Chemokine profiling of melanoma-macrophage crosstalk identifies CCL8 and CCL15 as prognostic factors in cutaneous melanoma.

During cancer evolution, tumor cells attract and dynamically interact with monocytes/macrophages. To find biomarkers of disease progression in human melanoma, we used unbiased RNA sequencing and secretome analyses of tumor-macrophage co-cultures. Pathway analysis of genes differentially modulated in human macrophages exposed to melanoma cells revealed a general upregulation of inflammatory hallmark gene sets, particularly chemokines. A selective group of chemokines, including CCL8, CCL15, and CCL20, was actively secreted upon melanoma-macrophage co-culture. Because we previously described the role of CCL20 in melanoma, we focused our study on CCL8 and CCL15 and confirmed that in vitro both chemokines contributed to melanoma survival, proliferation, and 3D invasion through CCR1 signaling. In vivo, both chemokines enhanced primary tumor growth, spontaneous lung metastasis, and circulating tumor cell survival and lung colonization in mouse xenograft models. Finally, we explored the clinical significance of CCL8 and CCL15 expression in human skin melanoma, screening a collection of 67 primary melanoma samples, using multicolor fluorescence and quantitative image analysis of chemokine-chemokine receptor content at the single-cell level. Primary skin melanomas displayed high CCR1 expression, but there was no difference in its level of expression between metastatic and nonmetastatic cases. By contrast, comparative analysis of these two clinically divergent groups showed a highly significant difference in the cancer cell content of CCL8 (p = 0.025) and CCL15 (p < 0.0001). Kaplan-Meier curves showed that a high content of CCL8 or CCL15 in cancer cells correlated with shorter disease-free and overall survival (log-rank test, p < 0.001). Our results highlight the role of CCL8 and CCL15, which are highly induced by melanoma-macrophage interactions in biologically aggressive primary melanomas and could be clinically applicable biomarkers for patient profiling. © 2024 The Pathological Society of Great Britain and Ireland.

Defining dipeptidyl peptidase-4 inhibitors-related bullous pemphigoid: A single-centre retrospective study.

BACKGROUND: Many studies have corroborated the association of dipeptidyl peptidase-4 inhibitors (DPP4i) use with bullous pemphigoid (BP). It has been speculated that this drug-induced variant presents with a different clinical spectrum than conventional BP. OBJECTIVE: To determine the prevalence of DPP4i-induced cases of BP and to evaluate whether gliptin-related BP has specific clinicopathological and immunological features. METHODS: We conducted a retrospective, observational study of BP cases attended at our centre between January 2000 and June 2020. Epidemiological, clinical, histopathological and laboratory data were collected. RESULTS: A total of 257 cases of BP were collected; 51 (24.3%) were on treatment with DPP4i. When analysing DPP4i-induced BP cases, generalized BP was the predominant pattern and scalp/mucosal involvement was found in 13 patients. Gliptin-related BP cases were associated to a decrease in the eosinophilic infiltrate (p = 0.000) and both the detection rate and concentration of anti-BP180 IgG were lower (p = 0.004, p = 0.001, respectively) than non-DPP4i cases. LIMITATIONS: Retrospective, single-centre study. CONCLUSION: Our large DPP4i-induced BP case series has highlighted that DPP4i-induced BP is characterized by generalized lesions and scalp involvement. Lower titres of anti-BP180 antibodies and a decrease in eosinophils infiltrating into the skin may be distinct features of DPP4i-related BP.

Histological findings after intralesional methotrexate treatment in cutaneous squamous cell carcinoma.

Intralesional methotrexate (il-MTX) has been reported as a useful therapy in keratoacanthoma (KA) and cutaneous squamous cell carcinoma (cSCC). However, the data available on the histological changes induced by this therapy are very scarce. We conducted a single center, prospective study that included 65 cases of cSCC treated with il-MTX before surgical treatment. Two histological studies were conducted in all patients: before intralesional treatment and after surgical removal. Lesions were assessed longitudinally both clinically and histologically. 60 patients (92.3%) responded to il-MTX treatment. There were no differences regarding aggressive histological features of the cSCC between responder and non-responder patients. All cases showed a chronic inflammatory infiltrate after il-MTX. Intratumoral necrosis areas were frequently observed. All cases showed local fibrosis with fine thickening of collagen bundles. Il-MTX induces a chronic lymphohistiocytic inflammatory reaction in both clinical responder and nonresponder patients. Tumor involution after il-MTX is followed by a fine fibrosis that explains the great cosmetic results and improves the accuracy of the follow-up.

Pigmented Dermatofibrosarcoma Protuberans: Description of a pediatric case. / Dermatofibrosarcoma protuberans pigmentado: Descripción de un caso pediátrico.

INTRODUCTION: Bednar tumor is a rare low-grade sarcoma considered the pigmented variant of dermatofibrosarco ma protuberans (DFSP). OBJECTIVE: To describe the clinical and histopathological characteristics, treatment and evolution of this rare neoplasm. CLINICAL CASE: A 9-year old female presented with a 2-year history of an indurated, asymptomatic papule on the back of her fourth left toe. The incisio nal biopsy was compatible with pigmented DFSP. The immunohistochemical study showed intense positivity for CD34 throughout the lesion, with negative factor XIIIa. We complemented the study with molecular cytogenetics (FISH) for PDGFB gene (22q13.1) which showed an abnormal pattern in tumor cells, but not in the melanocytes or the peritumoral skin. Delayed Mohs surgery and skin substitute dressing were performed without neoplastic recurrence at 5 years of follow up. Conclu sion: Pigmented DFSP is a low-grade sarcoma that is very rare in pediatric patients. The classical and pigmented variants should be suspected in the presence of a single papulonodular lesion of slow and progressive growth, with presence of spindle cells with storiform pattern in the biopsy and positive immunohistochemical study for CD34. It is an entity with good prognosis, with little risk of recurren ce and metastasis, if complete excision is achieved.

Langerhans cell histiocytosis mimicking lichen nitidus with bone involvement.

We report the case of a 6-month-old Hispanic boy with a 4-month history of widespread pruritic hypopigmented papules mimicking lichen nitidus. The final diagnosis was multisystem non-risk-organ Langerhans cell histiocytosis (LCH), with cutaneous and multiple bone involvement. With this patient and others previously reported in the literature, we suggest an early biopsy of the hypopigmented rash in children.

Sudden Onset of Papular Elastorrhexis After Immunologic Recovery in a Boy with Human Immunodeficiency Virus.

Papular elastorrhexis (PE) is an uncommon elastic tissue disorder clinically characterized by the onset of asymptomatic flesh-colored to whitish papules over the trunk and upper limbs in children. Its etiology remains unknown, although isolated familial cases have suggested that acquired and inherited forms of the disease may exist. We present the case of a 13-year-old boy with human immunodeficiency virus who presented with such lesions after immunological recovery from very low CD4+ counts after introducing highly active antiretroviral therapy. Because neutrophils and macrophages are implicated in elastin metabolism and degradation pathways, immune dysregulation might be another etiologic factor to be considered in this rare disease.

Self-Healing Extranodal Cutaneous Rosai-Dorfman in a Child.

Sinus histiocytosis with massive lymphadenopathy, or Rosai-Dorfman disease (RDD), is commonly characterized by painless cervical lymphadenopathy. Exclusively cutaneous Rosai-Dorfman disease is rare. In the absence of massive lymphadenopathy, the nonspecific skin lesions may complicate the diagnosis. To our knowledge, the case reported herein is the youngest case of extranodal cutaneous RDD.

Activin A Sustains the Metastatic Phenotype of Tumor-Associated Macrophages and Is a Prognostic Marker in Human Cutaneous Melanoma.

Tumor cells attract and dynamically interact with monocytes/macrophages to subvert their differentiation into tumor-associated macrophages (TAMs), which mainly promote immune suppression and neoplastic progression, but the pathways and microenvironmental cues governing their protumoral deviation are not completely understood. To identify the molecular pathways responsible for TAM differentiation, we screened the biomarkers secreted during melanoma‒macrophage interactions using Quantibody microarrays and RNA sequencing of macrophages. We found that activin A, a member of the transforming GF family, plays an instrumental role in the cross-talk between melanoma cells and monocytes/macrophages, which results in the upregulation of distinct tumor-sustaining genes and the achievement of proinvasive and immunosuppressive functions of TAMs. Blockade of activin reduces the upregulation of part of these genes and prevents the acquisition of protumoral functions, facilitating human melanoma rejection by transferred human lymphocytes in a xenograft mouse model. Remarkably, screening of two independent cutaneous primary melanoma collections showed that activin A is enriched in TAMs and melanoma cells from patients with worse outcomes and constitutes a new and independent prognostic marker. Thus, we identify activin A as a key intermediary in the protumoral and immunosuppressive functions of TAMs, with significant potential as a disease biomarker as well as an immunotherapeutic target.

When is it worth performing lymphadenectomy in patients with melanoma micrometastases? A 20-year experience retrospective analysis.

INTRODUCCIÓN: Actualmente existe controversia respecto a los beneficios de realizar linfadenectomía en pacientes de melanoma con una biopsia selectiva de ganglio centinela (BSGC) positiva. La carga tumoral > 1 mm se ha propuesto como el parámetro mas relevante asociado a una linfadenectomía positiva y un deterioro de la supervivencia libre de enfermedad. MATERIAL Y MÉTODOS: Se analizaron los datos de 119 pacientes de melanoma con BSGC positiva atendidos en el periodo entre Junio de 1997 y Junio de 2017. Los pacientes se clasificaron según la carga tumoral en dos grupos: ≤ 1 mm and > 1 mm. RESULTADOS: La linfadenectomía resultó positiva en sólo 6 (10%) pacientes con una carga tumoral ≤ 1 mm, y en 23 (37.7%) pacientes con carga tumoral > 1 mm (p < 0.001). En análisis univariante, la carga tumoral fue el único factor predictivo de linfadenectomía positiva (OR 5.24 (1.94-14.13)). En análisis multivariante, la carga tumoral fue la única variable independiente de supervivencia específica de melanoma (SEM). CONCLUSION: Aunque la realización de linfadenectomía debe individualizarse en cada caso, la carga tumoral > 1 mm puede ser un factor predictivo de la presencia de ganglios no centinelas positivos en piezas de linfadenectomía, y un factor pronostico independiente importante para la SEM. BACKGROUND: The benefits of complete lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node biopsy (SLNB) have been recently questioned. Sentinel node (SN) tumor burden > 1 mm has been proposed as the most reliable parameter associated with positive CLND and poorer disease-free survival. MATERIAL AND METHODS: Between June 1997 and June 2017, data from 119 melanoma patients with positive SLNB were analyzed. Patients were classified by SN burden in two groups: ≤ 1 mm and > 1 mm. RESULTS: CLND was positive in 6 (10%) patients with SN tumor burden ≤ 1 mm and in 23 (37.7%) patients with > 1 mm (p < 0.001). In univariable analysis, SN tumor burden was the only predictive factor of positive CLND (OR 5.24 [1.94-14.13]). In multivariable analysis, SN tumor burden was the only independent factor of melanoma-specific survival (MSS). CONCLUSION: Although CLND should still be considered individually in patients with positive SLNB, SN tumor burden >1 mm might be a good predictive factor of additional positive non-sentinel nodes and a strong independent prognostic factor in melanoma-specific survival.

First Report of an Invasive Infection by Cephalotrichum gorgonifer in a Neutropenic Patient with Hematological Malignancy under Chemotherapy.

The etiological agents of infrequent invasive fungal infections (IFI) are difficult to identify on the species level using classic morphological examination. We describe the first case of an IFI caused by Cephalotrichum gorgonifer in a neutropenic patient with a hematological malignancy and put it on the map as a new causative agent of IFI. Case report, microbiological findings and description of the etiological agent. A 60-year-old man was diagnosed with mantle cell lymphoma. A CT scan confirmed the presence of lung infiltrates located at the right upper lobe. Histological examination of one of the nodules showed a large number of narrow septate hyphae with acute-angle branching and irregular round cell morphology; vessels walls appeared infiltrated, proving an angioinvasive pulmonary IFI. Sample culture resulted positive and molecular identification proved the presence of Cephalotrichum gorgonifer. Voriconazole was used for 12 months and the patient did not report any complications or side effects. Complete remission of lymphoma was achieved later by the time chemotherapy, radiotherapy, and radioimmunotherapy consolidation were completed. We recommend the inclusion of Cephalotrichum gorgonifer in the list of opportunistic pathogens causing mycoses in neutropenic hematological patients with suspected mould-related IFI.

CCL20/TNF/VEGFA Cytokine Secretory Phenotype of Tumor-Associated Macrophages Is a Negative Prognostic Factor in Cutaneous Melanoma.

TAMs constitute a large fraction of infiltrating immune cells in melanoma tissues, but their significance for clinical outcomes remains unclear. We explored diverse TAM parameters in clinically relevant primary cutaneous melanoma samples, including density, location, size, and polarization marker expression; in addition, because cytokine production is a hallmark of macrophages function, we measured CCL20, TNF, and VEGFA intracellular cytokines by single-cell multiparametric confocal microscopy. The Kaplan-Meier method was used to analyze correlation with melanoma-specific disease-free survival and overall survival. No significant correlations with clinical parameters were observed for TAM density, morphology, or location. Significantly, higher contents of the intracellular cytokines CCL20, TNF, and VEGFA were quantified in TAMs infiltrating metastasizing compared to non-metastasizing skin primary melanomas (p < 0.001). To mechanistically explore cytokine up-regulation, we performed in vitro studies with melanoma-conditioned macrophages, using RNA-seq to explore involved pathways and specific inhibitors. We show that p53 and NF-κB coregulate CCL20, TNF, and VEGFA in melanoma-conditioned macrophages. These results delineate a clinically relevant pro-oncogenic cytokine profile of TAMs with prognostic significance in primary melanomas and point to the combined therapeutic targeting of NF-kB/p53 pathways to control the deviation of TAMs in melanoma.

Cutaneous infiltration by T-cell prolymphocytic leukemia in two adult patients. / Infiltración cutánea por leucemia prolinfocítica T en dos pacientes adultos.

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a T-cell lymphoproliferative disorder that frequently involves the skin. The objective was to describe two cases of T-PLL with cutaneous involvement and to present a review of the literature concerning the clinical characteristics, differential diagnosis and treatment of these patients. CASE REPORTS: 1) 79 year-old man, with a previous diagnosis of T-PLL based on a laboratory incidental finding. He had been treated with alemtuzumab, but it had to be interrupted due to recurrent infections. After interrupting the treatment, the patient developed a symmetrical rash on his extremities. The skin biopsy demonstrated TPLL infiltration. 2) 28 year-old man that presented with asthenia and lymphocytosis. He also showed a purpuric rash on his trunk and facial erythema. Histopathology of the skin and bone marrow confirmed the diagnosis of T-PLL with cutaneous involvement. CONCLUSIONS: T-cell prolymphocytic leukemia accounts for 2% of mature leukemias in adults. Skin involvement is reported in 20-50% of the patients. The characteristic features are facial involvement, purpuric lesions and symmetry of the rash, although there are atypical manifestations as well. Differential diagnosis includes other T-cell lymphoproliferative disorders with hematologic and skin involvement, such as Sézary syndrome. Patients with T-PLL may show cutaneous infiltration at the moment of debut or relapse of the disease. The skin is an accessible organ for taking samples to study and diagnose these patients.

INTRODUCCIÓN: La leucemia prolinfocítica T (LPL-T) es una neoplasia hematológica del grupo de síndromes linfoproliferativos T que con frecuencia produce infiltración cutánea. Se presentan dos casos de LPL-T con afectación cutánea y se revisa la literatura en cuanto a características clínicas, diagnóstico diferencial y tratamiento de estos pacientes. CASOS CLÍNICOS: 1) Varón de 79 años diagnosticado de LPL-T tras un hallazgo analítico incidental. Tras suspender el tratamiento con alemtuzumab por infecciones recurrentes, comenzó con lesiones cutáneas maculopapulosas eritematopurpúricas que afectaban la raíz de las extremidades. La biopsia cutánea confirmó la infiltración por su enfermedad de base. 2) Varón de 28 años que debutó con astenia y hallazgos analíticos de leucocitosis. Había comenzado además con lesiones purpúricas en el tronco y eritema malar bilateral. El estudio de médula ósea y la biopsia cutánea confirmaron el diagnóstico de LPL-T con infiltración cutánea. CONCLUSIONES: La LPL-T corresponde al 2% de las leucemias linfocíticas maduras en los adultos. Entre el 20% y el 50% de los pacientes presentan afectación cutánea, con predominio en la región facial, y son característicos el eritema, la púrpura y la simetría, aunque existen manifestaciones atípicas. El diagnóstico diferencial incluye otros síndromes linfoproliferativos T con afectación cutánea y en sangre periférica, entre los que destaca el síndrome de Sézary. Los pacientes con LPL-T pueden presentar afectación cutánea en el debut o en una recidiva de la enfermedad. La piel representa un órgano accesible para la toma de muestras y para el diagnóstico y el estudio de estos pacientes.