Mycosis Fungoides and Granulomatous Slack Skin: A Single Entity With Distinct Clinical Phenotypes.

ABSTRACT: Granulomatous cutaneous T-cell lymphoma includes mycosis fungoides with significant granulomatous inflammation (GMF) and granulomatous slack skin (GSS), listed in the WHO classification as a subtype of mycosis fungoides (MFs). 1 These overlapping entities have shared clinical and histopathologic features which can present a diagnostic challenge. The dominance of the granulomatous infiltrate and the often sparse lymphocytic infiltrate frequently with minimal cytological atypia are features that distract from the correct diagnosis, even when raised by the clinician. We describe the clinical and histopathologic characteristics of 3 cases of granulomatous cutaneous T-cell lymphoma, illustrate the close clinical and pathologic relationship between GMF and GSS and emphasize the diagnostic difficulties that the granulomatous infiltrate can present. Furthermore, we demonstrate, for the first time, considerable elastolysis in a significant proportion of classical (Alibert-Bazin) MF lesions and therefore postulate that the differences observed between GMF and GSS are one of degree and secondary to their anatomic location rather than reflecting meaningful separate entities.

Service improvement in a nurse-led clinic for extracorporeal photopheresis.

The skin tumour unit at one London hospital has been providing extracorporeal photopheresis (ECP) treatment since 2012, using an online fully integrated system. This report summarises 9 years of continuous process improvement, which has enabled the team to meet the growing demand for ECP treatments for cutaneous T-cell lymphoma (CTCL) and graft-versus-host disease (GvHD) patients. The unit formed a partnership with a lean-management company to go through the process of evaluation of capacity constraints, design layout and patient scheduling. METHODS: Increased capacity year-on-year and over the 9-year period was calculated based on data collected from records. The authors reviewed the nurse staffing resources allocated for ECP treatments over the same period, and financial value created by the continuous improvement (additional number of treatments multiplied by the national tariff for ECP treatments). RESULTS: In 2012 the average number of ECP treatments per nurse per week was 11. With the implementation of the new planning tool, and improved working practices, the average number of treatments per nurse per week has more than doubled to 23. Nurse staffing was maintained at 4 nurses per shift to deliver ECP treatments. The unit recorded additional revenue of approximately £3.2 million in 2020 compared with 2012. CONCLUSIONS: The team has successfully increased the capacity of the service to deliver treatments without incurring any additional nursing costs, resulting in more patients with CTCL and GvHD being able to access ECP treatment and a cost benefit for the Trust. The service continues in its mission to grow and provide a superior patient experience.

Follicular T-Helper Cells in Marginal Zone Lymphoma: Evidence of an Organoid Immune Response.

INTRODUCTION: Primary cutaneous marginal zone B-cell lymphoma (MZL) follows an indolent clinical course. Histopathologically, there is a polymorphous infiltrate that includes small lymphocyte-like and centrocyte-like B cells and plasma cells usually with a substantial T-cell fraction. Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, in which the signature cells have a follicular T-helper (TFH) phenotype and are admixed with numerous B cells. Thus, both present histologies of combined B-cell and T-cell infiltrates and represent differential diagnoses. The presence of TFH in MZL has yet to be elucidated. METHODS: Forty-one biopsies from 40 cases of MZL and 7 cases of lymphoid hyperplasia cutis (LCH) were stained with antibodies to follicular T-helper cells, including Bcl-6, PD-1, ICOS, and CD10, as part of their diagnostic workup, were reviewed, and the stained slides were evaluated semiquantitively. Five reactive lymph nodes were also evaluated as controls. RESULTS: All cases of MZL and LCH contained TFH, albeit usually in low proportions. There were repeated differences in levels of expression between TFH markers, with PD1 and Bcl-6 being the most prevalent. The pattern of involvement in MZL and LCH closely mirrored that observed in the reactive lymph nodes. CONCLUSION: MZL includes TFH cells, similar to reactive lymph nodes, and a complexity of cell types. This provides evidence of an organoid immune response challenging its simple categorization as a malignancy.

The Results of Low-Dose Total Skin Electron Beam Radiation Therapy (TSEB) in Patients With Mycosis Fungoides From the UK Cutaneous Lymphoma Group.

PURPOSE: Total skin electron beam radiation therapy (TSEB) is a very effective treatment of mycosis fungoides. Following reports of similar durations of response to lower doses of TSEB, a low-dose schedule of TSEB was introduced in the United Kingdom. METHODS AND MATERIALS: A protocol of 12 Gy in 8 fractions over a period of 2 weeks was agreed on by use of the Stanford University technique. Data were collected prospectively, and the results were analyzed according to the European Organisation for Research and Treatment of Cancer-International Society for Cutaneous Lymphomas endpoints (EORTC-ISCL). Toxicity was scored according to CTCAE v4.0 (Common Terminology Criteria for Adverse Events version 4.0). RESULTS: One hundred three patients received treatment, with a median follow-up period of 20.6 months (range, 3.3-53 months). Of these patients, 54 had stage IB disease, 33 had stage IIB, 12 had stage III, and 4 had stage IV. The median age was 68 years (range, 26-91 years). The complete response rate was 18%, the partial response rate was 69%, stable disease was present in 8%, and progression on treatment was found in 5%. In the patients who had a complete response, the median time to relapse was 7.3 months. The median response duration was 11.8 months. Median progression-free survival for all patients was 13.2 months. It was significantly longer, at 26.5 months, in patients with stage IB disease compared with 11.3 months in patients with stage IIB (P=.003; hazard ratio, 2.66) and 10.2 months in patients with stage III (P=.002; hazard ratio, 4.62). The treatment was well tolerated with lower toxicity than higher-dose schedules. CONCLUSIONS: The low-dose TSEB schedule of 12 Gy in 8 fractions over a period of 2 weeks is well tolerated and is an effective option for patients with mycosis fungoides.

The role of extracorporeal photopheresis in the management of cutaneous T-cell lymphoma, graft-versus-host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society.

Extracorporeal photopheresis (ECP) has been used for over 35 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic and acute graft-versus-host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP. The recent literature has been reviewed and considered when writing this update. Most notably, the national transition from the UVAR XTS® machine to the new CELLEX machine for ECP with dual access and a shorter treatment time has led to relevant changes in these schedules. This consensus statement updates the previous statement from 2007 on the treatment of CTCL and GvHD with ECP using evidence based medicine and best medical practise and includes guidelines for both children and adults.

Temozolomide for central nervous system involvement in mycosis fungoides.

BACKGROUND: The central nervous system (CNS) is one of the most commonly involved sites in the systemic progression of primary cutaneous T cell lymphomas (CTCLs) such as mycosis fungoides (MF). There is no consensus on the treatment of CNS progression in CTCL, but survival of 3-6 months is suggested when methotrexate-based chemotherapy and/or CNS irradiation is used. Temozolomide is active in earlier stages of MF and readily crosses the blood-brain barrier. There are no published data on its use in MF patients with CNS involvement. METHODS: Four MF patients were treated with oral temozolomide (200 mg/m(2) per day for 5 d on a 28-day cycle) for CNS progression. Two patients received temozolomide with low-dose CNS irradiation as initial treatment, and two received temozolomide following disease progression after methotrexate-based chemotherapy and CNS irradiation. All patients received dexamethasone. RESULTS: Temozolomide was well tolerated; there were no treatment withdrawals or dose reductions caused by toxicity. Patient 1 had an excellent partial response in pre-irradiated disease. Patient 2 showed disease stabilization following irradiation. Patient 3 showed a complete response after a partial response to irradiation. Patient 4 demonstrated continued stabilization after a partial response to irradiation. Overall survival ranged from 10 to 33 months. Patient 3 remains alive and symptom-free at 23 months following treatment. CONCLUSIONS: Temozolomide following low-dose CNS irradiation appears to be well tolerated and effective in MF patients with CNS progression. It may represent a less toxic alternative to chemotherapy containing methotrexate or an option for second-line therapy.

Chromosomal anomalies in primary cutaneous follicle center cell lymphoma do not portend a poor prognosis.

BACKGROUND: The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas but only rarely in primary cutaneous follicle center cell lymphomas (PCFCL). Recent studies have postulated that the translocation is more prevalent in PCFCL than previously described and that it might be a molecular prognostic marker. OBJECTIVES: The purpose of our study was to analyze cases of PCFCL for the presence of a t(14;18) translocation using fluorescence in situ hybridization to detect balanced translocations involving either the BCL2 or MALT1 loci and to correlate the results with growth pattern, immunophenotype, and clinical outcome. METHOD: In all, 57 patients with PCFCL were extracted from our cutaneous lymphoma database. Retrospective analysis of clinical parameters including lesion type, location, diagnostic stage, lactate dehydrogenase, initial treatment, relapse rate, and survival was performed. RESULTS: In all, 57 patients with PCFCL were included in this study. We detected 1 BCL2 chromosomal amplification, 4 translocations of BCL2, and 1 IGH/MALT1 translocation. LIMITATIONS: This was a case series retrospective study. CONCLUSIONS: PCFCL has an excellent 5-year overall survival (100% disease-specific survival). Chromosomal abnormalities of either BCL2 or MALT1 were detected in 10% of cases but do not correlate with a specific immune pathology or clinical outcome.

Evaluation of follicular T-helper cells in primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma and dermatitis.

BACKGROUND: CD4+ small/medium-sized pleomorphic T-cell lymphoma (SMPTCL) is a controversial primary cutaneous lymphoma, in which the candidate neoplastic cells express a follicular T-helper phenotype. We describe 16 cases of SMPTCL and compare expression of PD-1, CXCL-13 and ICOS in these tumors with 40 dermatitis cases. METHODS: Histopathologic examination and immunocytochemistry were performed for 16 tumors and 40 assorted dermatitis cases. RESULTS: All but one patient presented with solitary lesions. Each biopsy revealed a dense nodular non-epitheliotropic infiltrate of atypical T-cells. Neoplastic cells were CD3+/CD4+/CD8(-)/CD30(-). Cutaneous recurrence occurred in one patient over a median follow up of 8 months (range 5-36). All tumors widely expressed PD-1 and ICOS to a lesser extent. CXCL-13 stained much fewer cells. Of the dermatitis cases, PD-1 (most numerous) and ICOS labeled lymphoid cells in all cases, albeit fewer than in the tumors, and CXCL-13 was negative in 32. A rosette pattern of PD-1 expression was identified in all the SMPTCL cases but not in dermatitis. CONCLUSIONS: There remains uncertainty about the appropriate nosological status of SMPTCL, which some authors consider to be a pseudolymphoma. However, this study suggests a significant difference in the prevalence and pattern of follicular T-helper cell markers between this tumor and lymphoid proliferations known to be reactive.

Results of a 5-week schedule of modern total skin electron beam radiation therapy.

PURPOSE: To report the outcomes of a 5-week schedule of total skin electron beam radiation therapy (TSEB) for mycosis fungoides (MF). METHODS: Over 5 years, 41 patients with confirmed MF were treated with a modern TSEB technique delivering 30 Gy in 20 fractions over 5 weeks to the whole skin surface. Data were collected prospectively and entered into the skin tumor unit research database. Skin modified skin weighted assessment tool score data were collected to determine response, duration of response, survival, and toxicity. The outcomes were analyzed according to the patient's stage before TSEB, prognostic factors, and adjuvant treatments. RESULTS: Seventeen patients were stage 1B, 19 were stage IIB, 3 were stage III, and 2 were stage IV. The overall response rate was 95%, with a complete response rate of 51%. Seventy-six percent of patients had relapsed at median follow-up of 18 months. The median time to relapse was 12 months, to systemic therapy was 15 months, and to modified skin weighted assessment tool progression above baseline was 44 months. The complete response rate was 59% in stage IB and 47% in stage IIB patients. The median time to skin relapse was longer in stage IB compared with stage IIB, 18 months versus 9 months. The median time to systemic therapy was longer in stage IB compared with stage IIB, >56 months versus 8 months. The median overall survival was 35 months: >56 months for stage IB, 25 months for stage IIB, 46 months for stage III, and 23.5 months for stage IV. Fifteen patients received adjuvant psoralen + ultraviolet A treatment with no difference seen in the time to relapse. CONCLUSIONS: This 5-week schedule of TSEB for MF has a high response rate with comparable duration of response to other regimens. Future studies are needed to find adjuvant and combination treatments to improve the duration of response.

Indolent CD8(+) lymphoid proliferation of acral sites: a clinicopathologic study of six patients with some atypical features.

The authors report six further cases of a cutaneous lymphoid proliferation that share many of the features of a case series previously described as indolent CD8-positive lymphoid proliferation of the ear. Previous reports of this entity have described the slow growth of cutaneous papules and nodules, with a predilection for the ear, associated with specific histopathologic and immunophenotypic features and a benign clinical course. These include the presence of a clear Grenz zone without epidermotropism, and a CD8(+) granzyme B- immunophenotype with a low proliferative index. The current case series presents some atypical clinical features, including site of disease beyond the ear and recurrent disease. Despite this, indolent clinical evolution is apparent. Histopathologically, three of the six cases showed a moderate-high proliferative index, while two cases had very focal epidermotropism and Pautrier collections. A single example had significant granzyme B expression. These previously unreported features add to our understanding of this rare entity, which is not currently recognized in the World Health Organization (WHO)/European Organization for Research and Treatment of Cancer (EORTC) classification.

Solitary mycosis fungoides: a distinct clinicopathologic entity with a good prognosis: a series of 15 cases and literature review.

BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL), accounting for almost 50% of all primary cutaneous lymphomas. The occurrence of solitary lesions, which are clinically and histopathologically indistinguishable from classic MF has been described. OBJECTIVE: We describe 15 cases of solitary MF and discuss the relationship to classic MF, "reactive" processes and to other, rarer forms of CTCL that may present with solitary lesions. METHODS: We conducted a retrospective chart review and a PubMed search to identify all reported cases of solitary MF to date, as well as information about other CTCLs presenting as a solitary lesion. RESULTS: Fifteen patients were identified. Follow-up data were available on 10 patients with a median follow-up of 10 months (range, 1 to 48 months). Clinical, pathological, immunocytochemical, and molecular-genetic features were analyzed. Five cases were diagnosed as folliculotropic MF (FMF). Of the 10 cases with follow-up, 2 were treated with topical steroids, 2 were completely excised, 5 received radiotherapy, and 1 received tacrolimus. One hundred twenty-eight cases of solitary MF were identified in the literature and reviewed for commonalities to and differences with our cases and other CTCLs. LIMITATIONS: This study was retrospective; follow-up data were not available in some cases and were only short term in others. CONCLUSIONS: Solitary MF appears to have a good prognosis. In lesions that are not completely excised, curative radiotherapy can be used. Long-term follow up is advised.

Genomic alterations in blastic natural killer/extranodal natural killer-like T cell lymphoma with cutaneous involvement.

Natural killer and natural killer-like T cell lymphomas represent a rare type of non-Hodgkin's lymphoma originally described to involve the upper aerodigestive tract. This malignancy has been increasingly observed in other extranodal sites, particularly in the skin. Patients with cutaneous natural killer cell lymphoma generally have a poor prognosis; however, the etiology and the underlying molecular pathogenesis remain unclear. This study aimed to investigate comprehensively genomic changes in blastic natural killer and extranodal natural killer-like T cell lymphoma with cutaneous involvement. Comparative genomic hybridization showed chromosome imbalances in six of eight cases studied (75%). The mean number of chromosome imbalances per sample was 2.18+/-1.63 with similar number of gains (1.18+/-1.17) and losses (1.00+/-1.34). The most frequent DNA copy number changes observed were losses of 9/9p (83%), followed by loss of 13q and gain of 7 (67%). Similar patterns of chromosome imbalances were observed in both blastic natural killer and cutaneous natural killer-like T cell lymphomas. Loss of the RB1 gene at 13q14.2 was detected in one blastic natural killer cell lymphoma with 13q loss using a gene dosage assay, and in one cutaneous natural killer-like T cell lymphoma without 13q loss using fluorescent in situ hybridization. Genomic microarray analysis identified oncogene copy number gains of PAK1 and JUNB in three of four cases studied, and gains of RAF1, CTSB, FGFR1, and BCR in two cases. Real-time polymerase chain reaction detected amplification of CTSB and RAF1 in four of five cases analyzed, JUNB and MYCN in three cases, and REL and YES1 in two cases, respectively. In conjunction with this study, an extensive literature search for the published G-banded karyotypes of four subsets of natural killer cell lymphomas was conducted, which showed a nonrandom pattern of multiple chromosome aberrations. These results reveal consistent genetic alterations in cutaneous natural killer cell lymphomas, and provide a basis for further investigation of molecular pathogenesis in this malignancy.

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.

Inactivation of tumor suppressor genes p15(INK4b) and p16(INK4a) in primary cutaneous B cell lymphoma.

Primary cutaneous B cell lymphomas represent a distinct group of lymphoproliferative disorders that can be distinguished from systemic lymphoma by their good response to local treatment and favorable prognosis. In systemic B cell lymphoma, inactivation of p15(INK4b) and p16(INK4a) is frequently observed and may be associated with a poor prognosis. There have been no comprehensive studies in primary cutaneous B cell lymphomas, however. Mechanisms of p15/p16 inactivation include loss of heterozygosity, homozygous deletion, promotor region hypermethylation, and point mutation. We analyzed DNA from 36 cases of primary cutaneous B cell lymphomas, four systemic B cell lymphomas, and six benign B cell lymphoproliferative infiltrates for abnormalities of p15 and p16 using microsatellite markers for 9p21, methylation specific polymerase chain reaction, and polymerase chain reaction/single stranded conformational polymorphism analysis with exon specific primers. Expression of both p15 and p16 protein was assessed by immunohistochemistry. Loss of heterozygosity at 9p21 was identified in 2 out of 36 primary cutaneous B cell lymphomas. Hypermethylation of p15 and p16 promotor regions was identified in 8 of 35 (23%) and 15 of 35 (43%) cases, respectively. In two cases p16 hypermethylation was identified in recurrent disease but not in the initial tumor. No point mutations were identified. In seven patients, however, a polymorphism was observed in exon 3 of the p16 gene. In primary cutaneous B cell lymphomas with allelic loss or promotor hypermethylation of either p15 or p16, loss of expression in tumor cells was identified in 5 of 8 and 9 of 10 cases, respectively. Our findings suggest that p15(INK4b) and p16(INK4a) biallelic gene abnormalities are common in primary cutaneous B cell lymphomas, most frequently as a result of promotor hypermethylation. The presence of abnormalities in recurrent disease in some cases suggests that inactivation of p15 and p16 may be involved in disease progression.