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Cutaneous B-cell lymphomas (CBCL) are less common than cutaneous T-cell lymphomas (CTCL). Like CTCL, they are antigen driven processes. It appears that heavy chain genes (VH) of the B cells show significant mutations. Once this occurs, a neoplastic clone develops. There are definitely some environmental factors associated with this such as Borrelia burgdorferi infection (agent of Lyme disease). The term SALT (Skin Associated Lymphoid Tissue) has been applied to some of these B cell lymphomas, citing the similarity of CBCL with other B cell lymphomas arising within mucosa such as the salivary gland and gastrointestinal tract.

The similarities include:

Nonaggressive clinical behavior
Subtle histologic differences from true follicular center cells and intermediate cells of the lymph nodes
Tumor cells with unimodal morphometric features intermediate between centrocytes and centroblasts of nodal follicular center cells
Characteristic polymorphism of the neoplastic cellular infiltrate
Multiphasic histologic features with the various cell types often intermingled
Lymphoepithelial lesions
Frequent CD5- CD10- phenotype of neoplastic B cells
Nerve growth factor receptor+, CD14- CD21 +/- phenotype of associated dendritic cells
Lack of either t(11;14)/t(14;18) translocation or bcl-1/bcl-2 gene and c-myc oncogene rearrangements


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Europe vs. United States
J Am Acad Dermatol 2000;43:793-6
For reasons which are unclear, there is a much lower relative frequency of primary cutaneous B-cell lymphomas at US institutions (4.5%) versus the approximately 20% reported by European groups


B cell lymphoma in patient with WHIM syndrome

J Am Acad Dermatol 2001;44:124-128

WHIM=Warts, Hypogammaglobulinemia, Infections, and Myelokathexis

Single case

Multiple cutaneous immunocytoma with secondary anetoderma: a report of two cases.

Child FJ, Woollons A, Price ML, Calonje E, Russell-Jones R.

Skin Tumour Unit, St John's Institute of Dermatology, St Thomas' Hospital, London SE1 7EH, U.K.

Br J Dermatol 2000 Jul;143(1):165-70 Abstract quote

We describe two men with multiple erythematous dermal nodules which were clinically and histologically consistent with a diagnosis of primary cutaneous immunocytoma. Both patients exhibited the very unusual feature of secondary anetoderma occurring in spontaneously resolving lesions. There is one previous report of anetoderma in association with a plasmacytoma.

The pathogenesis remains unknown but release of cytokines such as interleukin-6 may be implicated.

Cutaneous marginal zone B-cell lymphoma in the setting of fluoxetine therapy: a hypothesis regarding pathogenesis based on in vitro suppression of T-cell-proliferative response.

College of Medicine, The Ohio State University, Columbus, OH 43210, USA.


J Cutan Pathol. 2006 Jul;33(7):522-8 Abstract quote

INTRODUCTION: Drugs may be an important cause of atypical lymphocytic infiltration. Oftentimes, these infiltrates are in the context of pseudolymphomata. We report a patient who developed lymphocytoma cutis temporally associated with initiation of fluoxetine therapy that later went on to develop cutaneous marginal zone B-cell lymphoma. The response of peripheral blood lymphocytes to fluoxetine and other drugs was examined in an attempt to ascertain the potential role for drugs in the propagation of these infiltrates.

MATERIALS AND METHODS: Routine light microscopic analysis and phenotypic studies were performed on tissue obtained from a skin biopsy. Lymphocyte mitogenic studies were carried out using increasing concentrations of fluoxetine, bupropion, and two anticonvulsants.

RESULTS: An initial biopsy was consistent with lymphocytoma cutis. The patient stopped fluoxetine associated with lesional regression. The lesions recurred despite being off fluoxetine; a repeat biopsy was compatible with marginal zone lymphoma. Lymphocyte proliferation assays revealed a suppressive effect on T-lymphocyte proliferation at physiologic concentrations. Other tested drugs did not have a similar suppressive effect.

CONCLUSIONS: Fluoxetine may be associated with pseudolymphomata and marginal zone lymphoma. The inhibitory effects on T-lymphocyte function and more specifically T-suppressor function may lead to excessive antigen-driven B-cell proliferation.



Primary Cutaneous B-Cell Lymphoma and Borrelia burgdorferi Infection in Patients From the Highlands of Scotland

John R. Goodlad, M.D.; Marilyn M. Davidson, F.R.C.Path.; Kevin Hollowood, M.D.; Claire Ling, M.Sc.; Carol MacKenzie, M.N.C.; Irene Christie, M.N.C.; Paul J. Batstone, B.Sc.; Darrel O. Ho-Yen, M.D.

From the Departments of Pathology (J.R.G., C.M., I.C., P.J.B.) and Microbiology (M.M.D., C.L., D.O.H.-Y.), Raigmore Hospital, Inverness, Scotland; and the Department of Cellular Pathology (K.H.), The John Radcliffe Hospital, Oxford, U.K.

Am J Surg Pathol 2000;24:1279-1285 Abstract quote

Although a link between primary cutaneous B-cell lymphoma (PCBCL) and Borrelia burgdorferi infection has long been suspected, previous studies have not demonstrated a significant association.

The authors looked for evidence of B. burgdorferi in 20 cases of PCBCL from the Scottish Highlands, an area with endemic Lyme disease, and compared their findings with those in 40 control patients (20 undergoing wide reexcision at sites of malignant melanoma and 20 biopsies of inflammatory dermatoses).

All studies were performed on formalin-fixed, paraffin-embedded tissues. The cases of PCBCL were classified according to criteria described by the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group using a combination of morphology, immunohistochemistry, and seminested polymerase chain reaction (PCR) for immunoglobulin heavy chain gene rearrangement. A nested PCR was performed on deoxyribonucleic acid (DNA) extracts from the lymphoma and control cases using primers to a unique conserved region of the B. burgdorferi flagellin gene. B. burgdorferi-specific DNA was detected in seven of 20 lymphoma cases (five of 12 marginal zone lymphomas, one of five primary cutaneous follicle center cell lymphomas, one of three diffuse, large B-cell lymphomas of the leg) and in one melanoma reexcision patient of 40 control subjects. The relationship between B. burgdorferi and PCBCL was significant when compared with the control groups separately (p <0.05) or in combination (p <0.01).

These results provide strong evidence to support the concept of B. burgdorferi-driven lymphomagenesis in the skin.

Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States

Gary S. Wood1,2, Nandan V. Kamath2, Joan Guitart3, Peter Heald4, Sabine Kohler5, Bruce R. Smoller6 and Lorenzo Cerroni7 1

Department of Medicine (Dermatology), University of Wisconsin and the Middleton Veterans Affairs Medical Center, Madison, Wisconsin, USA, 2 Department of Dermatology, Case Western Reserve University, the Ireland Comprehensive Cancer Center of University Hospitals of Cleveland, and the Louis Stokes Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA, 3 Department of Dermatology, Northwestern University, Chicago, Illinois, USA, 4 Department of Dermatology, Yale University, New Haven, Connecticut, USA, 5 Departments of Pathology and Dermatology, Stanford University, Stanford, California, USA, 6 Departments of Pathology and Dermatology, University of Arkansas, Little Rock, Arkansas, USA, 7 Department of Dermatology, University of Graz, Graz, Austria

J Cutan Pathol 2001;28 (10), 502-507 Abstract quote

Background: An association between Borrelia burgdorferi and cutaneous B-cell lymphoma (CBCL) has been made in several European countries. The evidence in favor of such an association has recently been based on more definitive tests for the pathogenetic role of B. burgdorferi in CBCL, including positive cultures or polymerase chain reaction (PCR) amplification of borrelial DNA from lesional skin. However, there is only one report of B. burgdorferi in four North American cases of B-cell lymphoma.

Methods: We retrieved 38 cases of primary and secondary CBCL from different geographic regions of the United States. Two separate techniques were used to detect borrelial DNA by PCR, a nested PCR method to amplify a B. burgdorferi-specific gene as well as a borrelial chromosomal Ly-1 clone amplification method. Southern blot hybridization was used for confirmation of the PCR results.

Results: No B. burgdorferi-specific DNA was detected in any of the 38 CBCL cases, whereas detectable PCR products were obtained with our positive controls.

Conclusions: Our findings, in light of previous studies, suggest that B. burgdorferi plays a minimal role in the development or pathogenesis of CBCL in the United States. The findings also suggest that the geographic variations in the clinical manifestations of B. burgdorferi are indeed real and may be secondary to the genetic and phenotypic differences between B. burgdorferi strains present in Europe and North America.

Cytogenetic and molecular analysis of 12 cases of primary cutaneous marginal zone lymphomas.

Laboratoire de Cytogenetique et Biologie Moleculaire, Centre Hospitalier Lyon Sud, Pierre Benite, France.


Am J Dermatopathol. 2006 Aug;28(4):287-92 Abstract quote

Primary low-grade B-cell lymphomas of the skin are separated into marginal zone and follicle center lymphomas according to the recent World Health Organization-European Organization for Research and Treatment of Cancer classification, with distinct histologic and immunohistochemical profiles. Some cases remain difficult to distinguish. The degree of relationship with their extracutaneous counterparts is currently being investigated on clinical, histologic and molecular grounds.

Cytogenetic analysis using fluorescence in situ hybridization was performed on 12 frozen samples of infiltrated skin that had been classified as marginal zone lymphoma (MZL). Chromosomal changes known to be recurrently observed in systemic MZL of the mucosa-associated lymphoid tissue type, and in follicular center lymphoma were analyzed. These included trisomy for chromosomes 3, 7, 12, and 18 as well as t(14;18) IGH/BCL2, t(14;18) IGH/MLT1, and t(11;18) API2/MLT1 translocations. Complementary molecular search of IGH/BCL2 rearrangement using a polymerase chain reaction technique and of API2/MLT1 mRNA expression by reverse transcriptase-polymerase chain reaction were performed. Two cases showed evidence of trisomy 3 at levels varying from 14% to 20% of the analyzed cells. No other chromosomal abnormalities were found with those techniques in the remaining cases.

These results demonstrate that known recurrent chromosomal abnormalities rarely occur in primary cutaneous MZLs and suggest the possibility of a variety of initial oncogenic events leading to a common downstream pathway. These data also underline that fluorescence in situ analysis on routine skin punch biopsies represents a reliable tool for the detection of chromosomal changes, but requires consistent dermal infiltration.
t(14;18)(q32;q21) involving IGH and MALT1 is uncommon in cutaneous MALT lymphomas and primary cutaneous diffuse large B-cell lymphomas.

Wongchaowart NT, Kim B, Hsi ED, Swerdlow SH, Tubbs RR, Cook JR.

Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.

J Cutan Pathol. 2006 Apr;33(4):286-92. Abstract quote  

Background: t(14;18)(q32;q21) involving IGH and MALT1 has been demonstrated in cutaneous MALT lymphomas and in one case of primary cutaneous diffuse large B-cell lymphoma (DLBCL). However, the incidence of IGH/MALT1 translocations in these forms of cutaneous lymphoma remains unclear.

Methods: We performed paraffin section interphase fluorescence in situ hybridization (FISH) analysis using MALT1 and IGH break-apart probes on 16 cutaneous MALT lymphomas and 16 primary cutaneous DLBCL in order to assess the frequency of IGH/MALT1 translocations and to screen for other potential translocations involving the IGH or MALT1 loci.

Results: Translocations involving MALT1 were not detected in any of 16 cutaneous MALT lymphomas or 16 primary cutaneous DLBCL. Of the 12 MALT lymphomas that could be analyzed for an IGH translocation, all were negative. In contrast, four of the 13 cases (31%) of primary cutaneous DLBCL that could be analyzed for translocations involving IGH were positive. Subsequent FISH analysis demonstrated one of these to be an IGH/BCL2 translocation and one to be a CMYC/IGH translocation, while the translocation partners in the remaining two cases are currently unidentified.

Conclusions: This study demonstrates that translocations involving MALT1, including IGH/MALT1, are uncommon in cutaneous MALT lymphomas and primary cutaneous DLBCL. Other translocations involving IGH also are not involved in the pathogenesis of at least most cutaneous MALT lymphomas. In contrast, primary cutaneous DLBCL may contain one of several IGH translocations in a minority of cases.
IgV(H) and bcl6 somatic mutation analysis reveals the heterogeneity of cutaneous B-cell lymphoma, and indicates the presence of undisclosed local antigens.

Franco R, Camacho FI, Fernandez-Vazquez A, Algara P, Rodriguez-Peralto JL, Rosa GD, Piris MA.

1Istituto dei Tumori G Pascale, Napoli, Italy.
Mod Pathol. 2004 Jun;17(6):623-30. Abstract quote

Our understanding of the ontology of B-cell lymphomas (BCL) has been improved by the study of mutational status of IgV(H) and bcl6 genes, but only a few cases of cutaneous BCL have been examined for this status.

We analyzed IgV(H) and bcl6 somatic mutations in 10 cutaneous BCL, classified as follicular (three primary and one secondary), primary marginal zone (two cases), and diffuse large BCL (three primary and one secondary). We observed a lower rate (<2%) of IgV(H) mutation in all marginal zone lymphomas, and a preferential usage of V(H)2-70 (one primary follicular and two primary diffuse large BCL). Fewer than expected replacement mutations in framework regions (FR) were observed in three primary follicular lymphomas (FLs) and in all diffuse large BCL, indicating a negative antigen selection pressure. Ongoing mutations were observed in eight of 10 cases. Only two primary FLs and two diffuse large BCL showed bcl6 somatic mutation.

These data support the heterogeneous nature of the different cutaneous BCL, and specifically the distinction between cutaneous follicular and marginal zone lymphomas. The biased usage of V(H)2-70, the low rate of replacement mutation in the FR, and the presence of ongoing mutation imply that local antigens could modulate the growth of primary cutaneous BCL.

Absence of the t(14;18) chromosomal translocation in primary cutaneous B-cell lymphoma.

Child FJ, etal.


Br J Dermatol 2001;44:735-744

t(14;18) does not appear to play a role in the pathogenetic mechanisms of cutaneous B-cell lymphoma

PCR study of 44 cutaneous B-cell lymphomas:
36 primary cutaneous B-cell lymphomas
4 follicular B-cell lymphomas
4 reactive B-cell infiltrates

No primary cutaneous follicular B-cell lymphomas or reactive B-cell infiltrates demonstrated bcl-2 overexpression

Epstein-Barr virus-associated B-cell lymphoma in the setting of iatrogenic immune dysregulation presenting initially in the skin.

Verma S, Frambach GE, Seilstad KH, Nuovo G, Porcu P, Magro CM.

School of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.
J Cutan Pathol. 2005 Aug;32(7):474-83. Abstract quote  

Background: Epstein-Barr virus (EBV) has been implicated in B-cell lymphoma associated with iatrogenic immune dysregulation, primarily in the context of extracutaneous lymphoma.

Methods: We describe six patients, five transplant recipients receiving cyclosporine and one patient with rheumatoid arthritis receiving methotrexate, who developed cutaneous presentations of EBV-associated B-cell lymphoma. Human herpesvirus 8 (HHV8) and EBV thymidine kinase (vTK) expression were also explored.

Results: The cases comprised plasmablastic lymphoma (one case), plasmacytic marginal zone lymphoma (two cases), and diffuse large B-cell lymphoma (three cases). There was a monoclonal gammopathy in one and concurrent extracutaneous disease in two of the six patients. EBV-associated latent small nuclear RNA was detected in all cases with coexpression of HHV8 in one of the five cases and of vTK in three of the six cases. Three patients responded to a reduction in the immunosuppressive regimen and antiviral therapy. Recurrent disease developed in two, with one patient succumbing to multiorgan dissemination.

Conclusions: EBV-associated cutaneous B-cell lymphoma is characterized by a long interval between the initiation of immunosuppression and the development of lymphoma. Although previous reports have reported an indolent clinical course, an aggressive clinical course may occur. HHV8 and lytic phase EBV antigens are detected in some cases, possibly suggesting a pathogenetic role.

Hepatitis C and G viruses in B-cell lymphomas of the skin.

Michaelis S, Kazakov DV, Schmid M, Dummer R, Burg G, Kempf W.

Unit of Dermatopathology, Department of Dermatology, University Hospital, Zurich, Switzerland.

J Cutan Pathol. 2003 Jul;30(6):369-72. Abstract quote

BACKGROUND: The etiology of B-cell lymphoproliferative disorders (LPDs) of the skin has still to be elucidated. So far, Borrelia sp. has been identified as the causative agent of some cases of B-cell LPDs of the skin. Apart from bacterial pathogens, recent studies suggested that also flaviviruses, in particular hepatitis C (HCV) and G (HGV) viruses, may be involved in the pathogenesis of B-cell non-Hodgkin's lymphomas (NHLs). Most studies were performed in patients with known HCV infection, but the overall frequency of HCV- and HGV-RNA in tumoral tissue of primary cutaneous B-cell lymphomas (CBCLs) is unknown.

METHODS: We examined 23 tumor biopsies of various forms of CBCLs by reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing for the presence of HCV and HGV.

RESULTS: HCV-RNA sequences were detected in seven of 23 (30%) of the tumor biopsies. In contrast, RNA sequences of HGV were not detected in any of the tumors.

CONCLUSIONS: Interestingly, the presence of HCV in our series of primary CBCLs was not restricted to a distinct clinicopathologic subform. HCV which can infect B cells, may play a role in pathogenesis of one-third of CBCLs, whereas HGV is not involved in CBCLs. Further molecular studies and therapeutic trials are needed to clarify the putative pathogenetic role of HCV in CBCLs.


Primary cutaneous large B-cell lymphoma shows activation of nuclear factor kappa B and low incidence of Epstein-Barr virus.

Bhagavathi S, Blenc AM, Amin M, Nikitin VD, Patel MC, Warren S, Malhotra RK.

Am J Dermatopathol. 2010 Jul;32(5):439-41. Abstract

Primary cutaneous lymphomas are defined as lymphomas, which are present in the skin without evidence of extracutaneous disease at the time of diagnosis. Primary cutaneous large B-cell lymphoma (PCLBCL) is a subtype of primary cutaneous B-cell lymphoma with a female predominance, occurring in elderly patients and known to have unfavorable prognosis.

We evaluated 10 cases of PCLBCL in immunocompetent patients between 2005 and 2008. A panel of immunoperoxidase stains; CD3, CD10, CD20, BCL2, BCL6, and MUM1 were performed on all cases. Nuclear factor kappa B (NF-kappaB) pathway activation was evaluated using an immunostain for P65. The presence of Epstein-Barr virus (EBV) was assessed using Epstein-Barr virus encoded RNA (EBER) in situ hybridization probe. All cases were CD20 positive and CD3 negative. CD10, BCL6, BCL2, and MUM1 were positive in 4/10 (40%), 6/10 (60%), 7/10 (70%), and 7/10 (70%) cases, respectively. NF-kappaB activation was detected in 7/10 (70%) cases. One (10%) case was positive for EBV by in situ hybridization. Interestingly, the EBV positive case was also positive for MUM1 and negative for CD10, indicating an activated immunophenotype.

In conclusion, majority of PCLBCL shows activation of NF-kappaB pathway with a low incidence of EBV.

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma.

1Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.


Mod Pathol. 2006 Sep;19(9):1270-6. Abstract quote

Expression patterns of eight transcription factors involved in different stages of B-cell development were investigated in a large group of primary cutaneous B-cell lymphomas and compared with expression patterns during normal B-cell development.

The following transcription factors were investigated: Pax-5, PU.1, Oct2, BOB.1, Bcl-6, Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous large B-cell lymphomas, leg type showed aberrant coexpression of Bcl-6 and Mum1/IRF4 and in addition strong expression of FOXP1. Expression of FOXP1 and Mum1/IRF4 strongly suggests an activated B-cell type of origin. In contrast, primary cutaneous follicle center lymphomas showed expression of Bcl-6, Pax-5, PU.1, Oct2 and BOB.1, but not of Mum1/IRF4, Blimp-1 and FOXP1.

Primary cutaneous marginal zone B-cell lymphoma showed expression of Pax-5, PU.1, Oct2 and BOB.1, but not Bcl-6 by the neoplastic B-cells, and Mum1/IRF4 and Blimp-1 by the neoplastic plasma cells. In conclusion, in primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma expression patterns were observed similar to their supposed benign counterparts, germinal center B-cells and postgerminal center B-cells, respectively, which might reflect their indolent clinical behaviour and excellent prognosis.

In contrast, the activated B-cell expression pattern in the group of primary cutaneous large B-cell lymphoma, leg type may contribute to its poor prognosis and Mum1/IRF4 and FOXP1 may serve as additional diagnostic markers for this type of primary cutaneous B-cell lymphoma.


Rapid Diagnosis of Clonal Immunoglobulin Heavy Chain Gene Rearrangements in Cutaneous B-Cell Lymphomas Using the LightCycler-Polymerase Chain Reaction with DNA Melting Curve Analysis.

Xu D, Du J, Kamino H, Ratech H.

*Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York; and daggerDermatopathology Section, Department of Dermatology, New York University Medical Center, New York, New York

Am J Dermatopathol. 2004 Oct;26(5):385-389. Abstract quote  

We have recently developed a novel Immunoglobulin heavy chain gene rearrangement (IgH-R) assay that combines polymerase chain reaction (PCR) amplification and analysis in the same closed capillary tube using the LightCycler System. IgH-R can be identified by DNA melting curve analysis within 40 minutes after DNA preparation and amplification.

To test the clinical utility of this new IgH-R assay for rapidly diagnosing cutaneous B-cell lymphomas, we prospectively analyzed 44 formalin-fixed, paraffin-embedded tissues suspected of B-cell malignant lymphoma: skin (n = 31), lymph node (n = 7), stomach (n = 3), spleen (n = 1), colon (n = 1), and soft tissue (n = 1).

We detected IgH-R in 12 DNA samples, including 8 skin biopsies, with the following diagnoses: B-cell chronic lymphocytic leukemia (n = 4), extranodal marginal zone B-cell lymphoma (n = 4), diffuse large B-cell lymphoma (n = 2), Burkitt lymphoma (n = 1), and precursor B-lymphoblastic lymphoma (n = 1). DNA melting curve analysis, compared with polyacrylamide gel electrophoresis, achieved a sensitivity equal to 92.3% and a specificity equal to 100%. There was a single false negative result because DNA melting curve analysis could not detect less than 10.0% clonal B-cells.

We conclude that this new, rapid PCR assay for detecting IgH-R based on DNA melting curve analysis can be clinically useful for confirming the initial diagnosis of B-cell malignant lymphoma.

Automated kappa and lambda light chain mRNA expression for the assessment of B-cell clonality in cutaneous B-cell infiltrates: its utility and diagnostic application.

Magro C, Crowson AN, Porcu P, Nuovo GJ.

Departments of Pathology and Medicine, Division of Hematology-Oncology, Ohio State University School of Medicine and Public Health, Columbus, OH, Departments of Dermatology and Pathology, University of Oklahoma, and Regional Medical Laboratory, Tulsa, OK, and Department of Medicine, Comprehensive Cancer Center, Ohio State University School of Medicine and Public Health, Columbus, OH, USA
J Cutan Pathol. 2003 Sep;30(8):504-511 Abstract quote.  

INTRODUCTION: Primary cutaneous B-cell lymphoma (1 degrees CBCL) accounts for 25% of all lymphomas. The difficulty in distinction of reactive from neoplastic B-cell infiltrates prompts the use of molecular diagnostic adjuncts. While T-cell clonality can be seen in various reactive states, clonal B-cell infiltrates are often neoplastic; standard assays employed include polymerase chain reaction (PCR) or Southern blot analysis to assess heavy chain rearrangement. We sought to assess the utility of kappa (kappa) and lambda (lambda) mRNA expression using the Ventana automated assay (Ventana Medical Systems, Tucson, AZ, USA) in the analysis of atypical cutaneous B-cell lymphoid infiltrates.

MATERIALS AND METHODS: Multiple 4 micro m sections of paraffin-embedded, formalin-fixed skin biopsies from 31 patients with CBCL were placed on silane-coated slides, deparaffinized, then digested in pepsin (5 mg/ml) for 30 min at 37 degrees C. Fluorescein-tagged oligoprobes and tissue mRNA were denatured at 80 degrees C for 5 min, hybridized for 2 h at 37 degrees C, and incubated with antifluorescein alkaline phosphatase conjugates. Detection of the probe target complex employed nitroblue tetrazolium and bromochloroindolyl phosphate conjugates with a nuclear fast red counterstain. A kappa : lambda ratio > 3 : 1 was held to represent kappa light chain restriction and a kappa : lambda ratio </= 1 : 1 to indicate lambda light chain restriction.

RESULTS: The diagnosis in each case was determined by careful integration of clinical, histologic, and phenotypic data. The diagnoses included: pseudolymphoma (PL), marginal zone lymphoma (MZL), 1 degrees CBCL of the trunk, scalp or leg, 2 degrees lymphoma, and plasma cell dyscrasia. All but one case of lymphoma were light chain restricted. All cases of PL were proven to be polyclonal by this methodology. In non-plasmacytic small cell lymphomas, only 5-10% of the infiltrate expressed kappa or lambda, with clonality established through the abnormal kappa : lambda ratio. Interpretations were most difficult in the 2 degrees small cell-dominant follicular center cell lymphomas and easiest in cases with significant plasmacytic differentiation (i.e. MZL, immunocytomas, or plasma cell dyscrasias).

CONCLUSION: The Ventana kappa/lambda assay is a reliable, quick, and inexpensive way to determine B-cell clonality in cutaneous lymphoid infiltrates in paraffin-embedded formalin-fixed tissue.



Primary Cutaneous B cell Lymphoma (CBCL)

Follicle center cell lymphoma
Immunocytoma (Marginal zone B-cell lymphoma)
Large B-cell lymphoma of the leg
Intravascular large B-cell lymphoma
T-Cell Rich B-Cell Lymphoma
Unusual cutaneous manifestations of B-cell chronic lymphocytic leukemia.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.


J Am Acad Dermatol. 2009 May;60(5):772-80. Abstract quote

BACKGROUND: B-cell chronic lymphocytic leukemia (B-CLL) is a low-grade lymphoproliferative disorder with characteristic histomorphologic features and an identifiable immunophenotype. The skin can be involved in the context of known disease, but cutaneous signs are rarely the presenting findings.

OBJECTIVE: Evaluation of unusual clinical cutaneous presentations of B-CLL.

METHODS: We conducted a retrospective case series analysis of 3 patients with unusual cutaneous clinicopathologic presentations of B-cell chronic lymphocytic leukemia, including erythematous plaques, angiomatosis/telangiectasia, and erosive skin changes, respectively, without a previous clinical history of chronic lymphocytic lymphoma. Main outcome measures were clinical cutaneous presentations and histopathologic results in the diagnosis of underlying disease.

RESULTS: In the 3 cases, lesion locations were the lower cheek, lower extremity, and penis (groin region). Histomorphologic testing showed mild to dense perivascular and periadnexal lymphoid aggregates throughout the dermis and extending into the panniculus, consistent with B-CLL. The diagnosis was confirmed with immunohistochemical studies that showed coexpression of CD5 and CD20 in the neoplastic lymphocytic infiltrate.


CONCLUSION: Cutaneous manifestations are an uncommon presentation of subclinical B-CLL. Cutaneous changes were the presenting features of underlying lymphoma in all 3 cases, highlighting the importance of maintaining a high index of suspicion for a lymphoproliferative process in cases with unusual or atypical clinicopathologic features. Additional investigations into the behavior of B-CLL in the skin may elucidate further the evolution of cutaneous lesions in this disease.

Primary cutaneous B-cell lymphoma.

Bogle MA, Riddle CC, Triana EM, Jones D, Duvic M.

Department of Dermatology, University of Texas and M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Am Acad Dermatol. 2005 Sep;53(3):479-84. Abstract quote  

Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma.

Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response.

We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6).

Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.
Disseminated cutaneous B-cell lymphoma mimicking pseudolymphoma over a period of six years.

Gutermuth J, Audring H, Roseeuw D.

Division of Environmental Dermatology and Allergy GSF/TUM, GSF-National Research Center For Environment and Health, and Department of Dermatology and Allergy Biederstein, Technical University of Munich, Germany.
Am J Dermatopathol. 2004 Jun;26(3):225-9. Abstract quote  

We describe a patient with a disseminated nodular cutaneous B-cell lymphoma, whose diagnosis was finally made after a long series of biopsies in different institutions in Europe and the United States.

The differential diagnosis between lymphoma and pseudolymphoma was the recurrent problem throughout the patient's history because histologic and immunophenotypic criteria alone were not sufficient for differentiation. Molecular biology inconsistently detected clonal immunoglobulin rearrangements, which proves that careful clinicopathologic correlation remains mandatory.

In contrast to a claimed "high-grade" malignant histology, this lymphoma responded with remission to PUVA therapy combined with intralesional corticosteroids, which is uncommon in the management of cutaneous B-lymphomas.

Primary cutaneous large B-cell lymphoma of the leg: histogenetic analysis of a controversial clinicopathologic entity.

Paulli M, Viglio A, Vivenza D, Capello D, Rossi D, Riboni R, Lucioni M, Incardona P, Boveri E, Bellosta M, Orlandi E, Borroni G, Lazzarino M, Berti E, Alessi E, Magrini U, Gaidano G.

Department of Pathology, IRCCS Policlinico S.Matteo/University of Pavia, Italy.

Hum Pathol 2002 Sep;33(9):937-43 Abstract quote

This study analyzes the pathologic and molecular features of 5 cases of primary cutaneous large B-cell lymphoma of the leg (PCLBCL-leg), recently included in the European Organization for Research and Treatment of Cancer (EORTC) classification of primary cutaneous lymphoma. PCLBCL-leg accounts for 5% to 10% of all primary cutaneous B-cell lymphoma (PCBCL), usually affects elderly patients and carries a worse prognosis than other forms of PCBCL.

It has been proposed that the malignant cells of PCLBCL-leg originate from germinal center (GC)-related cells, but their effective normal counterpart is unclear, and the rationale behind the inclusion of this lymphoma as a separate entity is based on its prognosis rather than on its proved histogenesis. All of our cases of PCLBCL-leg morphologically resembled diffuse large B-cell lymphoma (DLBCL), but to better define their histogenesis, we also analyzed various phenotypic and genotypic markers, including mutations of the Ig and of BCL-6 genes, as well as expression of the bcl-6, MUM1, and CD138/syndecan-1 proteins.

Immunohistochemically, all of our cases stained for the L-26/CD20cy and CD79a antigens and expressed the bcl-2, bcl-6, and MUM-1 proteins but were negative for both the CD10/CALLA and CD138 antigens. With respect to molecular analysis, the lymphoma population of all PCLBCL-leg carried hypermutation of Ig genes, and all but 1 case also harbored mutations of the BCL-6 gene.

Our results indicate that PCLBCL-leg are similar both under the morphofunctional and molecular profiles to most DLBCL of other sites. Thus, caution seems justified before definitely considering PCLBCL of the leg as a distinct entity.



Epidermotropic cutaneous B-cell lymphoma mimicking mycosis fungoides.

Chui CT, Hoppe RT, Kohler S, Kim YH.

Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305-5334, USA.

J Am Acad Dermatol 1999 Aug;41(2 Pt 1):271-4 Abstract quote

Cutaneous involvement by B-cell lymphoma is often secondary to systemic disease. Primary cutaneous B-cell lymphomas are less common, and patients generally have an excellent prognosis.

We present a patient with cutaneous B-cell lymphoma with clinical and histologic features mimicking mycosis fungoides. Although the patient was initially misdiagnosed as having a T-cell lymphoma, immunophenotypic studies demonstrated that this was a B-cell lymphoma.

Hyperplasia of hair follicles and other adnexal structures in cutaneous lymphoproliferative disorders: a study of 53 cases, including so-called pseudolymphomatous folliculitis and overt lymphomas.

Sikl Department of Pathology, Medical Military Academy, Saint Petersburg, Russia.

Am J Surg Pathol. 2008 Oct;32(10):1468-78 Abstract quote

We studied 53 cutaneous lymphoproliferative disorders, all of which manifested hair follicle hyperplasia. There were 42 cases conforming to the description of pseudolymphomatous folliculitis (PLF) and 11 cases of authentic lymphomas including mycosis fungoides, CD30+ anaplastic large cell lymphoma, diffuse large B-cell lymphoma, B-cell small cell lymphoma/leukemia, and peripheral T-cell lymphoma, not otherwise specified.

All patients with PLF clinically presented with a solitary nodule preferentially involving the face. Beside hair follicle hyperplasia, the typical features were a dense infiltrate of small well-differentiated lymphocytes, lymphoplasmacytoid cells, plasma cells, and epithelioid histiocytes forming tiny granulomas. Some unusual or worrisome features recognized included eccrine/apocrine duct hyperplasia, subcutis/muscle infiltration, lymphocyte "smudging," single file infiltration, and large atypical cells. Immunohistochemically, T-cell predominant cases dominated in the series. All 34 tested cases revealed a polyclonal pattern of kappa and lambda immunoglobulin (Ig) light chain expression. In 4 cases, scattered CD30+ cells were identified. Monoclonal rearrangements of T-cell receptor (TCR) and IgH genes were detected in 19 and 3 cases respectively, including 1 case with dual T-cell receptor/IgH rearrangement. Three of 30 tested cases proved positive for herpes simplex virus-1, whereas herpes simplex virus-2 always tested negative. Of 31 cases tested for Borrelia burgdorferi, 30 specimens were negative. In 9 cases, fluorescent in situ hybridization for t(11;18) and t(14;18) revealed none of the above translocations. The most common treatment modality was surgical removal.

Forty patients with a mean follow-up of 3.7 years included 39 patients with no evidence of disease and 1 individual with local recurrence. The comparison of "clonal cases of PLF" and those with polyclonal population or in which clonality remained undetermined revealed no differences between the 2 groups in the clinical presentation, pathologic, and immunohistochemical features.

We conclude that hyperplasia of hair follicles and other adnexa can be seen not only in the condition currently known as PLF, but also in genuine cutaneous lymphomas and may be just a happenstance secondary to a basic pathologic process.

Granuloma Annulare-Like Infiltrates With Concomitant Cutaneous Involvement by B-Cell Non-Hodgkin's Lymphoma: Report of a Case.

Fullen DR, Jacobson SN, Valdez R, Novice FM, Lowe L.

Am J Dermatopathol 2003 Feb;25(1):57-61 Abstract quote

Granulomatous infiltrates, including granuloma annulare-like changes, in patients with T-cell non-Hodgkin's lymphoma and Hodgkin's disease are well described but are exceedingly uncommon in B-cell non-Hodgkin's lymphoma.

Herein, we describe a 73-year-old male with a 10-year history of B-cell chronic lymphocytic leukemia who developed erythematous annular plaques symmetrically on his upper extremities. Biopsies of these lesions revealed both granuloma annulare-like areas, in conjunction with nodular atypical lymphoid infiltrates consistent with secondary involvement by B-cell chronic lymphocytic leukemia.

To our knowledge, this is the first report of cutaneous lesions resembling granuloma annulare with concomitant involvement by B-cell chronic lymphocytic leukemia. Awareness of this association may prevent nonrecognition of a neoplastic B-cell infiltrate in a granuloma annulare-like process.


Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathologic study of 24 asian cases.

Li C, Inagaki H, Kuo TT, Hu S, Okabe M, Eimoto T.


Am J Surg Pathol. 2003 Aug;27(8):1061-9. Abstract quote

Cutaneous marginal zone B-cell lymphoma is a recently proposed entity and constitutes a cutaneous counterpart of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT).

Borrelia burgdorferi infection has been suggested as a possible causative agent in European cutaneous cases of marginal zone B-cell lymphoma, whereas API2-MALT1 fusion and BCL10 mutation are highly associated with MALT lymphoma. Aberrant nuclear BCL10 expression may be closely correlated with API2-MALT1 fusion in gastric and pulmonary MALT lymphomas.

We examined 24 Asian cases of cutaneous marginal zone B-cell lymphoma for B. burgdorferi involvement, API2-MALT1 fusion, BCL10 cellular expression, and BCL10 mutation. Neither Borrelia DNA nor API2-MALT1 fusion transcript was detected. Nuclear BCL10 expression was evident in tumor cells of 11 of 24 cases, although BCL10 mutation was found in one case only. Clinicopathologically, nuclear BCL10 was more frequently expressed in macroscopically nodular lesions than in plaques or papules (p = 0.0031).

These data suggest that 1) B. burgdorferi infection may not play an important role in developing cutaneous marginal zone B-cell lymphoma in Asian cases, 2) neither API2-MALT1 fusion nor BCL10 mutation is closely associated with the pathogenesis, 3) aberrant nuclear BCL10 may frequently be expressed in the absence of these genetic abnormalities, and 4) nuclear BCL10 expression may be clinically important because it was observed in locally aggressive tumors.

Primary cutaneous marginal zone B-cell lymphoma: a report of 9 cases.

de la Fouchardiere A, Balme B, Chouvet B, Sebban C, Perrot H, Claudy A, Bryon PA, Coiffier B, Berger F.

Service d'Anatomie-Pathologique, Hopital Edouard-Herriot, 69437 Lyon Cedex 3, France.

J Am Acad Dermatol 1999 Aug;41(2 Pt 1):181-8 Abstract quote

BACKGROUND: Primary cutaneous B-cell lymphoma is a heterogeneous group among which marginal zone B-cell lymphoma (MZL) appears to be the most common subtype.

OBJECTIVE: We analyze clinical presentation, histologic aspects, and outcome of patients with primary cutaneous MZL.

METHODS: All samples classified as primary cutaneous lymphoma over the past 10 years were reviewed, and cases of primary MZL were identified.

RESULTS: Nine cases of MZL were analyzed, all from the upper body region, with a predominance in elderly women. Histologic aspects included a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocyte-like, plasmacytoid or monocytoid appearance. Surface expression of CD5, CD10, and CD23 was negative. Long survival was noted but relapses in the skin, nodes, orbit, salivary glands, and breast were observed.

CONCLUSION: MZL is the predominant primary cutaneous lymphoma of our study. It has distinctive histologic and clinical features as well as outcome.


A cutaneous multilobated B-cell lymphoma.

de la Torre C, Rodriguez T, Cruces MJ, Alvarez A, Yebra MT.

Service of Dermatology, Hospital Provincial Pontevedra, Hospital Juan Canalejo Coruna, Spain.

J Am Acad Dermatol 1993 Aug;29(2 Pt 2):359-62 Abstract quote

A patient with multilobated B-cell malignant lymphoma with lesions limited to the skin is described.

The light, electron microscopic, and immunohistochemical features of this unusual morphologic variant of non-Hodgkin's lymphoma are described. The nosologic position of this histologic subtype is discussed.

The clinical course, with lesions confined to the skin, and the response to treatment suggest a favorable prognosis.


Cutaneous B-Cell Lymphoma With Signet Ring-Cell Morphology A Clinicopathologic and Immunohistochemical Study of Three Cases

Cesar A. Moran, M.D.; Saul Suster, M.D.; Susan L. Abbondanzo, M.D.

From the Department of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, Alabama (C.A.M.); Department of Anatomic Pathology, Ohio State University, Columbus, Ohio (S.S.); and Department of Hematopathology, Armed Forces Institute of Pathology, Washington, District of Columbia (S.L.A.).

Am J Dermatopathol 2001;23:181-184 Abstract quote

Three cases of primary cutaneous B-cell lymphoma with prominent signet ring–cell features are presented. The patients were three men between the ages of 37 years and 74 years (average, 55.5 years).

Clinically, the three patients presented with multiple skin nodules. In one patient, the nodules had been present for approximately 5 weeks, although in the two other patients, the nodules were of unknown duration. The lesions were located in the upper extremities (forearm) and measured from 2 cm to 3 cm in diameter. No evidence of lymphadenopathy was observed in any of the patients. Surgical excision of the nodules was performed.

Histologically, in two cases, the superficial and deep dermis was replaced by a diffuse cellular proliferation, and in one patient, the tumor cell population adopted a nodular pattern of growth involving adnexal structures and infiltrating the subcutaneous fat. In all cases, the tumors were composed of cells showing signet ring–cell features, with striking indentation of the nuclei toward the periphery of the cell. Immunohistochemical studies using antibodies for B-cell and T-cell markers (L-26 and UCHL) as well as antibodies for leukocyte common antigen, keratin, and kappa and lambda light chains were performed in all cases. The tumor cells showed a positive reaction for leukocyte common antigen, L-26, and lambda light chain restriction. Follow-up information was only available in one patient, who has remained alive and well 2 years after diagnosis without evidence of progression of the disease.

The present cases highlight the importance of recognizing this unusual morphologic type of lymphoma so as to arrive at a correct diagnosis.


Giant Primary Cutaneous Spindle Cell B-Cell Lymphoma of Follicle Center Cell Origin.

Wang L, Lv Y, Wang X, Wei K, Zhang Y.

From the *Department of Dermatology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China; and daggerDepartment of Dermatology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

Am J Dermatopathol. 2010 Jun 17. [Epub ahead of print] Abstract quote

Spindle cell B-cell lymphoma is a rare morphologic variant of B-cell lymphoma that is generally associated with follicle center cell origin. It is typically found on the skin and presents as single nodule or plaque with a diameter of several centimeters. It is also characterized by abnormal spindle cells with elongated or spindle-shaped nuclei, and usually stained positive for Bcl-6 and negative for multiple myeloma oncogene 1 (MUM-1).

In this report, we describe a giant primary cutaneous spindle cell B-cell lymphoma measured 20 cm x 25 cm, substantially larger than all the previously reported cases.

Histologic examination revealed that the neoplasm was mainly located in the dermis and subcutaneous fat, and had infiltrated into striated muscles of the patient's back. The neoplasm cells contained elongated or spindle-shaped nuclei. Immunohistochemistry results demonstrated that the neoplasm cells were stained positive for CD20, CD79, and Bcl-6, negative for Bcl-2 and MUM-1, and focally positive for CD5, CD10, CD31, and CD43.

These results collectively indicated that the neoplasm was of follicle center cell origin. The neoplasm was excised and the patient was still alive without systemic involvement after 4 years of follow-up.

Cutaneous Sarcomatoid B-Cell Lymphoma.

From the *Department of Pathology, Memorial Medical Center of Long Beach, Long Beach, CA; daggerDermatopathology Laboratory, University of California Irvine Medical Center, Orange, CA; double daggerDermapathology Section, University of California, San Francisco, San Francisco, CA; and section signDepartments of Pathology and Dermatology, University of California at San Francisco, San Francisco, CA.


Am J Dermatopathol. 2007 Feb;29(1):96-98. Abstract quote

A rare case of a spindle cell (sarcomatoid) B-cell lymphoma is described. The patient, a 48-year-old male, presented with a several month history of an enlarging lesion on the scalp.

Although there have been a few recent reports of cutaneous sarcomatoid lymphomas, this case is especially unusual because it presented as a scarlike plaque rather than a tumor and microscopically exhibited a prominent myxoid matrix. Given these features, the lesion was initially interpreted as an atypical fibromucinosis.

The differential diagnosis included fibromucinous lesion consistent with variant of lichen myxedematosus, spindle cell carcinoma, spindle cell melanoma, atypical fibroxanthoma, and atypical smooth muscle tumors. Initial immunoperoxidase studies demonstrated negative staining for CD68, factor XIIIa, CD57, cytokeratin(AE1/AE3), S100, EMA, and vimentin, essentially ruling out the previously mentioned neoplasms. Subsequently, strong positive staining for LCA(CD45RB) and CD20 was demonstrated characteristic of a B-cell lymphoma. The patient underwent local radiotherapy with complete resolution.

Although all variants of cutaneous sarcomatoid B-cell lymphomas are rare, it is imperative to consider them in the differential diagnosis of otherwise difficult to categorize spindle cell proliferations. This includes neoplasms and, based on the current case, fibromucinoses as well.

Cutaneous spindle-cell B-cell lymphoma: a morphologic variant of cutaneous large B-cell lymphoma.

Cerroni L, El-Shabrawi-Caelen L, Fink-Puches R, LeBoit PE, Kerl H.

Department of Dermatology, University of Graz, Austria.

Am J Dermatopathol 2000 Aug;22(4):299-304 Abstract quote

The morphologic spectrum of large B-cell lymphoma is broad. Several unusual variants have been described such as lymphoma with myxoid stroma, sclerosing B-cell lymphoma, signet ring-cell lymphoma, and multilobated B-cell lymphoma among others.

We report on five cases of cutaneous large B-cell lymphoma in which the neoplastic cells were spindle-shaped. In two cases, the clinical features fulfilled those of a primary cutaneous lymphoma; in the three other cases, the lymphoma most likely arose primarily in the skin, but incomplete clinical workups precluded definite categorization. The patients ranged in age from 30 to 89 years and presented with solitary lesions on the trunk or head. Histopathologic examination revealed nodular or dense diffuse infiltrates involving the entire dermis as well as the subcutaneous fat in some cases. Thickened collagen bundles between the spindled cells were present in one case. Cytomorphologic analysis showed the presence of round or oval medium-sized and large-sized lymphocytes with features of centrocytes and centroblasts in some foci, with others dominated by cells with spindle-shaped, elongated, twisted nuclei with dispersed chromatin and scant cytoplasm. Immunohistologic analysis revealed that both round or oval and spindled cells were positive for CD20 in all cases; in all cases tested, these cells were also positive for MIB-1 and were negative for CD3, CD5, CD43, CD45RO, CD21, CD30, CD68, S-100, HMB-45, actin, smooth-muscle actin, and cytokeratin. Bcl-2 was expressed in one of three cases tested. Analysis of the rearrangement of the J(H) gene by polymerase chain reaction performed in one case showed a monoclonal pattern.

Spindle-cell large B-cell lymphoma represents a distinctive rare subtype of the cutaneous large B-cell lymphoma and can arise primarily in the skin in some cases. Recognition of this variant is necessary to avoid misdiagnosis of other cutaneous malignant spindle-cell tumors.


Special stains  

Reduced Number of CD1a+ Cells in Cutaneous B-Cell Lymphoma

Matthias Schmuth, MD, Alexis Sidoroff, MD, Barbara Danner, Gerda Topar, MD, and Norbert T. Sepp, MD

Am J Clin Pathol 2001;116:72-78 Abstract quote

Cutaneous B-cell lymphoma is difficult to distinguish from pseudolymphoma. The histologic pattern and monoclonal restriction (immunohisto-chemical analysis and molecular biology) are the criteria used for differentiating these entities. CD1a+ dendritic cells have been observed in the infiltrates of T-cell lymphoma, but the presence of these CD1a+ cells has not been compared in B-cell lymphoma and pseudolymphoma.

We studied the presence of CD1a+ cells on frozen sections of 23 B-cell lymphomas, 13 pseudolymphomas, and 17 T-cell lymphomas by immunohistochemical analysis.

We found abundant CD1a+ dendritic cells in only 1 (4%) of 23 B-cell lymphomas, whereas in 8 (62%) of 13 pseudo-lymphomas and 17 (100%) of 17 T-cell lymphomas, strong CD1a staining was present.

Our study demonstrates a distinct pattern of CD1a staining in the infiltrates of B-cell lymphoma and pseudolymphoma that may be of value in the differential diagnosis of these skin disorders.

Tumor-infiltrating T cells in primary cutaneous B-cell lympho-proliferative disorders

Jivko Kamarashev, Leo Schaerer, Günter Burg, Monika Hess Schmid, Beatrix Müller and Werner Kempf

Department of Dermatology, University of Zürich, Zürich, Switzerland

J Cutan Pathol 2001;28 (9), 448-452 Abstract quote

Background: Tumor-infiltrating lymphocytes (TILs) are considered to play an important role in the antitumoral immune response. The presence and percentage of CD8-positive tumor-infiltrating T cells have been shown to correlate with differentiation and prognosis in various neoplasms. The aim of this study was to determine the number of CD8-positive T cells in various primary cutaneous B-cell lymphoproliferative disorders and to evaluate its correlation with the histological type of tumor.

Methods: Fifty-three lesions were examined by immunohistochemistry with antibodies targeting CD3, CD4, CD8 and TIA-1. Thirty-two lesions had been diagnosed as primary cutaneous B-cell lymphomas (CBCL) and 21 as B-cell pseudolymphomas (B-PSL). CBCLs included 15 follicular lymphomas (FL), 6 marginal zone lymphomas (MZL), and 11 diffuse large B-cell lymphomas (LCL). The number of CD8-positive cytotoxic T cells was determined by computer-assisted morphometrical microscopy.

Results: No significant difference could be detected in the density of CD8-positive T cells in B-PSL (101/105mm2), FL (110/105mm2), and MZL (122/105mm2). In contrast, the number of CD8-positive cells (55/105mm2) in LCL was significantly lower (p<0.01) compared to B-PSL, FL and MZL.

Conclusions: In summary the number of CD8-positive T cells in B-cell lymphoproliferative disorders differs in regard to tumor type and differentiation with lowest numbers in diffuse large B-cell lymphomas. However, due to an overlap of the number of TILs, this parameter cannot be employed as a diagnostic parameter for individual cases.

Clinicopathologic Reassessment of Primary Cutaneous B-Cell Lymphomas With Immunophenotypic and Molecular Genetic Characterization

Bin Yang, M.D., Ph.D.; Raymond R. Tubbs, D.O.; William Finn, M.D.; Andrew Carlson, M.D.; James Pettay, B.S.; Eric D. Hsi, M.D.

From the Department of Clinical Pathology, The Cleveland Clinic Foundation (B.Y., R.R.T., J.P., E.D.H.); Department of Pathology, University of Michigan (W.F.); and Albany Medical College (A.C.).

Am J Surg Pathol 2000;24:694-702 Abstract quote

Primary cutaneous B-cell lymphomas (PCBLs) may have particular clinicopathologic characteristics distinct from their lymph node-based counterparts. It has been suggested that PCBLs should have a separate classification system.

The aim of this study was to determine whether the Revised European-American Lymphoid Neoplasms (REAL) classification is applicable to PCBL.

Thirty-nine cases of PCBL from 36 patients, consisting of 20 men and 16 women (median age 66 yrs), were included in this study. Paraffin-section immunohistochemistry for CD3, CD5, CD10, CD20, CD43, Bcl-2, Bcl-6, and cyclin D1 was performed in all cases. Immunostaining for immunoglobulin light chains was also performed on cases histologically diagnosed as extranodal marginal zone lymphoma (MZL) and primary cutaneous B-cell lymphoma unclassifiable (PCBLu). Polymerase chain reaction (PCR) analysis of t(14;18) was performed in all cases. Immunoglobulin heavy chain gene rearrangement (VDJ) was tested by PCR on all follicle center lymphoma (FCL), MZL, and PCBLu cases. The 39 cases consisted of 15 (39%) FCLs, 13 (33%) diffuse large B-cell lymphomas (DLCL), 9 (23%) extranodal MZL, and 2 cases of PCBLu.

Anatomically, 59% of PCBLs occurred in the head and neck, of which approximately 57% were FCL. Five of six cases presenting on the lower extremity were DLCL. Follow-up data was available from all 39 patients with a mean of 50.8 months. All but two patients are alive with or without disease at last contact. One patient with DLCL died of lung metastases and the other DLCL patient died of sepsis as a complication of therapy. In all 15 cases of FCL, CD10 and/or Bcl-6 expression supported the follicle center origin of the neoplastic cells. In contrast to previous reports, we found that 53% (8 of 15) of primary cutaneous FCL had either Bcl-2 protein expression or t(14;18).

Our data indicate that many cases of primary cutaneous FCL have Bcl-2 alterations similar to their nodal counterpart. We found that 95% (37 of 39) of PCBLs could be classified according to the REAL classification, supporting its applicability in cutaneous lymphomas.

The absence of CD20 messenger RNA in recurrent cutaneous B-cell lymphoma following rituximab therapy.

Rawal YB, Nuovo GJ, Frambach GE, Porcu P, Baiocchi RA, Magro CM.

Department of Oral and Maxillofacial Pathology, The Ohio State University, Athens, OH, USA.

J Cutan Pathol. 2005 Oct;32(9):616-21. Abstract quote  

Background: Rituximab has been used to treat relapsed low-grade or advanced non-Hodgkin's lymphoma since 1997, targeting the CD20 antigen expressed by B cells. Single-agent rituximab therapy is safe and well tolerated. Recurrences showing a loss of CD20 expression following rituximab therapy have been reported.

Methods: Four patients with CD20-positive cutaneous B-cell lymphoma received rituximab therapy with subsequent recurrences. The biopsies were assessed for cytoplasmic CD20 expression; CD20 messenger RNA was also assessed where tissue was available.

Results: Cutaneous relapses occurring within 1.5-3 months following the last dose of rituximab were CD20 negative. In three cases, subsequent relapses showed renewed expression of CD20. Those biopsies demonstrating a loss of surface and cytoplasmic CD20 by immunohistochemistry also showed no evidence of messenger RNA for CD20 using an in situ polymerase chain reaction-based methodology.

Conclusions: Rituximab may be associated with the emergence of CD20-negative B-cell clones, potentially rendering a tumor insensitive to this drug. Conversely, following cessation of the drug, a re-expression of CD20 within the neoplastic cells may occur allowing therapeutic intervention with this monoclonal antibody. The loss of CD20 expression appears to be a direct effect of the drug on CD20 messenger RNA synthesis.
The expression of CD23 and CD40 in primary cutaneous B-cell lymphomas.

Department of Pathology, Weill Medical College of Medicine, NY, USA.


J Cutan Pathol. 2007 Jun;34(6):461-6. Abstract quote

Background: CD23 expression in normal B lymphocytes is limited to autoreactive B cells, naïve B cells and mature B cells manifesting an activated phenotype. As a marker of hematologic dyscrasia/malignancy, expression of CD23 is associated with small lymphocytic lymphoma/chronic lymphocytic leukemia. An absence of CD23 expression within small lymphocytes is typically seen in marginal zone lymphoma and mantle cell lymphoma. Positive CD23 expression amidst neoplastic cells in primary cutaneous B-cell lymphoma is not a reported phenomenon.

Methods: This paper reports nine patients with cutaneous B-cell lymphoma manifesting CD23 expression.

Results: In seven of the nine cases CD23 expression was observed in the setting of recurrent disease, being present in both large and small lymphocytes. CD23 expression paralleled staining for CD40 in all but one case.

Conclusions: A potential mechanism of CD23 upregulation may involve the anti-apoptotic nuclear kappa beta CD40-CD40 ligand pathway. Neoplastic B cells manifesting CD23 expression could have a survival advantage, predisposing to recurrent disease and or oncogenic events permissive to disease progression.



Borrelia burgdorferi-associated lymphocytoma cutis simulating a primary cutaneous large B-cell lymphoma.

Grange F, Wechsler J, Guillaume JC, Tortel J, Tortel MC, Audhuy B, Jaulhac B, Cerroni L.

Department of Dermatology, Hopital Pasteur, Colmar, France.

J Am Acad Dermatol 2002 Oct;47(4):530-4 Abstract quote

The distinction between primary cutaneous B-cell lymphoma and B-cell pseudolymphoma on a histologic basis may be difficult, particularly in some cases of Borrelia burgdorferi-associated lymphoid proliferations.

We report two cases of B. burgdorferi-associated pseudolymphoma that showed a dense infiltrate with a predominance of large atypical B cells. Because of this misleading histologic feature, a diagnosis of primary cutaneous large B-cell lymphoma was first suspected in both cases. In one case, successive recurrences led to aggressive therapies before the B. burgdorferi infection was recognized. However, a detailed review of histologic and immunohistochemical features was finally suggestive of a B. burgdorferi-associated pseudolymphoma in both cases. The etiologic role of B. burgdorferi was confirmed by serology, polymerase chain reaction analysis of B. burgdorferi DNA within the lesional skin, and response to antibiotic therapy.

Because the distinction between B. burgdorferi-associated pseudolymphoma and primary cutaneous B-cell lymphomas may be difficult and true B. burgdorferi-associated B-cell lymphomas have been described, we suggest that antibiotic therapy should be considered as a first-line treatment in suspected or confirmed cases of primary cutaneous B-cell lymphoma in regions with endemic B. burgdorferi infection.


Primary Cutaneous Large B-Cell Lymphoma The Relation Between Morphology, Clinical Presentation, Immunohistochemical Markers, and Survival

Am J Surg Pathol 2001;25:307-315

Series of 32 cases of LBCL found in the skin

We reviewed the clinical findings and paraffin sections of the tumors from these 32 patients. The immunohistochemical study performed included p53, MIB1, Bcl2, Bcl6, and CD10 markers. We carried out statistical analysis of these data (univariate and multivariate), seeking an association between the features of the tumors and clinical outcome, as defined by failure-free survival time. Only one patient died as a consequence of the lymphoma. Nevertheless, the accumulated probability of survival without failure at 48 months was 0.46. The number, type, and localization of the lesions were not associated with variations in either survival or failure-free survival. The expression of p53 was negative in this group of CLBCL, whereas Bcl-2 expression or localization in the lower leg did not relate to any other significant feature. Histologic examination of the cases disclosed three different groups: Grade III follicular lymphomas (FLs), monomorphous large B-cell lymphomas (LBCL type I), and LBCL with an admixed component of small B-lymphocytes (LBCL type II). Grade III FL (11 cases) tended to be found in the head and neck and showed CD10 expression in a majority of cases. A higher probability of lymph node relapses was associated with cases located in the head and neck and with CD10+ tumors.

Cutaneous large B-cell lymphomas are indolent tumors, but follow an insidious course. Our data support the interpretation that CLBCL is a heterogeneous condition; comprises some LBCL derived from CD10+ germinal center cells which manifests more frequently as tumors in the head and neck region, with an increased probability of relapse in lymph nodes and has some distinctive morphologic features. The existence of a component of small B-cells within the other CLBCL could lend support to the theory that some of these tumors, more than arise de novo, may have originated in preexistent small B-cell lymphomas, but no firm evidence of this is provided in this study.


Frequency of central nervous system involvement in primary cutaneous B-cell lymphoma.

Bekkenk MW, Postma TJ, Meijer CJ, Willemze R.

Department of Dermatology of the Free University Hospital, Amsterdam, The Netherlands.

Cancer 2000 Aug 15;89(4):913-9 Abstract quote

BACKGROUND: Primary cutaneous B-cell lymphoma (CBCL) constitutes approximately 20% of all primary cutaneous lymphomas. Apart from primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL-leg), primary CBCLs run an indolent clinical course, rarely disseminate to extracutaneous sites, and have an excellent prognosis. Because of recent observations in two patients who developed central nervous system (CNS) involvement, follow-up data of all primary CBCL patients registered at the Dutch Cutaneous Lymphoma Group between 1985 and 1998 were investigated for evidence of CNS involvement.

METHODS: Follow-up data from 160 primary CBCLs were evaluated. This group included 122 primary cutaneous follicle center cell lymphomas (PCFCCLs), 16 primary cutaneous immunocytomas or marginal zone B-cell lymphomas, and 22 PCLBCL-leg. RESULTS: Of all 160 patients with primary CBCLs, 11 died of lymphoma, including 4 of 122 patients (3%) with PCFCCL and 7 of 22 patients (32%) with PCLBCL-leg. Four of these 11 patients, including 3 with PCFCCL and 1 with PCLBCL-leg, had developed CNS involvement 3-93 months (median, 30 months) after diagnosis. All patients died 1-9 months (median, 7 months) after the development of CNS involvement. In the group of 122 patients with PCFCCL, CNS involvement occurred in 3 of 7 patients (43%) who developed extracutaneous disease and accounted for 3 of 4 lymphoma-related deaths (75%).

CONCLUSIONS: The results of this study indicate that approximately 2% of all primary CBCLs may develop CNS involvement. Whereas, in rare PCFCCL patients, developing extracutaneous disease CNS involvement was an important cause of death, patients with PCLBCL-leg and secondary CBCL died more frequently due to involvement of non-CNS organ systems.


Primary cutaneous marginal center lymphoma - complete remission induced by interferon alpha2a.

Wollina U, Hahnfeld S, Kosmehl H.

Department of Dermatology, Friedrich-Schiller-University Jena, Germany.

J Cancer Res Clin Oncol 1999;125(5):305-8 Abstract quote

We report on a 53-year-old woman who developed disseminated primary cutaneous MZL with secondary lymph node involvement and perinodular spreading.

The tumor cell phenotype was characterized as CD20/CD79a/kappa/lambda+/ bcl-2-positive, CD3/5/15/39/bcl-1-negative. Ki-67 was expressed by 20-35% of tumor cells. There was no evidence of systemic (including bone marrow) involvement. The diagnosis of MZL with plasmacellular differentiation (Stage IVa) was made. The patient was treated with interferon alpha2a injected s.c. at 9x10(6) U 3 days a week for 1 year. During this time the skin lesions completely disappeared. No evidence of lymph node or extracutaneous disease was found. The patient remains in complete remission. Side effects were only of grade I (WHO); the Karnovsky index was 90%.

As shown for other types of primary cutaneous B-cell lymphoma, prolonged interferon alpha monotherapy may be effective in controlling the disease and/or inducing complete remission in MZL.

Results of radiotherapy in 153 primary cutaneous B-Cell lymphomas classified according to the WHO-EORTC classification.

Department of Dermatology, B1-Q, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.

Arch Dermatol. 2007 Dec;143(12):1520-6 Abstract quote

OBJECTIVE: To evaluate the results of radiotherapy in patients with primary cutaneous B-cell lymphoma (CBCL) classified according to the criteria of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification.

DESIGN: Multicenter, 20-year, retrospective, cohort analysis.

SETTING: Eight dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group.

PATIENTS: From 1985 until 2005, a total of 153 patients with CBCL were initially treated with radiotherapy with curative intent. These cases were classified according to the WHO-EORTC classification and consisted of 25 primary cutaneous marginal zone lymphomas (PCMZLs), 101 primary cutaneous follicle center lymphomas (PCFCLs), and 27 primary cutaneous large B-cell lymphomas, leg type (PCLBCLs, LT). Interventions Local radiotherapy with a median dose of 40 Gy (range, 20-46 Gy) applied to all visible skin lesions.

MAIN OUTCOME MEASURES: Complete remission rate, relapse rate, 5-year relapse-free survival, 5-year overall survival, and 5-year disease-specific survival. RESULTS: Complete remission was reached in 151 of 153 patients (99%). Relapse rates for PCMZL, PCFCL, and PCLBCL, LT were 60%, 29%, and 64%, and the 5-year disease-specific survival was 95%, 97%, and 59%, respectively. The PCFCLs presenting on the legs had a higher relapse rate (63%) and a much lower 5-year disease-specific survival (44%) than PCFCLs at other sites (relapse rate, 25%; 5-year disease-specific survival, 99%).

CONCLUSIONS: Radiotherapy is a suitable treatment for a large group of patients with CBCL. However, patients with PCFCL presenting with lesions on the leg and patients with PCLBCL, LT display a more unfavorable clinical course and should therefore be treated with more aggressive treatment modalities.
Treatment of primary cutaneous B-cell lymphoma with rituximab.

Fink-Puches R, Wolf IH, Zalaudek I, Kerl H, Cerroni L.

Department of Dermatology, Medical University of Graz, Graz, Austria.

J Am Acad Dermatol. 2005 May;52(5):847-53. Abstract quote  

BACKGROUND: Rituximab is a genetically engineered antibody directed against the CD20 antigen. Intravenous administration of rituximab has been used for the treatment of patients with low-, intermediate-, and high-grade B-cell non-Hodgkin's lymphomas and is a registered treatment modality for this indication. Treatment of primary cutaneous B-cell lymphoma (CBCL) with intralesionally or systemically administered rituximab has been described only in a few cases.

OBJECTIVE: Our purpose was to assess the efficacy of rituximab in the treatment of CBCL.

METHODS: We performed a retrospective study on 9 patients with CBCL who were treated with intralesional or systemic administration of rituximab.

RESULTS: Two patients treated with systemic rituximab achieved complete remission. Complete remission could be observed in 6 of 7 patients after 1 to 8 cycles of intralesional treatment with rituximab. In one patient one of two lesions showed a partial remission after 4 cycles of treatment, whereas the second showed complete remission. A local recurrence was observed in one patient after 27 months of follow-up and in two patients recurrences developed at other body sites after 12 and 14 months of follow-up. No severe side effect occurred except for slight pain during intralesional injection.

CONCLUSION: Rituximab therapy is a well-tolerated and effective treatment for primary CBCL. In comparison to intravenous administration, intralesional application of the drug allows the use of lower dosages. Intralesional therapy with rituximab deserves further investigation and comparison to systemic administration of the drug in controlled multicenter studies.

Systemic therapy with cyclophosphamide and anti-CD20 antibody (rituximab) in relapsed primary cutaneous B-cell lymphoma: a report of 7 cases.

Fierro MT, Savoia P, Quaglino P, Novelli M, Barberis M, Bernengo MG.

Department of Medical and Surgical Specialties, First Section of Dermatology, University of Turin, Torino, Italy.


J Am Acad Dermatol. 2003 Aug;49(2):281-7. Abstract quote

BACKGROUND: Rituximab, a chimeric antibody directed against CD20, has a high therapeutic value in refractory/relapsed low-grade or follicular B-cell non-Hodgkin's lymphomas as a monotherapy or in combination with polychemotherapy.

OBJECTIVES: We sought to evaluate the clinical activity and toxicity of a schedule foreseeing the use of intravenous rituximab preceded by single-dose cyclophosphamide in the treatment of patients with primary cutaneous B-cell lymphoma who progressed and relapsed after chemotherapy.

METHODS: A total of 7 patients were treated; 4 had both cutaneous lesions and nodal or visceral involvement. All the patients had been previously treated with at least 1 standard chemotherapy regimen, and 4 with 2 or more, with a median response duration of 8 months. Immunohistochemistry on frozen sections was performed with monoclonal antibodies directed against CD20, CD55, and CD59 before rituximab treatment.

RESULTS: The overall objective response rate was 85.7%, with a complete response in 5 patients; treatment was well tolerated in all cases. After a median follow-up of 13 months, 2 patients showed a cutaneous relapse. The response durations of the remaining patients who were disease-free are now 5, 7, 17, and 18 months. No relationship was found between CD55 and CD59 expression and the clinical outcome.

CONCLUSION: Although a longer follow-up period is needed to confirm these data, our results are encouraging, particularly in terms of disease-free survival.

Cutaneous B-cell lymphoma with loss of CD20 immunoreactivity after rituximab therapy.

Clarke LE, Bayerl MG, Ehmann WC, Helm KF.

Department of Pathology, Department of Medicine, and Department of Dermatology, The Pennsylvania State University College of Medicine/Hershey Medical Center, Hershey, PA, USA.

J Cutan Pathol. 2003 Aug;30(7):459-62. Abstract quote

BACKGROUND: Antibodies to the B-cell-specific antigen CD20 are widely used for immunohistochemical identification of B-cell lymphomas, approximately 95% of which are strongly CD20-positive.

METHODS: We report a 51-year-old male with a CD20-positive systemic B-cell lymphoma who developed a CD20-negative relapse with secondary cutaneous involvement after therapy with the anti-CD20 monoclonal antibody rituximab (Rituxan).

RESULTS: Biopsy of a skin nodule demonstrated an atypical lymphocytic infiltrate that was negative for CD20, CD3, lysozyme, and myeloperoxidase, but strongly positive for CD45rb (LCA) and the B-cell marker CD79a.

CONCLUSIONS: We conclude that loss of CD20 expression in cutaneous B-cell lymphoma (both primary and secondary) is important to recognize, that immunohistochemistry for CD79a, another widely expressed B-cell marker, is useful in the identification of CD20-negative B cells in such cases, and that loss of CD20 expression may become more common, as use of rituximab is expected to increase.

CD20-negative relapse of cutaneous B-cell lymphoma after anti-CD20 monoclonal antibody therapy

William Trent Massengale, MD
Elizabeth McBurney, MD
Jayne Gurtler, MD

New Orleans, Louisiana
J Am Acad Dermatol 2002;46:441-3 Abstract quote

Despite cutaneous B-cell lymphoma often having a relatively indolent course and low mortality, it is often resistant to conventional therapy and frequently relapses.

We describe a patient with widespread cutaneous B-cell lymphoma who was treated successfully with a recently approved chimeric monoclonal antibody directed against the CD20 antigen (rituximab) and the CD20-negative relapse that resulted.

Intralesional therapy with anti-CD20 monoclonal antibody rituximab in primary cutaneous B-cell lymphoma.

Heinzerling L, Dummer R, Kempf W, Schmid MH, Burg G.

Department of Dermatology, University Hospital Zurich, Switzerland.

Arch Dermatol 2000 Mar;136(3):374-8 Abstract quote

BACKGROUND: We report the use of a new treatment modality in 2 patients with primary cutaneous B-cell lymphoma. In a 58-year-old woman with progressive nodular lesions on the scalp and face, several treatment attempts either failed or could not be used because of severe adverse effects and underlying epilepsy. The patient declined radiotherapy. A 30-year-old man presented with recurrence of tumor nodules occipitally, thoracically, on the arm, and on the right thigh after several excisions.

OBSERVATIONS: Intralesional injection of rituximab, a chimeric antibody directed against the CD20 transmembrane antigen present in malignant and normal B cells, resulted in partial regression of tumor nodules. No adverse effects occurred except pain during or shortly after injection and, in one patient, a slight rise in body temperature. Due to the treatment a prolonged complete disappearance of B cells from peripheral blood samples was observed.

CONCLUSION: Intralesional rituximab therapy is a nontoxic and effective treatment for cutaneous B-cell lymphoma that deserves further investigation in larger clinical trials.

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