Robin Russell-Jones

WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects.

Abstract:  The new WHO/EORTC classification for cutaneous lymphomas comprises mature T‐cell and natural killer (NK)‐cell neoplasms, mature B‐cell neoplasms, and immature hematopoietic malignancies. It reflects the unique features of lymphoproliferative diseases of the skin, and at the same time it is as compatible as possible with the concepts underlying the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. This article reviews the histological, phenotypical, and molecular genetic features of the various nosological entities included in this new classification. These findings always have to be interpreted in the context of the clinical features and biologic behavior.

A Shift in the Phenotype of Melan-A-Specific CTL Identifies Melanoma Patients with an Active Tumor-Specific Immune Response

In a significant proportion of melanoma patients, CTL specific for the melan-A26/7–35 epitope can be detected in peripheral blood using HLA-A2/peptide tetramers. However, the functional capacity of these CTL has been controversial, since although they prove to be effective killers after in vitro expansion, in some patients they have blunted activation responses ex vivo. We used phenotypic markers to characterize melan-A tetramer+ cells in both normal individuals and melanoma patients, and correlated these markers with ex vivo assays of CTL function. Melanoma patients with detectable melan-A tetramer+ cells in peripheral blood fell into two groups. Seven of thirteen patients had a CCR7+ CD45R0− CD45RA+ phenotype, the same as that found in some healthy controls, and this phenotype was associated with a lack of response to melan-A peptide ex vivo. In the remaining six patients, melan-A tetramer+ cells were shifted toward a CCR7− CD45R0+ CD45RA− phenotype, and responses to melan-A peptide could be readily demonstrated ex vivo. When lymph nodes infiltrated by melan-A-expressing melanoma cells were examined, a similar dichotomy emerged. These findings demonstrate that activation of melan-A-specific CTL occurs in only some patients with malignant melanoma, and that only patients with such active immune responses are capable of responding to Ag in ex vivo assays.

Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sézary syndrome and mycosis fungoides

Background Data on genome‐wide surveys for chromosome aberrations in primary cutaneous T‐cell lymphoma (CTCL) are limited.

Comparison of Positron Emission Tomography Scanning and Sentinel Node Biopsy in the Detection of Micrometastases of Primary Cutaneous Malignant Melanoma

PURPOSE Sentinel node biopsy (SNB) is a surgical technique for detecting micrometastatic disease in the regional draining nodes. 2-fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scanning is an imaging technique that can detect clinically undetectable metastases. This prospective study was undertaken to compare the sensitivity of FDG-PET scanning with SNB in the detection of micromatastatic malignant melanoma. PATIENTS AND METHODS Fifty consecutive patients (23 women, 27 men; mean age, 53 years) with primary melanoma >1 mm thick or lymphatic invasion were recruited (mean, 2.41 mm). Primary lesions had been narrowly excised (<1 cm). Patients underwent PET scanning followed by SNB, using a dual technique. Preoperative lymphoscintigraphy was used to identify the draining basin. Lymph nodes were examined histologically and immunostained for S100 and HMB 45. RESULTS The sentinel node (SN) was identified in all patients. Fourteen patients (28%) had positive SNBs, including eight patients with melanoma <1.5 mm thick. In none of these 14 patients did PET scans identify metastatic disease in the SN or draining basin. In seven patients, the PET scans were positive in other locations, and in four cases, this was suspicious of metastatic disease. However, no patient has developed recurrent melanoma (mean follow-up, 15 months). All patients with positive SNBs underwent therapeutic lymph node dissection. Further lymph node involvement was found in two patients (primary lesions, 1.3 mm and 3.5 mm thick). CONCLUSION This study demonstrates the limitations of FDG-PET scanning in staging patients with primary melanoma. SNB is the only reliable method for identifying micrometastatic disease in the regional draining node.

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

Background The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas and in a lower percentage of systemic high‐grade diffuse large B‐cell lymphomas. The translocation results in the juxtaposition of the bcl‐2 gene on chromosome 18 with the immunoglobulin heavy chain joining region on chromosome 14. Bcl‐2 protein prevents apoptosis and the translocation leads to overexpression of a functionally normal Bcl‐2 protein that prevents apoptosis of neoplastic cells.

Evidence-based practice of photopheresis 1987-2001: a report of a workshop of the British Photodermatology Group and the U.K. Skin Lymphoma Group.

Photopheresis or extracorporeal photochemotherapy (ECP) is a novel immunomodulatory therapy which involves separation of the patients leucocyte‐rich plasma, followed by ex vivo administration of a photosensitizer and ultraviolet A radiation, before reinfusion. ECP has been used successfully for the treatment of cutaneous T‐cell lymphoma (CTCL: Sézary syndrome), graft‐versus‐host disease (GVHD) and cardiac transplant rejection. ECP has a dose‐sparing effect on concurrent immunosuppressive therapy. The procedure induces apoptosis of the irradiated lymphocytes, but the exact mechanism by which ECP exerts its therapeutic effect in these different conditions is uncertain. The treatment has very few adverse effects and in particular is not associated with an increased incidence of opportunistic infections. The evidence for the efficacy of ECP has been appraised by a combined British Photodermatology Group and U.K. Skin Lymphoma Group workshop on the basis of evidence published up to the end of 2001 and on the consensus of best practice. There is fair evidence for the use of ECP in erythrodermic CTCL and steroid‐refractory GVHD, but randomized controlled studies are needed. There is good evidence supporting the use of ECP in preventing cardiac rejection following transplantation. Randomized controlled trials have also shown a therapeutic benefit in type 1 diabetes mellitus, but the inconvenience associated with the procedure outweighed the clinical benefit. There is fair evidence not to use ECP for the treatment of systemic sclerosis and multiple sclerosis, and good evidence not to use ECP for other forms of CTCL.

Outcome in 34 patients with juvenile-onset mycosis fungoides - A clinical, immunophenotypic, and molecular study

Mycosis fungoides (MF) is predominantly a disease of older patients, but occasionally occurs in children. The aims of the current study were to describe the clinical presentation, pathologic features, and disease progression (DP) in patients who developed MF before age 16 years.

Comparative genomic hybridization analysis of primary cutaneous B-cell lymphomas: Identification of common genomic alterations in disease pathogenesis

To investigate genetic alterations in primary cutaneous B‐cell lymphomas (PCBCLs), we have analyzed 29 cases of PCBCL. Comparative genomic hybridization showed chromosome imbalances (CIs) in 12 cases (41%). The mean number of CIs per sample was 2.05 ± 2.97, with gains (1.48 ± 2.38) more frequent than losses (0.56 ± 1.40). The common regions of gains were 18/18q (50%), 7/7p (42%), 3/3q (33%), 20 (33%), 1p (25%), 12/12q (25%), and 13/13q (25%), whereas loss of 6q was frequent (42%). Among the different subsets of PCBCLs, CI was seen in 50% of diffuse large‐cell lymphomas (DLCLs), 33% of marginal zone lymphomas, and 8% of follicle center cell lymphomas and unclassified lymphomas. A similar pattern of CI was observed in these lymphomas, but loss of 6q and gains of 3/3q were present only in DLCLs. Microarray‐based genomic analysis of four DLCL cases identified oncogene gains of SAS/CDK4 (12q13.3) in three cases and MYCL1 (1p34.3), MYC (8q24), FGFR2 (10q26), BCL2 (18q21.3), CSE1L (20q13), and PDGFB (22q12–13) in two cases, whereas losses of AKT1 (14q32.3), IGFR1 (15q25–26), and JUNB (19p13.2) were identified in three cases, and losses of FGR (1p36), ESR (6q25.1), ABL1 (9q34.1), TOP2A (17q21–22), ERBB2 (17q21.2), CCNE1 (19q13.1), and BCR (22q11) were each identified in two cases. In addition, real‐time–polymerase chain reaction detected amplification of BCL2 in 5 of 29 cases. These findings suggest that there are complex but consistent genetic alterations associated with the pathogenesis of PCBCLs.

Molecular cytogenetic characterization of Sézary syndrome.

Sézary syndrome (SS) is a rare form of erythrodermic cutaneous T‐cell lymphoma with hematological involvement and a poor prognosis. At present little is known about the molecular pathogenesis of this malignancy. To address this issue, we analyzed 28 SS cases through the use of molecular cytogenetic techniques. Conventional cytogenetic analysis showed 12 of 28 cases with clonal chromosome abnormalities (43%). Seven cases had aberrations affecting chromosomes 1 and 17; five demonstrated rearrangement of chromosomes 10 and 14; four presented with an abnormality of 6q. Multiplex‐fluorescence in situ hybridization (M‐FISH) revealed complex karyotypes in 6 of 17 cases (35%), and recurrent der(1)t(1;10)(p2;q2) and der(14)t(14;15)(q;q?) translocations were each identified in two cases, and confirmed by dual‐color FISH. There was an overall difference in the incidence of clonal abnormalities detected by G‐banded karyotyping and M‐FISH. In addition, comparative genomic hybridization studies revealed chromosome imbalances (CIs) in 9 of 20 cases (45%), with a mean DNA copy number change per sample of 1.95 ± 2.74, and losses (mean: 1.25 ± 1.77) more frequent than gains (mean: 0.7 ± 1.26). The most common CIs noted were loss of 1p, followed by losses of 10/10q, 17p, and 19, and gains of 17q and 18. Furthermore, in conjunction with this study a systematic literature review was conducted, which showed a high frequency and consistent pattern of chromosome changes in SS. These findings suggest that chromosomal instability is common in SS, although there are specific chromosomal abnormalities that appear to be characteristic, and the identification of two different recurrent chromosome translocations provides the basis for further studies.

Bexarotene therapy for mycosis fungoides and Sézary syndrome

Background  Bexarotene (Targretin®) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T‐cell lymphoma (CTCL).