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Background: Primary cutaneous B-cell lymphoma (PCBCL) classically presents with papules, plaques, and nodules/tumors. Previous reports of PCBCL manifesting with macular lesions are scarce and focused on primary cutaneous follicle-center cell lymphoma (PCFCL). Objectives: The objective of this study was to report our experience with PCBCL presenting with erythematous macules. Methods: Patients with low-grade PCBCL manifesting with erythematous patches, diagnosed and managed between January 2000 through December 2019 at 2 tertiary cutaneous-lymphoma outpatient clinics, were included. Clinical data were retrospectively collected, and biopsy specimens of the macules, and if present of the typical nodular/tumoral lesions, were reviewed. Results: There were 14 patients, aged 16–67 years, 8 had PCFCL and 6 marginal zone lymphoma (PCMZL). All had 1–15 cm erythematous macules, mimicking: interstitial granuloma annulare/vascular tumors/early-stage folliculotropic mycosis fungoides, or presenting with figurate erythema or livedo reticularis-like/net-like pattern. In 3 patients, macules were the presenting lesions, in 2 as the sole manifestation, whereas in 12 patients, typical PCBCL lesions were observed during disease course. The macules showed in all, superficial and deep perivascular infiltrates, and in most, periadnexal infiltrates. Micronodules were observed in 11 specimens, with nodular infiltrates also observed in 4. B cells comprised the majority of the lymphocytes in only 4. Seven of 11 cases tested showed immunoglobulin heavy chain monoclonality. Conclusions: PCMZL and PCFCL may manifest with erythematous macules. Physicians should be aware of this unusual manifestation of low-grade PCBCL, which may represent a clinicopathological diagnostic pitfall.

BACKGROUND Literature regarding exosomes as mediators in intercellular communication to promote progression in mycosis fungoides (MF) is lacking. OBJECTIVES To characterize MF-derived exosomes and their involvement in the disease. METHODS Exosomes were isolated by ultracentrifugation from cutaneous T-cell lymphoma (CTCL) cell lines, and from plasma of patients with MF and controls (healthy individuals). Exosomes were confirmed by electron microscopy, NanoSight and CD81 staining. Cell-line exosomes were profiled for microRNA array. Exosomal microRNA (exomiRNA) expression and uptake, and plasma-cell-free microRNA (cfmiRNA) were analysed by reverse-transcriptase quantitative polymerase chain reaction. Exosome uptake was monitored by fluorescent labelling and CD81 immunostaining. Migration was analysed by transwell migration assay. RESULTS MyLa- and MJ-derived exosomes had a distinctive microRNA signature with abundant microRNA (miR)-155 and miR-1246. Both microRNAs were delivered into target cells, but only exomiR-155 was tested, demonstrating a migratory effect on target cells. Plasma levels of cfmiR-1246 were significantly highest in combined plaque/tumour MF, followed by patch MF, and were lowest in controls (plaque/tumour > patch > healthy), while cfmiR-155 was upregulated only in plaque/tumour MF vs. controls. Specifically, exomiR-1246 (and not exomiR-155) was higher in plasma of plaque/tumour MF than in healthy controls. Plasma exosomes from MF but not from controls increased cell migration. CONCLUSIONS Our findings show that MF-derived exosomes promote cell motility and are enriched with miR-155, a well-known microRNA in MF, and miR-1246, not previously reported in MF. Based on their plasma expression we suggest that they may serve as potential biomarkers for tumour burden.

Data on Demodex in the immunosuppressed state is limited, focusing mainly on patients with human immunodeficiency virus and hematological malignancies. The aim of this study was to describe the manifestations of facial demodicosis in diverse immunosuppressive states.The medical records of all patients followed at a Demodex outpatient clinic of a tertiary medical center from January 2008 to November 2020 were retrospectively reviewed. Data on patients who were immunosuppressed while with demodicosis were retrieved.The cohort included 28 patients (17 women and 11 men; median age, 58 years). Types of immunosuppression included treatments with hydroxyurea for polycythemia vera/essential thrombocytosis, mycophenolic acid, tacrolimus, and prednisone for liver and/or kidney transplantation, prednisone with cyclosporine/methotrexate/azathioprine/rituximab mainly for autoimmune diseases, mercaptopurine with/without anti-tumor necrosis factor alpha (TNF-α) for Crohn's disease, chemotherapy for neoplasms, anti-TNF-α for psoriasis, and Cushing's syndrome. The clinical types of demodicosis included: papulopustular, erythematotelangiectatic and fulminant rosacea, hyperpigmented, pityriasis folliculorum, pustular folliculitis, and dermatitis. The diverse clinical presentations led to various differential diagnoses. Topical treatment with ivermectin (monotherapy/combination with other treatments) was effective.Clinicians treating immunosuppressed patients should be familiar with the different forms of demodicosis and include them in the differential diagnosis of facial eruptions.

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, typically presents in its early stage as inflammatory erythematous patches or plaques, with epidermotropism as the histopathologic hallmark of the disease. Over the past 30 years, numerous atypical types of MF, which deviate from the classic Alibert-Bazin presentation of the disease, have been described. These variants can simulate a wide variety of benign inflammatory skin disorders either clinically, both clinically and histopathologically, or mainly histopathologically. We have summarized the many faces of the disease, which set MF as a "great imitator," with special focus on the differential diagnosis and its benign mimickers.

Interleukin-17A inhibitors are a promising alternative to tumor necrosis factor-α inhibitors for the treatment of psoriasis. In-class switch has been hardly investigated for interleukin-17A inhibitors. We report the experience (2017-2018) of a tertiary medical center with interleukin-17A-inhibitor switch in patients with moderate-to-severe psoriasis. Patient-, disease- and outcome-related data were retrospectively collected from the electronic files of 25 patients switched to ixekizumab following secukinumab failure. Mean ± standard deviation patient age was 56.7 ± 12.2 years. Mean baseline Psoriasis Area and Severity Index was 25. Secukinumab was discontinued due to primary failure in 7 patients and secondary failure in 18. Ixekizumab was administered for 7.3 ± 2.8 months; 22 patients were still on ixekizumab at the end of the study. Mean ± standard deviation Psoriasis Area and Severity Index reduction from baseline at study end was 75.5±20.0%. Patients with moderate-to-severe psoriasis seem to be amenable to treatment with ixekizumab following secukinumab failure. Further large multicenter studies are needed.

Background: Primary cutaneous lymphoproliferative disorders in solid organ recipients are rare. Reports of mycosis fungoides (MF) diagnosed in these patients are limited to less than 30 cases, with a heterogeneous disease course. Furthermore, management in terms of type and modulation of the preceding immunosuppressive treatments after MF diagnosis was not uniform. Objective: To report the characteristics of MF, treatment response, disease course, and status of immunosuppressive therapy in patients who are solid organ recipients, or under similar immunosuppression. Methods: The medical files were retrospectively reviewed for all solid organ transplant patients/patients who are under similar immunosuppression for other indications, who were also diagnosed with MF, and were followed at the cutaneous lymphoma outpatient clinics of 2 tertiary medical centers from 1/2010 to 12/2020. Results: The cohort included 11 patients (8 male; median age at organ transplantation/immunosuppressive state, 33 years). Transplanted organs involved the liver (n=5), kidney (n=3), liver and kidney (n=1), or heart (n=1). Patients were treated with mycophenolic acid, tacrolimus, and prednisone (n=5) or tacrolimus (n=5). One patient with nephrotic syndrome received cyclosporine. Median age at diagnosis of MF was 48 years, 45% were diagnosed before the age of 18 years, median time from organ transplantation/immunosuppressive state to diagnosis of MF was 8 years (range 0.5–22 years). Ten patients had early stage, (IA, 5; IB, 5), 50% of whom had early folliculotropic MF (FMF), (in some combined with classic/hypopigmented MF). One patient had advanced MF (IIIA) with folliculotropic erythroderma. Early-stage patients were treated mainly with skin-directed therapies, achieving either partial (50%) or complete response (50%). The erythrodermic patient achieved partial response after being treated with ultraviolet A and narrow-band ultraviolet B with acitretin. Immunosuppressive treatment was modulated in 4/11 patients, (cyclosporine switched to mycophenolic acid, 1; mycophenolic acid stopped and tacrolimus continued, 1; tacrolimus continued at a lower dose, combined with mycophenolic acid and prednisone, 1; tacrolimus stopped, 1). Median time of follow-up was 4 years (range 1–8 years), with no stage progression noted. At the last visit, 6 had no evidence of disease, and 5 had active disease (IA, 4; III, 1). Conclusions: Most solid organ recipient MF patients present with early-stage disease, similar to MF in the general population, with over representation of FMF, and over representation among children. Treatment is challenging due to the notorious higher risk of non-melanoma skin cancer in organ transplant recipients. Furthermore, immunosuppressive therapy modifications to improve MF should be balanced against the risk of solid organ rejection. Response to treatment and course do not seem to differ from MF in the general population, although longer follow-up is needed.

Background The molecular basis of unilesional mycosis fungoides (MF), characterized by a solitary lesion that is clinicopathologically indistinguishable from multifocal patch or plaque MF (early MF), is unknown. Objectives To investigate the microRNA profile in unilesional MF distinguishing it from early MF. Methods Biopsy samples of unilesional MF and early MF were evaluated with the Affymetrix microRNA array, with further comparison with inflammatory dermatosis, using quantitative polymerase chain reaction. NanoString technology was applied to analyse the gene expression of T helper (Th)1 immune markers, and immunohistochemistry was used to evaluate CXCR3 and GATA-binding protein 3 (GATA3) markers for Th1 and Th2 cells, respectively. Results Unilesional MF had a significantly higher level of expression of all members of the microRNA miR-17~92 cluster than early MF. Specifically, unilesional MF had a higher miR-17 level than early MF and inflammatory dermatoses. There was downregulation of the expression of phosphatase and tensin homolog (PTEN) and CREB1, known targets of miR-17~92 members; higher gene expression of interleukin-2 and interferon-γ; and a statistically lower average percentage of GATA3+ dermal cells (6·7% vs. 42·3%), were detected in unilesional MF compared with early MF. High immunoreactivity of CXCR3 was noted in both unilesional and early MF. Conclusions Unilesional MF exhibits a microRNA profile distinct from that of conventional early MF, with a higher level of miR-17~92 members along with Th1 skewing. These findings suggest a robust reactive T-cell immune response in unilesional MF and might account for the localized nature of this disease.

Data on the treatment of early folliculotropic mycosis fungoides, a recently defined clinicopathological subgroup of folliculotropic mycosis fungoides with an indolent course, is limited. Treatment outcomes were studied in a retrospective cohort of 47 adults with early folliculotropic mycosis fungoides, with a focus on psoralen plus ultraviolet A (PUVA) monotherapy, including dosimetric data, and the findings were compared with data for PUVA in 18 adults with early-classic mycosis fungoides. PUVA was given to 27 patients with early folliculotropic mycosis fungoides: 70% achieved complete response and 26% partial response. Significantly more treatments were needed to achieve complete response in stage IB compared with stage IA. There was no significant difference in the complete response rate from classic plaque-stage disease, although the early folliculotropic mycosis fungoides group required more treatments to achieve complete response, and a higher cumulative dose of UVA. Thus, PUVA is an effective treatment for early folliculotropic mycosis fungoides. Its complete response rate might be equal to early-classic mycosis fungoides; however, a longer induction phase is needed to achieve complete response.

SummaryBackground Primary cutaneous marginal zone B-cell lymphoma (PCMZL) has rarely been reported in patients younger than 20 years. Objectives To report our experience with PCMZL in the paediatric/adolescent age group. Methods Medical records of patients diagnosed with PCMZL before age 20 years and managed at two cutaneous lymphoma clinics in the United States and Israel in 1992-2015 were reviewed. Results The study group included 11 patients (6 girls) of median age 16 years (range 6–19.5); 10 had generalized/multifocal (T3) and 1 had regional/localized (T2) disease. Lesions were located on the limbs in all patients and the trunk in 6; 2 had facial lesions. Staging in all but one was based on whole-body computed tomography or positron emission tomography. Initial management in most patients included non-radiation modalities: 1 patient with localized disease received intralesional steroids; 6 patients with multifocal disease received the following: 3 - topical/intralesional steroids, 2 - excision, 1 - “watch and wait”. No extracutaneous progression was noted during a median follow-up of 5.5 years (mean 7.5, range 0.5-14). At present, 5/11 patients are in complete remission. Conclusions Based on our data (largest series in the literature with the longest follow up); the clinico-pathological presentation and course of PCMZL in the paediatric/adolescent age group are similar to adults. Given the indolent course and the long life expectancy of these young patients, the cumulative risk of imaging studies and the age-related potential toxicity of treatment, especially radiation, should be taken into consideration. This article is protected by copyright. All rights reserved.

Background In the literature, there are minimal data for the treatment of grade 2 or 3 morbilliform/atypical target lesion rashes secondary to sorafenib or vemurafenib given for patients with advanced stage cancer. This poses a dilemma for clinicians, particularly in patients with advanced neoplastic disease for whom other optional treatments are limited. Methods The cohort included data on all patients attending the dermato-oncological clinic at a tertiary medical center that presented in 2011–2014 with a widespread rash following treatment with sorafenib or vemurafenib. All patients were prospectively followed. Results Eight patients met the study criteria. Five, under sorafenib, aged 50–65 years, presented with an extensive grade 2 (involving 20–30% of the body surface area, two patients) or grade 3 (three patients) morbilliform rash, 5–10 days after onset of the drug. Two had atypical target lesions. The dosage was temporarily reduced in only two patients, and oral steroids were added in four. Under vemurafenib, three patients presented with an extensive grade 3 morbilliform rash 5–10 days after onset of treatment. Two had atypical target lesions. The dose was temporarily reduced in one, and another patient stopped the drug at her own initiative; both also received steroids. The rash subsided after 2–3 weeks in all eight patients, allowing continuation of the treatment at the regular dose. Conclusion Our cohort suggests that not all cases of widespread morbilliform rash or atypical erythema multiforme, which occur under treatment with sorafenib or vemurafenib, given for advanced cancer, require discontinuation of therapy.

Pediatric mycosis fungoides (MF) is a rare disease characterized by over-representation of atypical clinical variants, with a different prognosis from adult MF. Several human leukocyte antigen (HLA) alleles have been associated with MF in certain adult populations, including Israeli Jews. However, HLA data on pediatric MF as a group are lacking. To evaluate the possible association of the HLA system with pediatric MF, 59 Israeli Jewish patients diagnosed with MF at age ≤ 18 years underwent high- and intermediate-resolution genotyping for HLA class I (HLA-A*, HLA-B*) and class II (HLA-DRB1*, DQB1*) loci. The results were compared with data on 4169 umbilical cord blood units retrieved from a public cord blood bank in Jerusalem and samples from 252 healthy, unrelated Israeli Jewish volunteers. No statistically significant associations were found between pediatric MF and any of the alleles examined except HLA-B*73. However, given the extremely low frequency of B*73 in both the control group (0.1%) and the study group (2%), the biological significance of this finding is questionable. Further subgroup analyses by ethnicity (Ashkenazi and non-Ashkenazi) and clinicopathologic variant (follicular and non-follicular) yielded no significant between-group differences. These results suggest that the associations with the HLA system, reported previously in adult MF, do not hold true for pediatric MF. Thus, pediatric MF differs from its adult counterpart not only in clinical manifestations and course, but apparently also in the underlying immuno-pathogenetic mechanism.

Background Unilesional folliculotropic mycosis fungoides (UFMF) has been rarely reported. Objective The aim of this study was to describe our experience with UFMF. Methods Data were collected on all patients with clinicopathological UFMF who attended the Department of Dermatology of a tertiary university-affiliated medical centre in 1996–2013 and were followed prospectively. Results The sample included seven patients (five male, two female) of mean age 38 years at diagnosis; two were aged

Background The literature on mycosis fungoides (MF) in children/adolescents is sparse. Objective We sought to evaluate the characteristics of juvenile MF in a large cohort. Methods Data were collected on all patients with MF, aged 18 years or younger at the time of clinicopathologic diagnosis, who attended the Rabin Medical Center Dermatology Department, Petach Tikva, Israel, between 1994 and 2012 and were followed up prospectively. Results There were 50 patients (30 male; mean age 11.4 years at diagnosis); 18 (36%) had Fitzpatrick skin type IV or higher. All were given a diagnosis of early-stage disease (IA-IIA) except 1 (tumor stage, IIB). Eight had classic MF lesions only and 42 had other variants, alone or in combination; these were mainly hypopigmented MF (n = 29) and cases with subtle but clear clinicopathologic features of folliculotropic MF (FMF) (n = 18). Among the various skin-targeted therapies, psoralen plus ultraviolet A (systemic/bath) proved beneficial for FMF. During a follow-up period of 0.25 to 15 years (mean 4.5), 2 patients progressed from stage IA to IB or IIA. Limitations Relatively short follow-up is a limitation. Conclusions This case series shows that FMF is not uncommon in children and adolescents. It is characterized by more superficial clinical features and less heavy perifollicular lymphocytic infiltrates than adult FMF, and responds well to psoralen plus ultraviolet A. The prognosis of childhood FMF remains unclear.

OBJECTIVES: Nilotinib and dasatinib are second generation tyrosine kinase inhibitors approved for the treatment of chronic myeloid leukemia (CML). In clinical trials, they have both been reported to cause rash in a significant number of patients, but its incidence varies significantly and has not been characterized clinically or histologically. The aim of this study was to determine the incidence of rash with nilotinib and dasatinib, and to provide a clinical and histopathological description of the rash. METHODS: We conducted a meta-analysis of clinical trials evaluating nilotinib and dasatinib to determine and compare the incidence of rash with these medications. Additionally, we performed a retrospective chart review to analyze the clinical presentation and histology of patients presenting with rash. RESULTS: The incidence of all-grade (grade 1-4) rash with nilotinib was 34.3% (95% CI, 27.9-41.3%), higher (P=0.017) than with dasatinib (23.3%; 95% CI, 18.8-28.6%). Similarly, the incidence of high-grade rash with nilotinib (2.6%; 95% CI, 2.1-3.4%) was higher (P=0.002) than for dasatinib (1.1%; 95% CI, 0.8-1.6%). The clinical presentation often consisted of a pruritic, perifollicular hyperkeratotic, occasionally erythematous papular rash affecting most areas of the body, depending on the severity. CONCLUSIONS: Both nilotinib and dasatinib are associated with rash in a significant number of patients. Further studies to prevent and treat rash from nilotinib and dasatinib are required to improve patient quality of life, adherence with therapy and oncologic outcome. © 2012 John Wiley a Sons A/S.

Background Human herpesvirus (HHV) 8, an essential etiologic agent of Kaposi sarcoma, is also associated with several lymphoproliferative disorders. The involvement of HHV 8 in mycosis fungoides (MF) and large plaque parapsoriasis (LPP) is controversial, with contradictory reports from various countries worldwide. Objective We sought to investigate the presence of the HHV 8 genome in skin lesions of LPP and early-stage sporadic, familial, and juvenile MF in patients in Israel. Methods Archival paraffin-embedded and frozen samples from skin biopsies of untreated patients with LPP and early-stage MF performed in 1990 through 2006 were randomly collected from the department of dermatology of a tertiary medical center in central Israel. DNA was extracted, and a TaqMan-based real-time polymerase chain reaction assay specific for the K6 gene region was used to detect the HHV 8 genome. Results A total of 46 biopsies were sampled from 11 patients with LPP and 35 with early-stage MF (17 adults with sporadic MF, 10 children, and 8 patients with familial MF). In all, 44 samples were negative for HHV 8 DNA; two samples from adults with sporadic MF were positive. Limitations The presence of HHV 8 antibodies or virus sequences was not assessed in peripheral blood. Conclusion The results of this study, conducted in a region relatively endemic for HHV 8, support most earlier studies showing a lack of association of HHV 8 infection with LPP and sporadic adult-type MF. To our knowledge, the lack of association of HHV 8 infection with juvenile and familial MF has not been previously reported.

Objective. Cutaneous eruptions, mainly papulopustular, are the most common associated side effects of epidermal growth factor receptor inhibitors (EGFRIs). This study investigated the possible role of bacterial infection in EGFRI-induced eruptions and its relation to clinical morphology. Patients and Methods. The study group consisted of all 29 patients referred for dermatologic evaluation of side effects of cetuximab or erlotinib from March 2008 to November 2009. Specimens were taken for bacterial culture from pustules in patients with grade >1 papulopustular rash and from periungual secretions in patients with paronychia. Results. Twenty-four of 29 patients had a papulopustular reaction; five of 29 had paronychia/xerosis. Of the papulopustular eruption patients, time to rash appearance yielded two distinct groups: early-phase, median 8 days after drug initiation, located mainly on the face (n = 17) and late-phase, median ∼200 days after drug initiation, located mainly on the trunk (n = 7). Bacterial culture grew Staphylococcus aureus (SA) in seven of 13 early-phase patients tested and in all late-phase patients. Treatment consisted of topical steroids with or without topical/systemic antibiotics. All patients had a clear improvement in their cutaneous symptoms within a few days. Dose reduction or temporary discontinuation of the EGFRI was necessary in only four of 29 patients. Conclusions. As described in the literature, EGFRI-induced papulopustular eruption may appear early and probably is an inflammatory process with or without SA secondary infection. The papulopustular eruption may also appear as a late phase, described here for the first time, which is an infectious process with all patients being SA+. The >50% overall incidence of SA infection in our study highlights the need for routine bacterial cultures from EGFRI-induced eruption.

Summary Background 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. Objectives 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. Methods 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. Results 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. Conclusions 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.

Imatinib mesylate is the first of a novel group of drugs that specifically target protein tyrosine kinases, which are central to the pathogenesis of human cancer. It has been approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumor and has been found efficacious in other neoplastic diseases. Nilotinib and dasatinib, a second-generation of tyrosine kinase inhibitors (TKIs), were developed in response to findings of emerging imatinib resistance or intolerance to the drug. Cutaneous reactions are the most common nonhematologic side effect of these drugs, and their management is challenging especially in the absence of alternative anticancer agents. The present review focuses on the clinical characteristics and the hypothesized molecular pathogenesis of these first- and second-generation TKIs' cutaneous side effects, and approaches to their treatment. The wide range of adverse effects clarifies the difficulty in designing a truly antitumoral TKI.