Heterogeneous IL-9 Production by Circulating Skin-Tropic and Extracutaneous Memory T Cells in Atopic Dermatitis Patients.

Interleukin (IL)-9 is present in atopic dermatitis (AD) lesions and is considered to be mainly produced by skin-homing T cells expressing the cutaneous lymphocyte-associated antigen (CLA). However, its induction by AD-associated triggers remains unexplored. Circulating skin-tropic CLA+ and extracutaneous/systemic CLA- memory T cells cocultured with autologous lesional epidermal cells from AD patients were activated with house dust mite (HDM) and staphylococcal enterotoxin B (SEB). Levels of AD-related mediators in response to both stimuli were measured in supernatants, and the cytokine response was associated with different clinical characteristics. Both HDM and SEB triggered heterogeneous IL-9 production by CLA+ and CLA- T cells in a clinically homogenous group of AD patients, which enabled patient stratification into IL-9 producers and non-producers, with the former group exhibiting heightened HDM-specific and total IgE levels. Upon allergen exposure, IL-9 production depended on the contribution of epidermal cells and class II-mediated presentation; it was the greatest cytokine produced and correlated with HDM-specific IgE levels, whereas SEB mildly induced its release. This study demonstrates that both skin-tropic and extracutaneous memory T cells produce IL-9 and suggests that the degree of allergen sensitization reflects the varied IL-9 responses in vitro, which may allow for patient stratification in a clinically homogenous population.

Primary cutaneous blastic marginal zone lymphoma: A comprehensive clinical, light microscopic, phenotypic and cytogenetic appraisal.

BACKGROUND: Primary cutaneous marginal zone lymphoma (PCMZL) is a form of indolent lymphoproliferative disease where the disease is largely a cutaneous confined process. It is typically a neoplasm composed of post germinal small B-cells and light chain restricted plasma cells in a background of reactive T-cell hyperplasia and benign germinal centers. Rarely a significant degree of large cell infiltration occurs warranting the categorization as blastic marginal zone lymphoma. MATERIALS AND METHODS: We reviewed our data base over a time period of 2016 to 2022 for cases diagnosed as blastic MZL. Twelve cases were identified. The clinical records and pathological data were reviewed. RESULTS: Nine of the cases represented de novo forms of blastic MZL while in three cases there was a prior history of MZL. Multifocal cutaneous disease was not uncommon and one quarter of the cases had evidence of extracutaneous dissemination. All patients except three achieved remission with varied therapeutic interventions depending on the extent of the disease ranging from conservative re-excision to chemotherapy. No patient died from lymphoma. Light microscopically, there was evidence of a background of conventional MZL in the majority of cases. The large cell component was typically characterized by multiple micronodular aggregates throughout the dermis although in three cases there was a striking diffuse large cell component as the dominant infiltrate. Phenotypically, a third of the cases showed either CD5 or CD23 positivity amidst neoplastic B cells. Significant staining for BCL-2 was noted in the majority of cases tested while extensive MUM-1 positivity was observed in half of the cases tested. Kappa or lambda light chain restriction was seen in most. The Ki67 proliferation index exceeded 30 % in all cases. There was C-MYC positivity in two cases. While most cases did not detect cytogenetic abnormalities, one case had multiple cytogenetic hits that are associated with diffuse large B cell lymphoma. Next generation sequencing showed a Ten-eleven translocation 2 mutation in the earlier biopsy prior to transformation and in the later biopsy after transformation along with an additional B2M mutation in the transformed biopsy. Both types of mutations are very uncommon but held to contribute to tumor progression in the setting of diffuse large B cell lymphoma. CONCLUSION: Blastic MZL is associated with a more aggressive clinical course. Even when there is disseminated disease patients while not always cured did not have a fatal course in this series. The light microscopic findings are reproducible. The background of MZL, identification of larger cells in significant numbers without a follicle center phenotype, at times expressing CD5 or CD23 with variable positivity for MUM1, BCL-2 and C-MYC and a high proliferation index define the pathology in most. Certain cytogenetic abnormalities and genetic mutations implicated in large cell transformation into a diffuse large B cell lymphoma are seen in blastic MZL with earlier biopsies prior to transformation potentially harboring at risk genetic mutations.

Clinical characteristics of 47 children with pigmentary mosaicism: A cross-sectional study.

BACKGROUND: Pigmentary mosaicism (PM), also known as Blaschkoid dyspigmentation, is a rare pigmentary anomaly. Although several case reports have been published describing extracutaneous manifestations associated with PM, there are very few studies on the clinical characteristics of patients with PM. AIM: To describe the clinical characteristics of patients with PM. PATIENTS AND METHODS: This descriptive cross-sectional study was conducted among 47 children examined by a dermatologist and a pediatrician. The pattern and location of the PM, type of pigmentation and extracutaneous manifestations were documented. RESULTS: The most common pattern of PM was narrow-band PM, followed by broad-band and checkerboard patterns. The trunk was the most affected region, followed by the legs and arms. PM manifested as hypopigmentation in 51.1% of cases, as hyperpigmentation in 27.6%, and as hypo/hyperpigmentation in 21.2%. Accompanying diseases were present in 40.4% of patients: neuropsychiatric diseases were the most common, followed by endocrinological or hematological diseases and growth/developmental delay. CONCLUSION: PM has been associated with several extracutaneous findings but there is still some debate whether these associations reflect different PM phenotypes or whether they are simply coincidental. Our study suggests that extracutaneous involvement in PM patients is frequent, thus warranting careful examination of PM patients.

Melanoma arising in extracutaneous cellular blue naevus: report of two cases with comparison to cutaneous counterparts and uveal melanoma.

AIMS: Blue naevi are benign melanocytic lesions that typically occur in the dermis. Melanoma arising in blue naevus is rare, and shows a molecular profile distinct from conventional forms of cutaneous melanoma and more similar to uveal melanoma and central nervous system (CNS) melanocytomas. In contrast to conventional cutaneous melanoma, these tumour types typically show activating driver mutations in GNAQ or GNA11, a low mutational burden without evidence of a UV signature and a reproducible pattern of chromosomal copy number changes. Blue naevi can also occur at extracutaneous sites. Here we report two cases of melanoma arising in extracutaneous blue naevus and compare their molecular features to cohorts of melanoma arising in cutaneous blue naevus (five patients) and uveal melanoma (six patients). METHODS AND RESULTS: We describe the clinical, histomorphological, immunohistochemical and molecular findings in these two cases of melanoma arising in extracutaneous blue naevus. We compare their molecular profiles to melanomas arising in cutaneous blue naevus and uveal melanoma using a targeted next-generation DNA sequencing platform and find striking similarities between all three groups. CONCLUSIONS: The close relationship between blue naevus-associated melanomas, regardless of their anatomical site, supports and validates the concept of melanoma arising in extracutaneous blue naevus and suggests that the two groups share common pathogenic mechanisms. The similarity of both groups to uveal melanoma in turn supports the close relationship between blue naevus-associated melanoma, uveal melanoma and CNS melanocytoma, and their distinction from conventional UV-associated melanoma. These findings have important implications for prognosis and therapy.

Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges.

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.

Hip dislocation based on Developmental Dysplasia of the Hip (DDH) in a patient with Giant Congenital Melanocytic Nevus (GCMN): A rare coexistence.

Giant congenital melanocytic nevus (GCMN) is a rare congenital benign neoplasm with the potential to become malignant. Various extracutaneous malformations may accompany GCMN. Acetabular dysplasia accompanying GCMN was described in previous studies. To the best of our knowledge, this case report of ours is the first reported case of GCMN diagnosed and treated with hip dislocation based on developmental dysplasia of the hip (DDH). The rare coexistence prompted us to report this case.

Extracutaneous involvement is common and associated with prolonged disease activity and greater impact in juvenile localized scleroderma.

OBJECTIVE: The aim of this study was to evaluate factors associated with extracutaneous involvement (ECI) in juvenile localized scleroderma (jLS). METHODS: A prospective, multicentre, 6-month observational study was performed. The data collected included disease features, global assessments, and subject symptoms. Bivariate and linear multilevel regression analyses were performed. RESULTS: A total of 86 jLS subjects (80% female, 80% Caucasian), median age of disease onset 7.7 years, were evaluated. Most had linear scleroderma or mixed morphea. Of the 86 subjects, 49 (57%) had 125 extracutaneous problems {median 2 [interquartile range (IQR) 1, 3] per subject} from nine organ systems. Most of these subjects had multiple musculoskeletal problems. ECI was associated with more extensive cutaneous involvement, higher number of symptoms, family history of autoimmunity, and ANA and RF positivity. Subjects with ECI had higher scores for physician global assessment of damage (PGA-D), and parental global assessment of disease impact, but not baseline physician global assessment of disease activity (PGA-A). Although subjects with ECI received more MTX and glucocorticoid treatment, they had a slower reduction in PGA-A scores and symptoms over time, suggesting a poorer response to treatment. In logistic regression modelling, female sex had the largest effect on parental impact scores. CONCLUSION: ECI occurred in the majority of subjects with jLS, and was associated with more medication use, longer treatment duration, higher PGA-D scores, and higher parental assessment of disease impact. Our findings suggest that jLS subjects with ECI have greater overall disease burden, both cutaneous and extracutaneous, and poorer response to treatment. More study of the treatment needs of this population is warranted.

Long-term outcomes of children with extracutaneous juvenile xanthogranulomas in Japan.

BACKGROUND: Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis in children. The mortality and morbidity of JXG with extracutaneous lesions remain unclear. METHODS: Data of patients aged < 18 years who were diagnosed with JXG between 2001 and 2010 were retrospectively collected through a nationwide survey. RESULTS: Twenty patients (11 male and nine female) had extracutaneous lesions. The median observation time was 10 years (range, 0-17). Six patients presented with symptoms at birth. The median age at diagnosis was 8.5 months (range, 0 month-13 years). Fifteen patients underwent treatment for JXG, including chemotherapy (n = 11), and five did not receive treatment. All patients except one survived; 17 were disease-free and two survived with disease. One newborn-onset patient with liver, spleen, and bone marrow involvement died of the disease. Permanent sequelae included central diabetes insipidus, growth hormone deficiency, and panhypopituitarism detected at diagnosis in three, one, and two patients, respectively. Four patients had visual impairment (optic nerve compression and intraocular invasion in two each), three had epilepsy, one had mental retardation, and one had a skin scar. Eight patients who had intracranial lesions were older at diagnosis, and had a higher frequency of disease-related comorbidities and permanent sequelae than those without intracranial involvement. CONCLUSIONS: Patients with extracutaneous JXG had good outcomes, although those with intracranial lesions had serious permanent sequelae. Effective and safe treatment regimens for patients with intracranial JXG need to be developed.

Predictors of mucosal melanoma survival in a population-based setting.

BACKGROUND: Mucosal melanomas are rare and aggressive neoplasms, with little published population-based data on predictors of survival. OBJECTIVE: We sought to assess the influences of race/ethnicity, sex, tumor stage, tumor thickness, and anatomic site on mucosal melanoma survival estimates. METHODS: We analyzed 132,751 cases of melanoma, including 1824 mucosal melanomas, diagnosed between 1994 and 2015 and reported to the California Cancer Registry. Kaplan-Meier survival analysis and Cox proportional hazards regression assessed the prognostic variables. RESULTS: The 5-year relative survival for mucosal melanomas (27.64% [95% confidence interval {CI} 25.42-29.91) was significantly lower than for cutaneous melanomas (76.28% [95% CI 76.03-76.53]). Stage independently influenced survival, and thickness did not predict survival for neoplasms of known depth. Less common anatomic sites conferred worse prognoses (hazard ratio 1.93 [95% CI 1.41-2.64]). LIMITATIONS: The lack of a standardized staging system may have resulted in misclassification of stage for some neoplasms. The influence of genetics is unknown because our database did not contain genetic characteristics. CONCLUSIONS: Stage and anatomic site, but not thickness (ie, Breslow depth), race, or ethnicity, determine the prognosis of mucosal melanomas. Considering the poor prognosis for all stages of mucosal melanoma, dermatologists should incorporate examination of the oropharynx and genitalia in the full body skin examination.

Ocular pyoderma gangrenosum: A systematic review.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare, ulcerative cutaneous disorder. Ophthalmic involvement in PG is atypical, but can have devastating consequences. OBJECTIVE: We sought to characterize ocular PG to allow for earlier diagnosis and therapy. To our knowledge, this is the first systematic review summarizing this clinical variant. METHODS: A systematic review was conducted using PubMed and Web of Science. Data were extracted and studies were qualitatively assessed and analyzed. RESULTS: We identified all 34 cases of PG involving the eye and periorbital area, and categorized them into 4 different subtypes. Common presenting signs include ulceration, peripheral ulcerative keratitis, and decreased visual acuity. Although it is often difficult to biopsy ocular PG, histologic features are nonspecific. Combined therapy using corticosteroids and further surgical reconstruction as needed is the mainstay of treatment. Cases of the eye/orbit in particular should be treated aggressively, as these are more likely to relapse compared with cases of the periorbital area. LIMITATIONS: Use of case reports, paucity of ocular PG cases, and heterogeneity of studies are limitations. CONCLUSION: PG should be considered in the differential diagnosis of ulceration of ocular/periocular tissues. An aggressive, early, multimodal treatment strategy should be used to prevent relapse, especially in cases of the eye/orbit.

Mucosal melanomas in the racially diverse population of California.

BACKGROUND: Mucosal melanomas are rare, poorly understood neoplasms without a consensus standard of care. OBJECTIVE: We sought to define mucosal melanoma tumor characteristics and the racial/ethnic attributes of patients with mucosal melanomas. METHODS: We analyzed 130,920 cutaneous melanomas and 1919 mucosal melanomas recorded in the population-based California Cancer Registry from 1988 to 2013. RESULTS: Although only 1% of melanomas occurring in nonHispanic whites were mucosal, other racial/ethnic groups had a higher proportion of mucosal melanomas (15% for Asian/Pacific Islanders, 9% for nonHispanic blacks, and 4% for Hispanics). Anorectal mucosal melanomas were most common in female Asian/Pacific Islanders, whereas genitourinary mucosal melanomas were highest in nonHispanic whites, and head and neck tumors were most common among Hispanics. Stage at presentation was not uniform among racial/ethnic groups, with Asian/Pacific Islanders having the highest rates of metastasis. LIMITATIONS: The lack of a standardized staging system for mucosal melanomas confounds classification and knowledge regarding metastasis. Small sample size limits comparative analysis across race, stage, site, and depth. CONCLUSION: Mucosal melanomas differ by race/ethnicity with regard to anatomic site, stage, and depth. Because early detection offers the best chance of increased survival, greater awareness will aid clinicians who care for patients at risk for these aggressive tumors.

[Bullous Sweet's syndrome with pulmonary involvement]. / Bullöses Sweet-Syndrom mit pulmonaler Beteiligung.

Acute febrile neutrophilic dermatosis (Sweet's syndrome) is a rare dermatosis characterized by painful papules and plaques accompanied by cutaneous infiltration with neutrophilic granulocytes. Bullous changes are observed in some cases. We report about a patient with osteomyelofibrosis who developed fever accompanied by painful plaques and confluent papules on both arms and thighs. The course of the disease was complicated by blistering and pulmonary infiltrates. After the diagnosis of bullous Sweet's syndrome was established, systemic therapy with glucocorticoids was successful in treating skin lesions and dyspnea.

Mucosal melanomas: Site-specific information, comparisons with cutaneous tumors, and differential diagnosis.

Melanoma of the skin is the fifth leading new cancer diagnosis, having accounted for almost 77,000 cases and more than 9000 deaths in the United States in 2013. Although cutaneous neoplasms of this type are relatively common, their mucosal counterparts are not. Mucosal melanomas comprise approximately 1.3% of all melanocytic malignancies. Although they are rare, these lesions present at an advanced stage with more adverse prognoses. In addition, at a molecular level, they have proven to be distinct entities because they possess genetic mutations not usually seen in their cutaneous counterparts. Conversely, a sizable proportion of mucosal melanomas lack the gene aberrations seen in cutaneous melanomas. Such findings indicate different pathways in tumorigenesis for the two subtypes. Because melanomas arising from the mucosae are not often encountered, very little has been published on staging guidelines and prognostic factors. This causes dilemmas for both patients and physicians. Further work is necessary to define staging systems for all mucosal locations, so that accurate prognoses can be assigned to such lesions.

[Multiple abscesses after a cruise along the Latin American coast]. / Multiple Abszesse nach Südamerikakreuzfahrt.

We report a case of an extracutaneous involvement of pyoderma gangrenosum. The patient initially presented with multiple sterile abscesses of the skin, heart, prostate, and kidney. Extracutaneous involvement in pyoderma gangrenosum is very rare. Confirmation of the diagnosis was only possible after exclusion of other relevant differential diagnoses. Continuous search for microbes proved negative and after an empiric therapeutic attempt with prednisolone, the patient improved quickly. However, each time we reduced the steroids even in combination with methotrexate or with azathioprine the patient relapsed. Only after therapy with the tumor necrosis factor-α-inhibitor infliximab was permanent remission achieved.

A multidisciplinary study of the extracutaneous pigment system of European sea bass (Dicentrarchus labrax L.). A possible relationship between kidney disease and dopa oxidase activity level.

Infectious diseases and breeding conditions can influence fish health status. Furthermore it is well known that human and animal health are strongly correlated. In lower vertebrates melano-macrophage centres, clusters of pigment-containing cells forming the extracutaneous pigment system, are widespread in the stroma of the haemopoietic tissue, mainly in kidney and spleen. In fishes, melano-macrophage centres play an important role in the immune response against antigenic stimulants and pathogens. Hence, they are employed as biomarker of fish health status. We have investigated this cell system in the European sea bass (Dicentrarchus labrax L.) following the enzyme activities involved in melanin biosynthesis. We have found a possible relationship between kidney disease of farmed fishes and dopa oxidase activity level, suggesting it as an indicator of kidney disease. Moreover variations of dopa oxidase activity in extracutaneous pigment system have been observed with respect to environmental temperature. At last, for the first time, using femtosecond transient absorption spectroscopy (Femto-TA), we pointed out that pigment-containing cells of fish kidney tissue present melanin pigments.

Clinicopathologic features, demographics, disease burden, and therapeutics in alopecic sarcoidosis: a case series and systematic review.

Background: Alopecic sarcoidosis is an uncommon cutaneous manifestation of sarcoidosis. Scarring and nonscarring alopecic sarcoidosis have been reported; however, information on the epidemiology, systemic disease associations, and treatment efficacy is limited. Objective: To address these gaps, we conducted a retrospective chart review and systematic literature review of alopecic sarcoidosis cases. Methods: Full-text English publications from PubMed, Scopus, and Google Scholar from inception to August 2023 were analyzed. Treatment evidence quality was assessed using the modified Oxford Centre for Evidence-Based Medicine rating scale. Three patients with biopsy-proven alopecic sarcoidosis were included as a case series, all demonstrating systemic sarcoidosis and 2 requiring multiple therapies. Among 1778 search results, 60 articles representing 77 cases of alopecic and scalp sarcoidosis were included. Patients were categorized into 4 distinct alopecic subgroups. Black patients constituted the majority of all subgroups. Results: Extracutaneous sarcoidosis burden was high across all alopecic subgroups, with ocular disease appearing overrepresented. Topical and oral corticosteroids were the main treatments. Though scarring alopecia patients had poor outcomes despite receiving immunomodulators/cx, limited data suggest potential efficacy of tumor necrosis factor-alpha inhibitors. Limitations: This study has a small sample size. Conclusion: Our findings underscore the importance of evidence-based strategies for improving alopecic sarcoidosis management. Prompt diagnosis and systemic evaluation, especially for scarring alopecia, are essential for timely intervention to optimize patient outcomes.

An Extremely Rare Case of Primary Malignant Melanoma of the Kidney.

Malignant melanoma (MM) is a tumor that usually occurs in the skin, but this malignant tumor can also develop in extracutaneous tissues, including urogenital tissues. In regard to MM occurring in urogenital tissues, bladder origin is common but renal primary MM is extremely rare. In the Department of Emergency and Urology at Gifu Municipal Hospital, a tumor of the right kidney was detected in a computed tomography scan to determine the cause of severe pain in the lower extremities of a 45-year-old Japanese woman. With the clinical diagnosis of renal cell carcinoma, resection of the right kidney was performed under laparoscopy. The cut surface of the tumor encapsulated by a thick fibrous capsule was dark brown, and the tumor cells with large nuclei, large nucleoli, acidophil cytoplasm, and numerous melanin granules showed papillary, solid, or alveolar growth. Immunohistochemically, the tumor cells were positive for Melan A and human melanoma black 45 (HMG45) but negative for transcription factor E3 (TFE3), transcription factor EB (TFEB), cytokeratin 7 (CK7), carbonic anhydrase 9 (CA9), and AEl/AE3. We conducted careful and detailed examinations, including an association of the patient's medical history, but there were no indications for tumors, particularly MM, in any organs. Therefore, she was ultimately diagnosed with primary kidney MM.

Challenges and complications in juvenile localized scleroderma: A practical approach.

Juvenile localized scleroderma is characterised by inflammation which drives fibrosis in skin and soft tissues. The more severe subtypes of localized scleroderma such as linear and craniofacial are more common in children. Additionally, extracutaneous involvement is seen in half of all children and is associated with poorer treatment outcomes and health-related quality of life. Evidence for the management of craniofacial and extracutaneous involvement is lacking and therefore poses a challenge to clinicians. This review aims to provide a practical approach to management of these most challenging features of juvenile localized scleroderma through case studies where we present the available evidence, current recommendations and considerations for management.

Sweet syndrome in pregnancy: A narrative review.

The aim of this review is to increase obstetrician awareness of pregnancy-associated Sweet syndrome. Patients present with fever, leukocytosis, and skin eruption, which can mimic other infectious or inflammatory conditions, but do not respond to antibiotics. A search using PubMed, EMBASE, and Web of Science Core Collection was conducted to review all reported cases of pregnancy-associated Sweet syndrome, an acute febrile neutrophilic dermatosis occurring during pregnancy or postpartum. A total of 33 episodes among 30 patients were identified, with the majority (54.5% [18]) of cases occurring within the second trimester. Among the 30 patients, skin lesions most commonly affected the head and neck (73.3% [22]), with rare oral or ocular involvement. Leukocytosis was the most common laboratory finding, reported in 96.7% [29] of patients, with neutrophil predominance noted in 70.0% [21]. The diagnosis was confirmed for all patients with pathognomonic results of skin biopsies. Of the 27 cases detailing treatment, systemic corticosteroids were most frequently used (19 cases), followed by conservative management (seven cases), and dapsone (one case). The dapsone-treated patient and 15 of the 19 steroid-treated patients experienced resolution, but additional management strategies were required in the remaining four individuals. Spontaneous resolution occurred during pregnancy in six of the seven conservatively managed individuals, with one patient experiencing spontaneous abortion shortly after skin eruption at 10 weeks of gestation. No associated maternal deaths were reported. Obstetric complications of pregnancy-associated Sweet syndrome included endomyometritis, sterile placental abscesses, and abdominal wall necrosis. Delivery of healthy infants occurred in 24 of the 25 cases that presented fetal outcome, which included two infants who underwent medically indicated preterm deliveries.