Low-grade Cutaneous B-cell Lymphoma Research Articles

Utility of Systemic Staging in Low Grade B-Cell Lymphomas Presenting in the Skin

Introduction: Cutaneous marginal zone lymphoma (CMZL) and cutaneous follicle center lymphoma/systemic follicular lymphoma presenting in the skin with follicle center histology (CFCL) are low grade cutaneous B-cell lymphomas (CBCL) that present in the skin primarily or involve the skin secondarily as part of a systemic lymphoma. While primary CBCL is unlikely to progress to involve extracutaneous sites, the incidence of secondary skin involvement by a systemic BCL with initial symptoms in the skin is unknown, hence standards of care recommend imaging as an essential part of the initial staging. Our aim was to evaluate the utility of imaging studies and incidence of systemic involvement in patients with low grade BCL presenting initially in the skin.Methods: We retrospectively reviewed medical records of patients with CFCL diagnosed between 1997-2016 evaluated at MSKCC only, and patients with CMZL diagnosed between 1998-2016, evaluated at MSKCC or at Stanford University. Patients were included based on the following inclusion criteria: CMZL/CFCL was diagnosed histologically and confirmed by pathologists at MSKCC / Stanford; skin was the initial site of involvement by the CBCL disease; imaging study (positron emission tomography scan and/or chest, abdomen and pelvic computed tomography scan) was completed within 12 months of diagnosis as part of the initial workup.One hundred and five patients with CFCL patients met all inclusion criteria at MSKCC. Three hundred and six patients with CMZL met all inclusion criteria at MSKCC/Stanford: 183 at MSKCC and 124 at Stanford, 1 patient was seen at both centers. Imaging scan was considered as positive for extracutaneous disease if it was considered by the clinician as suspicious for lymphoma involvement (Table 1).Results: At initial staging, extracutaneous disease was confirmed by biopsy in 3.3% of patients with CMZL vs 13.3% of patients with CFCL. Eleven percent (33/306) CMZL cases vs 30% (31/105) CFCL cases were deemed suspicious for systemic disease on imaging studies by clinicians: of those 45% (15/33) CMZL cases and 58% (18/31) CFCL cases with imaging suggestive of extracutaneous disease were false positives: biopsy was negative for lymphoma or resolution on subsequent imaging. Of the patients with positive imaging followed without histological confirmation: 2/11 CMZL patients and 3/4 CFCL patients progressed with adenopathy, none died of disease (Figures 1A&1B).Among primary CMZL and primary CFCL with a follow up longer than 6 months, 1.5% and 5.6% developed extracutaneous disease. All CMZL cases were clued in by clinical symptoms subsequently confirmed by imaging and biopsy. In the CFCL cases, 3/4 cases were identified by routine imaging and 1/4 by physical examination; 3/4 cases presented with BCL2 positivity on initial pathology.In 13 patients with CMZL patients who had systemic involvement, 2 died due to MZL, one with transformed disease. Among 18 patients with CFCL who had systemic involvement, 2 died secondary to systemic follicular lymphoma, and 1 patient died of complications from bone marrow transplant. Overall clinical outcome for CMZL showed a 10-year disease specific and overall survivals at 97.4% and 90.9% respectively; CFCL showed a 10-year disease specific and overall survivals at 97.3% and 91.3% respectively (Table 2).Conclusion: This study confirms the overall excellent prognosis of both CMZL and CFCL. Incidence of extracutaneous disease was higher in FCL histology than MZL, which should be considered while counseling patients at initial visits and considering imaging studies. After negative initial staging, CMZL patients may be followed clinically without routine imaging. For CFCL, extracutaneous disease was most frequently identified by imaging studies although false positive rates were high. Risk of developing systemic disease is low for both type of CBCLs but higher in primary CFCL. This is the largest study to-date demonstrating the yield of imaging studies at initial staging and for detection of systemic involvement in patients with low grade B-cell lymphomas presenting in the skin. [Display omitted] DisclosuresMoskowitz:Incyte: Research Funding; Seattle Genetics: Honoraria, Research Funding; ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Takeda: Honoraria. Kim:Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Research Funding; Portola: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Horwitz:Forty-Seven: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding.

Expression profile of immunological and vascular mediators in an unusual case of paravertebral primary cutaneous non-Hodgkin lymphoma

Primary cutaneous follicle center lymphoma (PCFCL) is a rare type of indolent, low-grade cutaneous B-cell lymphoma, most frequent in trunk, particularly the head and scalp.

Role of imaging in low-grade cutaneous B-cell lymphoma presenting in the skin

Whole-body imaging is the current standard of care for staging all patients presenting with skin lesions of B-cell lymphomas (BCLs), regardless of skin disease extent; however, supporting data are lacking. To determine the clinical utility of imaging in the detection of systemic involvement in low-grade cutaneous BCLs in the skin. Retrospective cohort analysis of patients presenting with cutaneous lesions of BCLs at Memorial Sloan Kettering Cancer Center and Stanford University during 1997-2016. At initial staging, of the 522 patients, extracutaneous disease was noted in 3.6% and 8.8% of patients with marginal zone lymphoma (MZL, n=306) and follicle center lymphoma (FCL, n=216) histology, respectively. In patients with systemic involvement, imaging alone identified 81.8% (9/11) of MZL cases and 89.4% of follicular lymphoma cases. In primary cutaneous MZL, 1.7% of patients subsequently had extracutaneous involvement (median follow-up 45months), and in primary cutaneous FCL. 3.0% subsequently had extracutaneous involvement (median follow-up 47months). This was a retrospective study. Imaging is effective at identifying patients with systemic involvement in indolent BCLs present in the skin; however, incidence is low. After negative initial staging, primary cutaneous MZL patients may be followed clinically without routine imaging.

Evaluation of the Role of Radiological Imaging and Bone Marrow Biopsy in Staging of Cutaneous B-Cell Lymphoma

Background: Primary cutaneous B-cell lymphoma (PCBCL) refers to B-lymphocyte derived lymphoma that develops in the skin without any extracutaneous involvement at the time of diagnosis. Primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous large B-cell lymphoma (PCLBCL) are the three major entities of PCBCL under the World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification of cutaneous lymphomas. Current guidelines recommend obtaining staging Positron emission tomography/computed tomography (PET/CT) scan or CT scan for all PCBCL, and bone marrow biopsy for at least PCLBCL-leg type variant. However, evidence supporting these recommendations, especially radiological imaging, is lacking.Methods: Data including demographics, white blood cell (WBC) count at diagnosis, lactate dehydrogenase (LDH) at diagnosis, and results of staging CT-scan, PET/CT-scan, single-photon emission computed tomography scan (SPECT-scan), and bone marrow biopsy were collected through chart review on all patients seen at Roswell Park Cancer Institute between 2001-2016 who presented with a skin lesion and had a biopsy diagnostic of B-cell lymphoma. Patients without any radiological imaging at diagnosis and those diagnosed of diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL) prior to cutaneous manifestation were excluded.Results: 67 patients met criteria for this study of whom 97% were Caucasian and 60% were male. Cutaneous biopsies noted follicle center cell histology (16 patients; 24%), marginal zone histology (32 patients; 48%), or large B-cell histology (19 patients; 29%). Staging CT-scan, functional imaging (PET/CT-scan or SPECT-scan), and bone marrow biopsy were performed for 59 (88%), 48 (72%), and 36 (54%) patients respectively (distribution across B-cell lymphomas shown in Figure 1). Radiological imaging studies were over-interpreted in 13 patients. Radiological imaging upstaged diagnosis in 13 patients (8 DLBCL, 3 MZL, 2 FL) while bone marrow biopsy alone upstaged diagnosis in only 1 patient (DLBCL). Together, work-up upstaged diagnosis in patients with cutaneous high-grade lymphoma (large B-cell lymphoma) significantly more than it did for cutaneous low-grade lymphoma (follicle center cell and marginal zone lymphoma) histology (47% vs. 10%; p=0.0018). Presence of B-symptoms correlated with systemic disease (0 patients with PCBCL vs. 4 patients with systemic disease; p=0.0013). However, age (p=0.059), gender (p=0.5418), WBC (p=0.6676), and LDH (p=0.1736) had no correlation with systemic disease.Conclusion: Our single center retrospective analysis showed that staging work-up including radiological imaging (CT-scan or functional imaging like PET/CT-scan) and bone marrow biopsy upstaged the diagnosis in a small minority (10%) of low-grade cutaneous B-cell lymphomas. However, nearly half (47%) of those with cutaneous large B-cell lymphoma histology were found to have systemic disease upon staging. Given the aggressive disease course of large B-cell lymphomas, staging through radiological imaging and bone marrow biopsy should be pursued as currently recommended. However, for low-grade B-cell lymphomas, where even observation is a reasonable management option in selected stage IV patients, staging radiological imaging and bone marrow biopsies could be avoided unless dictated by clinical judgment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Blastic Marginal Zone Lymphoma

Blastic transformation (BT) of marginal zone lymphoma or mucosa-associated lymphoid tissue lymphoma has been mainly reported in the spleen and stomach. Primary cutaneous marginal zone lymphoma that undergoes BT is rare and not well documented. We describe 8 patients with blastic primary cutaneous marginal zone lymphoma and compare the clinical, pathologic, and molecular findings of these patients with 10 cases previously reported in the literature. The cases of blastic marginal zone lymphoma could be categorized into cases of de novo blastic marginal zone lymphoma and large-cell transformation arising in a background of a history of biopsy proven marginal zone lymphoma. The cases of de novo blastic marginal zone lymphoma occurred in elderly patients without any medical history. In each of the cases, the lesions were radiated, not treated, or treated with complete excision without any death due to lymphoma nor was there any evidence of extracutaneous dissemination. Large-cell transformation arising in background of marginal zone lymphoma typically occurred in patients who were younger; 2 of the 4 cases were immunocompromised. The clinical course in each of the cases was aggressive with 3 of the 4 patients succumbing to disseminated disease while 1 patient developed extracutaneous nodal disease. Phenotypically, there was an expression of CD5 in a total of 3 of the 8 cases and CD23 in 3 of the 8 cases. Commonality of B-cell clones was demonstrated in 2 cases where biopsies were available of both the less aggressive appearing marginal zone lymphoma and the transformed biopsies. Cytogenetic abnormalities associated with BT included a deletion of chromosome 7q in all cases tested. Large-cell transformation arising in a patient with a history of marginal zone lymphoma portends a worse prognosis, including death from disseminated disease, whereas a de novo presentation of blastic marginal zone lymphoma may define a clinical course similar to other forms of low-grade cutaneous B-cell lymphoma. The expression of CD5 and CD23 may define a phenotypic profile associated with BT. It is possible that marginal zone lymphomas associated with CD5 and CD23 positivity should be followed more closely and/or treated with radiation and/or complete excision.

Juvenile onset of primary low-grade cutaneous B-cell lymphoma

Cutaneous lymphomas rarely occur in children and adolescents, and are mostly of the T-cell lineage. Low-grade primary cutaneous B-cell lymphoma (CBCL) is extremely rare in individuals under 18 years old. Only 11 patients under 20 years old have been reported in the literature. To evaluate the number of patients younger than 18 years with primary CBCL diagnosed at our centre and to investigate its clinicopathological features, treatment and course in this age group. We reviewed the files of all 90 patients with primary CBCL who attended the Department of Dermatology of our tertiary care university-affiliated centre from 1992 to 2007. Four patients who met study criteria were identified: three girls and one boy. Mean age at diagnosis was 16.6 years (range 16-17). Three patients had cutaneous marginal zone lymphoma (CMZL), and one had a spindle-cell (sarcomatoid) lymphoma, most probably follicular centre cell type. All were treated with the standard regimen used in adults. The mean duration of follow up was 45 months. No extracutaneous progression was noted. At present two of the four patients are in complete clinical remission. In Israel, primary CBCL apparently occurs more often in young patients than reported in the literature. CMZL is the most frequent type. Long follow up is mandatory to assess the biological behaviour of CBCL in the paediatric/adolescent age group.

Low-Dose Palliative Radiotherapy for Cutaneous B- and T-Cell Lymphomas

To determine the efficacy of low-dose palliative radiotherapy for both low-grade malignant cutaneous B-cell lymphomas (CBCLs) and cutaneous T-cell lymphomas (mycosis fungoides). A total of 18 patients with low-grade CBCL (10 primary cutaneous marginal zone B-cell and 8 primary cutaneous follicle center lymphomas) with 44 symptomatic plaques and tumors underwent low-dose (4 Gy in two fractions) local radiotherapy. A total of 31 patients with mycosis fungoides were treated at 82 symptomatic sites, initially with 4 Gy and later with 8 Gy in two fractions. The complete response rate for CBCL lesions was 72%. Of the 44 B-cell lymphoma lesions, 13 were re-treated to the same site after a median of 6.3 months because of persistent (n = 8) or recurrent (n = 5) symptomatic disease. Of the mycosis fungoides patients treated with 4 Gy in two fractions (17 lesions), 70% failed to respond. Increasing the dose to 8 Gy in two fractions yielded a complete response rate of 92% (60 of 65 lesions). The patients in whom low-dose radiotherapy failed were retreated with 20 Gy in eight fractions. Our results have demonstrated that low-dose involved-field radiotherapy induces a high response rate in both CBCL and cutaneous T-cell lymphoma lesions without any toxicity. Therefore, this treatment is now our standard palliative treatment. At progression, it is safe and feasible to apply greater radiation doses.

Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma

Primary cutaneous marginal zone lymphoma is recognized as a unique subset of low-grade cutaneous B-cell lymphoma with indolent course in the current World Health Organization-European Organization on Research and Treatment of Cancer classification system. However, few large series on this entity have been reported, including the new TNM (tumor, (lymph) node, metastasis) classification for non-mycosis fungoides cutaneous lymphomas. We aimed to characterize the clinical features including new TNM classification for non-mycosis fungoides cutaneous lymphomas, as well as outcomes and responses to therapy in 30 patients with primary cutaneous marginal zone lymphoma. Primary cutaneous marginal zone lymphoma typically presents with deep-seated nodular or papular lesions on the upper extremities or trunk (25/30). Disease course is indolent and none of 30 patients died of disease. Sustainable complete remissions were obtained only in patients with T1a (n = 3) and T2a (n = 1) disease. Most patients have persistent stable disease independent of treatment. Two patients developed systemic disease and 5 developed large cell transformation. The average follow-up time was 63 months (range, 3-204 months). Longer follow-up time is needed to determine whether patients with untreated persistent stable disease are at greater risk relative to patients treated aggressively early in the disease course. Primary cutaneous marginal zone lymphoma is a distinct subtype of marginal zone lymphoma with an indolent disease course. Patients with T1a or T2a disease (ie, single lesions or a localized cluster of lesions) may achieve sustained complete remission, whereas patients with multiple nonlocalized lesions are unlikely to maintain complete remission independent of treatment modality. Systemic involvement is typically preceded by large cell transformation and may be an indication for more systemic therapy. Death from disease is rare.

Cutaneous B-cell Pseudolymphoma at the Site of Vaccination

Pseudolymphomas are a rare complication of vaccination, presenting with dense lymphoid infiltrates and prominent follicular pattern. We report our observations on 4 patients with vaccination-induced B-cell pseudolymphoma (all females; age range 19 to 60 years; median: 34.5 years). Clinically 3 patients presented with subcutaneous nodules and 1 presented with a large, indurated, erythematous plaque. Histology revealed in all cases dense lymphoid infiltrates in the subcutaneous fat with prominent follicular pattern. The follicles displayed features of reactive germinal centers (normal mantle zone, presence of tingible body macrophages, normal proliferation). Necrotic areas surrounded by palisaded histiocytes were seen in 3 biopsies from 2 patients. A mixed-cell infiltrate with eosinophils and plasma cells was present in all cases. In addition, histiocytes with granular basophilic cytoplasm could be observed around the focal area of necrosis or within the inflammatory infiltrate. Follow-up was available for 3 patients. One patient was alive with persistent disease 6 months after the first observation. Two patients were treated with local radiotherapy and are alive and free of disease after 12 and 72 months, respectively. One of these two patients had a second pseudolymphoma on the contralateral arm after a new injection of vaccine. Cutaneous pseudolymphoma after vaccination should be distinguished histopathologically from low-grade cutaneous B-cell lymphomas (follicle center cell lymphoma, marginal zone lymphoma) and from other B-cell pseudolymphomas with prominent follicular pattern requiring different treatment (eg, Borrelia burgdorferi-induced lymphocytoma cutis).

Late lethal hepatitis B virus reactivation after rituximab treatment of low-grade cutaneous B-cell lymphoma

The chimeric anti-CD20 monoclonal antibody, rituximab, is a promising treatment for cutaneous B-cell lymphomas. Classically used in combination with a multiagent-chemotherapy regimen, it can sometimes give excellent results alone. Because of its selective action on B lymphocytes, it is considered a moderate immunosuppressant in terms of infection. We describe a woman with relapsed cutaneous follicular centre B-cell lymphoma and secondary lymph-node involvement treated with rituximab alone, which induced a complete remission. One year later, she experienced a fatal hepatitis B virus (HBV) reactivation. Several such HBV reactivations were reported after combined rituximab and multiagent chemotherapy for B-cell lymphomas. This is the first case of HBV reactivation occurring during the year following rituximab monotherapy in the absence of any other immunosuppressive factor.

Cutaneous B-cell lymphoma responds to rituximab: A report of five cases and a review of the literature

Optimal treatment of cutaneous B-cell lymphoma (CBCL) is yet to be established. We treated five patients, each with either extensive lesions, severe comorbidities or who refused treatment with radiation therapy, with rituximab given as a single agent for four weekly intravenous infusions of 375 mg/m2. Maintenance therapy, if initiated, was given at 375 mg/m2 once every 2 – 3 months. Objective clinical responses occurred in all five patients. Three patients have ongoing complete clinical remissions with a median follow-up of 17, 19 and 39 months post achievement of complete remission. One patient died at age 87 years from a non-related cause after 5.5 years of complete remission. One patient received local radiotherapy to a solitary cutaneous site of large-cell lymphoma that developed after 3 years in remission from the low-grade CBCL; no recurrences of either grade CBCL have yet occurred. Treatment was well tolerated. Rituximab is safe and effective in treating of CBCL, either primary CBCL or low-grade lymphomas with relapses limited to the skin. Rituximab appears to present an attractive alternative when radiation therapy is contraindicated or unwanted. Additional collaborative studies are needed to assess the role of rituximab in various clinicopathologic presentations of CBCL.

BCA-1, A B-cell chemoattractant signal, is constantly expressed in cutaneous lymphoproliferative B-cell disorders

We analysed the immunophenotypic and molecular expression of BCA-1 (B-cell-specific chemokine) and CXCR5 (BCA-1 receptor) in normal skin and different cutaneous lymphoproliferative disorders (cutaneous T-cell lymphoma (CTCL); cutaneous B-cell lymphoma (CBCL); cutaneous B-cell pseudolymphoma (PCBCL)), with the aim of investigating their possible involvement in the pathogenesis of cutaneous B-cell disorders. BCA-1 and CXCR5 were constantly expressed in CBCL and PCBCL, but not in normal skin and CTCL. BCA-1 and CXCR5 were constantly coexpressed by CD22+ B-cells, while CD35+ follicular dendritic cells coexpressed BCA-1 in PCBCL cells only. In low grade CBCL, as compared with high grade CBCL, the intensity of CXCR5 expression on neoplastic CD22+ cells was lower than that of BCA-1. The image analysis of reverse transcriptase-polymerase chain reaction (RT-PCR) products showed a significant quantitative difference between PCBCL/low grade CBCL and high grade CBCL. The above findings, although only observed in a small series of patients, are in keeping with findings in MALT gastric and gastric MALT lymphomas, adding further evidence of the close similarities between CBCL and MALT lymphomas.