Dermoscopy can be safely and reliably used in ophthalmology.

Objective: To determine if dermoscopy, a technique widely utilized in dermatology for improved diagnosis of skin lesions, can be used comfortably for evaluating periorbital, eyelid, and conjunctival lesions. Design: Proof-of-concept study in which a technique for performing dermoscopy near the eye was developed, related educational material was prepared, and a protocol for dermoscopic image capture was created. Methods: Technicians used the developed materials to learn to take high-quality pictures with a 10x dermoscope attached to a standard cell phone camera. The images were assessed for diagnostic utility by an oculoplastic surgeon and two dermatologists. Participants: 115 patients recruited from ophthalmology clinics from July 2021 to April 2023 were photographed, yielding 129 lesions with high-quality dermoscopic images as assessed by an oculoplastic surgeon and two dermatologists. Results: Technicians reported a significant increase in confidence (measured on a 1-10 scale) with dermoscopy after training (pre-instruction mean = 1.72, median = 1, mode = 1, IQR = 1.25 vs mean = 7.69, median = 7.75, mode = 7 and 8, IQR = 1.5 post-instruction. Wilcoxon rank sum test with continuity correction, W = 0, p < 0.001, paired t = 13.95, p < 0.0001). Incorporating a contact plate with a 4 × 4mm reticule on the dermoscope aided in photographing ocular and periocular lesions. Conclusion: Medical support staff in eye-care offices can be taught to use dermoscopes to capture high-quality images of periorbital, eyelid, and conjunctival lesions. Dermoscopy illuminates diagnostic features of lesions and thus offers a new avenue to improve decision-making in ophthalmology. Dermoscopy can be incorporated into telemedicine evaluations by ophthalmologists, oculoplastic surgeons, or affiliated dermatologists for triage of or rendering advice to patients and for planning of surgery if needed.

Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling.

BACKGROUND: Multiple treatment options are available for the management of psoriasis, but clinical response varies among individual patients and no biomarkers are available to facilitate treatment selection for improved patient outcomes. OBJECTIVES: To utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis. METHODS: We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1942 genotyped patients with psoriasis. We examined 6 502 658 genetic markers to model their associations with response to six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomics, transcriptomics and a longitudinal clinical cohort to provide biological implications for the topmost signals associated with drug response. RESULTS: Two novel markers were revealed to be associated with treatment response: rs1991820 (P = 1.30 × 10-6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P = 2.94 × 10-6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (P = 1.0 × 10-12) and CD200 (P = 5.4 × 10-6). We demonstrated that KLK7 expression was increased in the psoriatic epidermis, as shown by immunohistochemistry, as well as single-cell RNA sequencing, and its responsiveness to anti-TNF treatment was highlighted. By inhibiting the expression of KLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF. CONCLUSIONS: Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7.

Cutaneous B-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). DIAGNOSIS: Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. RISK-STRATIFICATION: Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. RISK-ADAPTED THERAPY: PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.

CD30 expression in cutaneous B-cell lymphomas.

INTRODUCTION: CD30 expression has been infrequently described in cutaneous B-cell lymphomas (CBCLs). We examined CD30 expression in reactive lymphoid hyperplasia (RLH) and CBCL and correlated expression with clinicopathologic features. METHODS: CD30 was examined in 82 CBCL patients and 10 RLH patients that had been evaluated in our cutaneous lymphoma clinics. The CBCL patients included: primary cutaneous follicle center lymphoma (PCFCL), Grade 1/2 systemic/nodal follicular lymphoma (SFL); primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD); systemic marginal zone lymphoma (SMZL); primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT); and extracutaneous/systemic diffuse large B-cell lymphoma (eDLBCL). We scored CD30 expression for intensity and extent and related CD30 expression to age at first diagnosis, sex, site of biopsy, clinical appearance, extracutaneous involvement, multiple cutaneous lesions, B-symptoms, lymphadenopathy, positive positron emission tomography/computed tomography (PET/CT), elevated lactate dehydrogenase (LDH), and positive bone marrow biopsy. RESULTS: CD30 expression was identified in 35% of CBCL, ranging from few, weak, scattered cells to strong and diffuse expression. It was most common in PCFCL and was not expressed in PCDLBCL-LT. Rare PCFCL expressed strong, diffuse CD30. Some cases of PCMZL/LPD, SMZL, FL, and RLH showed scattered, strongly positive cells. CD30 expression in CBCL was associated with favorable clinical features: younger age, negative PET/CT, and an LDH within normal limits. CONCLUSIONS: CD30 may be expressed in CBCL, possibly causing diagnostic confusion. CD30 expression was most commonly identified in PCFCL and is associated with favorable clinical features. In cases with strong and diffuse expression, CD30 could be a therapeutic target.

Cutaneous T-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or the blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Two cases of challenging cutaneous lymphoid infiltrates presenting in the context of COVID-19 vaccination: A reactive lymphomatoid papulosis-like eruption and a bona fide lymphoma.

COVID-19 infection and vaccination may be associated with a wide variety of cutaneous and immune manifestations. Here, we describe two patients who presented with monoclonal cutaneous T-cell infiltrates that showed cytologic and immunophenotypic features concerning for lymphoma shortly following COVID-19 vaccination. In one case, the eruption completely resolved. The second patient showed initial resolution, but her disease recurred and progressed following a breakthrough SARS-CoV-2 infection. These cases suggest that immune stimulation following exposure to SARS-Cov-2 protein(s) in vaccine or infection may facilitate the development of a lymphoma or lymphoproliferative disorder in susceptible individuals. Moreover, they show that separating these cases from pseudolymphomatous reactive conditions is often challenging and requires close clinical correlation.

GATA-3 is a proto-oncogene in T-cell lymphoproliferative neoplasms.

Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients.

Predictors of large cell transformation in patients with Sezary Syndrome-A retrospective analysis.

BACKGROUND: Large cell transformation (LCT) of Sezary Syndrome (SS) is a rare phenomenon. To date, there are no rigorous studies identifying risk factors for its development. OBJECTIVES: Here, we seek to characterize the clinicopathologic risk factors that predispose patients with SS to develop LCT. METHODS: We retrospectively evaluated all SS patient records available in the Michigan Medicine Cancer Registry from 2010-2021. Clinical and pathologic variables were compared between groups. The Kaplan-Meier method and log-rank test were used to assess overall survival. RESULTS: Of 28 SS patients identified, eight patients experienced LCT, and 20 did not (NLCT). Peak lactate dehydrogenase (LDH) before LCT (p = 0.0012), maximum total body surface area (TBSA) involvement before LCT (p = 0.0114), absolute CD8+ cell count measured on flow cytometry at diagnosis of SS (p = 0.0455) and at the most recent blood draw (p = 0.00736), and ulceration on biopsy (p = 0.0034) were significant clinicopathologic variables identified between the SS patients that developed LCT versus those that did not. CONCLUSIONS: Maximum TBSA involvement, peak LDH, presence of ulceration, and decreased levels of CD8+ cells in the peripheral blood may predict the development of LCT in patients with SS.

Dermoscopy practice guidelines for use in telemedicine.

Teledermoscopy, or the utilization of dermatoscopic images in telemedicine, can help diagnose dermatologic disease remotely, triage lesions of concern (i.e., determine whether in-person consultation with a dermatologist is necessary, biopsy, or reassure the patient), and monitor dermatologic lesions over time. Handheld dermatoscopes, a magnifying apparatus, have become a commonly utilized tool for providers in many healthcare settings and professions and allows users to view microstructures of the epidermis and dermis. This Dermoscopy Practice Guideline reflects current knowledge in the field of telemedicine to demonstrate the correct capture, usage, and incorporation of dermoscopic images into everyday practice.

Patch/plaque mycosis-fungoides-like presentations of DUSP22-translocated T-cell lymphomas.

The DUSP22-IRF4 gene rearrangement results in downregulation of DUSP22, a presumed tumor suppressor in T-cell lymphomagenesis. It has been described in some cases of primary cutaneous and systemic anaplastic large-cell lymphoma, lymphomatoid papulosis, and transformed mycosis fungoides. Here we describe two patients with clinical lesions resembling patch/plaque mycosis fungoides that did not meet WHO criteria for large-cell transformation on histopathology yet showed a DUSP22 translocation. One patient who had a history of systemic anaplastic large-cell lymphoma with DUSP22 translocation presented with cutaneous involvement by his systemic lymphoma along with lymphomatoid papulosis and mycosis-fungoides-like lesions, all showing an identical immunophenotype and T-cell clone. These cases expand the spectrum of DUSP22-rearranged lymphomas to include mycosis-fungoides-like presentations without large-cell transformation.

International Dermoscopy Society criteria for non-neoplastic dermatoses (general dermatology): validation for skin of color through a Delphi expert consensus.

BACKGROUND: The International Dermoscopy Society (IDS) recently released a set of five basic dermoscopic parameters (vessels, scales, follicular findings, "other structures," and specific clues) encompassing a total of 31 subitems to standardize the use of dermoscopy in non-neoplastic dermatoses, yet they have been developed taking into account Caucasian/Asian skin, with consequent possible limitations if used in dark skin. OBJECTIVES: To validate the abovementioned criteria for the use in dark-skinned patients (phototypes IV-VI) through an expert consensus. METHODS: The two-round Delphi method was adopted, with an iterative process consisting of two rounds of email questionnaires. Potential panelists were recruited via e-mail from all over the world based on their expertise on dermoscopy of non-neoplastic dermatoses in skin of color. RESULTS: Twenty-two panelists took part in the validation process. All of the five originally proposed parameters and subitems reached agreement during the first round, aside from "follicular red dots." Additionally, during round 1, five new subitems were proposed (perifollicular scales distribution, follicular openings obliteration, broken hairs, eccrine pigmentation, and eccrine ostia obliteration), along with the possibility to change the denomination of parameter 3 (from "follicular findings" to "follicular/eccrine findings") and split it into two subparameters ("follicular findings" and "eccrine findings"). All such proposals reached agreement during the second round and therefore were included in the final list, for a total of 37 items. CONCLUSIONS: Although nearly all the dermoscopic criteria originally proposed by the IDS are applicable even to darker phototypes, several additional variables need to be assessed.

PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma.

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-κB axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma.

Cutaneous T-cell lymphomas: 2021 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Dermoscopic Features of Mycosis Fungoides and Its Variants in Patients with Skin of Color: A Retrospective Analysis.

BACKGROUND: Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that disproportionately affects people with skin of color and is difficult to diagnose. OBJECTIVE: This study characterized the dermoscopic features of MF and its subtypes in patients with skin of color. METHODS: Dermoscopic images of patients with skin of color seen at the cutaneous T-cell lymphoma clinic at Michigan Medicine Dermatology between 2018 and 2019 were reviewed. Specific dermoscopic features were identified and summarized for each subtype of MF. RESULTS: A total of 33 dermoscopic images from 11 patients with skin of color were reviewed. Four patients had classic MF (18 dermoscopic images), 4 had hypopigmented MF (9 dermoscopic images), 1 had folliculotropic MF (4 dermoscopic images), and 2 had verrucous MF (2 dermoscopic images). Classic MF was characterized by striking pigmentary change, thick black lines, white rosettes, and geometric white lines. Hypopigmented MF was characterized by the loss of the patient's natural pigment network. In folliculotropic MF, follicular plugging and hyperpigmented to violaceous perifollicular halos were observed. In verrucous MF, large, yellow-gray amorphous structures with yellow-gray ridges and comedo-like openings were observed within hyperkeratotic areas. Overall, vessel morphology was difficult to discern on dermoscopy. CONCLUSIONS: Dermoscopic features of MF in patients with skin of color are predominantly characterized by striking pigmentary alteration. Vessel morphology is not a reliable diagnostic feature. As patients with MF and skin of color have a worse prognosis than light-skinned individuals, a better understanding of dermoscopic features may aid in early diagnosis and improve outcomes in this group.

Immunophenotypic switch in cutaneous T-cell lymphoma: A series of three cases and review of the literature.

Primary cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well-recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.