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ABSTRACT: Primary cutaneous T-cell lymphomas (CTCL) excluding mycosis fungoides (MF) were discussed in 2 sessions of the 2011 Society for Hematopathology/ European Association of Haematopathology Workshop, Los Angeles, CA. Session 2 focused on primary cutaneous CD30+ T-cell lymphoproliferative disorders and their differential diagnosis, including systemic CD30+ T-cell lymphoma secondarily infiltrating the skin. Interesting features like special morphologic variants and atypical phenotypes were presented. In addition, the possibility of rare ALK+ primary cutaneous lymphomas was discussed. Session 3 examined other more uncommon non-MF CTCLs, including subcutaneous panniculitis-like T-cell lymphoma, extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and rare subtypes of primary cutaneous peripheral T-cell lymphoma, not otherwise specified. In addition, systemic T-cell lymphomas involving the skin secondarily, such as angioimmunoblastic T-cell lymphoma, were included in this session. In this report, novel findings, areas of special interest, and diagnostic challenges emerging from the cases submitted to the workshop will be highlighted. The necessity to integrate histologic, immunophenotypical, genetic, and in particular, clinical data to arrive at the correct diagnosis, and subsequently provide adequate treatment, is emphasized.
American Journal of Clinical Pathology 04/2013; 139(4):491-514. · 2.60 Impact Factor
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ABSTRACT: OBJECTIVE To determine if there are differences in the expression of programmed death-1 (PD-1) between SS and MF, and in particular erythrodermic MF (E-MF). PD-1 is a marker of follicular helper T (TFH) cells and is expressed by the neoplastic T cells of some types of malignant T-cell lymphoma, including mycosis fungoides (MF) and Sézary syndrome (SS). Reported results of PD-1 staining in MF and SS are, however, conflicting. DESIGN Formalin-fixed, paraffin-embedded skin biopsy specimens were stained for PD-1. In addition, PD-1+ cases were stained with antibodies against BCL6, CXCL13, and CD10 to find possible relationship with TFH cells. SETTING Tertiary referral center for cutaneous lymphomas. PATIENTS Twenty-seven patients with SS and 60 patients with MF, including 8 patients with E-MF. RESULTS In patients with SS, expression of PD-1 by more than 50% of the neoplastic T cells was observed in 24 of 27 cases (89%). In contrast, PD-1 expression by more than 50% of neoplastic T cells was found in only 8 of 60 patients with MF (13%), including only 1 of 8 patients with E-MF (12%). In PD-1+ cases, serial skin sections showed that CXCL13 and BCL6 generally stained 25% to 50% of the PD-1+ cells, while expression of CD10 was uncommon. CONCLUSION The results of the present study show differential expression of PD-1 between SS and MF/E-MF, which provides further support for the view that SS and MF are distinct entities.
Archives of dermatology 12/2012; 148(12):1379-85. · 4.76 Impact Factor
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ABSTRACT: Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma (CTCL). To identify a molecular signature characteristic of MF tumor stage, we used a bioinformatic approach involving meta-analysis of publicly available gene expression data sets combined with previously generated gene expression data. Results for a selection of genes were further refined and validated by quantitative PCR and inclusion of additional controls. With this approach, we identified a profile specific for MF tumor stage, consisting of 989 aberrantly expressed genes, the majority of which (718 genes) are statistically significantly more expressed in MF compared with normal skin, inflamed skin, and normal T cells. As expected, the signature contains genes reflecting the highly proliferative characteristic of this T-cell malignancy, including altered expression of cell cycle and kinetochore regulators. We uncovered details of the immunophenotype, suggesting that MF originates from IL-32-producing cells and identified previously unreported therapeutic targets and/or diagnostic markers, for example, GTSF1 and TRIP13. Loss of expression of the NF-κB inhibitor, NFKBIZ, may partly explain the enhanced activity of NF-κB, which is a hallmark of MF and other CTCLs.
Journal of Investigative Dermatology 04/2012; 132(8):2050-9. · 6.31 Impact Factor
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ABSTRACT: In this study we investigated whether programmed death-1 (PD-1) could serve as a useful diagnostic marker to differentiate between primary cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (PCSM-TCL) and cutaneous pseudo-T-cell lymphomas on the one hand and other types of cutaneous T-cell lymphomas (CTCLs) on the other. Formalin-fixed, paraffin-embedded skin biopsies from 26 patients with PCSM-TCL or pseudo-T-cell lymphoma, including 1 patient with a lymphomatoid drug eruption, and 52 skin biopsies from other types of CTCLs were stained for PD-1. In addition, PD-1-positive cases were stained with antibodies against BCL6, CXCL13, and CD10 to determine a possible relationship with follicular helper T (TFH) cells. In all 26 cases of PCSM-TCL or pseudo-T-cell lymphoma, the medium-sized to large-sized atypical T cells consistently expressed PD-1, BCL6, and CXCL13 but not CD10. PD-1 expression was found in only 2 of 21 cases of mycosis fungoides and in only 2 of 16 cases of cutaneous peripheral T-cell lymphoma, unspecified. All 4 patients with an aggressive epidermotropic cytotoxic CD8 CTCL and all 11 cases with a primary cutaneous CD30 lymphoproliferative disorder were negative for PD-1. In conclusion, PD-1 is typically expressed by atypical cells in PCSM-TCL and pseudo-T-cell lymphoma but is not expressed or is rarely expressed in other types of CTCLs. Therefore, it may serve as a suitable adjunct in differential diagnosis. Our results demonstrate that the atypical cells in PCSM-TCL and pseudo-T-cell lymphomas share a common TFH phenotype and support the view that most cases classified nowadays as PCSM-TCL are identical to cutaneous pseudo-T-cell lymphomas described previously.
The American journal of surgical pathology 01/2012; 36(1):109-16. · 4.06 Impact Factor
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ABSTRACT: Large cell transformation (LCT) in mycosis fungoides (MF) is generally associated with an aggressive clinical course and poor survival, requiring aggressive therapeutic approach. However, a proportion of cases may follow an indolent clinical course. To identify prognostic factors, we analyzed the prognostic relevance of clinical, histologic, and immunophenotypical features in a large cohort of transformed MF patients, including 75 patients with only skin lesions, 19 patients with LCT in skin and lymph nodes, and 6 patients with LCT in lymph nodes only. Multivariate analysis of the total group showed that CD30 negativity, folliculotropic MF, extent of skin lesions and extracutaneous transformation were associated with reduced disease-specific survival (DSS) and, except for CD30 negativity and folliculotropic MF, also overall survival. In a multivariate analysis of 75 patients with only skin lesions at the time of LCT, CD30 negativity, folliculotropic MF and extent of skin lesions were independent parameters for both DSS and overall survival. Using the most discriminating parameters as a prognostic index, in both study groups differences in DSS between patients with 0-1 unfavorable prognostic factor(s) and ≥ 2 unfavorable prognostic factors were statistically significant (P < .001). This prognostic index may be helpful in predicting prognosis and selecting the most appropriate treatment in patients with transformed MF.
Blood 12/2011; 119(7):1643-9. · 9.90 Impact Factor
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ABSTRACT: In the World Health Organization (WHO) 2008 classification 2 main types of primary cutaneous large B-cell lymphomas (PCLBCLs) are distinguished: primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous large B-cell lymphoma, leg type (PCBCL-LT). PCFCL has a 5-year overall survival rate of 95%, and PCBCL-LT of approximately 50%. Expression profiling studies have shown higher RNA expression of the IgM heavy chain in PCBCL-LT compared with PCFCL. To find out whether this difference could also be demonstrated at the protein level, we performed immunohistochemical staining for B-cell receptor heavy and light chains on skin biopsies from 53 patients with PCFCL and 40 patients with PCBCL-LT. All 40 cases of PCBCL-LT consistently showed cytoplasmic staining for IgM, in 18 of them with coexpression of IgD. In contrast, only 5 of the PCFCL cases showed cytoplasmic staining for IgM and/or IgD, including all 3 PCFCLs presenting on the leg. Hence, staining for IgM on paraffin-embedded sections seems to be an additional tool for differentiating between the 2 entities in clinical pathology practice. Analogous to other nodal and extranodal large B-cell lymphomas, expression of IgM in PCLBCL seems to be related to an activated B cell-like phenotype. Finally, the expression of IgM (and IgD) in this type of lymphoma might imply defective class switch recombination.
The American journal of surgical pathology 07/2010; 34(7):1043-8. · 4.06 Impact Factor
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Acta Dermato-Venereologica 11/2009; 89(6):653-4.
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Rein Willemze, Patty M Jansen,
Lorenzo Cerroni,
Emilio Berti,
Marco Santucci,
Chalid Assaf,
Marijke R Canninga-van Dijk,
Agnes Carlotti,
Marie-Louise Geerts,
Sonja Hahtola, [......],
Marco Paulli,
Tony Petrella,
Annamari Ranki,
José L Rodriguez Peralto,
Alistair Robson,
Nancy J Senff,
Maarten H Vermeer,
Janine Wechsler,
Sean Whittaker,
Chris J L M Meijer
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ABSTRACT: In the WHO classification, subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a distinct type of T-cell lymphoma with an aggressive clinical behavior. Recent studies suggest that distinction should be made between SPTL with an alpha/beta T-cell phenotype (SPTL-AB) and SPTL with a gammadelta T-cell phenotype (SPTL-GD), but studies are limited. To better define their clinicopathologic features, immunophenotype, treatment, and survival, 63 SPTL-ABs and 20 SPTL-GDs were studied at a workshop of the EORTC Cutaneous Lymphoma Group. SPTL-ABs were generally confined to the subcutis, had a CD4-, CD8+, CD56-, betaF1+ phenotype, were uncommonly associated with a hemophagocytic syndrome (HPS; 17%), and had a favorable prognosis (5-year overall survival [OS]: 82%). SPTL-AB patients without HPS had a significantly better survival than patients with HPS (5-year OS: 91% vs 46%; P<.001). SPTL-GDs often showed (epi)dermal involvement and/or ulceration, a CD4-, CD8-, CD56+/-, betaF1- T-cell phenotype, and poor prognosis (5-year OS: 11%), irrespective of the presence of HPS or type of treatment. These results indicate that SPTL-AB and SPTL-GD are distinct entities, and justify that the term SPTL should further be used only for SPTL-AB. SPTL-ABs without associated HPS have an excellent prognosis, and multiagent chemotherapy as first choice of treatment should be questioned.
Blood 01/2008; 111(2):838-45. · 9.90 Impact Factor
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Nancy J Senff,
Juliette J Hoefnagel, Patty M Jansen,
Maarten H Vermeer,
Joop van Baarlen,
Willeke A Blokx,
Marijke R Canninga-van Dijk,
Marie-Louise Geerts,
Konnie M Hebeda,
Philip M Kluin,
King H Lam,
Chris J L M Meijer,
Rein Willemze
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ABSTRACT: In the new WHO-European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas three major groups of primary cutaneous B-cell lymphoma (CBCL) are distinguished: primary cutaneous marginal zone B-cell lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) with a good prognosis, and primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT), with an intermediate-level prognosis. This study aimed to assess the clinical significance of the new classification compared with previous classification schemes (EORTC 1997; WHO 2001) and to define prognostic factors within the newly defined categories.
In the present study clinical data and histologic sections of 300 patients with CBCL, formerly classified according to the EORTC classification, were reviewed and reclassified according to the WHO and the new WHO-EORTC classification schemes.
After reclassification, the study comprised 71 patients with PCMZL, 171 patients with PCFCL, and 58 patients with PCLBCL-LT, showing 5-year disease-specific survivals of 98%, 95%, and 50%, respectively. When compared with the EORTC and WHO schemes, 5.3% and 36.3% of patients with CBCL were reclassified into another prognostic category. Multivariate analysis of PCFCL revealed localization on the leg and expression of FOXP1 as independent parameters associated with a poor prognosis. Expression of Bcl-2 or MUM-1 had no significant effect on survival in this group. In PCLBCL-LT, no independent prognostic parameters were found.
These results emphasize the clinical significance of the WHO-EORTC classification, but suggest that within the group of PCFCL, distinction should be made between lymphomas presenting on the legs and lymphomas presenting at other sites.
Journal of Clinical Oncology 05/2007; 25(12):1581-7. · 18.37 Impact Factor
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ABSTRACT: Expression patterns of eight transcription factors involved in different stages of B-cell development were investigated in a large group of primary cutaneous B-cell lymphomas and compared with expression patterns during normal B-cell development. The following transcription factors were investigated: Pax-5, PU.1, Oct2, BOB.1, Bcl-6, Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous large B-cell lymphomas, leg type showed aberrant coexpression of Bcl-6 and Mum1/IRF4 and in addition strong expression of FOXP1. Expression of FOXP1 and Mum1/IRF4 strongly suggests an activated B-cell type of origin. In contrast, primary cutaneous follicle center lymphomas showed expression of Bcl-6, Pax-5, PU.1, Oct2 and BOB.1, but not of Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous marginal zone B-cell lymphoma showed expression of Pax-5, PU.1, Oct2 and BOB.1, but not Bcl-6 by the neoplastic B-cells, and Mum1/IRF4 and Blimp-1 by the neoplastic plasma cells. In conclusion, in primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma expression patterns were observed similar to their supposed benign counterparts, germinal center B-cells and postgerminal center B-cells, respectively, which might reflect their indolent clinical behaviour and excellent prognosis. In contrast, the activated B-cell expression pattern in the group of primary cutaneous large B-cell lymphoma, leg type may contribute to its poor prognosis and Mum1/IRF4 and FOXP1 may serve as additional diagnostic markers for this type of primary cutaneous B-cell lymphoma.
Modern Pathology 10/2006; 19(9):1270-6. · 4.79 Impact Factor
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Sietske A Riemersma,
Joost J Oudejans,
Marcel J Vonk,
Enno J Dreef,
Frans A Prins, Patty M Jansen,
Maarten H Vermeer,
Paul Blok,
Robbie E Kibbelaar,
Jettie J F Muris,
Ed M D Schuuring,
Philip M Kluin
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ABSTRACT: Loss of both HLA class I and class II expression in B cell lymphomas is a mechanism of escape from a cytotoxic T lymphocyte (CTL) immune response and will therefore give a strong selective survival advantage in tumours expressing strong immunogenic antigens. We investigated loss of HLA expression using specific antibodies on tissue sections from 254 B cell lymphomas originating from nodal and different extranodal sites in relation to numbers of tumour-infiltrating T cells. Complete loss of HLA class I and II was observed in a minority of the nodal, stomach, and skin lymphomas but in the majority of the lymphomas originating from the testis and the CNS. Interestingly, relatively high percentages of activated CTLs were detected in both primary testicular and CNS lymphomas compared to lymphomas at other sites, with highest percentages in the testis (p < 0.0001). We conclude that loss of both HLA class I and II expression occurs very frequently in lymphomas originating from the testis and the CNS as compared to nodal and some other extranodal sites. The presence of high percentages of activated CTLs in the testicular and CNS lymphomas suggests that loss of HLA expression provides a strong growth advantage for lymphoma cells in these immune-privileged sites.
The Journal of Pathology 07/2005; 206(3):328-36. · 6.32 Impact Factor
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ABSTRACT: In the European Organization for Research and Treatment of Cancer (EORTC) classification 2 types of primary cutaneous large B-cell lymphoma (PCLBCL) are distinguished: primary cutaneous follicle center cell lymphomas (PCFCCL) and PCLBCL of the leg (PCLBCL-leg). Distinction between both groups is considered important because of differences in prognosis (5-year survival > 95% and 52%, respectively) and the first choice of treatment (radiotherapy or systemic chemotherapy, respectively), but is not generally accepted. To establish a molecular basis for this subdivision in the EORTC classification, we investigated the gene expression profiles of 21 PCLBCLs by oligonucleotide microarray analysis. Hierarchical clustering based on a B-cell signature (7450 genes) classified PCLBCL into 2 distinct subgroups consisting of, respectively, 8 PCFCCLs and 13 PCLBCLsleg. PCLBCLs-leg showed increased expression of genes associated with cell proliferation; the proto-oncogenes Pim-1, Pim-2, and c-Myc; and the transcription factors Mum1/IRF4 and Oct-2. In the group of PCFCCL high expression of SPINK2 was observed. Further analysis suggested that PCFCCLs and PCLBCLs-leg have expression profiles similar to that of germinal center B-cell-like and activated B-cell-like diffuse large B-cell lymphoma, respectively. The results of this study suggest that different pathogenetic mechanisms are involved in the development of PCFCCLs and PCLBCLs-leg and provide molecular support for the subdivision used in the EORTC classification.
Blood 06/2005; 105(9):3671-8. · 9.90 Impact Factor
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Sietske A Riemersma,
Joost J Oudejans,
Marcel J Vonk,
Enno J Dreef,
Frans A Prins, Patty M Jansen,
Maarten H Vermeer,
Paul Blok,
Robbie E Kibbelaar,
Jettie JF Muris,
Ed MD Schuuring,
Philip M Kluin
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ABSTRACT: Loss of both HLA class I and class II expression in B cell lymphomas is a mechanism of escape from a cytotoxic T lymphocyte (CTL) immune response and will therefore give a strong selective survival advantage in tumours expressing strong immunogenic antigens. We investigated loss of HLA expression using specific antibodies on tissue sections from 254 B cell lymphomas originating from nodal and different extranodal sites in relation to numbers of tumour-infiltrating T cells. Complete loss of HLA class I and II was observed in a minority of the nodal, stomach, and skin lymphomas but in the majority of the lymphomas originating from the testis and the CNS. Interestingly, relatively high percentages of activated CTLs were detected in both primary testicular and CNS lymphomas compared to lymphomas at other sites, with highest percentages in the testis (p < 0.0001). We conclude that loss of both HLA class I and II expression occurs very frequently in lymphomas originating from the testis and the CNS as compared to nodal and some other extranodal sites. The presence of high percentages of activated CTLs in the testicular and CNS lymphomas suggests that loss of HLA expression provides a strong growth advantage for lymphoma cells in these immune-privileged sites. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 05/2005; 206(3):328 - 336. · 6.32 Impact Factor
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Jettie J F Muris,
Saskia A G M Cillessen,
Wim Vos,
Inge S van Houdt,
J Alain Kummer,
Johan H J M van Krieken,
N Mehdi Jiwa, Patty M Jansen,
Hanneke C Kluin-Nelemans,
Gert J Ossenkoppele,
Chad Gundy,
Chris J L M Meijer,
Joost J Oudejans
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ABSTRACT: We used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL.
Blood 05/2005; 105(7):2916-23. · 9.90 Impact Factor
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Blood 01/2004; 102(12):4243. · 9.90 Impact Factor
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ABSTRACT: In the present study the clinicopathologic and immunophenotypic features of 82 patients with a CD30- peripheral T-cell lymphoma, unspecified, presenting in the skin were evaluated. The purpose of this study was to find out whether subdivision of these lymphomas on the basis of cell size, phenotype, or presentation with only skin lesions is clinically relevant. The study group included 46 primary cutaneous CD30- large cell lymphomas and 17 small/medium-sized T-cell lymphomas as well as 17 peripheral T-cell lymphomas with both skin and extracutaneous disease at the time of diagnosis. Patients with primary cutaneous small- or medium-sized T-cell lymphomas had a significantly better prognosis (5-year-overall survival, 45%) than patients with primary cutaneous CD30- large T-cell lymphomas (12%) and patients presenting with concurrent extracutaneous disease (12%). The favorable prognosis in this group with primary cutaneous small- or medium-sized T-cell lymphomas was particularly found in patients presenting with localized skin lesions expressing a CD3+CD4+CD8- phenotype. In the primary cutaneous T-cell lymphoma (CTCL) group and in the concurrent group, neither extent of skin lesions nor phenotype had any effect on survival. Our results indicate that peripheral T-cell lymphomas, unspecified, presenting in the skin have an unfavorable prognosis, irrespective of the presence or absence of extracutaneous disease at the time of diagnosis, cell size, and expression of a CD4+ or CD8+ phenotype. The only exception was a group of primary cutaneous small- or medium-sized pleomorphic CTCLs with a CD3+CD4+CD8- phenotype and presenting with localized skin lesions.
Blood 10/2003; 102(6):2213-9. · 9.90 Impact Factor
