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This is a category of skin lymphomas comprised of B cells. These lymphomas typically present with nodules, tumors, or infiltrative plaques and may occur in many areas including the head and neck, trunk, and back. The tumors have an indolent course but progress with time. The 5 year survival rate is >90%.

Under the microscope, these tumors share histologic similarity to follicular center cell (FCC) lymphomas arising within the lymph nodes. These lymphomas are present as nodular and diffuse infiltrates that usually spare the overlying epidermis, separated by a thin Grenz zone. Some pathologists have divided this lymphoma into two types, based upon the cellular morphology, a large cell type and a round cell type. The large cell type contains large cleaved cells while the round cell type has noncleaved cells. Immunohistochemistry reveals positive staining for surface or cytoplasmic Ig and positive staining for CD19, CD20, CD22, and CD79 alpha. The cells are usually bcl-2 negative, unlike follicular center cell lymphomas of the lymph node.


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t(14;18) AND bcl-2  
Molecular Cytogenetic Evidence of t(14;18)(IGH;BCL2) in a Substantial Proportion of Primary Cutaneous Follicle Center Lymphomas.

Streubel B, Scheucher B, Valencak J, Huber D, Petzelbauer P, Trautinger F, Weihsengruber F, Mannhalter C, Cerroni L, Chott A.

*Departments of Pathology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria daggerDermatology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria section signMedical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna General Hospital, Vienna, Austria double daggerDepartment of Dermatology, Krankenhaus Rudolfstiftung, Vienna, Austria parallelDepartment of Dermatology, Medical University of Graz, Graz, Austria.

Am J Surg Pathol. 2006 Apr;30(4):529-536. Abstract quote  

In contrast to nodal follicular lymphoma, limited data exist on genetic changes in primary cutaneous follicular lymphoma (primary cutaneous follicle center lymphoma according to WHO-EORTC). The detection rate of the BCL2 rearrangement, representing the characteristic t(14;18)(q32;q21) underlying follicular lymphoma, by polymerase chain reaction (PCR) has been reported to vary over a wide range (0%-41%), and only a few cases have been studied by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH).

In this study, 27 primary cutaneous follicle center lymphomas were analyzed by FISH and the results compared with those obtained by PCR. FISH demonstrated translocations affecting the immunoglobulin heavy chain locus (IGH) in 14 of 27 cases (52%): a t(14;18)(q32;q21) involving BCL2 was found in 11 cases (41%), a t(3;14)(q27;q32) affecting BCL6 in 2 cases (7%), and in 1 case the partner gene of IGH could not be identified. Interestingly, PCR did not detect BCL2 rearrangement in any case.

These data suggest that the t(14;18)(q32;q21) frequently occurs in primary cutaneous follicular lymphoma. The reason(s) why BCL2 rearrangements escape the detection by PCR is (are) not clear but could be due to BCL2 mutations, breakpoints outside the amplified DNA, or a high load of somatic mutations.
Neoplastic cells do not carry bcl2-JH rearrangements detected in a subset of primary cutaneous follicle center B-cell lymphomas.

Vergier B, Belaud-Rotureau MA, Benassy MN, Beylot-Barry M, Dubus P, Delaunay M, Garroste JC, Taine L, Merlio JP.

Equipe Histologie et Pathologie Moleculaire, Universite Victor Segalen, Bordeaux, France
Am J Surg Pathol. 2004 Jun;28(6):748-55. Abstract quote  

Whether primary cutaneous follicular lymphoma (PCFL) may or not represent a cutaneous equivalent to nodal follicular lymphoma (FL) is not determined.

We have therefore investigated a series of PCFL to determine if tumoral cells carry or not the t(14;18)(q32;q21) translocation, a cytogenetic hallmark of nodal FL. Thirty cases of PFCL were selected according to the criteria of both the European Organisation for Research and Treatment of Cancer and the World Health Organization with 21 cases classified as grade 1 or 2 and 9 cases as grade 3.

First, cutaneous tumors were studied by PCR for the amplification of bcl-2/JH rearrangements and by interphase fluorescence in situ hybridization using a dual color probe spanning t(14;18) breakpoints. Second, we tried to determine the origin of bcl2-JH-positive cells by a parallel bcl2-JH and immunoglobulin heavy chain gene amplification of blood mononuclear cells DNA and of DNA extracted from single microdissected B cells. Bcl2-JH rearrangements were amplified by PCR in skin of 9 of 30 (30%) patients with a similar-sized bcl2-JH rearrangement detected in the blood of 7 of these 9 cases. No t(14;18) breakpoint was detected by interphase fluorescence in situ hybridization analysis of 11 bcl2-JH-negative and 5 bcl2-JH-positive PCFL in contrast with its detection in the secondary cutaneous FL and in the nodal FL cases. Single-cell/multigene analysis showed that no single monoclonal B cells of PCFL carried the bcl2-JH rearrangement. Bystander or nontumoral t(14;18)+ B cells emigrating from blood may account for the detection of bcl2-JH rearrangements within PCFL material.

Our study also underlines the diagnostic value of interphase fluorescence in situ hybridization to discriminate between t(14;18)-negative PCFL and extracutaneous FL involving the skin.
The t(14;18) and bcl-2 Expression Are Present in a Subset of Primary Cutaneous Follicular Lymphoma
Association With Lower Grade

Lyle C. Lawnicki, MD, Dennis D. Weisenburger, MD, Patricia Aoun, MD, Wing C. Chan, MD, Robert S. Wickert, MS, and Timothy C. Greiner, MD

Am J Clin Pathol 2002;118:765-772 Abstract quote

According to the European Organization for Research and Treatment of Cancer classification, primary cutaneous follicle center cell lymphoma is not associated with the t(14;18)(q32;q21) and only rarely expresses bcl-2 protein.

To further investigate this issue, we evaluated a series of 20 patients (14 men, 6 women) with primary cutaneous follicular lymphoma (PCFL). The presenting skin lesion was located in the head and neck region in 16 of 20 patients. Most cases were grade 2 (6/20) or grade 3 (13/20), and all had a follicular architecture.

Immunohistochemical analysis demonstrated bcl-2 expression in 8 cases (40%), and expression was inversely related to the grade. Of 7 grade 1 or 2 cases, 5 (71%) were positive, whereas only 3 (23%) of 13 grade 3 cases were positive for bcl-2. Clonal immunoglobulin heavy chain gene rearrangements were detected in 9 (45%) of 20 cases. In 4 (20%) of 20 cases, we identified the major breakpoint of the t(14;18) by polymerase chain reaction, 3 of which were grade 1 or 2.

We conclude that bcl-2 protein expression and the t(14;18) are present in a subset of PCFL, particularly in lower grade cases.



Clinicopathologic, Immunophenotypic, and Molecular Characterization of Primary Cutaneous Follicular B-Cell Lymphoma

Reuven Bergman, etal.

Arch Dermatol. 2001;137:432-439 Abstract quote

To determine the clinicopathologic, immunophenotypic, and molecular characteristics of primary follicular cutaneous B-cell lymphoma (CBCL) as defined by the revised European-American lymphoma classification.

A retrospective survey of the medical records, an immunohistochemical study of archival biopsy specimens. and molecular studies of preserved DNA of all patients with follicle center lymphoma-follicular (FCL-F) primary CBCL from 1987 to 1997.

A single-center outpatient specialty clinic at an academic medical center.

Twenty-one patients (68% of all new primary CBCL cases), including 14 men and 7 women (age range, 33-88 years; mean, 55 years).

The head and neck region was the most frequent primary site. Following treatment, recurrences were relatively frequent, but the overall mortality rate during 1.0 to 11.3 years (mean, 6.3 years) of follow-up was 4.8%. Immunohistochemical analysis for B- and T-cell lineages was helpful in enhancing the folliclelike structures. CD10, bcl-2, and CD43 were expressed by the neoplastic cells in 9 (47%) of 19 cases, 4 (21%) of 19 cases, and 2 (13%) of 16 cases, respectively. Immunohistochemical detection of cytoplasmic immunoglobulin light chains, using steaming in EDTA as the antigen-retrieval technique, was successful in 12 (71%) of 17 cases. The Ig heavy-chain gene rearrangements, using the Southern blot technique, detected clonality in 17 (94%) of 18 cases. The bcl-2 gene rearrangements were detected in only 2 (13%) of 15 of the primary cutaneous FCL-F cases, compared with 9 (75%) of 12 of the primary nodal FCL-F cases (P = .002).

Primary cutaneous FCL-F is a relatively common subtype of CBCL, with a relatively indolent course. It has many features in common with primary nodal FCL-F, except for low rates of bcl-2 expression and bcl-2 gene rearrangements.

Cutaneous Follicular B-Cell Lymphoma Description of a Series of 18 Cases

Renato Franco, M.D.; Amalia Fernandez-Vazquez, M.D.; José Luis Rodriguez-Peralto, M.D.; Carmen Bellas, M.D.; Fernando López-Ríos, M.D.; Anabel Sáez, M.D.; Raquel Villuendas, Ph.D.; Mercedes Navarrete, B.Sci.; Isabel Fernandez, B.Sci.; Carlos Zarco, M.D.; Miguel A. Piris, M.D.

From the Molecular Pathology Program of the Centro Nacional de Investigaciones Oncologicas-Carlos III (R.F., A.F.-V., A.S., R.V., M.N., I.F., M.A.P.); the Departments of Pathology (J.L.R.P., F.L.-R.) and Dermatology (C.Z.), 12 Octubre Hospital; the Department of Pathology, Ramon y Cajal Hospital (C.B.), Madrid, Spain; and the Department of Pathology, Federico II University, Naples, Italy.

Am J Surg Pathol 2001;25:875-883 Abstract quote

The lack of precise and homogeneous criteria for the recognition of primary cutaneous follicular lymphoma has hindered gaining data on the frequency and clinical and molecular features of this entity. In the course of a review of a series of primary cutaneous lymphoma from different Spanish hospitals, we collected a series of 18 cases of primary cutaneous follicular lymphoma and analyzed its clinical, morphologic, and biologic characteristics.

In this review only cases with a follicular pattern of growth, germinal center cytology, and restriction to the skin in a minimum follow-up of 6 months have been included. Cases of primary cutaneous follicular lymphoma were characterized by the expression of classic markers of the germinal center, such as bcl6, CD10, and the presence of aggregates of follicular dendritic cells. They frequently express bcl2 protein, although classical t(14;18) was not found in any of the cases analyzed. Analysis of the bcl6 noncodifying first exon showed somatic mutations in two of four cases analyzed, as would be expected in lymphoma deriving from the germinal center. Clinically, most cases showed initial involvement of the head and neck, with relapses in eight cases (involving the skin in five cases, both skin and lymph node in two cases, and lymph node in one case). No death attributable to the tumor was recorded.

These data seem to imply that follicular lymphoma may present initially in the skin, lacking the characteristic t(14;18) and having a relatively indolent course. Recognition of these tumors and elucidation of their molecular alterations could lead to properly adapted staging and treatment protocols for these patients.

Cutaneous Follicle Center Cell Lymphoma, Follicular Type

Lorenzo Cerroni, M.D.; Helmut Kerl, M.D.

From the Department of Dermatology, University of Graz, Austria.

Am J Dermatopathol 2001;23:370-373 Abstract quote

This article discusses the clinicopathologic and molecular features of primary cutaneous follicle center cell lymphoma, follicular type. Synthesis of morphologic, immunohistochemical, and molecular studies have clearly characterized this peculiar morphological variant of the cutaneous B-cell lymphomas.

Although local recurrences can be frequently observed, the overall prognosis of these patients is very good and extracutaneous dissemination is very rare.

Primary cutaneous follicular lymphoma: a clinicopathologic and molecular study of 16 cases in support of a distinct entity.

Goodlad JR, Krajewski AS, Batstone PJ, McKay P, White JM, Benton EC, Kavanagh GM, Lucraft HH; Scotland and Newcastle Lymphoma Group.

Department of Pathology, Raigmore Hospital, Inverness, UK.

Am J Surg Pathol 2002 Jun;26(6):733-41 Abstract quote

Primary cutaneous B-cell lymphomas displaying a prominent follicular growth pattern are rare and remain poorly defined, particularly in terms of the frequency of detection of t(14;18) and whether or not, as a group, they represent an entity distinct from follicular lymphoma arising in lymph nodes.

The morphologic, immunophenotypic, and clinical features of 16 cases of primary cutaneous follicular lymphoma, identified during a review of all PCBCL in the Scotland and Newcastle Lymphoma Group database, were studied and the number of cases harboring t(14;18) assessed by polymerase chain reaction using primers to the major breakpoint cluster region. Comparisons were made with stage I follicular lymphoma arising in lymph nodes and follicular lymphoma secondarily involving the skin. All cases of primary cutaneous follicular lymphoma had undergone thorough staging, including physical examination and CT scans of chest and abdomen, with 15 of 16 cases also having bone marrow aspiration and/or trephine performed. The morphology and immunophenotype of the lesions were similar to that expected in lymph nodes.

All cases displayed a follicular architecture complete with follicular dendritic cell networks and comprised an admixture of CD10 and/or bcl-6-positive neoplastic centrocytes and centroblasts with 13 of 16 cases also expressing bcl-2 protein. None harbored t(14;18), a significantly different finding compared with cases of stage I nodal follicular lymphoma (p <0.001) and secondary cutaneous follicular lymphoma (p <0.039).

Relapses occurred in five of 15 patients with a median time to first relapse of 20 months (range 1-73 months; mean 27.2 months). These were multiple in two patients and involved extracutaneous sites in two patients. The propensity for relapse was similar to that in a comparative cohort of stage I nodal follicular lymphoma, but the group of primary cutaneous follicular lymphoma were significantly more likely to attain complete remission; all cases of primary cutaneous follicular lymphoma were in complete remission when last seen compared with 49 of 87 patients with stage I nodal follicular lymphoma (p <0.005). No lymphoma-related deaths were encountered in 15 cases with a mean follow-up >60 months (range 5-119 months).

These results support the concept of a subtype of follicular lymphoma lacking t(14;18) involving the major breakpoint cluster region, and with a propensity to arise in the skin. Despite a high relapse rate patients with primary cutaneous follicular lymphoma are more likely to achieve complete remission and may ultimately have a more favorable long-term prognosis than those with equivalent nodal disease.


Special stains  

Cutaneous B-Cell Lymphomas of Follicular and Marginal Zone Types Use of Bcl-6, CD10, Bcl-2, and CD21 in Differential Diagnosis and Classification

Laurence de Leval, etal.

Am J Surg Pathol 2001;25:732-741 Abstract quote

Cutaneous follicular lymphomas (FLs) and cutaneous B-cell lymphomas of extranodal marginal zone (MZL)/mucosal-associated lymphoid tissue (MALT) type may have morphologic overlap, despite the fact that they are thought to be of distinct derivation (germinal center vs. postgerminal center). The problem is compounded by the reported absence of bcl-2 expression by many cutaneous FLs, leading to speculation that cutaneous FL may be unrelated to nodal FL.

The authors analyzed the expression of the germinal center-associated antigens bcl-6 and CD10 and of bcl-2 in 18 cutaneous B-cell lymphomas (10 FLs and eight MZLs), in relationship to CD21+ follicular structures, to clarify the relationship of nodal to cutaneous FLs and to explore the value of these antigens in differential diagnosis.

The authors studied 10 cutaneous FLs (seven primary and three secondary) and eight MZLs (six primary and two secondary). The FLs (found in six men and four women age 45–75 years) involved the trunk (n = 3) and scalp, face and neck (n = 7). The MZLs (found in five women and three men age 34–81 years) involved the trunk (n = 4), face and neck (n = 2), and arm (n = 2). Immunostaining for CD21, bcl-6, CD10, and bcl-2 allowed the delineation of compartments within the tumors and yielded distinct patterns of staining in FL and MZL.

In both follicular and interfollicular/diffuse areas of FL the neoplastic cells were bcl-6+ (10 of 10), often CD10+ (seven of 10, four of seven primary), and bcl-2+ (nine of 10, six of seven primary). Only three of seven cases (one of five primary) had bcl-2 rearrangement detectable by polymerase chain reaction. In the MZLs, the neoplastic B-cells were bcl-6–, CD10–, and bcl-2+ (eight of eight). Three patterns of CD21+ follicles were identified in MZL: reactive germinal centers, uniformly bcl-6+, CD10+, and bcl-2– (five of eight MZLs); colonized follicles, both bcl-6–, bcl-2+, and L26+ cells, and bcl-6+ and bcl-2– cells (five of eight MZLs); and expanded/colonized follicular dendritic cell meshworks, bcl-6– and bcl-2+ B cells with rare residual bcl-6+ and bcl-2– cells (four of eight MZLs).

The authors conclude that cutaneous FLs express bcl-6 uniformly, usually express CD10 and bcl-2, and have a follicular pattern similar to nodal FL and consistent with a germinal center origin. The immunophenotype of cutaneous FL is distinct from that of cutaneous MZL, which is negative for bcl-6 and CD10. Colonized follicles in MZL, identified by CD21+ follicular dendritic cell meshworks, contained numerous bcl-6– and bcl-2+ B cells, and were readily distinguished from neoplastic follicles in FL. Conversely, CD21– interfollicular and diffuse areas in FLs contained bcl-6+ and CD10+ cells, which were not seen in diffuse areas of MZLs.

Thus, the combination of bcl-2, bcl-6, and CD21 staining is useful for the distinction of cutaneous MZL from cutaneous FL.

Cutaneous Follicle Center Lymphoma: A Clinicopathologic Study of 19 Cases

N.S.I. Aguilera, M.D., M.-M. Tomaszewski, M.D., J.C. Moad, M.D., F.A. Bauer, M.D., J.K. Taubenberger, M.D., PhD. and S.L. Abbondanzo, M.D.

Departments of Hematopathology (NSIASLA), Dermatopathology (MMT, JCM), and Cellular Pathology (JKT), Armed Forces Institute of Pathology, Washington, District of Columbia; and Saint Francis Hospital and Medical Center (FAB), Hartford, Connecticut

Mod Pathol 2001;14:828-835 Abstract quote

Cutaneous follicle center lymphoma (FCL) is reported to have a unique immunophenotype and clinical course as compared with nodal FCL.

We studied 19 cases of FCL of the skin using paraffin embedded tissue.

An immunohistochemistry panel included CD45, CD3, CD20, CD43, CD21, bcl-2, bcl-6, CD5, and CD10. Molecular studies were performed by polymerase chain reaction for immunoglobulin heavy chain (IgH) and t(14;18). Trisomy 3 was performed by fluorescent in situ hybridization (FISH) in 13 cases. Follow up was obtained in 17 cases (range 3 to 137 months). Patients included 10 females and 9 males ranging in age from 33 to 88 years at first presentation (mean, 64). Twelve of 19 presented in the head and neck and 6 in the trunk and 1 on the arm. All had no known lymph node disease at presentation. Seventeen patients had no nodal disease with a minimum 3 month follow-up; 2/19 had unknown lymph node status with no follow-up.

All cases were immunoreactive with CD20 and negative with CD3. Bcl-2 was immunoreactive in 11/18 cases, bcl-6 in 15/15, CD10 in 14/17, CD43 in 2/16 (both were CD10 immunoreactive) and CD5 in 1/15 (it was also bcl-6 immunoreactive). Eight of 18 cases were monoclonal for IgH. Three of 17 showed the presence of t(14;18). FISH was positive in 4 cases for trisomy 3 ranging from 16 to 22% (12% threshold). Follow-up showed no evidence of disease in 14/17 patients (4 to 137 mos). 3/17 patients are alive with disease (17 to 100 mo), and no patients died of disease.



Differential diagnosis of cutaneous infiltrates of B lymphocytes with follicular growth pattern.

Leinweber B, Colli C, Chott A, Kerl H, Cerroni L.

Department of Dermatology, University of Graz, Austria.
Am J Dermatopathol. 2004 Feb;26(1):4-13. Abstract quote  

The differential diagnosis of cutaneous B-cell infiltrates with follicular pattern of growth is one of the most vexing problems in dermatopathology.

In this study we focused on histopathologic, immunophenotypic, and molecular differential diagnostic criteria between Borrelia burgdorferi (Bb)-associated lymphocytoma cutis (LC), primary cutaneous follicle center cell lymphoma (FCCL), and primary cutaneous marginal zone lymphoma (MZL) with reactive germinal centers (GCs). A total of 47 patients were included in the study, including 12 cases of LC (M:F = 2:1; mean age: 38.0; median: 31; range: 9-75), 29 cases of FCCL (M:F = 1.2:1; mean age: 57.5; median: 57; range: 24-97), and 6 cases of MZL (M:F = 1:1; mean age: 63.8; median: 67.5; range: 38-86). In all cases complete phenotypic data were available. In addition, the IgH gene rearrangement and the t(14;18) were analyzed using the polymerase chain reaction technique (PCR) in 41 (FCCL = 27, LC = 10, MZL = 4) and 18 cases (FCCL = 15, LC = 2, MZL = 1), respectively.

Histology revealed in all cases of FCCL one or more atypical feature of the follicles including the lack of or a reduced mantle zone, lack of polarization, tendency to confluence, and absence of tingible body macrophages. In most cases of Bb-associated LC, the GCs were devoid of mantle zone, lacked polarization, and revealed tendency to confluence as well, but all cases showed the presence of several tingible body macrophages. In MZL, follicles showed typical features of reactive GCs. Immunohistology revealed a reduced proliferative activity of neoplastic follicles as detected by MIB-1 antibody in 23 of 29 cases of FCCL (79.3%), but only in 1 case of LC (8.3%). Proliferation of the GCs was normal in all cases of MZL. Positivity for CD10 and/or Bcl-6 was found in small clusters outside the follicles in 19 cases of FCCL (65.5%), and in 3 cases of LC (25%), but in no case of MZL. The intensity of CD10 staining on follicular cells on average was stronger in cases of FCCL, but overlapping features could be observed. Finally, staining for Bcl-2 protein was consistently negative on GC cells in cases of LC and MZL, and was positive on a variable proportion of the cells in 8 cases of FCCL (28.6%).

Molecular analyses showed no evidence of the t(14;18) in all cases tested. Analysis of the IgH gene rearrangement revealed a monoclonal pattern in 1 of 10 cases of LC (10%), 14 of 27 cases of FCCL (51.9%), and 2 of 4 cases of MZL (50%) tested. In summary, Bb-associated LC and FCCL show sometimes overlapping histopathologic, immunohistochemical, and molecular features, whereas follicles in MZL show clear-cut aspects of reactive GCs. Absence of tingible body macrophages within follicles, reduced proliferation of the follicles as detected by immunohistology, presence of positivity for Bcl-2 protein within follicular cells, and monoclonality by PCR are the main criteria suggestive of malignancy.

Diagnosis of cutaneous infiltrates of B lymphocytes with follicular growth pattern should be achieved by integration of clinical data with histopathologic, immunohistochemical, and molecular features of the lesions.

Cutaneous Presentation of Follicular Lymphomas

Renato Franco, M.D., Amalia Fernández-Vázquez, M.D., Manuela Mollejo, M.D., Miguel A. Cruz, M.D., Francisca I. Camacho, M.D., Juan F. García, M.D., Mercedes Navarrete, B.Sc. and Miguel A. Piris, M.D.

Department of Biomorphological and Functional ScienceFederico II University of Napoli, Italy (RF); Department of Molecular Pathology, Centro Nacional de Investigaciones Oncologicas Carlos III, Majadahonda-Madrid (AFV, FIC, JFG, MN, MAP), Madrid, Spain; and Departments of Pathology (MM) and Oncology (MAC), Virgen de la Salud Hospital, Toledo, Spain

Mod Pathol 2001;14:913-919 Abstract quote

The description of primary cutaneous follicular lymphoma has raised interest in the differential diagnosis of this versus disseminated follicular lymphoma involving the skin.

We report here on four cases of Stage IV follicular lymphoma, diagnosed in skin biopsy, in which cutaneous lesion was the most noticeable feature of clinical presentation. In all cases, the morphological features were superimposed over typical nodal follicular lymphoma. Apart from classic B-cell markers, they were characterized by CD10 and bcl6 positivity, markers of follicle germinal center cells; and bcl2 expression, with a corresponding t(14;18) translocation in three of three cases examined. In all four cases, bone marrow study and clinical staging revealed disease that had disseminated since diagnosis. Follow-up showed relapsing cutaneous and nodal disease in two cases.

The only difference observed with a control group of 10 cases of primary cutaneous follicular lymphoma was the absence in this group of t(14; 18).

Disseminated classical follicular lymphoma has to be considered in the differential diagnosis of follicular lymphoma presenting in the skin. This series of cases suggests that the presence of t(14;18) could imply the existence of disease that has disseminated beyond the skin and that cases harboring this translocation could be candidates for systemic polychemotherapy.

Clinicopathologic, Immunophenotypic, and Molecular Cytogenetic Fluorescence In Situ Hybridization Analysis of Primary and Secondary Cutaneous Follicular Lymphomas.

Kim BK, Surti U, Pandya A, Cohen J, Rabkin MS, Swerdlow SH.

From the *Department of Pathology, Division of Hematopathology and daggerPittsburgh Cytogenetics Laboratory, University of Pittsburgh Medical Center, Pittsburgh, PA; double daggerDepartment of Dermatology, University of Texas Southwestern, Dallas, TX; and section signRabkin Dermatopathology, Pittsburgh, PA.
Am J Surg Pathol. 2005 Jan;29(1):69-82. Abstract quote

Although primary cutaneous follicular lymphoma (FL) is considered a distinct variant of FL in the World Health Organization classification ("cutaneous follicle center lymphoma"), its biologic relationship to nodal FL remains controversial.

The clinical, morphologic, immunophenotypic, and molecular cytogenetic features of 17 patients with primary cutaneous FL were studied and compared with 16 patients with secondary cutaneous FL. The head and neck region was the most frequent site at initial skin presentation in both the primary and secondary cases. Among the primary cases, 29% of the 31 biopsies were grade 1, 48% grade 2, 13% grade 3, and 10% grade 3 with diffuse large B-cell (DLBCL) areas.

Among the secondary cases, 38% of the 29 skin biopsies were grade 1, 45% grade 2, 3% grade 3, and 7% grade 3 with DLBCL areas with two not evaluable. A floral-like pattern was observed in 32% of primary FL but only 5% of secondary cases. Histologic progression was found in 21% of patients. CD10 expression was demonstrated in 90% (27 of 30) of primary cases and 96% (22 of 23) of secondary cases. Bcl-6 was expressed in all cases tested. Bcl-2 expression was detected in 57% (17 of 30) of the primary cases (100% of grade 1, 43% of grade 2, 40% of grade 3), whereas all secondary cases were bcl-2 positive (P = 0.0002). The t(14;18) translocation was identified by interphase fluorescence in situ hybridization (FISH) in biopsies from 31% (4 of 13) of the patients with primary FL compared with 77% (10 of 13) of those with secondary lymphoma (P < 0.05). Seven of the 17 (41%) patients with primary disease had cutaneous relapse, including 1 who also developed nodal disease. Bcl-2 positivity was seen in 4 of these 7 patients. Eight of the 16 (50%) patients with secondary FL had cutaneous relapse.

Primary and secondary cutaneous FL share many clinical and phenotypic features, but primary cases may have some distinctive morphologic features, more frequently lack bcl-2 protein, and often lack the t(14;18) translocation. These findings suggest that primary cutaneous FL are distinctive and often but not always have a pathogenesis different from most of nodal and secondary cutaneous FL.



Primary cutaneous large cell lymphomas of follicular center cell origin. A clinical follow-up study of nineteen patients.

Willemze R, Meijer CJ, Sentis HJ, Scheffer E, van Vloten WA, Toonstra J, van der Putte SC.

J Am Acad Dermatol 1987 Mar;16(3 Pt 1):518-26 Abstract quote

In this study the clinical characteristics and follow-up data of nineteen patients with a diffuse large cell lymphoma of follicular center cell (B cell) origin, with only skin lesions at presentation, are reported.

Sixteen of nineteen patients came to us with localized nodules or tumors, preferentially on the trunk, scalp, and lower legs. Remarkably, eight of eleven patients with disease confined to a limited area on the trunk had a history of slowly progressive papular lesions that had been present for 1 to 20 years prior to the development of rapidly growing skin tumors. Initial treatment, generally radiotherapy and/or polychemotherapy, resulted in complete remissions in seventeen of nineteen patients. Only three patients developed extracutaneous disease, whereas two other patients had recurrent disease in the skin at sites distant from the original skin lesions. Excluding three patients who had just finished initial treatment at the time of writing, twelve of sixteen patients were currently alive and in complete remission with a median survival of 44 months. Four patients died, three of whom were elderly women who had skin tumors on the lower legs when first seen.

These results suggest that patients with a primary cutaneous large cell lymphoma of follicular center cell origin with disease confined to the trunk of scalp have a very favorable prognosis.

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.

Cutaneous Follicle Center Lymphoma: A Clinicopathologic Study of 19 Cases

N.S.I. Aguilera, M.D., M.-M. Tomaszewski, M.D., J.C. Moad, M.D., F.A. Bauer, M.D., J.K. Taubenberger, M.D., PhD. and S.L. Abbondanzo, M.D.

Departments of Hematopathology (NSIASLA), Dermatopathology (MMT, JCM), and Cellular Pathology (JKT), Armed Forces Institute of Pathology, Washington, District of Columbia; and Saint Francis Hospital and Medical Center (FAB), Hartford, Connecticut

Mod Pathol 2001;14:828-835 Partial abstract quote

Cutaneous follicle center lymphoma (FCL) is reported to have a unique immunophenotype and clinical course as compared with nodal FCL.

We studied 19 cases of FCL of the skin using paraffin embedded tissue.

Follow-up showed no evidence of disease in 14/17 patients (4 to 137 mos). 3/17 patients are alive with disease (17 to 100 mo), and no patients died of disease.

Primary cutaneous large B-cell lymphoma: the relation between morphology, clinical presentation, immunohistochemical markers, and survival.

Fernandez-Vazquez A, Rodriguez-Peralto JL, Martinez MA, Platon EM, Algara P, Camacho FI, Lopez-Rios F, Zarco C, Sanchez-Yus E, Fresno MF, Barthe L, Aliaga A, Fraga M, Forteza J, Oliva H, Piris MA.

Programa de Patologia Molecular, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.

Am J Surg Pathol 2001 Mar;25(3):307-15 Abstract quote

The histogenesis, morphology, immunophenotype, and clinical behavior of cutaneous large B-cell lymphomas (CLBCL) are largely a matter of controversy.

We performed an investigation to determine whether CLBCL have features that differentiate them from other large B-cell lymphomas and whether CLBCL is itself a heterogeneous group.

To this end, we reviewed the main characteristics of a 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 [1] 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.

Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study.

Grange F, Bekkenk MW, Wechsler J, Meijer CJ, Cerroni L, Bernengo M, Bosq J, Hedelin G, Fink Puches R, van Vloten WA, Joly P, Bagot M, Willemze R.

Department of Dermatology, Hopital Pasteur, Colmar, France.

J Clin Oncol 2001 Aug 15;19(16):3602-10 Abstract quote

PURPOSE: Most primary cutaneous B-cell lymphomas have an excellent prognosis. However, primary cutaneous large B-cell lymphomas (PCLBCLs) of the leg have been recognized as a distinct entity with a poorer prognosis in the European Organization for Research and Treatment of Cancer (EORTC) classification. This distinction on the basis of site has been debated. Our aim was to identify independent prognostic factors in a large European multicenter series of PCLBCL.

PATIENTS AND METHODS: The clinical and histologic data of 145 patients with PCLBCL were evaluated. According to the EORTC classification, 48 patients had a PCLBCL of the leg and 97 had a primary cutaneous follicle center-cell lymphoma (PCFCCL). Data from both groups were compared. Univariate and multivariate analyses of specific survival were performed using a Cox proportional hazards model.

RESULTS: Compared with PCFCCL, PCLBCL-leg were characterized by an older age of onset, a more recent history of skin lesions, a more frequent predominance of tumor cells with round nuclei and positive bcl-2 staining, and a poorer 5-year disease-specific survival rate (52% v 94%; P <.0001). Univariate survival analysis in the entire study group showed that older age, a more recent onset of skin lesions, the location on the leg, multiple skin lesions, and the round-cell morphology were significantly related to death. In multivariate analysis, the round-cell morphology (P <.0001), the location on the leg (P =.002), and multiple skin lesions (P =.01) remained independent prognostic factors. The round-cell morphology was an adverse prognostic factor both in PCLBCL-leg and in PCFCCL, whereas multiple skin lesions were associated with a poor prognosis only in patients with PCLBCL-leg.

CONCLUSION: With site, morphology, and number of tumors taken into account, guidelines for the management of PCLBCL are presented.


Treatment of primary cutaneous B-cell lymphomas of follicle center cell origin: a clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy.

Rijlaarsdam JU, Toonstra J, Meijer OW, Noordijk EM, Willemze R.

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

J Clin Oncol 1996 Feb;14(2):549-55 Abstract quote

PURPOSE: Primary cutaneous follicle center cell lymphomas (PCFCCL) are a distinct group of cutaneous B-cell lymphomas with a favorable prognosis after radiotherapy (RT) or polychemotherapy (PCT). In the literature, conflicting data exist regarding the efficacy and the relapse rate of both treatment modalities. In the present study, treatment results and follow-up data of a large group of PCFCCL are evaluated.

PATIENTS AND METHODS: Fifty-five patients with a PCFCCL who presented with skin lesions on either the head (n = 12), the trunk (n = 35), or lower legs (n = 8), and who were initially treated with RT (40 cases) or PCT (15 cases) were studied.

RESULTS: RT resulted in a complete remission in all 40 cases. Eight cases relapsed and three of these patients died as a result of their lymphoma. The estimated 5-year survival was 89%. Four of eight relapses and all three lymphoma-related deaths occurred in the group of patients presenting with tumor(s) on the lower legs. Treatment with cyclophosphamide, doxorubicin vincristine, and prednisone (CHOP) or cyclophosphomide, vincristine, and prednisone (COP) resulted in a complete remission in 14 of 15 cases. All four cases treated with COP relapsed, whereas only two of 11 patients treated with CHOP had a relapse. The estimated 5-year survival rate of the PCT group was 93%.

CONCLUSION: Both RT and CHOP PCT are highly effective modes of treatment for PCFCCL. In localized PCFCCL, RT is the treatment of choice. In patients with multiple tumors involving anatomic nonrelated parts of the skin, CHOP rather than COP PCT is the preferred mode of treatment. PCFCCL on the lower legs, a subgroup that characteristically occur in elderly patients, have a higher relapse rate and a less favorable prognosis than PCFCCL presenting on the head or trunk.

Systemic polychemotherapy in the treatment of primary cutaneous lymphomas: a clinical follow-up study of 81 patients treated with COP or CHOP.

Fierro MT, Quaglino P, Savoia P, Verrone A, Bernengo MG.

Department of Medical and Surgical Specialties, University of Turin, Italy.

Leuk Lymphoma 1998 Nov;31(5-6):583-8 Abstract quote

The efficacy of systemic polychemotherapy in the treatment of primary cutaneous B-cell lymphomas (CBCL) or T-cell lymphomas (CTCL) is still controversial. A series of 81 patients (46 primary CBCL and 35 CTCL) were treated with COP or CHOP regimens.

In primary CBCL, the overall objective response rate (RR) was 98%, with an 89% CR rate and a 33% relapse-rate. Five-year disease-free survival was 70%, 5-year survival 97%. Patients with leg or widespread lesions showed a higher relapse-rate (55% vs 26%) than those with trunk or head lesions. The overall objective RR was 40% in CTCL patients, with a 23% CR rate; median response duration was 5.7 months, median survival 19 months.

The results confirm both the good prognosis of primary CBCL and the efficacy of polychemotherapy. CHOP regimen is to be preferred to COP in as much as it reduces relapse rates. Conversely, there are no indications for the use of COP/CHOP regimens as first-line chemotherapy in CTCL patients.

Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients.

Bekkenk MW, Vermeer MH, Geerts ML, Noordijk EM, Heule F, van Voorst Vader PC, van Vloten WA, Meijer CJ, Willemze R.

Departments of Dermatology and Pathology, Free University Hospital, Amsterdam.

J Clin Oncol 1999 Aug;17(8):2471-8 Abstract quote

PURPOSE: Although patients with primary cutaneous B-cell lymphoma (CBCL) and localized skin lesions are generally treated with radiotherapy and have an excellent prognosis, the clinical behavior and optimal treatment of CBCL presenting with multifocal skin lesions are less well defined. In this study, we evaluated the clinical behavior of and results of treatment for multifocal CBCL in 29 patients, and we formulated therapeutic guidelines.

PATIENTS AND METHODS: The study group included 16 patients with primary cutaneous follicular center-cell lymphoma (PCFCCL), eight with primary cutaneous immunocytoma (PCI), and five with primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL of the leg).

RESULTS: Only one of the 24 patients with multifocal PCFCCL or PCI developed extracutaneous disease, and no patient died from lymphoma (median follow-up, 54 months). In patients with PCFCCL, treatment with either multiagent chemotherapy (nine patients) or radiotherapy directed toward all skin lesions (five patients) proved equally effective in terms of complete remission, relapse, and survival. In contrast, all five patients with PCLBCL of the leg developed extracutaneous disease, and four of the five died from systemic lymphoma, 8 to 36 months (median, 21 months) after diagnosis.

CONCLUSION: The results of these preliminary studies suggest that patients with PCFCCL or PCI presenting with multifocal skin lesions have the same excellent prognosis that patients with localized PCFCCL or PCI have and that radiotherapy directed toward all skin lesions is as effective as multiagent chemotherapy. Patients with PCLBCL of the leg have a more unfavorable prognosis, particularly patients presenting with multifocal skin lesions. This last group should always be treated with multiagent chemotherapy.

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