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Background
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.
OUTLINE
PATHOGENESIS CHARACTERIZATION 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, MDAm 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.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS 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 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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