Radiotherapy as a Treatment Option for Local Disease Control in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

BACKGROUND: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is an aggressive lymphoma variant. Anthracycline-based chemotherapy with rituximab is recommended as first-line treatment. Radiotherapy (RT) has been considered as a therapeutic option for local disease control in patients with solitary or localized lesions. METHODS: We report the results of a retrospective analysis of PCDLBC, LT patients treated either with RT alone or with physician's decision as first-line treatment, aiming to assess disease progression and/or first recurrence in these treatment groups. RESULTS: We retrospectively analyzed 20 patients treated either with RT alone (n = 8) or with investigator's choice treatment (n = 12), which included chemotherapy alone or combined with local therapy (RT and wide local excision). Complete response (CR) was achieved in 8 patients from the first group and 9 patients from the second group, with 1 treatment failure. Six patients treated with RT alone progressed with a median time to progression (TTP) of 12.5 months. In the second group, 5 patients progressed with a median TTP of 5.2 months. RT showed good local disease control in both groups without any skin relapses during the follow-up period. CONCLUSION: RT as first-line monotherapy followed by watchful waiting did not significantly improve the overall risk of disease progression but resulted in good local disease control. After progression, RT could still easily be combined with systemic treatment. The strength of this analysis needs to be evaluated in a larger patient cohort.

Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two CARD11-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator, NFKBIE. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance.

Primary cutaneous B-cell lymphomas with large cell predominance-primary cutaneous follicle center lymphoma, diffuse large B-cell lymphoma, leg type and intravascular large B-cell lymphoma.

In this review, we present clinical features and detailed histopathologic, immunologic, and molecular information regarding primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type which together represent two of the three most common types of primary cutaneous B-cell lymphoma recognized in the current WHO classification system.1,2 Overall, B-cell lymphomas represent 19-27% of primary cutaneous lymphomas in most large European and American studies3-6 and together, primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type account for approximately 2/3 to ¾ of these cases.5,7-11 Both subtypes can contain a high content of large B-lymphocytes, although most cases of primary cutaneous follicle center lymphomas exhibit a range in cell size and cytology. Intravascular large B-cell lymphoma, a less commonly-encountered EBV-negative primary cutaneous B-cell lymphoma composed of large cells, will be more briefly discussed in this report as well.

Primary cutaneous diffuse large B-cell lymphoma presenting as chronic non-healing ulcer.

Primary cutaneous diffuse large B-cell lymphoma is an uncommon and aggressive lymphoproliferative disorder with a rapid growth rate and dismal prognosis. We present the case of a 91-year-old female with an unusual manifestation of primary cutaneous diffuse large B-cell lymphoma, mimicking other more prevalent diseases like chronic non-healing venous ulceration. Dermatopathologic evaluation rendered the correct diagnosis. A discussion of this rare presentation is important for clinician consideration to prevent misdiagnosis and prolongation of proper management in patients with chronic non-healing leg ulcers.

Spontaneous regression of primary diffuse large B-cell lymphoma, leg type.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL LT) accounts for approximately 20% of all primary cutaneous B-cell lymphomas and tends to present as infiltrated nodules, tumors, and plaques on the legs in the elderly. Unlike other primary cutaneous large B-cell lymphomas, it has a poor prognosis and tends to require treatment with systemic chemotherapy. We present the case of an 82-year-old patient with a 1-year history of nodules and plaques on her right leg. Biopsy led to a diagnosis of PCLBCL LT and the lesions resolved without treatment within 1 month of the first visit. This is an atypical course of PCLBCL LT and we believe that it is the first such case to be reported in the literature.

Rituximab in the treatment of primary cutaneous B-cell lymphoma: a review.

Rituximab is a chimeric mouse-human antibody that targets the CD20 antigen, which is found in both normal and neoplastic B cells. In recent years, it has been increasingly used to treat cutaneous B-cell lymphoma and is now considered an alternative to classic treatment (radiotherapy and surgery) of 2 types of indolent lymphoma, namely, primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma. Rituximab is also administered as an alternative to polychemotherapy in the treatment of primary cutaneous large B-cell lymphoma, leg type. Its use as an alternative drug led to it being administered intralesionally, with beneficial effects. In the present article, we review the literature published on the use of rituximab to treat primary cutaneous B-cell lymphoma.

Primary cutaneous B-cell lymphomas: part II. Therapy and future directions.

The choice of therapy for primary cutaneous B-cell lymphoma (PCBCL) relies on correct histopathologic classification and the exclusion of systemic disease. In part II of this continuing medical education article, we will review the available therapies for the different types of PCBCL. Primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are indolent tumors with an excellent prognosis. They are managed similarly with local therapy, such as radiotherapy or surgical excision, for isolated disease and observation for asymptomatic multifocal presentations. Relapses are common in both PCFCL and PCMZL, but overall survival remains excellent. Primary cutaneous diffuse large B-cell lymphoma (both leg type and other) has a much poorer prognosis than indolent PCBCL, and it often requires an aggressive approach with radiation therapy and/or multiagent chemotherapy. Investigational approaches hold promise for the treatment of these malignancies, particularly primary cutaneous diffuse large B-cell lymphoma.

Primary cutaneous B-cell lymphomas: part I. Clinical features, diagnosis, and classification.

Primary cutaneous B-cell lymphomas (PCBCLs) are defined as lymphomas with a B-cell phenotype that present in the skin without evidence of systemic or extracutaneous disease at initial presentation, after adequate staging. In non-Hodgkin lymphomas, the skin is the second most common site of extranodal involvement after the gastrointestinal tract. PCBCLs are histologically very similar to their nodal counterparts, and these histologic similarities can lead to confusion about both therapy and prognosis. This article will summarize the clinical, pathologic, and diagnostic features of the 3 main types of PCBCL: primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg-type, and the appropriate evaluation and staging procedures for each of these entities.

F-18 FDG PET/CT in staging and response assessment of primary cutaneous diffuse large B-cell lymphoma (leg type).

Primary cutaneous Diffuse Large B-Cell Lymphoma-leg type (PCDLBCL-LT) is a rare subtype of cutaneous lymphomas, with high frequency of extra-cutaneous relapse and poor prognosis. We report a case of 70-year-old lady who was diagnosed with PCDLBCL-LT on biopsy and underwent a baseline F-18 FDG PET/CT, followed by interim and post-treatment PET/CTs. With this case report, we highlight the findings of F-18 FDG PET/CT in the staging of this cutaneous lymphoma, and also emphasize on its role in the response assessment.

Case report: Cryoablation as a novel bridging strategy prior to CAR-T cell therapy for B cell malignancies with bulky disease.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy in relapsed/refractory (R/R) hematological malignancies, especially in R/R B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). To prevent disease progression and reduce tumor burden during CAR-T cell manufacturing, bridging therapies prior to CAR-T cell infusion are crucial. At present, it has been demonstrated that targeted therapy, radiotherapy and autologous stem cell transplantation (ASCT) could serve as effective bridging strategies. However, whether cryoablation could serve as a novel bridging strategy is unknown. In this paper, we report 2 cases of R/R B cell malignancies with bulky disease that were successfully treated with a combination of cryoablation and CAR-T cell therapy. Patient 1 was a 65-year-old female who was diagnosed with R/R MM with extramedullary disease (EMD). She was enrolled in the anti-BCMA CAR-T cell clinical trial. Patient 2 was a 70-year-old man who presented with a subcutaneous mass in the right anterior thigh and was diagnosed with primary cutaneous diffuse large B cell lymphoma, leg type (PCLBCL-LT) 1 year ago. He failed multiline chemotherapies as well as radiotherapy. Thus, he requested anti-CD19 CAR-T cell therapy. Unfortunately, they all experienced local progression during CAR-T cell manufacturing. To rapidly achieve local tumor control and reduce tumor burden, they both received cryoablation as a bridging therapy. Patient 1 achieved a very good partial response (VGPR) 1 month after CAR-T cell infusion, and patient 2 achieved a partial response (PR) 1 month after CAR-T cell infusion. In addition, adverse effects were tolerable and manageable. Our study demonstrated the favorable safety and efficacy of combination therapy with cryoablation and CAR-T cell therapy for the first time, and it also indicates that cryoablation could serve as a novel therapeutic strategy for local tumor control in B cell malignancies.

Primary cutaneous diffuse large B-cell lymphoma, leg type, in a patient with rheumatoid arthritis undergoing etanercept therapy.

An 84-year-old woman, who was diagnosed with rheumatoid arthritis (RA) and was treated with methotrexate and, subsequently, etanercept (ETN) for 6 years, presented with rapidly progressing painful cutaneous mass on the right medial malleolus. The patient was eventually diagnosed with primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT). ETN therapy was promptly discontinued expecting spontaneous regression of the lymphoma, which was thought to have developed as other iatrogenic immunodeficiency-associated lymphoproliferative disorders. However, no tumour regression was noted. Chemoimmunotherapy was subsequently initiated, which resulted in partial remission. PCLBCL-LT rarely occurs in patients with RA. Here, we report the first case of PCLBCL-LT that developed in a patient with RA receiving ETN therapy.

Spontaneous regression of primary cutaneous diffuse large B-cell lymphoma, leg type with significant T-cell immune response.

We report a case of histologically confirmed primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) that subsequently underwent spontaneous regression in the absence of systemic treatment. The case showed an atypical lymphoid infiltrate that was CD20+ and MUM-1+ and CD10-. A subsequent biopsy of the spontaneously regressed lesion showed fibrosis associated with a lymphocytic infiltrate comprising reactive T cells. PCDLBCL-LT is a cutaneous B-cell lymphoma with a poor prognosis, which is usually treated with chemotherapy. We describe a case of clinical and histologic spontaneous regression in a patient with PCDLBCL-LT who had a negative systemic workup but a recurrence over a year after his initial presentation.

A Literature Revision in Primary Cutaneous B-cell Lymphoma.

The term "Primary Cutaneous B-Cell Lymphoma" (PCBCL) comprehends a variety of lymphoproliferative disorders characterized by a clonal proliferation of B-cells primarily involving the skin. The absence of evident extra-cutaneous disease must be confirmed after six-month follow-up in order to exclude a nodal non-Hodgkin's lymphoma (NHL) with secondary cutaneous involvement, which may have a completely different clinical behavior and prognosis. In this article, we have summarized the clinico-pathological features of main types of PCBCL and we outline the guidelines for management based on a review of the available literature.

TOX expression in cutaneous B-cell lymphomas.

Thymocyte selection-associated high-mobility group box (TOX) is aberrantly expressed in cutaneous T-cell lymphomas. In a recent study, TOX expression was noted unexpectedly in the follicle center (germinal center) B-cells of reactive lymph nodes and tonsils, used as external controls. To evaluate whether TOX is also expressed by cutaneous B-cell lymphomas, TOX immunohistochemistry was performed on skin biopsies of 44 patients with primary and secondary cutaneous B-cell proliferations. TOX was expressed not only in the reactive follicle center cells of lymph nodes, tonsils, cutaneous lymphoid hyperplasia, and primary cutaneous marginal zone lymphomas, but also by the neoplastic follicle center cells of 16/17 patients with primary cutaneous follicle center lymphoma (PCFCL) and 7/7 patients with cutaneous manifestations of systemic follicular lymphoma (FL). Notably, TOX showed a very similar expression pattern as BCL6, a marker of germinal center B-cells. In 4/10 patients with a BCL6(+) primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT) and in 2/2 patients with a secondary cutaneous BCL6(+) diffuse large B-cell lymphoma (DLBCL), TOX was expressed by more than 50 % of the neoplastic B-cells. In contrast, in 3/3 BCL6(-) PCDLBCL,LT, TOX was completely negative or weakly expressed by a minor proportion of the neoplastic B-cells. In conclusion, TOX is expressed not only by neoplastic T-cells, but also by both reactive and neoplastic follicle center (germinal center) B-cells and a proportion of BCL6(+) PCDLBCL,LT and secondary cutaneous BCL6(+) DLBCL. The functional significance of TOX expression in reactive and neoplastic B-cells remains to be elucidated.

[Primary cutaneous B-cell lymphomas: study of 22 cases]. / Linfomas B cutáneos primarios: estudio de 22 casos.

INTRODUCTION AND OBJECTIVES: Primary cutaneous B-cell lymphoma (CBCL) is a very low prevalence neoplasm and constitutes 25% of all primary cutaneous lymphomas. Our objective was to discover the epidemiological, clinic and histologic characteristics of CBCL in our area. METHODS: Retrospective descriptive study with patients with histologic diagnosis of CBCL followed up in our department between 2004 and 2015. RESULTS: Twenty-two patients with CBCL were included; 65% were men and 35% were women. Follicle centre lymphoma was the most common subtype (41%). Only 3 cases presented with node involvement and one with bone marrow invasion. Five recurrences were detected and one patient died because of the CBCL. DISCUSSION AND CONCLUSIONS: This is one of the first CBCL series in theSpanish population. The incidence, sex, age, subtype distribution, clinical features and immunohistochemical patterns are very similar to those of the other series.