Atypical fibroxanthoma (AFX), pleomorphic dermal sarcoma (PDS), and undifferentiated sarcoma, pleomorphic subtype (US) are rare malignant neoplasms of mesenchymal origin with many shared clinicopathologic features. AFX are usually superficial at time of diagnosis with low risk for recurrence or metastasis following surgical extirpation. In contrast, PDS and US display greater adverse histopathological features and subcutaneous invasion which portend higher risk for local recurrence, metastasis, and death. AFX and PDS form a biological spectrum defined by shared ultraviolet (UV)-signature mutations and arise on sun-exposed skin. Malignant fibrous histiocytoma (MFH), later termed undifferentiated pleomorphic sarcoma (UPS), has been repeatedly reclassified since the 1960s, leading to ambiguity in the literature. Although histopathology may overlap with AFX and PDS, US (former MFH/UPS) lacks UV-associated mutations, shows a complex karyotype, occurs on sun-protected areas, and is a diagnosis of exclusion once lineage-defined sarcomas are ruled out by ancillary studies. Due to the rarity of these tumors, definitive diagnostic, management, and surveillance guidelines have not been established. Multidisciplinary teams are recommended in more advanced cases. For unresectable, recurrent, or metastatic disease, adjunctive therapies including radiation, chemotherapeutics, and immunotherapies have been utilized with varying efficacy.

Ponatinib is a tyrosine kinase inhibitor used in children with chronic myeloid leukemia. We report a case of neutrophilic panniculitis following ponatinib administration in a child. With the expanded use of immunomodulatory medications in the pediatric population, this report aims to expand knowledge regarding potential drug-related adverse events and the inclusion of ponatinib-related adverse events in the differential diagnosis of neutrophilic panniculitis.

Cutaneous hematologic neoplasms in children are relatively rare and encompass a wide range of lymphoproliferative and myeloproliferative disorders. This review explores and updates the classification, clinical presentation, diagnostic challenges, histopathology, and management of pediatric lymphomas, lymphoproliferations, and leukemias that may be seen in the skin. The most frequent of them are lymphomatoid papulosis (LyP) and mycosis fungoides (MF), and are discussed first, with a particular focus on differential diagnosis and overlaps with benign lesions-mainly pityriasis lichenoides-which raises questions regarding the delineation of these entities and their potential interconnection. It is important to underline that most cutaneous lymphoproliferations are indolent in children: primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, subcutaneous panniculitis-like T-cell lymphoproliferation (non-associated with HAVCR2 mutations), primary cutaneous marginal zone lymphoproliferative disorder, and EBV-related lymphoproliferative disorders. However, aggressive hematologic malignancies, although rarer, must not be missed; these are mostly leukemias (but not all forms) and blastic plasmacytoid dendritic cell neoplasm. We emphasize the importance of clinical-pathological correlation, with clonality studies playing a crucial role in some cases. Management strategies are briefly reviewed, ranging from skin-directed therapies like phototherapy and corticosteroids to systemic treatments for more aggressive forms of leukemia cutis and lymphomas.

Dermatomyofibroma (DMF), rare in the pediatric population, is a benign dermal tumor composed of myofibroblasts and fibroblasts. We identified 21 histologically confirmed cases of pediatric DMF from our institution's dermatopathology database. Most cases occurred in male children, were located on the neck, and were difficult to distinguish clinically from lesions such as dermatofibromas and cysts. Following chart review of seven patients who received dermatologic care at our institution, we report unusual presentations of DMF and describe post-biopsy follow-up evaluations.

Preferentially Expressed Antigen in Melanoma (PRAME) is an immunohistochemical marker utilized in the diagnosis of melanocytic neoplasms. While still considered highly specific, both diffuse and variable PRAME immunoreactivity have been demonstrated in benign melanocytic lesions. This phenomenon is widely documented, as well as the phenomenon of eruptive melanocytic nevi (EMN) arising in the context of BRAF-inhibition. We report here a patient on encorafenib who developed numerous new pigmented lesions within 3 weeks of therapy. Initial biopsy suggested evolving melanoma in situ with 70%-75% intraepidermal melanocytes strongly PRAME positive, prompting additional testing. Two subsequent lesions demonstrated only focal PRAME staining and lacked malignant features, leading to the reclassification of the initial lesion as a compound nevus with unusual features. This case underscores that BRAF inhibition may enhance PRAME expression in benign melanocytic nevi, potentially through mechanisms involving mitogen-activated protein kinase (MAPK) activation, altered Erk phosphorylation, or disruption of retinoic acid (RA) signaling. This case also brings awareness to the potential of medication-induced PRAME expression and encourages both dermatologists and dermatopathologists to avoid overdiagnosis as PRAME continues to gain prominence as a diagnostic biomarker.

T-cell receptor beta-chain constant region 1 (TRBC1) immunohistochemistry (IHC) identifies clonal αβ T-cell populations on tissue sections, but its real-world performance across cutaneous T-cell lymphoma (CTCL) and related infiltrates is uncharacterized. The analytic cohort comprised 665 biopsies (566 patients) with paired T-cell receptor (TCR) clonality testing, classified clinicopathologically as mycosis fungoides (MF-Patch, MF-Plaque, MF-Tumor, MF-Folliculotropic), MF/Sézary syndrome, primary cutaneous small/medium T-cell lymphoproliferative disorder, other CTCL-cutaneous lymphoproliferative disorder, or reactive. At the primary <15%/>85% threshold, TRBC1 IHC achieved 85.8% sensitivity (337/393), 79.8% specificity (217/272), 86.0% positive and 79.5% negative predictive value, and 83.3% accuracy, lowest in MF-Patch (84.2%). Three-reader agreement (Fleiss' κ = 0.943) fell to κ = 0.776 in 176 reflexed biopsies, with disagreement concentrated in MF-Patch and CD30-positive lymphoproliferative disorders. Monotypic TRBC1 predicted neoplasia, with odds rising with infiltrate density: MF-Patch (odds ratio 5.41), MF-Plaque (10.40), MF/Sézary syndrome with MF-Tumor (15.19), and CTCL-cutaneous lymphoproliferative disorder (18.16). Polytypic TRBC1 was associated with reactive disease (odds ratio 53.65), effectively excluded clonality (negative likelihood ratio 0.18); and was uniformly observed in an independent 270-biopsy reactive cohort. For observer-independent validation, digital image analysis-derived TRBC1 quantification (QuPath) was applied to a stratified random subset of 250 biopsies representative of the cohort's tumor-burden distribution. The digital read tracked molecular clonality (85.1% sensitivity, 80.1% specificity against TCR; area under the curve 0.842) and agreed with the dermatopathologist manual read in 87.6% of cases (κ = 0.752), with the data-derived cutoff matching the pre-specified <15%/>85% threshold. Discordance was directional for both manual scoring and digital quantification: in MF-Patch, 25/38 (65.8%) and 12/17 (70.6%) cases were polytypic with monoclonal TCR (false-negative-dominant); in reactive biopsies, 34/45 (75.6%) and 19/20 (95%) were monotypic with polyclonal TCR (false-positive-dominant). These findings support a TRBC1-first approach, reserving reflex TCR testing for borderline expression or clinicopathologic discordance, preserving diagnostic accuracy while reducing molecular testing and reimbursement-based costs.

Adult T-cell leukemia/lymphoma (ATLL) is a rare aggressive mature T-cell neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). The disease predominantly affects patients from endemic regions of Japan, the Caribbean, Sub-Saharan Africa, and South America. Cutaneous involvement of ATLL is common and may appear before or in the absence of systemic involvement. However, the lesions are non-specific and often mimic more common inflammatory and neoplastic skin diseases, making diagnosis challenging. Moreover, morphology is variable among patients, ranging from macules and papules to tumors and erythroderma. Recent data suggests that the presence of cutaneous lesions and lesion morphology are important for prognostication and for guiding treatment. Here, we provide an overview of the spectrum of cutaneous findings in ATLL, highlighting their diagnostic, prognostic, and therapeutic implications. We emphasize the importance of early recognition and workup of suspicious skin lesions, particularly in endemic regions or high-risk populations. Finally, we describe fundamental concepts and controversies, and highlight current knowledge gaps.

e19075 Background: Bone marrow biopsy (BMB) is widely used to evaluate extracutaneous involvement in cutaneous T-cell lymphoma (CTCL), particularly in advanced disease stages (≥IIB) or given suspicion for systemic involvement. However, the routine implementation of BMB lacks standardization in clinical practice, leading to variability in its perceived utility and frequency of use. This study aimed to assess expert opinions regarding the role of BMB in the diagnosis, staging, and prognosis of CTCL, focusing on specialty-based differences among dermatologists, pathologists, and hematologists/oncologists. Methods: We developed a mixed-methods, 36-question electronic survey targeting 116 clinicians affiliated with USCLC/NCCN. Survey domains included participant demographics, BMB rationale, prognostic implications, and narrative feedback. Responses were analyzed using descriptive statistics, Fisher’s exact test, and UpSet plots to evaluate response patterns. Free-text responses underwent content analysis by two independent reviewers. Results: Among 102 respondents (41 dermatologists, 40 hematopathologists, 21 hematologists/oncologists), BMB was primarily performed to assess for unexplained hematologic abnormalities (23% dermatologists vs. 85% hematopathologists vs. 81% hematologists/oncologists; p<0.001) followed by the differential diagnosis of other T-cell lymphomas (46% dermatologists vs. 33% hematopathologists vs. 33% hematologists/oncologists; p=0.40). Dermatologists selectively utilized BMB for staging purposes (56% vs. 24% hematologists/oncologists, p=0.03). BMB findings rarely altered management (<25% of cases for 85% of respondents). Despite discrepancies in practice patterns, most experts agreed on work-up modalities including marker selection for flow cytometry and immunohistochemistry (CD3, CD4, CD5, CD7, and CD8) and inclusion of PET-CT (73.8%). A significant proportion of respondents (34%) reported that BMB findings are “not applicable” to their current practice, reflecting a combination of unclear guidelines, knowledge gaps, and genuine clinical irrelevance. Conclusions: These survey findings indicate that BMBs currently have minimal impact on patient management and outcomes. Observed practice pattern discrepancies among specialties highlight the need for updated evidence-based guidelines and targeted educational measures to improve the management of CTCL.

2522 Background: Sézary syndrome (SS) is a rare and aggressive cutaneous T-cell lymphoma, which commonly expresses KIR3DL2, a killer immunoglobulin-like receptor, reported in ≥ 85% of patients. SS is characterized by erythroderma, significant blood involvement, lymphadenopathy and poor prognosis (10-20% 5-year survival). Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. Methods: TELLOMAK is an international, Phase 2 trial with multiple cohorts (NCT03902184). We report here long term follow-up results from Cohort 1, evaluating lacutamab in patients with relapsed/refractory (R/R) SS after at least 2 prior systemic therapies including mogamulizumab. Lacutamab 750 mg is administered until progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to the International Consensus criteria Olsen 2011. Secondary endpoints included but were not limited to duration of response (DOR), progression free survival (PFS), safety, and quality of life assessments. Results: As of October 17, 2024, recruitment was completed with 63 SS patients enrolled. Median age was 69 years (range: 42-86), the median prior lines of systemic therapies were 5.0 (range: 2-13), 65.1% and 34.9 % patients had stage IVA1 and stage IVA2 at baseline respectively, all patients had blood involvement (B2), 63.5% had confluence of erythema covering ≥ 80% body surface area (T4), 34.9% had lymph node lymphoma involvement (N3). Median follow-up was 25.1 months (95% CI 21.0-29.4). Global confirmed ORR was 42.9% (CI 31.4-55.1) including 6 (9.5%) CRs who are all still in CR; with a median time to response of 2.8 months (range 1-10) and a median duration of response of 25.6 months (CI 11.0, NE). According to each compartment, ORR in skin was 52.4% (CI 40.3-64.2) including 9 (14.3%) CRs, ORR in blood was 50.8% (CI 38.8-62.7) including 21 (33.3) CRs, and ORR in lymph nodes was 28.8% (CI 18.3-42.3) including 9 (17.3) CRs. Median PFS was 8.3 months (CI 5.1-18.7). Grade ≥ 3 related Treatment-Emergent Adverse Events (TEAEs) were observed in 20.6% patients. Serious related TEAEs were observed in 9.5% patients and related TEAEs leading to study drug discontinuation in 6.3% patients. Data from additional key endpoints will be presented. Conclusions: The long term follow-up data from TELLOMAK study in a R/R SS population previously treated with 2 or more prior systemic therapies including mogamulizumab, confirm that lacutamab shows promising clinical activity with ORR 42.9% (95% CI 31.4-55.1) and median duration of response of 25.6 months (11.0, NE) and an overall favourable safety profile. These data support the further development of lacutamab in an effort to bring improved treatments to patients with SS. Clinical trial information: NCT03902184 // EU CT number: 2023-507777-18-00.

In recent classifications several cutaneous lymphomas were reclassified as lymphoproliferative disorder (LPDs). These include primary cutaneous CD4+ small/medium T-cell LPD (PCSM-TCLPD), primary cutaneous acral CD8+ T-cell LPD (acral CD8+ TCLPD) and primary cutaneous marginal zone lymphoma/LPD (PCMZL/LPD). The latter is still classified as primary cutaneous marginal zone lymphoma (PCMZL) in the 5th edition of the World Health Organization classification. A survey was previously carried out among 30 cutaneous lymphoma centres on the effects of this new terminology on clinical management. The results revealed considerable heterogeneity and emphasized the need to develop uniform recommendations for management and treatment of these disorders. Our objective was to develop consensus recommendations for staging, treatment and follow-up in PCSM-TCLPD, acral CD8+ TCLPD and PCMZL/LPD. Two surveys with questions regarding staging, treatment and follow-up of cutaneous LPDs were distributed among 30 cutaneous lymphoma expert centres collaborating within the EORTC-CLTG, USCLC and ISCL. Consensus recommendations were formulated based on these surveys, an extensive literature search, two rounds of feedback and a final consensus meeting. Important changes compared with current practice and literature are as follows. (i) Staging examinations, other than thorough clinical examination of skin and peripheral lymph nodes, are not required in typical cases of PCSM-TCLPD and acral CD8+ TCLPD. (ii) Low-dose radiotherapy (4-8 Gy) can be used rather than dose ≥ 20 Gy for PCSM-TCLPD and acral CD8+ TCLPD, and 4 Gy can be used for PCMZL/LPD. The dose can be escalated to 20-24 Gy in the case of local failure. (iii) Intralesional corticosteroids are also recommended as initial treatment in all three LPDs. (iv) A limited follow-up period (2 years) is acceptable in PCSM-TCLPD and acral CD8+ TCLPD LPD. These EORTC/USCLC/ISCL consensus recommendations reflect the state-of-the-art management and treatment as agreed upon by major cutaneous lymphoma centres. They may contribute to uniform staging, treatment and follow-up policy in patients with cutaneous LPDs.

Melanoma, an aggressive skin cancer, presents significant therapeutic challenges. Consequently, innovative treatment strategies beyond conventional chemotherapy, radiation, and surgery are actively explored. This review discusses the evolution of immunotherapy in advanced melanoma, highlighting PD-1/PD-L1 inhibitors, mRNA vaccines, Talimogene Laherparepvec (T-VEC), and tumor-infiltrating lymphocyte (TIL) therapies. PD-1/PD-L1 inhibitors such as pembrolizumab and nivolumab block immune checkpoints, promoting T-cell cytotoxic activity and improving overall survival in patients with advanced melanoma. T-VEC, a modified oncolytic herpes virus, promotes a systemic anti-tumor response while simultaneously lysing malignant cells. mRNA vaccines, such as Moderna’s mRNA-4157/V940, take advantage of malignant-cell-specific neoantigens to amplify the adaptive immune response while protecting healthy tissue. TIL therapy is a form of therapy involving ex vivo expansion and reinfusion of the patient’s tumor-specific lymphocytes and has been shown to provide durable tumor control. While these therapies have demonstrated promising clinical outcomes, challenges such as tumor resistance, high financial burden, and limited accessibility pose challenges to their widespread use. This review explores combination therapies such as PD-L1 inhibitors with mRNA vaccines, or TIL therapy, which aim to enhance treatment through synergistic approaches. Further research is required to optimize these combinations, address barriers preventing their use, and control adverse events.

Acute myeloid leukemia is a cancer involving uncontrolled proliferation of hematopoietic cells. Cutaneous involvement is referred to as leukemia cutis (LC). The histopathologic presentation of LC is variable, and may present with perivascular, periadnexal, dermal, or subcutaneous infiltrate. Epidermotropism is notably absent. We report an unusual case of acute myeloid LC with epidermotropism in a 68-year-old man. A punch biopsy revealed a mononuclear myeloblast infiltrate involving the dermis and subcutaneous tissue. The epidermis was focally acanthotic, with several vesicles and atypical epidermotropic cells. Mitotic figures and apoptotic cells were present. Immunohistochemistry showed the blasts to be positive for CD56, CD123, and lysozyme, and weakly positive for CD4 and CD163. Negative immunostaining included CD3, CD20, CD34, TdT, and CD117. Epstein-Barr virus in situ hybridization was negative. A bone marrow biopsy revealed the same myeloblast population with identical phenotype to the skin. The blasts were negative for CD34, CD117, CD3, CD19, CD163, CD68, CD61, myeloperoxidase, pankeratin, E-cadherin, CD4, and transcription factor 4. A diagnosis of acute myeloid leukemia with monocytic differentiation and leukemia cutis was established. These findings suggest that the differential diagnosis for conditions with epidermotropism may be even broader than previously thought.

BACKGROUND:Primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP) are indolent CD30-positive lymphoproliferative disorders that rarely express TCR-γδ. However, primary cutaneous gamma-delta T-cell lymphoma (pcGDTCL), characterized by TCR-γδ expression on neoplastic cells, is a rare, aggressive cutaneous T-cell lymphoma with a poor prognosis. Accurate differentiation is essential due to distinct clinical behavior and treatment. METHODS:We identified 11 TCR-γδ-positive pcALCL cases from internal and consultation files, verified by two cutaneous lymphoma experts, with clinicopathologic data recorded. RESULTS:The median age was 68 years (range 38-95). Most cases presented as a single dermal lesion on the upper extremities. All were ALK-negative, CD30-positive (> 90% tumor cells), TCR-βF1-negative, and diffusely TCR-γδ-positive. CD4-/CD8- (54.5%) and CD4+/CD8- (45.5%) immunophenotypes were observed. CD2 (63.6%) and CD3 (54.5%) were the most common T-cell antigens. Ulceration, inflammation (both 45.5%), and necrosis (36.4%) were frequent. Angiotropism, angiocentricity, and myxoid stroma appeared in one case; epidermotropism in two. Four of ten tested were DUSP22-rearranged, and TP63 was negative in all eight tested. CONCLUSIONS:Most ALK-negative TCR-γδ-positive pcALCL were CD4-/CD8-, followed by CD4+/CD8-. DUSP22 rearrangement occurred in 40% of cases, similar to reports in typical pcALCL. Its prognosis and the role of DUSP22 are yet to be clarified.

2523 Background: The most common type of cutaneous T-cell lymphoma is Mycosis Fungoides (MF) accounting for 50-60% of cases. Extracutaneous involvement occurs mainly in lymph nodes or blood; 25% of patients are diagnosed at advanced stage with a 5-year survival of 15-25%. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. KIR3DL2 is a killer immunoglobulin-like receptor expressed in MF patients. Methods: TELLOMAK is an international, multi-cohort phase 2 trial (NCT03902184). MF patients who had received at least 2 prior systemic therapies were treated with lacutamab 750 mg until disease progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to the International Consensus criteria Olsen 2011. Key secondary endpoints included duration of response (DoR), progression free survival (PFS), safety, and quality of life. Here we report long term follow-up data of MF patients. Results: As of October 17, 2024, recruitment was completed, with 107 MF patients enrolled. The median age was 62 years. The median number of previous systemic lines was 4 (range: 1-14). Median follow-up was 22.1 months (m) (95% CI 19.4, 23.6). Global confirmed ORR was 19.6% (CI 13.2, 28.1; Olsen 2011), and response in skin was 29.0% (CI 21.2, 38.2). Median time to response was 2.8 m (min, max 1-37) and median DoR was 13.8 m (7.4, NE), median PFS was 10.2 m (CI 8.0, 15.4). Among the KIR3DL2 ≥1% pts (N = 48), ORR was 20.8% (CI 11.7, 34.3; Olsen 2011), and response in skin was 33.3% (CI 21.7, 47.5), median DoR was 13.8 m (CI 4.6, NE) and median PFS 11.8 m (CI 5.6, 16.8). Among the KIR3DL2 < 1% pts (N = 59), ORR was 18.6% (CI 10.7;30.4; Olsen 2011), and response in skin was 25.4 (CI 16.1, 37.8), median DoR was 15.7 m (CI 5.1, NE) and median PFS 9.5 m (CI 6.5;16.6). Grade ≥ 3 related Treatment-Emergent Adverse events (TEAEs) were observed in 5/107 (4.7%) patients, serious related TEAEs in 4/107 (3.7%) patients and related TEAEs leading to study drug discontinuation in 3/107 (2.8%) patients. The most common ( > 10%) related TEAEs were fatigue (12.1%), nausea (13.1%), asthenia (11.2%) and arthralgia (11.2%). Data from additional key endpoints and translational data will also be presented. Conclusions: The long-term follow-up data from the heavily pre-treated MF population enrolled to the TELLOMAK study confirms promising clinical activity of lacutamab regardless of KIR3DL2 expression, with ORR 20.8%, a median duration of response of 13.8 m, a median PFS of 10.2 m and a favorable safety and tolerability profile. These data support the further development of lacutamab in an effort to bring improved treatments to patients with MF. Clinical trial information: NCT03902184 // EU CT number: 2023-507777-18-00 .

Cutaneous plasmacytosis has &lt;60 cases worldwide, typically characterized by multiple asymmetric facial and truncal cutaneous nodules and plaques. We describe the case of a 68-year-old woman with erythematous plaques on the feet who had a biopsy showing primary cutaneous plasmacytosis and subsequent workup revealing celiac disease. Our patient's clinical presentation of symmetric plaques on the dorsal feet is previously unreported. Additionally, plasmacytosis occurs predominantly in Japanese patients and men younger than 40. Cutaneous plasmacytosis is hypothesized to be reactive from overreaction to stimuli including trauma, infections, or malignancies. The origin of our patient's reactive process could be related to celiac disease or could be unknown. Plasmacytosis in bone marrow has been reported with celiac disease, but to our knowledge, this is the first report of cutaneous plasmacytosis in a patient with celiac disease.