41%). They sequenced the breakpoints and specifically noted that their assay should not pick up the rare BCL2/IGH+ cells that may be present in the absence of neoplasia. [28]

A limited number of gene expression profiling studies have also been performed comparing 1º and 2º cutaneous lymphomas of FCC origin. Storz, et al [33] reported that "Primary and secondary follicular B-cell lymphomas were closely related, despite previously reported genetic and phenotypic differences. In contrast primary and secondary cutaneous diffuse large B cell lymphomas were less related to each other." Another gene expression profiling of "DLBCL-type" PCFCL found that they were similar to the GC type of DLBCL. [34] An array-based CGH study of PCFCL "with the histology of a DLBCL" found that PCFCL were characterized by frequent c-REL amplifications – a feature of DLBCL-GC type. [35] PCFCL also had frequent (68%) 14q32.33 deletions (consistent with a reported frequent absence of immunoglobulin).

How do PCFCL compare to other extranodal FL or other subsets of FL?
It has been reported that extranodal FL in general are distinct from nodal FL with perhaps less bcl-2 protein expression and infrequent BCL2/IGH. [36] Careful analysis of this topic is beyond our discussion today; however, it is probably important to look at each site before making generalizations as for example, duodenal FL are bcl-2+. [37] Pediatric FL seem to share many features with PCFCL, as they are often grade 2 or 3, most curable sometimes without chemotherapy and many lack bcl-2 protein and BCL2/IGH rearrangements. [38] Testicular FL in children are even more like the PCFCL. An interesting case of a 34 year old male with bilateral isolated epidymal (minimal testicular) FL that was untreated and who, 4 years later, developed a cutaneous grade 3 FL of his forehead has been reported. [39] Both lymphomas were BCL2/IGH+.

Where do we stand?
The PCFCL remains an area with many unresolved issues. One possibility is that PCFCL include two types of cases, both of which have an indolent behavior and which are present in very different proportions in different reports. One type is much more like nodal FL in terms of CD10, bcl-2, BCL2/IGH and morphologic findings. The other type is much less like nodal FL in terms of each of these features. Although not clearly documented in limited gene profiling studies, this latter type is also distinct from many DLBCL, even of germinal center type, in terms of its phenotype/genotype and its indolent clinical behavior.

References
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