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.
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.  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.  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.
Some have found even more striking differences with an absence of
t(11;18) and any 14q32 translocations in the CMZL.
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.
However, studies from the U.S. and Japan have failed to identify any such cases.
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. 
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.  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
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
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.  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).  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.
 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
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.
Only one series reported 6% lymph node
only relapses.  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.
 Furthermore, about 25% of our cases had extracutaneous relapses without further skin
Are PCFCL morphologically distinct?
Many PCFCL are diffuse and include many large centrocytes.  In
addition, we found a floral-like growth pattern to be more common in 1º (32%) comparted to 2º (5%)
cutaneous FL. 
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.  Hoefnagel, et al, reported
CD10+ in only 1/24 PCFCL and Bcl-2+ in only 2/24 cases.  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).  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
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  , cytogenetic FISH
studies have also documented the translocation.
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).
 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.
CD10 is also less common in 1º cutaneous FL and PCFCL especially those with more
transformed cells and those that are diffuse.
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!
 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.
A limited number of gene expression profiling studies have also been performed
comparing 1º and 2º cutaneous lymphomas of FCC origin. Storz, et al  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.  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.  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.  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+.  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.  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.  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
- Burg G, Jaffe ES, Kempf W, et al. WHO/ EORTC Classification of cutaneous lymphomas. In: LeBoit PE, Burg G, Weedon D, Sarasin A, eds. World Health Organization Classification of Tumours: Pathology & Genetics: Skin Tumours. Lyon: IARCPress; 2006:168.
- Kempf W, Ralfkiaer E, Duncan L, et al. Cutaneous marginal zone B-cell lymphoma. In: LeBoit PE, Burg G, Weedon D, Sarasin A, eds. World Health Organization Classification of Tumours: Pathology & Genetics: Skin Tumours. Lyon: IARCPress; 2006:194-195.
- Kim BK, Inagaki H, Li C, Pandya A, Rabkin M, Swerdlow SH. Cutaneous extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type: a multiparameter study, including molecular analyses for Borrelia Burgdorferi DNA and AP12-MALT fusion transcripts (abstract). Mod Pathol. 2003;16:240A.
- Streubel B, Simonitsch-Klupp I, Mullauer L, et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia. 2004;18:1722-1726.
- Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia. 2005;19:652-658.
- Wongchaowart NT, Kim B, Hsi ED, Swerdlow SH, Tubbs RR, Cook JR. t(14;18)(q32;q21) involving IGH and MALT1 is uncommon in cutaneous MALT lymphomas and primary cutaneous diffuse large B-cell lymphomas. J Cutan Pathol. 2006;33:286-292.
- Goodlad JR, Davidson MM, Hollowood K, et al. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland. American Journal of Surgical Pathology. 2000;24:1279-1285.
- Roggero E, Zucca E, Mainetti C, et al. Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Human Pathology. 2000;31:263-268.
- Slater DN. Borrelia burgdorferi-associated primary cutaneous B-cell lymphoma. Histopathology. 2001;38:73-77.
- Li C, Inagaki H, Kuo TT, Hu S, Okabe M, Eimoto T. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathologic study of 24 asian cases. Am J Surg Pathol. 2003;27:1061-1069.
- Wood GS, Kamath NV, Guitart J, et al. Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States. J Cutan Pathol. 2001;28:502-507.
- Bogle MA, Riddle CC, Triana EM, Jones D, Duvic M. Primary cutaneous B-cell lymphoma. J Am Acad Dermatol. 2005;53:479-484.
- Bahler DW, Kim BK, Gao A, Swerdlow SH. Analysis of immunoglobulin VH genes suggests cutaneous marginal zone B-cell lymphomas recognise similar antigens. British Journal of Haematology. 2006;132:571-575.
- Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785.
- Pimpinelli N, Berti E, Burg G, et al. Cutaneous follicle centre lymphoma. In: LeBoit PE, Burg G, Weedon D, Sarasin A, eds. World Health Organization Classification of Tumours: Pathology & Genetics: Skin Tumours. Lyon: IARCPress; 2006:196-197.
- Anghel G, Pulsoni A, De Rosa L. Primary cutaneous follicle center cell lymphoma and limited stage follicular non-Hodgkin's lymphoma: a comparison of clinical and biological features. Leuk Lymphoma. 2002;43:2109-2115.
- Goodlad JR, Krajewski AS, Batstone PJ, et al. Primary cutaneous follicular lymphoma: a clinicopathologic and molecular study of 16 cases in support of a distinct entity. Am J Surg Pathol. 2002;26:733-741.
- Anonymous. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 1997;89:3909-3918.
- Rosenwald A, Wright G, Chan WC, et al. The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma. N Engl J Med. 2002;346:1937-1947.
- Dijkman R, Tensen CP, Buettner M, Niedobitek G, Willemze R, Vermeer MH. Primary cutaneous follicle center lymphoma and primary cutaneous large B-cell lymphoma, leg type are both targeted by aberrant somatic hypermutation but demonstrate differential expression of AID. Blood. 2006.
- Kim BK, Surti U, Pandya A, Cohen J, Rabkin MS, Swerdlow SH. Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas. Am J Surg Pathol. 2005;29:69-82.
- Franco R, Fernandez-Vazquez A, Rodriguez-Peralto JL, et al. Cutaneous follicular B-cell lymphoma: description of a series of 18 cases. American Journal of Surgical Pathology. 2001;25:875-883.
- Zinzani PL, Quaglino P, Pimpinelli N, et al. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol. 2006;24:1376-1382.
- Hoefnagel JJ, Vermeer MH, Jansen PM, Fleuren GJ, Meijer CJLM, Willemze R. Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lymphoma: further support for a follicle centre cell origin and differential diagnostic significance. Br J Dermatol. 2003;149:1183-1191.
- Cerroni L, Arzberger E, Putz B, et al. Primary cutaneous follicle center cell lymphoma with follicular growth pattern. Blood. 2000;95:3922-3928.
- de Leval L, Harris NL, Longtine J, Ferry JA, Duncan LM. Cutaneous b-cell lymphomas of follicular and marginal zone types: use of Bcl-6, CD10, Bcl-2, and CD21 in differential diagnosis and classification. American Journal of Surgical Pathology. 2001;25:732-741.
- Lawnicki LC, Weisenburger DD, Aoun P, Chan WC, Wickert RS, Greiner TC. The t(14;18) and bcl-2 expression are present in a subset of primary cutaneous follicular lymphoma: association with lower grade. Am J Clin Pathol. 2002;118:765-772.
- Mirza I, Macpherson N, Paproski S, et al. Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol. 2002;20:647-655.
- Vergier B, Belaud-Rotureau MA, Benassy MN, et al. Neoplastic cells do not carry bcl2-JH rearrangements detected in a subset of primary cutaneous follicle center B-cell lymphomas. Am J Surg Pathol. 2004;28:748-755.
- Streubel B, Scheucher B, Valencak J, et al. Molecular cytogenetic evidence of t(14;18)(IGH;BCL2) in a substantial proportion of primary cutaneous follicle center lymphomas. Am J Surg Pathol. 2006;30:529-536.
- Kim BK, Surti U, Pandya AG, Swerdlow SH. Primary and secondary cutaneous diffuse large B-cell lymphomas: a multiparameter analysis of 25 cases including fluorescence in situ hybridization for t(14;18) translocation. Am J Surg Pathol. 2003;27:356-364.
- Xie X, Sundram U, Kohler S, et al. BCL-6 negativity, female gender, and morphologic type, predict poor overall survival in primary cutaneous large B-Cell lymphomas with a diffuse architecture. Laboratory Investigation. 2006;86:252A-252A.
- Storz MN, van de Rijn M, Kim YH, Mraz-Gernhard S, Hoppe RT, Kohler S. Gene expression profiles of cutaneous B cell lymphoma. J Invest Dermatol. 2003;120:865-870.
- Hoefnagel JJ, Dijkman R, Basso K, et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood. 2005;105:3671-3678.
- Dijkman R, Tensen CP, Jordanova ES, et al. Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma. J Clin Oncol. 2006;24:296-305.
- Goodlad JR, MacPherson S, Jackson R, Batstone P, White J. Extranodal follicular lymphoma: a clinicopathological and genetic analysis of 15 cases arising at non-cutaneous extranodal sites. Histopathology. 2004;44:268-276.
- Shia J, Teruya-Feldstein J, Pan D, et al. Primary follicular lymphoma of the gastrointestinal tract: a clinical and pathologic study of 26 cases. Am J Surg Pathol. 2002;26:216-224.
- Swerdlow SH. Pediatric follicular lymphomas, marginal zone lymphomas, and marginal zone hyperplasia. Am J Clin Pathol. 2004;122 Suppl:S98-109.
- McDermott MB, O'Briain DS, Shiels OM, Daly PA. Malignant lymphoma of the epididymis. A case report of bilateral involvement by a follicular large cell lymphoma. Cancer. 1995;75:2174-2179.