Challenges in utilizing ALK expression to distinguish primary cutaneous from systemic anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a CD30+ peripheral T-cell lymphoma with a clinical spectrum including cutaneous and systemic presentations. While primary cutaneous ALCL (pcALCL) has a favorable prognosis, systemic ALCL (sALCL) has poorer survival outcomes. Expression of anaplastic lymphoma kinase (ALK) by malignant cells has been suggested to distinguish sALCL from pcALCL. However, there have been documented cases of ALK-positive ALCL confined to the skin. The present study reviewed characteristics of published cutaneous ALK-positive ALCL cases to distinguish between these two entities. In 23 identified adults with ALK-positive pcALCL, 26% developed systemic involvement and 74% had skin-limited disease. In 14 pediatric patients, 36% had both cutaneous and systemic involvement and 64% had cutaneous disease only. This analysis revealed that pcALCL and sALCL could not reliably be distinguished by ALK expression or nuclear vs. cytoplasmic localization. Localized treatment with frequent monitoring may be sufficient in ALK-positive pcALCL until there is evidence of progression. Physicians should be aware of the overall spectrum of ALCL, including cutaneous limited disease, systemic disease, disease with NPM-ALK translocation, disease with ALK positivity and disease with skin recurrence.

Multidisciplinary atopic dermatitis program: A novel approach to managing difficult-to-control atopic dermatitis patients.

BACKGROUND/OBJECTIVES: Disease improvement for difficult-to-control pediatric atopic dermatitis may be more challenging to achieve when directed by single specialties due to disjointed and conflicting dialogue with patients. METHODS: The Multidisciplinary Atopic Dermatitis Program (MADP) was developed through collaborations with the Rady Children's Hospital and UC San Diego Health Divisions of Dermatology, Allergy & Immunology and Clinical Pharmacy, to create team-based evaluation and management of children and adolescents with atopic dermatitis (AD). The MADP allows concurrent, comprehensive evaluations by multiple specialists to develop treatment plans. The program includes extensive patient education to support shared decision making, incorporating patient and family's perspectives along with those of clinical experts into their care. Objective severity measures and patient reported outcome data were collected, along with assessment of patient and family satisfaction with the MADP. RESULTS: Data showed significant improvement in AD severity as assessed by providers, patients and families by the first follow-up visit. BSA mean percentage decreased by up to 56% by the 7th visit, and pruritus (NRS), CLDQI and POEM mean scores decreased by more than 4 points, 12 points, and over 11 points, respectively. After management was initiated in the MADP, 72.73% of patients achieved an EASI 50 and 47.73% achieved an EASI 75 from a baseline mean of 21.7. Patients who continued in clinic beyond the second visit showed further clinically significant decreases in disease measures. CONCLUSIONS: The multidisciplinary approach shows success in the treatment of difficult-to-control AD patients with improvements in clinician and patient reported outcome measures.

Neutrophilic panniculitis associated with myelodysplastic syndrome/myeloproliferative neoplasm: a case report and literature review.

Introduction: Neutrophilic panniculitis (NP) is a rare subtype of neutrophilic dermatosis, a group of neutrophil-rich inflammatory skin disorders that can present in association with myeloid neoplasms. NP is defined by the presence of a neutrophilic infiltrate in the fat lobules of the subcutis in the absence of either infection or vasculitis. We herein describe a 65-year-old woman with a recent diagnosis of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome (MDS/MPN) who abruptly developed painful, pruritic nodules consistent with NP. Case presentation: A 65-year-old woman with MDS/MPN presented for evaluation of painful and pruritic nodules on her upper and lower extremities. A biopsy revealed a lobular neutrophilic infiltrate in the subcutis without evidence of microorganisms or vasculitis. The patient was diagnosed with NP and treated with oral prednisone. Within 1 month of treatment, she reported complete resolution of the nodules. Discussion: Similar to other neutrophilic dermatoses, NP may arise in association with hematologic malignancies of myeloid origin, such as MDS/MPN. A literature review revealed that most cases of NP associated with MDS occur after the onset of MDS and respond to systemic corticosteroids, not antibiotics. Infection should be ruled out before initiating treatment with systemic steroids. Conclusion: Although the mechanism is still unknown, it is important for clinicians to be aware that NP is associated with MDS; thus, hematological malignancies should be investigated upon diagnosis of NP. Once diagnosed, NP is easily treated and has an excellent response to systemic corticosteroids.

Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature.

ABSTRACT: We report a 48-year-old man with CD30+ large cell transformation of mycosis fungoides (tMF) with distinctive anaplastic morphology. The patient initially presented with folliculotropic and syringotropic mycosis fungoides (MF) manifested as occipital scalp plaque and trunk and extremities patches. Six years later, he progressed to the tumor stage from his scalp lesion and developed cervical lymphadenopathy. Lymph node and scalp biopsies showed diffuse infiltration of CD30+ anaplastic cells with multinucleated, hallmark-like, Hodgkin-Reed-Sternberg-like, histiocytoid forms, indistinguishable from anaplastic large cell lymphoma (ALCL). T-cell receptor gamma gene (TCRg) rearrangement studies revealed identical clones in the initial MF scalp lesion and nodal anaplastic lesion, confirming the transformation. Ancillary studies showed absence of IRF4/DUSP22 and ALK rearrangements and positive RB1, SMARCA4, SOCS1, and TP53 mutations. The patient achieved partial response with systemic chemotherapy. Our case is an example of tMF presenting as the morphology and phenotype of ALCL. Because clinical behavior and therapeutic options of tMF and primary cutaneous ALCL may be different, it is clinically relevant to differentiate these 2 entities. The proof of clonal relationship may be useful in diagnostically challenging cases with features overlapping between tMF and primary cutaneous ALCL.

Recalcitrant Cutaneous Mastocytosis Treated With Genetically Informed Targeted Therapy: A Case Report.

Mastocytosis, a clonal proliferation of mast cells commonly involving the skin and bone marrow, has a varied clinical presentation ranging from cutaneous lesions to systemic disease. Cutaneous mastocytosis is managed symptomatically, but systemic mastocytosis is treated with targeted therapy against the mutated receptor tyrosine kinase c-KIT, the pathogenic driver of mastocytosis. However, there are no guidelines for the treatment of cutaneous mastocytosis refractory to symptomatic management. We herein report a method to select genetically informed therapy for symptomatic and recalcitrant cutaneous mastocytosis. Case presentation: We performed a mutational analysis of dermal mast cells after enrichment by laser capture in a 23-year-old woman with recalcitrant cutaneous mastocytosis. The analysis revealed a aspartic acid to valine substitution at codon 816 (D816V) mutation in the protein c-KIT. Based on these results, we initiated treatment with the multi-kinase/KIT inhibitor midostaurin, a treatment effective against the D816V c-KIT mutation. After 3 months of treatment, the patient exhibited a reduction in the number and size of cutaneous lesions and reported resolution of pruritus and decreased severity of other mast cell-related symptoms. Discussion: The treatment of mastocytosis relies heavily on whether the disease is limited to the skin or systemic. However, there are no guidelines for cutaneous mastocytosis that does not respond to symptomatic management. In the present report describing a patient with recalcitrant cutaneous mastocytosis, we describe a strategy in which skin mutational analysis is used to guide the selection of targeted therapy. Conclusion: Performing mast cell mutational analyses in the skin provides a means to select targeted therapy for symptomatic and refractory cutaneous mastocytosis.

Utility of T-cell immunosequencing in distinguishing mycosis fungoides progression from treatment related cutaneous adverse events.

Cutaneous adverse events of both topical and systemic drugs in patients with mycosis fungoides (MF) present a diagnostic challenge as it is often difficult to distinguish drug associated rash from disease progression in the skin. Mogamulizumab and mechlorethamine gel are approved treatments for MF, both of which can cause treatment related cutaneous adverse events. It can often be challenging to distinguish mogamulizumab associated rash (MAR) and mechlorethamine gel associated hypersensitivity dermatitis from MF progression both clinically and histologically. High-throughput sequencing (HTS) of the T-cell receptor (TCR), also known as immunosequencing, can be used to assess T-cell clonality to support a diagnosis of MF. After identification of the malignant TCR clone at baseline, immunosequencing can track the established malignant TCR sequence and its frequency over time with high sensitivity. As a result, immunosequencing clone tracking can aid in distinguishing disease progression from treatment side effects. Here, we present a case series to demonstrate how monitoring of the malignant T-cell frequency by immunosequencing can aid in diagnosis of mogamulizumab and mechlorethamine gel cutaneous adverse events.

Immunosequencing applications in cutaneous T-cell lymphoma.

Immunosequencing has emerged as a newer clinical test for assessment of T-cell clonality in the blood and skin of cutaneous T-cell lymphoma (CTCL) patients. Utilization of immunosequencing, also known as high-throughput sequencing of the T-cell receptor (HTS-TCR), enables identification and quantification of the precise genetic signature of dominant T-cell clones. Although immunosequencing is more sensitive than commonly used methods such as polymerase chain reaction (PCR) paired with capillary electrophoresis or flow cytometry, it remains underutilized for CTCL management. Nonetheless, incorporation of HTS-TCR in clinical practice offers distinct advantages compared to other molecular analyses that may improve diagnostic evaluation, prognostication, and disease monitoring in CTCL. The objective of this comprehensive review is to provide a thorough explanation of the application of immunosequencing in the context of CTCL. We describe the significance of T-cell clonality and the methods used to detect it, including a detailed comparison between PCR paired with capillary electrophoresis and HTS-TCR. The utilization of immunosequencing in the blood and skin of CTCL patients is discussed in depth, specifically outlining how HTS-TCR can assist in diagnosing CTCL, predicting outcomes, and tracking disease progression. Finally, we address the potential applications of immunosequencing in clinical management and research as well as the novel challenges it presents.

Recalcitrant Subcutaneous Panniculitis-Like T-Cell Lymphoma Responsive to Histone Deacetylase Inhibitor.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of cutaneous T-cell lymphoma that usually presents with tender subcutaneous nodules on the trunk and extremities. Immunosuppressive therapy is considered first-line treatment for SPTCL, while multiagent chemotherapy is used for SPTCL complicated by hemophagocytic lymphohistiocytosis (HLH). Here, we report a 42-year-old Hispanic man that presented with a 5-year history of recurrent painful subcutaneous lesions in the absence of constitutional symptoms, lymphadenopathy, and hepatosplenomegaly. A punch biopsy revealed an atypical lymphoid infiltrate in between subcutaneous adipose lobules. Lymphocytes expressed CD3, CD8, and Beta F-1 and did not express CD4 and CD56. Based on clinical and histologic findings, the patient was diagnosed with SPTCL. In addition, laboratory findings did not demonstrate any evidence of HLH. He was initially started on both prednisone and hydroxychloroquine with no improvement. A trial of cyclosporine and methotrexate yielded no clinical improvement. As the lesions failed to resolve after treatment with multiple immunosuppressive agents, romidepsin, an intravenous histone deacetylase (HDAC) inhibitor, was initiated. After two cycles of romidepsin, the patient achieved complete clinical response. He continues to be in remission 12 months later with monthly maintenance therapy. This case illustrates that romidepsin can be useful as monotherapy for refractory SPTCL without HLH.

Update on pediatric atopic dermatitis.

Recent studies have led to new insights into atopic dermatitis (AD) pathogenesis and epidemiology as well as its impact on the quality of life of affected children and adolescents. In addition, there are several novel topical and systemic agents recently approved and in late-stage clinical development programs. Epidemiologic insights include relative prevalence rates in different countries and studies of subsets of pediatric patients with different disease longevity and persistence. Studies on quality of life have shown tremendous impact on sleep, not only in affected individuals but in their parents/guardians. The impact of bathing regimens is discussed. Newer topical therapies are reviewed, including topical crisaborole, with a new indication for infants as young as 3 months of age. Topical Janus kinase (JAK) inhibitors are being developed, with some studies including adolescents and children. Other novel therapies include the topical aryl hydrocarbon receptor agonist tapinarof and oral JAK inhibitors; adolescents are being included in the initial clinical trials for several of these therapies. Dupilumab, the first biologic agent approved for AD, has now been well studied in patients aged 6 years and older, with expanded indication down to 6 years of age.