Primary cutaneous marginal zone lymphoproliferative disorder following COVID-19 vaccination.

During the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccines were administered worldwide. A number of skin reactions, including primary cutaneous T-cell lymphoproliferative disorders (LPDs) were reported following COVID-19 vaccination. We report a case of primary cutaneous marginal zone lymphoproliferative disorder (PCMZLPD) secondary to COVID-19 vaccination. A 57-year-old man presented with an erythematous nodule on his left arm at the site of vaccine inoculation following his first dose of the Moderna (mRNA-1273) vaccine a few weeks prior. The nodule continued to progress in size after the second dose. A skin biopsy specimen of the nodule showed a diffuse dermal infiltrate of small to medium-sized lymphocytes with plasma cells and histiocytes. The infiltrate was composed of CD3+ T cells with CD20+ and CD79a+ B cells. The neoplastic B cells reacted with BCL-2 and were negative for BCL-6 and CD10. Kappa light chain restriction was identified by in situ hybridization. Gene rearrangement studies revealed kappa light chain monoclonality, confirming the diagnosis of PCMZLPD. The temporal association with the Moderna vaccination and the occurrence of the lesion at the inoculation site indicate a COVID-19 vaccination-induced PCMZLPD. This is one of the rare cases of PCMZLPD following COVID-19 vaccination.

Primary cutaneous lymphoproliferations in the gray zone between marginal zone lymphoma and CD4+ small/medium T-cell lymphoproliferative disease.

BACKGROUND: Primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disease (CD4+ TLPD) are two distinct entities with excellent prognosis; however, they show profound clinical and histopathological similarities, leading to differential diagnostic uncertainty. AIMS: Our aim was to review and reanalyze cases of primary cutaneous lymphoproliferations diagnosed at Semmelweis University, featuring characteristics of PCMZL and CD4+ TLPD. MATERIALS AND METHODS: Cutaneous lymphoma biopsy specimens between 2018 and 2022 were collected and re-evaluated. Medical history, clinical picture, imaging, and laboratory findings were collected. Immunohistochemical staining for CD20, CD3, BCL6, CD10, PD1, CD3, CD4, CD8, and PCR tests for IGH, IGK, TCRB, and TCRG were repeated in selected cases. RESULTS: Among 55 cases diagnosed as PCMZL (16) or CD4+ TLPD (39), 3 patients had been diagnosed with both LPDs at different time points of their disease course. Four additional patients were identified with single lesions featuring overlapping histopathological characteristics of both LPDs and both monoclonal IGH and TCR rearrangements. All patients are currently in complete remission with local treatment. CONCLUSION: We propose that besides the overlapping histopathological, molecular, and clinical features, the subsequent appearance of PCMZL and CD4+ TLPD in a short timeframe in the same patients may suggest a common pathogenic background.

Cutaneous lymphoproliferative disorders: Back to the future.

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan-T-cell antigens and clonal T-cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T-cell proliferations, and monotypic immunoglobulin light-chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B-cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T-cell lymphoma (PCSM-TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T-cell or B-cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low-grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease-specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low-grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM-TCL as primary cutaneous CD4+ small/medium T-cell LPD and primary cutaneous acral CD8+ T-cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term "primary cutaneous marginal zone LPD," in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

Long-term Therapeutic Success of Intravenous Rituximab in 26 Patients with Indolent Primary Cutaneous B-cell Lymphoma.

Systemic monotherapy with rituximab is a well-known treatment approach for primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone lymphoma. Both have excellent prognosis despite high relapse rates. To investigate the long-term effectiveness and clinical outcome of intravenous rituximab at a dose of 375 mg/m2 once weekly, data for 26 patients (17 primary cutaneous follicle centre lymphoma and 9 primary cutaneous marginal zone lymphoma) were analysed retrospectively. Complete remissions occurred in 20 (77%) and partial remissions in 6 patients (23%), demonstrating an overall response rate of 100%. The relapse rate was 52.9% in primary cutaneous follicle centre lymphoma and 88.9% in primary cutaneous marginal zone lymphoma. Ongoing complete remissions after therapy with rituximab were observed in 9 patients (34.6%) with a median progression-free survival of 161 months (13.4 years). These results confirm that intravenous rituximab is an effective and well-tolerated treatment with durable responses in a relevant percentage of patients at a median follow-up of 148 months (12.3 years).

Nodules on the Knee in a Child: A Quiz.

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Cutaneous marginal zone lymphomas.

Primary cutaneous marginal zone lymphoma (CMZL) is one of the major primary B-cell lymphomas of skin. Two types are recognized: a more common class-chain switched CMZL, and a much less common IgM+ CMZL. The extremely indolent course, together with other features distinct from most other MALT lymphomas, has led some to question whether at least the class-switched cases should be considered an overt lymphoma.

Marginal zone lymphoma with severe rashes: A case report.

BACKGROUND: Marginal zone lymphoma (MZL) is an indolent subtype of non-Hodgkin lymphoma (NHL), which is rare clinically with severe rashes as the initial symptom. CASE SUMMARY: This study reports a case of MZL with generalized skin rashes accompanied by pruritus and purulent discharge. First-line treatment with rituximab combined with zanubrutinib had poor effects. However, after switching to obinutuzumab combined with zanubrutinib, the case was alleviated, and the rashes disappeared. CONCLUSION: For patients with advanced stage MZL not benefiting from type I anti-CD20 monoclonal antibody (mAb) combination therapy, switching to a type II anti-CD20 mAb combination regimen may be considered. This approach may provide a new perspective in the treatment of MZL.

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.

Incidence of cutaneous melanoma and Merkel cell carcinoma in patients with primary cutaneous B-cell lymphomas: A population study of the SEER registry.

Introduction: The increased incidence of cutaneous melanoma (CM) and Merkel cell carcinoma (MCC) in patients with hematologic malignancies (HM) is well established. While the risk of CM has been assessed in some subtypes of HM including cutaneous T-cell lymphoma, the incidence in patients with primary cutaneous B-cell lymphoma (PCBCL) has not been interrogated. Methods: Here we evaluated the standardized incidence ratio (SIR) of CM and MCC in 5,179 PCBCL patients compared to approximately 1.5 billion individuals in the general population using the Surveillance, Epidemiology and End Results (SEER) database. Among patients with PCBCL, we identified subgroups that were at increased risk for CM or MCC as a second primary cancer. Results: We found 36 cases of CM in the PCBCL cohort (SIR, 1.35; 95% CI, 0.94-1.86), among which SIR was significantly elevated for non-Hispanic White patients compared to the general population (SIR, 1.48; 95% CI, 1.03-2.06). Males had a significantly increased risk of developing CM after a diagnosis of PCBCL (SIR, 1.60; 95% CI, 1.10-2.26). We found that males in the age group of 50-59 were at increased risk for CM development (SIR, 3.02; 95% CI, 1.11-6.58). Males were at increased risk of CM 1-5 years after PCBCL diagnosis (SIR, 2.06; 95% CI, 1.18-3.34). Patients were at greater risk of developing MCC within 1 year of diagnosis of PCBCL (SIR, 23.60; 95% CI, 2.86-85.27), particularly in patients who were over the age of 80 (SIR, 46.50; 95% CI, 5.63-167.96). Males aged 60-69 with PCBCL, subtype marginal zone, were also at increased risk for MCC (SIR, 42.71; 95% CI, 1.08-237.99). Conclusion: There is an increased incidence of CM in White, middle-aged males within 5 years of diagnosis of PCBCL and an increased risk of MCC in elderly patients within 1 year of PCBCL diagnosis. These data suggest that certain subgroups of patients with PCBCL may require more rigid surveillance for CM and MCC.

A Practical Review of the Presentation, Diagnosis, and Management of Cutaneous B-Cell Lymphomas.

This review of cutaneous B-cell lymphoma (CBCL) is focused on the clinical presentation, treatment, and workup of each type of lymphoma. Part 1 is an overview of each of the CBCLs, including clinical presentation, recent advances in the pathobiology, and evidence regarding treatment strategies. Part 2 is a detailed guide to the steps in diagnosis and workup of a newly diagnosed CBCL according to the International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer and NCCN guidelines.

Cutaneous Involvement in Diseases with Plasma Cell Differentiation: Diagnostic Approach.

Neoplasms with plasma cell differentiation may occasionally involve the skin. Cutaneous lesions may represent the first sign of an underlying systemic plasma cell malignancy, such as multiple myeloma, or the skin itself may be the primary site of occurrence of a hematological tumor with plasma cell differentiation. Starting from examples encountered in our daily practice, we discussed the diagnostic approach pathologists and clinicians should use when faced with cutaneous lesions with plasma cell differentiation. Cases of primary cutaneous marginal zone lymphoma, localized primary amyloidosis/amyloidoma, and cutaneous manifestations (secondary either to multiple myeloma or to plasmablastic lymphoma) are discussed, focusing on the importance of the adequate patient's work-up and precise clinicopathological correlation to get to the correct diagnosis and appropriate treatment. The pertinent literature has been reviewed, and the clinical presentation, pathological findings, main differential diagnoses, treatment, and outcome of neoplasms with plasma cell differentiation involving the skin are discussed.

Characterization of Primary and Secondary Cutaneous B-Cell Lymphomas: A Population-Based Study of 4758 Patients.

INTRODUCTION/BACKGROUND: Cutaneous B-cell lymphomas are a heterogeneous group of rare malignancies whose specific site tropisms and site-specific survival have not been well documented. In this study, we seek to investigate the frequency and survival for primary and secondary cutaneous MZL (pcMZL and scMZL), primary and secondary cutaneous FCL (pcFCL and scFCL), and primary and secondary cutaneous DLBCL (pcDLBCL and scDLBCL) to better understanding their prognosis and natural history. MATERIALS AND METHODS: A total of 4758 cases of CBCL diagnosed between 1975 and 2016 were identified in the SEER-18 database. Statistical analysis was performed to identify the frequency of location and survival. RESULTS: pcMZL was disproportionately likely to present on the face and upper limb while those of scMZL approximated the expected ratios based on body surface area. pcFCL and scFCL were more likely to present on the face and scalp/neck. pcDLBCL and scDLBCL were more likely to present on the face, scalp/neck, and lower limb. Patients with systemic MZL or FCL, but not DLBCL, had significantly better survival than those diagnosed in the skin than at other sites. CONCLUSIONS: All of these lymphomas demonstrate site-specific tropisms and survival. Molecular characterization of cutaneous lymphomas with analyses of tumor microenvironment are the next steps in understanding disease biology.

Treatment of Indolent Cutaneous B-Cell Lymphoma with Intralesional or Intravenous Rituximab.

Indolent cutaneous B-cell lymphomas (CBCL) are a rare disease for which the therapeutic recommendations are based on clinical reports. Recommendations for solitary lesions include surgery or irradiation. However, the high relapse rates may require less invasive repeatable therapy. This study seeks to retrospectively assess the efficacy of intralesional rituximab (ILR) for indolent CBCL when compared with intravenous rituximab (IVR). Patients treated for indolent CBCL with ILR or IVR at the Division of DermatoOncology of the University Hospital Heidelberg were eligible for this study. Characteristics of lymphoma, treatment response, and adverse events were assessed. Twenty-one patients, 67% male at a median age of 52 (range 17-80), were included. Nineteen (90%) had only localized lymphoma (stage T1 and T2). Complete response was achieved in 92% (11/12) of ILR after a median of one cycle (three injections) and 78% (7/8) of IVR patients after a median of six cycles. Half of ILR patients and 78% of IVR patients showed relapse after a median of 15 and 23 months, respectively. Adverse reactions were usually mild and were limited to the first injection of ILR. One patient with IVR contracted a pulmonary infection. ILR may be an alternative to the intravenous administration of rituximab for localized indolent CBCL.

How I Diagnose Primary Cutaneous Marginal Zone Lymphoma.

OBJECTIVES: Primary cutaneous marginal zone lymphoma (PCMZL) is 1 of the 3 major subtypes of primary cutaneous B-cell lymphoma. The diagnosis of PCMZL may be challenging, as the differential diagnosis includes benign cutaneous lymphoproliferations as well as other primary or secondary cutaneous B-cell or T-cell lymphomas. This review describes our approach to the diagnosis of PCMZL. METHODS: Two cases are presented that illustrate how we diagnose each of the 2 subtypes of PCMZL. The clinicopathologic features of PCMZL and the ways in which these cases can be distinguished from both benign and other neoplastic entities are emphasized. RESULTS: A definitive diagnosis of PCMZL requires the incorporation of histologic and immunophenotypic features, molecular genetic studies in some cases, and just as importantly, clinical findings. Emerging data suggest that the heavy chain class-switched cases may be more like a clonal chronic lymphoproliferative disorder. CONCLUSIONS: The 2 subtypes of PCMZL create different diagnostic challenges and require the use of a multiparameter approach. Although very indolent, it is important to distinguish PCMZLs from reactive proliferations, because they frequently recur and may require antineoplastic therapies. It is also critical to distinguish PCMZLs from other B- or T-cell lymphomas so that patients are properly evaluated and not overtreated.

Primary Cutaneous B-Cell Lymphomas: An Update.

Primary cutaneous B-cell lymphomas (PCBCLs) comprise a group of extranodal B-cell non-Hodgkin lymphomas B-cell derived, which primarily involve the skin without evidence of extracutaneous disease at the time of diagnosis. They include ~25% of all cutaneous lymphomas and are classified in three major subgroups (World Health Organization (WHO) 2017): primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle-center cell lymphoma (PCFCL), and diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). This classification also includes some less common entities such as intravascular large B-cell lymphoma. Recently, WHO-EORTC added Epstein-Barr virus positive (EBV+) mucocutaneous ulcer, as a new provisional distinct entity, to cutaneous B-cell lymphomas. PCBCLs are classically characterized by patches, plaques, or nodules showing great variability for color, shape, and location. Diagnosis requires histological examination with immunohistochemical staining. In general, therapeutic options depend on the exact histological and immunohistochemical classification, disease presentation, and risk assessment. PCMZL and PCFCL are considered indolent lymphomas with a good prognosis and are associated with 5-year disease-specific survival ≥ 95%. In contrast, PCDLBCL, LT is considered an aggressive lymphoma with a survival rate in 5 years of lower than 60%. Patients with a solitary lesion or limited lesions in a single anatomical site require different treatments as compared to patients with generalized lesions or refractory disease or extracutaneous involvement. Therapeutic choice includes observation, local, or systemic therapy based on histology and disease extension. Patient management is multidisciplinary, including dermatologists, pathologists, hemato-oncologists, and radiation oncologists.

Cutaneous B-Cell Lymphoma.

Primary cutaneous B-cell lymphomas are non-Hodgkin lymphomas that present in the skin without evidence of extracutaneous involvement at diagnosis. There are 3 types of primary cutaneous B-cell lymphomas: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg-type. Because it is most frequently diagnosed on skin biopsy, intravascular large B-cell lymphoma is commonly included with pcBCL. A complicating factor in diagnosing primary cutaneous B-cell lymphomas is that they can appear histologically identical to their extracutaneous counterparts. This review summarizes the clinical presentation, histopathology, evaluation, treatment, and differential diagnosis of these lymphomas.

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.