Langerhans cell histiocytosis (LCH) is a rare malignancy marked by clonal proliferation of Langerhans cells, with BRAF V600E mutations identified in over 50% of the cases. BRAF inhibitors (BRAFi), such as dabrafenib, have shown efficacy in treating BRAF V600E-mutant LCH. However, BRAFi therapy is associated with cutaneous adverse effects, including the development of new melanocytic nevi, verrucae, and keratinocyte carcinoma (KC). This case report describes a 78-year-old woman with BRAF V600E-mutant LCH who developed multiple dermatologic side effects following dabrafenib salvage therapy. Seven weeks into treatment, the patient presented with eruptive palmoplantar nevi, verrucae, and a basal cell carcinoma (BCC). Biopsies revealed endophytic verruca vulgaris and acral junctional melanocytic nevus. A previous history of KC and photodamage likely contributed to the development of BCC. Additionally, the patient experienced arthralgias and Dupuytren’s contracture, consistent with known BRAFi side effects. While the cutaneous manifestations observed here have been documented in BRAF V600E-mutant melanoma, this case is unique in its presentation in LCH patients. This report emphasizes the need for routine dermatologic monitoring and awareness of potential skin malignancies and other side effects in adults undergoing BRAFi therapy for LCH.

The most common subtype of cutaneous T-cell lymphoma, mycosis fungoides (MF), is characterized by proliferation of malignant T cells in the skin. In the more clinically aggressive folliculotropic MF (FMF), malignant T cells localize to follicular epithelium, whereas in classic MF, they infiltrate the dermis and epidermis. How the localization of neoplastic T cells to the follicular niche contributes to the clinical aggression in FMF is unclear. To uncover the tumor microenvironmental differences between perifollicular FMF and dermal classic MF regions, we analyzed patient samples using spatial transcriptomics. Transcripts were collected from specific cell subsets within follicular (FMF) and dermal (classic MF) regions of interest to compare gene expression, spatial deconvolution, and pathway activity. Our work revealed that the neoplastic CD4 T cells around the hair follicles in FMF had a highly inflammatory phenotype, better adaptation to cellular starvation, higher metabolic activity, and enhanced antigen presentation. In contrast, cutaneous T-cell lymphoma-associated macrophages in FMF exhibited an immunosuppressive phenotype with decreased IL-2 and IFN signaling. These findings suggest that the follicular microenvironment may provide survival advantages to malignant T cells while promoting a dysregulated antitumor immune response. These observations provide insight into the mechanisms underlying the more aggressive clinical features of FMF versus classic MF.

Background: Efficient management of acute ischemic stroke is critical to reducing disability and mortality. The hub-and-spoke telestroke model has been developed to extend specialized stroke care to regions with limited resources, ensuring timely diagnosis and treatment. Objective: To evaluate the effectiveness of a large-scale hub-and-spoke telestroke network in delivering acute stroke care, focusing on the rates of thrombolysis and mechanical thrombectomy, treatment timelines, and patient outcomes. Methods: We conducted a retrospective analysis of 9,702 patients treated within a 38-hospital telestroke network from December 2014 to January 2018. Data collected included patient demographics, stroke characteristics, treatment interventions, and outcomes. Key measures included the proportion of patients receiving intravenous tissue plasminogen activator (IV tPA), mechanical thrombectomy, time from stroke onset to treatment, and rates of complications and discharge outcomes. Results: Of the 9,702 patients included, 83.1% were diagnosed with a true stroke, and the mean NIHSS score on admission was 6.2. IV tPA was recommended for 16.3% of patients, with 61.7% receiving the treatment. Mechanical thrombectomy was performed in 2.3% of cases, with an average procedure duration of 46.2 minutes. The median time from stroke onset to IV tPA administration was 114.2 minutes. Hemorrhagic transformation occurred in 19.4% of patients who received thrombolysis, and the overall mortality rate was 17.4%. The average NIHSS score at discharge improved to 4.4, with 54.9% of patients discharged home. Conclusion: The hub-and-spoke telestroke network demonstrated significant efficacy in delivering timely, specialized stroke care across a large and diverse patient cohort. By reducing treatment delays and optimizing access to advanced interventions, this model has the potential to transform stroke care in underserved regions, reducing both mortality and long-term disability.

Cutaneous melanoma is the fifth most common cancer in the United States and is associated with an increased risk of second primary malignancies (SPMs) in survivors. However, the risk of SPMs in melanoma patients has not been revisited in over 10 years.

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.

A 68-year-old woman with a history of seizures on cenobamate presented with an itchy rash all over her body. The rash started about one month prior to her presentation to the dermatology clinic. The rash was initially treated with topical triamcinolone with improvement at one-month follow-up. However, four months later the rash flared and there was concern that cenobamate was the cause. Biopsy was performed showing vacuolar interface dermatitis with atrophy, suggestive of subacute lupus erythematosus. Blood work revealed positive antinuclear antibody, anti-ribonucleoprotein antibody, Sjogren Anti-SS-A and positive histone antibody. Given the worsening rash, positive labs, and cenobamate as the only changed drug several months before initial onset, she was diagnosed with drug-induced subacute cutaneous lupus erythematous and her cenobamate was discontinued. To the best of your knowledge, this is the first reported case of a medication in the carbamate family leading to drug induced subacute cutaneous lupus erythematosus.

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma. The overall risk of developing DLBCL is increased in patients with other lymphomas, such as mycosis fungoides (MF). In this report, we present an 81-year-old female with early-stage MF who simultaneously progressed to tumor stage, large-cell transformed (LCT) MF and developed a primary DLBCL in a lymph node (LN). She presented with a tumor on her leg and new lymphadenopathy in her right axilla. Skin biopsy of the tumor revealed infiltration of large atypical CD3+, CD4+, and CD30+ cells, and a smaller portion of CD8+ cells in the dermis, consistent with LCT MF. Biopsy of the axillary LN revealed diffuse sheets of CD20+, BCL-2+, c-MYC+, and CD10- cells, highly suggestive of double expressor DLBCL. High-throughput sequencing revealed monoclonal T cells in the skin tumor and a monoclonal B-cell population in the LN. The above findings led to simultaneous diagnoses of LCT MF and nodal double expressor DLBCL. Our case demonstrates the importance of performing a full pathological workup in cutaneous T-cell lymphoma patients presenting with lymphadenopathy.

Cancer survivors have an increased risk of developing second primary malignancies. We aimed to identify whether certain cancers lead to an increased risk of developing melanoma among cancer survivors. We evaluated the risk of developing cutaneous melanoma after the 20 most common cancers in the United States through the Surveillance, Epidemiology, and End Results database. We identified 9 primary cancers linked to increased risk of developing a subsequent cutaneous melanoma: cutaneous melanoma (standardized incidence ratio [SIR] = 9.65), leukemia (SIR = 1.76), non-Hodgkin lymphoma (SIR = 1.33), thyroid cancer (SIR = 1.32), brain and nervous system cancer (SIR = 1.31), myeloma (SIR = 1.23), breast cancer (SIR = 1.13), oral cavity/pharynx cancer (SIR= 1.12), and prostate cancer (SIR = 1.03). The risk of developing melanoma was highest 1-5 years after diagnosis of most primary cancers. Notably, individuals aged under 50 years with a prior melanoma had a 14-fold increased risk. Our findings highlight specific at-risk groups-such as those aged under 50 years with recent melanoma, individuals in their 60s diagnosed with leukemia, and those aged over 80 years with recent thyroid cancer-who may benefit from heightened clinical vigilance and tailored melanoma screening strategies.

Background: Primary cutaneous B-cell lymphomas (PCBCLs) are a subset of non-Hodgkin lymphomas originating in the skin. The risk of developing other malignancies in PCBCL patients is not known. We evaluated the risk of developing a second primary malignancy after a PCBCL diagnosis. Methods: We utilized the surveillance, epidemiology, and end results (SEER-17) data registry of 9,208,295 patients from 2000-2020 to generate a cohort of 5,435 patients with PCBCL to identify patients at risk for a second primary malignancy. Relative risk was calculated by using the Standardized Incidence Ratio (SIR), defined as the ratio between observed cases (O) and expected cases (E) of malignancies (SIR = O/E). Statistical significance was established based on 95% confidence intervals (CI). Results: Of the 5,435 patients with PCBCL, 847 (16%) received diagnoses of a second malignancy, identifying a higher risk than the general population (SIR, 1.54; 95% CI, 1.43-1.64). Males had a higher chance of developing prostate cancer (SIR, 1.29; 95% CI, 1.07-1.54), melanoma (SIR, 1.49; 95% CI, 1.03-2.09), and bladder cancer (SIR, 1.42; 95% CI, 1.01-1.94). Females were more predisposed to cancers of the lung (SIR, 1.69; 95% CI, 1.25-2.24), thyroid (SIR, 3.06; 95% CI, 1.63-5.23), and kidney (SIR, 2.13; 95% CI 1.06-3.81). For males with PCBCL, there was an increased risk of prostate cancer in patients 60-69 (SIR, 1.53; 95% CI, 1.14-2.02). For females, there was an increased risk of lung cancer in patients over 70, especially in the age group of 70-79 (SIR, 1.84; 95% CI, 1.12-2.84). For cutaneous melanoma, bladder, renal, and thyroid cancer, there was no age group identified to be at a significantly greater risk. Prostate cancer risk was increased within the first year (SIR, 2.09; 95% CI, (1.28 - 3.23) and between 5-10 years after PCBCL diagnosis (SIR, 1.45; 95% CI, 1.04-1.97) .For males, melanoma and bladder cancer were associated with an increased risk between 1-5 years after PCBCL (SIR, 1.91; 95% CI, 1.09-3.11 and SIR, 1.7; 95% CI, 1.01-2.68). Females were at the highest risk of developing thyroid cancer within the first year of PCBCL diagnosis (SIR, 21.11; 95% CI, 10.12-38.83) and lung cancer 1-5 years after PCBCL diagnosis (SIR, 1.7; 95% CI, 1.04-2.62). For renal cancer, there was no latency identified carrying an increased risk. Conclusion: These data, should inform screening strategies for melanoma, prostate, bladder, lung, renal, and thyroid cancer in patients with PCBCL. Males 60-69 within 10 years of PCBCL can benefit from prostate screening. Males within 1-5 years of PCBCL diagnosis can benefit from screening for melanoma and bladder cancer. Females can benefit from thyroid, lung, and renal cancer surveillance. Specifically for females over 70, screening for lung cancer should be considered, and for females within the first year of PCBCL diagnosis, thyroid cancer screening should be considered.

Background: Cancer survivors have an increased risk of developing second primary malignancies (SPMs). We aimed to identify whether certain cancers lead to an increased risk of developing melanoma amongst cancer survivors.

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.

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.

INTRODUCTION: Stroke is a leading cause of death and disability worldwide. According to the World Health Organization, stroke patients should be treated in dedicated stroke units. However, stroke units require multidisciplinary stroke expertise which is usually scarce in rural areas. METHODS: This is a retrospective single-center study encompassing patients suffering from strokes and receiving pre-hospital and in-hospital tele-stroke expertise based on a spoke/hub stroke network. Data from 38 hospital networks between December 2014 and January 2018 were collected. RESULTS: The study cohort consisted of 9702 patients. The majority were females (n = 3556, 55.3%) and the mean age was 67 (67 +16.7, 66.7 - 67.4, 26 -122). Of all patients, tissue plasminogen activator (tPA) was recommended in 1313 (16.3%) patients, and from these, 810 (61.7%) patients were actually given tPA. As for endovascular intervention, only 187 (2.3%) patients underwent mechanical thrombectomy at our institution. CONCLUSIONS: Tele-stroke networks have proven to be a pivotal development in the treatment of strokes, especially those that are remote. With the additional expertise and the shorter duration from onset to diagnosis to treatment, these networks have substantially improved patient care and decreased healthcare costs, avoiding unnecessary transfers from spoke hospitals to hub.

Introduction: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma that initially starts in the skin but can progress to involve blood with significant mortality in late stages. Even in early stages and in the absence of blood involvement, changes in blood T-cell receptor (TCR) repertoire have been observed in MF patients. While prior work has explored the significance of dominant blood T-cell clones in the prognosis of early MF, the relationship between TCR sequences and T-cell repertoires of blood and skin in early-stage MF patients has not been characterized. Objectives: To determine the relationship of blood and skin T-cell repertories and to reassess the impact of dominant blood T-cell clones on selected outcome endpoints in early-stage MF. Materials and Methods: We used high-throughput sequencing to interrogate TCR sequences in blood and skin of MF patients without blood involvement at the Jefferson Cutaneous Lymphoma Clinic (Adaptive Biotechnologies). ImmunoSEQ Analyzer provided T-cell repertoire overlap metric (Morisita's index) and diversity measure (Simpson's clonality score). Time to systemic treatment (TTST) was calculated as the time from initial diagnosis to initiation of first systemic therapy. Results: 60 MF patients with no blood involvement were enrolled. 28% had a dominant clone in blood; of these, 18% were identical to dominant skin clones and 82% were distinct from the dominant clones identified in skin. We found that MF patients with discordant dominant T-cell clones in blood and skin had a longer TTST when compared to the identical clone cohort (P=0.0057) (Figure 1A). Furthermore, patients with discordant dominant clones had a lower degree of T-cell repertoire overlap between blood and skin (P<0.0001) and higher blood T-cell repertoire diversity scores (P=0.013) when compared to the identical clone group (Figure 1B). In all patients, the degree of T-cell overlap in blood and skin did not significantly change over a period of months to years or among skin biopsies obtained from different anatomical locations. Finally, in a subset of patients with discordant clones, the dominant skin clone did not appear to be detected in blood even at low frequencies. Conclusion: Our data highlight the importance of establishing clonal associations between dominant T-cell clones of the skin and blood in MF. We propose that early-stage MF patients with dominant clones in blood segregate into two cohorts with distinct prognoses and T-cell repertoires based on the identity of their peripheral T-cell clones. In addition, our findings suggest that not all MF patients have reservoirs of malignant T-cell clones readily available in peripheral circulation to seed new lesions in skin. Figure 1: A: Kaplan-Meier analyses of time to systemic treatment (TTST) in skin-limited mycosis fungoides (MF) patients with an identical dominant T-cell clone in blood and skin, a discordant dominant T-cell clone in blood and skin, and no dominant blood clones. NS- not significant (P =0.5274), ** (P =0.0057), *** (P <0.0003). B: Average Morisita's index for blood and skin overlap for patients in indicated groups of I: identical dominant clones in blood and skin, D: discordant dominant clones in blood and skin, and N: no dominant clone in blood. **** (P <0.0001).

IntroductionThe 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.MethodsHere 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.ResultsWe 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).ConclusionThere 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.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma that initially starts in the skin but can progress to involve blood and extracutaneous sites with significant mortality in late stages. The presence of a dominant T-cell clone in the blood of early-stage MF patients appears to be associated with a poor prognosis. However, the identity of dominant blood T-cell clones and the degree of overlap between T-cell repertoires of blood and skin in MF have not been fully interrogated. Here, we evaluated the relationship of blood and skin T-cell repertoires and their relevance to prognosis in MF. We used high-throughput sequencing to interrogate the T-cell receptor (TCR) complementarity determining region 3 sequences in blood and skin of MF patients at the Jefferson Cutaneous Lymphoma Clinic (Adaptive Biotechnologies). ImmunoSEQ Analyzer provided T-cell repertoire overlap metric (Morisita’s index) and diversity measure (Simpson’s clonality score). Time to systemic treatment (TTST) was calculated as the time from initial diagnosis to initiation of first systemic therapy. 59 MF patients with no blood involvement at diagnosis were enrolled. 29% had a dominant clone in blood; of these, 18% were identical to dominant skin clones and 82% were distinct from the dominant clones identified in skin. We found that MF patients with discordant dominant TCR clones in blood and skin had a longer TTST compared to those with identical dominant TCR clones (P =0.0009). Furthermore, patients with discordant dominant clones had a lower degree of overall T-cell repertoire overlap between blood and skin (P <0.05) and higher blood T-cell repertoire diversity scores (P<0.05) when compared to patients with identical dominant clones in blood and skin. Our data highlights the importance of establishing clonal associations between dominant T-cell clones of the skin and blood in MF. We propose that MF patients with dominant clones in blood segregate into two cohorts with distinct prognoses based on the identity of their peripheral T-cell clones.

The increased incidence of cutaneous melanoma (CM) and Merkel cell carcinoma (MCC) development in patients with hematologic malignancies (HM) is well established. While the risk of these second primary cancers has been assessed in some subtypes of HM including cutaneous T-cell lymphoma (CTCL), the CM and MCC incidence in patients with primary cutaneous B-cell lymphoma (PCBCL) has not been interrogated. In our cutaneous lymphoma tertiary referral center, CM was observed occurring at a higher-than-expected incidence rate in our PCBCL patients with an incidence of 16.21% (95% CI: 7.65-31.1) which was increased compared to the incidence in the general population of 0.022% (95% CI, 0.068, 0.327). This prompted a retrospective analysis of the standardized incidence ratios (SIR) in a population-level Surveillance, Epidemiology and End Results (SEER) cohort of 5,321 PCBCL patients for both second primary melanoma and Merkel cell carcinoma. There were 38 cases of CM in PCBCL SEER cohort patients (SIR, 1.37; 95% CI, 0.97-1.88). Males aged 50-54 with subtype of primary cutaneous follicle center lymphoma (PCFCL) had a significantly increased risk of CM development (SIR, 8.31; 95% CI, 1.01-30.03). In the SEER cohort, we found that factors associated with development of CM in PCBCL patients were male gender, age over 50 years old, latency of 1-5 years after diagnosis of PCBCL, and PCFCL subtype. Regarding MCC, we found that patients were most at risk if within their first year of diagnosis of PCBCL (SIR, 22.77; 95% CI, 2.76-82.25) and even more so if they were over 85 years old (SIR, 75.07; 95% CI 9.09-271.19). Although PCBCL is generally indolent, middle-aged to older patients should undergo careful annual screening for CM and MCC in the first five years after diagnosis of PCBCL.