Originally published as JCO Early Release 10.1200/JCO.2008.16.1307 on June 9 2008

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Primary Cutaneous Small/Medium CD4⁺ T-Cell Lymphomas: A Heterogeneous Group of Tumors With Different Clinicopathologic Features and Outcome

Adriana Garcia-Herrera, Luis Colomo, Mireia Camós, Joaquín Carreras, Olga Balague, Antonio Martinez, Armando Lopéz-Guillermo, Teresa Estrach, Elias Campo

From the Hematopathology Section, Department of Pathology, Department of Hematology, and Dermatology, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

Corresponding author: Elias Campo, MD, Hematopathology Section, Hospital Clínic, Villarroel 170, 08036-Barcelona, Spain; e-mail: ecampo{at}clinic.ub.es

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To define the clinical and pathologic characteristics of primary cutaneous small/medium CD4⁺ T-cell lymphoma (PCSM-TCL) and identify parameters of prognostic significance.

Patients and Methods We have investigated 24 patients with primary cutaneous lymphomas composed of small/medium mature T-cells with a βF1, CD3, CD4⁺ and/or noncytotoxic, CD8^– and CD30^– phenotype. The proliferation index and CD8⁺ infiltrating cells were quantified with an automated image analysis system.

Results Sixteen patients presenting with solitary or localized plaques or small nodules (< 3 cm) had an indolent course. Only three patients experienced repeated cutaneous relapses, and none of them died as a result of the disease after 1 to 168 months (median, 17 months) of follow-up. The tumors had a low proliferation (median Ki-67, 9% ± 5%) and an intense infiltrate of reactive CD8⁺ (median, 20% ± 11.7%). Five patients presenting with rapidly evolving large tumors or nodules ( 5 cm) had an aggressive disease and died with extracutaneous dissemination 18 to 36 months after diagnosis (median, 23 months). These tumors had a significantly higher proliferation (median Ki-67, 22% ± 11.3%; P < .05) and lower number of infiltrating CD8⁺ (median, 1% ± 3%; P < .05) than the previous group. A third group of three patients had a peculiar clinical presentation with multifocal relapsing lesions without extracutaneous dissemination after a long period of follow-up ranging from 41 to 92 months. Histologically, these cases had an intense infiltrate of eosinophils.

Conclusion PCSM-TCL is a heterogeneous group of tumors with differentiated clinical and pathological characteristics with impact in the outcome of the patients.

	INTRODUCTION

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Primary cutaneous lymphomas encompass a heterogeneous group of neoplasms with clinical and biologic behavior that are different from secondary cutaneous involvement of systemic lymphomas.¹ The recent WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification has clarified some relevant aspects and proposed a consensus framework for further studies of entities not yet well characterized.² Among T-cell lymphomas, the category of unspecified primary cutaneous peripheral T-cell lymphoma remains scarcely defined. Tumors included in this class represent a heterogeneous group of mature T-cell neoplasms that do not fulfill the diagnostic criteria of the other, better-defined subtypes. This term is restricted to tumors composed predominantly of mature CD30^– large T-cells, and the prognosis is usually poor. In addition, three provisional entities with particular clinicopathologic features have been recognized: primary cutaneous small/medium CD4⁺ T-cell lymphoma (PCSM-TCL), primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, and cutaneous / T-cell lymphoma. Patients with PCSM-TCL usually present with solitary plaques or tumors and have a favorable clinical evolution.^3-5 Multifocal skin lesions may occur but always without the clinical progression from patches to plaques and tumors typical of mycosis fungoides (MF). Histologically, these neoplasms are characterized by a proliferation of small/medium-sized lymphocytes with pleomorphic morphology, as well as an admixture of reactive lymphocytes and histiocytes.^3,4,6 The current consensus WHO-EORTC classification has restricted this category to cases with a CD4⁺ phenotype on the basis of observations suggesting that tumors with a CD8 phenotype may follow a more aggressive clinical behavior.^7-10 However, previous studies describing these tumors are based on small number of patients, not always well characterized, and include tumors CD8⁺ or CD4^–/CD8^– that may correspond to other entities. Therefore, the precise clinicopathologic features of these neoplasms are not well characterized.

In this study, we have examined a series of patients with PCSM-TCL diagnosed according to the current WHO-EORTC criteria to define their clinicopathologic features and determine the potential parameters that may be useful to predict their outcome.

	PATIENTS AND METHODS

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Case Selection
Thirty-two patients diagnosed with a primary cutaneous peripheral T-cell lymphoma composed predominantly of small-/medium-sized cells were retrieved from the files of the Departments of Dermatology and Pathology at Hospital Clínic (Barcelona, Spain) covering the period 1987 to 2006. In all cases, original tissue sections were reviewed. Additional immunohistochemical and molecular studies were performed from the paraffin blocks available. The tumors were reclassified according to the new WHO-EORTC classification of cutaneous lymphomas.¹¹ Eight cases were excluded for further analysis. Two of them were reclassified as a tumoral MF, two as a primary cutaneous CD30 lymphoproliferative disorder, three were βF1 negative and a / phenotype could not be ruled out, and one was reclassified as an unspecified primary cutaneous peripheral T-cell lymphoma. All of the remaining patients were considered PCSM-TCL with no evidence of extracutaneous disease at time of diagnosis or presence of prior or concurrent patches typical of MF. Clinical information, including medical history, clinical presentation, staging, therapy, and follow-up, was obtained from the medical records and from information provided by the patients’ physicians.

Immunohistochemistry
Immunophenotyping was performed in all cases with a panel of antibodies reactive in paraffin-embedded tissues (Appendix Table A1, online only) using a peroxidase or alkaline phosphatase-labeled detection system, standard antigen retrieval protocols, and an automated immunostainer (TechMate 500/500 Plus, DAKO, Copenhagen, Denmark) as previously described.¹²

The number of Ki-67 and CD8⁺ cells were quantified in all samples using an automated scanning microscope and image analysis system (Ariol 2.1, SL-50; Applied Imaging Corporation, Newcastle on Tyne, United Kingdom) as previously described.¹³

Molecular Studies
In situ hybridization for Epstein-Barr virus (EBV) was examined using the EBV-encoded early nuclear RNAs (EBER-1 and EBER-2) as previously described.^14-16 Polymerase chain reaction analysis of TCR- and/or TCR-β genes were performed using previously described protocols,^17,18 and DNA extracted from formalin-fixed tissues using the QUIamp DNA mini kit (Qiagen, Crawley, West Sussex, United Kingdom; Appendix, online only).

Statistical Analysis
Comparisons between different subgroups of patients were performed using the Fisher's exact test for categoric variables (cross table) or the Mann-Whitney test for continuous variables. For statistical analysis the software package for social sciences (SPSS 13.0; SPSS Inc, Chicago, IL) was used.

	RESULTS

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Patients were 13 women and 11 men, with a median age of 58 years (range, 28 to 85 years). At presentation, 17 patients (70%) had solitary plaques, nodules or tumors, three had localized lesions, and four had multifocal lesions that were mostly located on the extremities (n = 11), the back (n = 5), and head and neck (n = 5). The median duration of the skin lesions before diagnosis was 4 months (range, 1 to 18 months). Two patients had a previous history of cancer. Patient 20 had been diagnosed with an acral lentiginous melanoma and a renal clear-cell carcinoma 11 years and 2 months earlier, respectively, and patient 24 had an invasive ductal carcinoma of the breast 5 years earlier. No evidence of these neoplasms was observed at the time of diagnosis of the cutaneous lymphoma.

The initial treatment was topical steroids in two patients, surgical resection alone in eight, local radiation therapy in six, chemotherapy in five, and immunotherapy with interferon- in one; one elderly patient did not receive any specific treatment. Information on the initial treatment was not available in one case. The median follow-up of the cases was 24 months (range, 1 to 168 months).

Morphologically, all tumors were composed of a population of small/medium-sized atypical lymphocytes with less than 30% large cells and a variable background of reactive cells. All cases expressed βF1 and CD3, and were CD30^–, CD8^–, and CD56^–. CD4 was positive in 21 tumors in which the staining was technically satisfactory, but partial loss was observed in five cases.

Although all patients shared these histologic and phenotypic characteristics, they could be grouped in three different categories according to the clinical presentation and outcome. Thus, 16 patients had small lesions and followed an indolent clinical course; five patients showed rapidly progressive large nodules or tumors with an aggressive clinical evolution, eventually dying as a result of the disease; and three patients presented with multifocal and relapsing skin lesions, but with no systemic dissemination or lymphoma-related deaths. The clinical and pathologic characteristics of these groups are described separately (Appendix Tables A2-A7, online only).

PCSM-TCL With Indolent Clinical Course
These 16 patients were nine women and seven men with a median age at diagnosis of 55 years (range, 28 to 85 years; Table 1). Most patients (14 of 16) had solitary stable lesions that were plaques or small nodules and tumors between 1 and 3 cm in diameter (Fig 1). Fourteen patients were treated with local therapy (eight excision, five radiotherapy, and one topical steroids), one patient received no therapy, and treatment is unknown in another. A complete remission was achieved in 12 of the 14 patients with assessable response. Three patients experienced repeated cutaneous relapses with persistence of the disease at the last follow-up in two of them. All of these patients were alive after 1 to 168 months (median, 17 months) of follow-up.

View larger version (83K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Primary cutaneous small/medium CD4+ T-cell lymphoma with indolent clinical course. (A) Gross appearance of a solitary plaque. (B, C) Diffuse dermal involvement by irregular small-/medium-sized cells. (D-F) The cells express CD3 and CD4, but CD7 is lost. (G) High numbers of reactive CD8+ cells and (H) low proliferation index (Ki-67) are typical in this group. (I) Clonal rearrangement of TCR-β gene. Image magnifications were (B) x40 and (C to H) x400.

Immunohistochemically, all cases examined expressed CD5 (n = 12). Marked loss of CD7 was observed in 13 of 15 cases. Only two cases showed CD4 loss of expression in a proportion of cells. Cytotoxic granules were seen only in one case (patient 16). The proliferative index of these tumors was low (median Ki-67, 9%; range, 1% to 20%). Most tumors had an intense infiltration of CD8⁺ T cells varying from 9% to 47% (median, 20%; Fig 1). B cells were also relatively common, and in 11 cases tended to form nodular aggregates that, in four cases, had a small meshwork of follicular dendritic cells. In two tumors, the aggregates of plasma cells showed a monotypic light-chain restriction (patients 11 and 12). These two cases have been included in a recent published study.¹⁹ The ISH for the EBV was negative in both tumors as well as in eight additional cases studied. Molecular studies demonstrated a clonal rearrangement of the TCR gene in 11 (TCR- 9; TCR-β 8) of the 12 cases with DNA available, including in patient 11 with a light-chain restriction in the plasma cells.

PCSM-TCL With an Aggressive Clinical Outcome
These patients were four men and one woman with a median age of 65 years (range, 52 to 78 years; Table 1). All of them had rapidly growing and bulky tumors or nodules ( 5 cm in diameter; Fig 2). Two of them became ulcerated in the following weeks. All patients had ambulatory performance status (Eastern Cooperative Oncology Group performance status of 0 to 1) and normal serum lactate dehydrogenase levels. Four patients were treated with multiagent systemic chemotherapy regimens resulting from the rapid progression of the cutaneous lesions, whereas the remainder received local radiation therapy. Only two patients achieved complete remission, one had a partial remission, and two showed progressive disease. Two patients had cutaneous relapses, and all of them developed extracutaneous dissemination (median time to relapse, 14 months; range, 9 to 11 months), including two cases in the lymph nodes and three with suspected (patient 19) or documented (patients 20 and 21) CNS involvement. All patients died as a result of the disease between 18 and 36 months after the initial diagnosis (median survival, 23 months).

View larger version (113K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Primary cutaneous small/medium CD4+ T-cell lymphoma with an aggressive clinical outcome. (A, B) Clinical presentation with tumoral lesions. (C, D) Neoplastic small-/medium-sized cells infiltrating the dermis. The inset demonstrates neural invasion. The cells express CD3 and CD4 (E, F), but this group shows (G) few and isolated reactive CD8+ lymphocytes and (H) high proliferation index (Ki-67). Image magnifications were (C) x40 and (D to H) x400.

Immunohistochemically, CD4 was expressed in four cases with partial loss in two, and was technically unsatisfactory in one. CD7 was decreased or lost in all cases. Patient 21 showed aberrant coexpression of CD20 in the tumor cells. The proliferative index in this group of tumors was significantly higher that in the previous one (median Ki-67, 22%; range, 15% to 43%; P < .05). CD8⁺ tumor-infiltrating lymphocytes were also significantly lower than in the previous group (median, 1%; range, 0.3% to 7.7%; P < .05; Fig 2). B cells were scarce and disperse without forming aggregates.

A clonal TCR- and TCR-β gene rearrangement was observed in one of the two cases with available material (patient 20). The LC sarcoma of this patient showed a germ-line configuration of the TCR gene.

PCSM-TCL With Prominent Eosinophilia
Three patients had a peculiar clinical presentation with recurrent multifocal skin plaques or nodules in the extremities and abdomen (Table 1). One patient (22) had a long history of recurrent cutaneous lesions that had been interpreted as "reactive lymphoid and histiocyte hyperplasia" before definitive diagnosis of cutaneous lymphoma. Persistent eosinophilia in the peripheral blood was observed in this case. At last follow-up examination, two patients were alive with skin disease (follow-up, 72 and 96 months), and one died 41 months after diagnosis of lymphoma resulting from metastatic breast cancer. Morphologically, these tumors showed a dermal infiltrate of atypical small-/medium-sized lymphocytes admixed with numerous eosinophils (Fig 3). Partial loss of CD4 was observed in patient 23. The median percentage of Ki-67 positive cells was 5% (range, 1% to 24%). The number of infiltrating CD8⁺ lymphocytes was moderate (median, 10%; range, 9% to 13%) whereas many scattered or small clusters of CD20⁺ B cells were present. A TCR gene clonal rearrangement was detected in the three cases and in the peripheral blood (PB) of one (patient 22). This latter case showed 33% of T lymphocytes in the PB with anomalous phenotype (partial loss of CD7 and CD3).

View larger version (96K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Primary cutaneous small/medium CD4+ T-cell lymphoma with prominent eosinophilia. (A) Clinical presentation with multiple violaceous plaques in the legs. (B, C) Band-like infiltrate with atypical small lymphocytes mixed with high number of eosinophils. (D,E) CD3 and CD4 expression. (F) CD7 is lost in this case. (G) Clonal rearrangement of TCR- gene. Image magnifications were (B) x40 and (C to F) x400.

	DISCUSSION

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View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Box plots representing percentage of (A) CD8+ cells and (B) Ki-67 expression in groups of primary cutaneous small/medium CD4+ T-cell lymphoma (PCSM-TCL) quantified in all samples using an automated scanning microscope and image analysis system (Ariol 2.1, SL-50; Applied Imaging Corp, Newcastle on Tyne, United Kingdom). Boxes represent the quartiles, and circles show atypical values (1.5x to 3x the length of the box).

Three of the five patients who died as a result of the lymphoma developed CNS involvement. This complication has been documented in patients with cutaneous lymphomas.^30-34 Interestingly, we observed focal endoneural infiltration of small nerves in the initial cutaneous biopsy of two of these patients, suggesting that this finding may raise the suspicion of an aggressive behavior. The tumor cells of one of these cases (patient 21) coexpressed CD20. Aberrant expression of CD79a and CD20 has been described in a small number of PTCL, including one primary cutaneous T-cell lymphoma.^35-37 Curiously, most of these cases were cytotoxic lymphomas expressing CD8⁺, whereas our case expressed CD4 and was negative for cytotoxic granules. One patient (20) had a simultaneous LC sarcoma with cutaneous and lymph-node involvement. LCH has been observed in association with other lymphoproliferative disorders including cutaneous lymphomas.³⁸ Interestingly, a clonal relationship between LCH and T-cell lymphoblastic lymphoma has been documented.³⁹ However, in our case, the TCR clonal rearrangement detected in the PCSM-TCL was not observed in the LC sarcoma, suggesting that they were two separate neoplasms.

The differential diagnosis between the indolent PCSM-TCL and cutaneous pseudo–T-cell lymphomas may be difficult since they share some overlapping features.^40-43 Most of our patients had small lesions with a high infiltrate of CD8⁺ and B-cells that are also a common finding in pseudo–T-cell lymphomas. However, our patients had a constellation of findings favoring the diagnosis of PCSM-TCL. Thus, none of our cases had a history of spontaneous regression of the lesions or previous medication, insect bite or systemic immunologic disorders that have been associated with pseudo–T-cell lymphomas.⁴⁴ Histologically, the tumor cells showed common epidermotropism (six of 16), had frequent loss of T-cell antigens, and, molecularly, a clonal TCR rearrangement was demonstrated in virtually all cases examined. These findings would support the idea of these lesions as indolent lymphomas. However, to determine the boundaries between PCSM-TCL and cutaneous pseudo–T-cell lymphomas in some cases may be difficult and debatable, and require the combination of clinical, pathologic, and molecular criteria.^43,45-48 From a practical point of view, it is important to recognize that patients with the indolent form of PCSM-TCL have a good clinical evolution with only local therapy.

In our study, we identified three additional patients with a peculiar clinical and pathologic presentation that differs from the previous cases. Although these tumors had certain morphologic and phenotypic similarities with group 1, the patients had recurrent multifocal skin lesions but no systemic dissemination or lymphoma-related deaths. Histologically, the CD4⁺ T cells were associated with a prominent eosinophilic infiltrate but a low number of CD8⁺ or B cells. The clonal TCR rearrangement detected in the three patients, one of them also in the blood associated with eosinophilia, and the persistence of the lesions suggest that they are a peculiar form of primary cutaneous indolent T-cell lymphoma.

In summary, our observations indicate that PCSM-TCL may present with different clinical and pathologic characteristics that are associated with the biologic behavior of the tumors. Patients presenting with small lesions, low proliferative index, and an intense infiltration of the tumor by reactive CD8⁺ cells have an excellent prognosis with only occasional cutaneous relapses, whereas patients with rapidly growing lesions, high proliferative tumors, and low infiltrate of CD8⁺ cells develop extracutaneous dissemination and have a poor prognosis. These patients have a biologic behavior that is more related to the aggressive primary cutaneous T-cell lymphomas, unspecified, despite the small/medium size of the tumor cells.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Adriana Garcia-Herrera, Luis Colomo, Antonio Martinez, Teresa Estrach, Elias Campo

Financial support: Teresa Estrach, Elias Campo

Provision of study materials or patients: Mireia Camos, Joaquín Carreras, Olga Balague, Armando Lopéz-Guillermo, Teresa Estrach, Elias Campo

Collection and assembly of data: Adriana Garcia-Herrera, Luis Colomo

Data analysis and interpretation: Adriana Garcia-Herrera, Luis Colomo, Joaquín Carreras, Antonio Martinez, Armando Lopéz-Guillermo, Teresa Estrach, Elias Campo

Manuscript writing: Adriana Garcia-Herrera, Luis Colomo, Mireia Camos, Joaquín Carreras, Olga Balague, Antonio Martinez, Armando Lopéz-Guillermo, Teresa Estrach, Elias Campo

Final approval of manuscript: Adriana Garcia-Herrera, Luis Colomo, Mireia Camos, Joaquín Carreras, Olga Balague, Antonio Martinez, Armando Lopéz-Guillermo, Teresa Estrach, Elias Campo

	Appendix

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T-Cell Receptor Gene Clonality Studies
For TCR gene rearrangement analysis, we extracted DNA from formalin-fixed tissues using the QUIamp DNA mini kit. In all cases, two independent DNA extractions were performed from each sample. To assess the TCR gene clonality, studies of both TCR- and TCR-β genes were performed. TCR- was analyzed using a single polymerase chain reaction (PCR) based on reported conditions (Dippel E, Assaf C, Hummel M, et al. J Pathol 188:146-154, 1999) and the TCR-β was studied following the multiplex PCR method designed by the European BIOMED-2 collaborative study group (BMH4-CT98-3936; Dongen JJ, Langerak AW, Bruggemann M, et al. Leukemia 17:2257-2317, 2003). Briefly, we used a PCR method to amplify different variable (V), diversity (D), and joining (J) segments of the TCR- and TCR-β genes and subsequent high-resolution separation of the amplified product with GeneScanning analysis (Applied Biosystems, Foster City, CA) for fragment size analysis and measurement of fluorescence intensity. The scanning results were interpreted as follows: One or two prominent and isolated peaks indicated monoclonality, three to five prominent peaks indicated oligoclonality, and more than five peaks indicated polyclonality (Dippel E, Assaf C, Hummel M, et al. J Pathol 188:146-154, 1999). Each monoclonal image had to be confirmed by repeating the study and showing a reproducible result. In contrast, if the size of the various clones constituting the oligoclonal profiles differed between determinations a pseudo-oligoclonality was assumed. In case of a clonal population mixed with a polyclonal background, the magnitude of the dominant peak had to be at least two times greater than the next largest peak to be declared a clonal result (Lee SC, Berg KD, Racke FK, et al. J Mol Diag 2:145-152, 2000; Plaza JA, Morrison C, Magro CM, et al. J Cutaneous Pathol [Epub ahead of print November 1, 2007]). The tumor was considered clonal when a clonal peak was detected in either or both TCR- and TCR-β genes (Brüggemann M, White H, Gaulard P, et al. Leukemia 21:215-221, 2007). Standard positive and negative controls were performed in parallel for all samples. A set of control gene primers designed to amplify products of 100, 200, 300, 400, and 600 base pairs were also included to test for the overall integrity of DNA.

A literature review of TCR rearrangements in cutaneous reactive lesions described clonal peaks in 0% to 15% of the cases, with most of the studies reporting clonal rearrangements in around 10% of the cases. (Ponti R, Quaglino P, Novelli M, et al. Br J Dermatol 153:565-573, 2005; Sandberg Y, Heule F, Lam K, et al. Hematologica 88:659-670, 2003; Langerak AW, Molina TJ, Lavender FL, et al. Leukemia 21:222-229, 2007; Dippel E, Assaf C, Hummel M, et al. J Pathol 188:146-154, 1999; Sandberg Y, Heule F, Lam K, et al. Haematologica 88:659-670; Dippel E, Klemke D, Hummel M, et al. Blood 98:247-248, 2001). The data in our laboratory is in agreement with these results since in our control series we have detected clonal peaks in 10% of reactive inflammatory cutaneous lesions.

	NOTES

 
published online ahead of print at www.jco.org on June 9, 2008.

Supported by the Spanish Comisión Interministerial de Ciencia y Tecnología SAF05-5855 (E.C.), Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (PI050458-TE and PI070409-ALG), Red Temática de Investigación Cooperativa de Cáncer (RET 20 39), and Instituto de Salud Carlos III (where O.B. is a fellow).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted January 10, 2008; accepted April 4, 2008.

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