Stenotrophomonas maltophilia skin infection in an immunocompetent patient: Primary cutaneous CD30+ T-cell lymphoproliferative disorder or pseudolymphoma?

Cutaneous pseudolymphomas are a wide group of diseases mimicking cutaneous lymphoma. They comprise several skin conditions with different etiopathogenesis, clinical-pathological features, and prognosis, which may occur in the absence of an identifiable trigger factor or after administration of medications or vaccinations, tattoos, infections, or arthropod bites. They present with different manifestations: from solitary to regionally clustered lesions, up to generalized distribution and, in rare cases, erythroderma. They persist variably, from weeks to years, and resolve spontaneously or after antibiotics, but may recur in some cases. CD30+ T-cell pseudolymphomas are characterized by the presence of large, activated lymphoid cells, generally in response to viral infections, arthropod assault reactions, and drug eruptions. Stenotrophomonas maltophilia is a ubiquitous Gram-negative bacillus responsible for opportunistic infections in immunocompromised patients. Infection of intact skin in immunocompetent patients is particularly rare. Here, we report a case of a man presenting an isolated nodule histopathologically mimicking a primary cutaneous CD30+ T-cell lymphoproliferative disorder.

Molecular Profile of Subungual Melanoma: A MelaNostrum Consortium Study of 68 Cases Reporting BRAF, NRAS, KIT, and TERT Promoter Status.

BACKGROUND: Subungual melanoma (SM) is an unusual type of melanocytic tumor affecting the nail apparatus. The mutational prevalence of the most prominently mutated genes in melanoma has been reported in small cohorts of SM, with unclear conclusions on whether SM is different from the rest of melanomas arising in acral locations or not. Hence, the molecular profile of a large series of SM is yet to be described. OBJECTIVES: The aim of this study was to describe the molecular characteristics of a large series of SM and their association with demographic and histopathological features. METHODS: Patients diagnosed with SM between 2001 and 2021 were identified from six Spanish and Italian healthcare centers. The mutational status for BRAF, NRAS, KIT, and the promoter region of TERT (TERTp) were determined either by Sanger sequencing or next-generation sequencing. Clinical data were retrieved from the hospital databases to elucidate potential associations. RESULTS: A total of 68 SM cases were included. Mutations were most common in BRAF (10.3%) and KIT (10%), followed by NRAS (7.6%), and TERTp (3.8%). Their prevalence was similar to that of non-subungual acral melanoma but higher in SM located on the hand than on the foot. CONCLUSIONS: To date, this study represents the largest cohort of SM patients with data on the known driver gene mutations. The low mutation rate supports a different etiopathogenic mechanism for SM in comparison of non-acral cutaneous melanoma, particularly for SM of the foot.

Alpha, Beta, and Gamma Human Papillomaviruses in Genital Lichen Sclerosus: A Retrospective Cross-Sectional Study.

BACKGROUND: Lichen sclerosus (LS) is an inflammatory disease mostly arising at the genital level. It is unclear whether human papillomaviruses (HPVs) have an etiological significance in LS, and data on their prevalence in patients with LS are controversial. OBJECTIVES: The authors assessed alpha, beta, and gamma HPV prevalence in patients with genital LS. The association of HPV positivity with demographic and clinical factors was also investigated. METHODS: One hundred thirty-two formalin-fixed, paraffin-embedded LS samples (2016-2020) were retrieved from the archives of a pathology department. Alpha HPVs were genotyped with the INNO-LiPA HPV Genotyping Extra II kit. Beta and gamma HPVs were searched by multiplex Polymerase Chain Reaction. Immunostaining for p16 INK4a was performed on high-risk HPV-positive samples. RESULTS: Patients had a median age of 61 years, were mostly women ( n = 73, 55.3%), and with an early disease stage ( n = 79, 59.8%). Alpha HPVs were detected in 12/132 cases (9.1%). Among the 5 high-risk HPV-positive cases, only 2 displayed a strong and diffuse p16 INK4a staining. Beta genus was the most prevalent (35/132, 26.5%) and HPV5 was the most frequent beta genotype (25/132, 18.9%). There were 3 gamma HPV-positive cases among those with a valid result (3/131, 2.3%). Multiple infections with genotypes belonging to different genera were infrequent (3/131, 2.3%). No significant differences in the prevalence of the individual genera were observed according to sex and disease stage. CONCLUSIONS: Of the 3 HPV genera, beta genus showed the highest prevalence. Further research is needed to clarify whether the presence of beta HPVs in genital LS has a clinical significance.

Targeting Fatty Acid Amide Hydrolase Counteracts the Epithelial-to-Mesenchymal Transition in Keratinocyte-Derived Tumors.

The endocannabinoid system regulates physiological processes, and the modulation of endogenous endocannabinoid (eCB) levels is an attractive tool to contrast the development of pathological skin conditions including cancers. Inhibiting FAAH (fatty acid amide hydrolase), the degradation enzyme of the endocannabinoid anandamide (AEA) leads to the increase in AEA levels, thus enhancing its biological effects. Here, we evaluated the anticancer property of the FAAH inhibitor URB597, investigating its potential to counteract epithelial-to-mesenchymal transition (EMT), a process crucially involved in tumor progression. The effects of the compound were determined in primary human keratinocytes, ex vivo skin explants, and the squamous carcinoma cell line A431. Our results demonstrate that URB597 is able to hinder the EMT process by downregulating mesenchymal markers and reducing migratory potential. These effects are associated with the dampening of the AKT/STAT3 signal pathways and reduced release of pro-inflammatory cytokines and tumorigenic lipid species. The ability of URB597 to contrast the EMT process provides insight into effective approaches that may also include the use of FAAH inhibitors for the treatment of skin cancers.

Italian expert-based recommendations on the use of photo(chemo)therapy in the management of mycosis fungoides: Results of an e-Delphi consensus.

BACKGROUND: Phototherapy is a mainstay for the treatment of MF. However, there is scarce evidence for its use, mostly due to the lack of a unified schedule. AIMS: The primary aim of this study was to establish the first structured, expert-based consensus regarding the indications and technical schedules of NB-UVB and PUVA for MF. The secondary aim was to determine the consensus level for each specific item. MATERIALS & METHODS: E-delphi study. Item-specific expert consensus was defined as the number of "Totally Agree" results to ≥80% of the panelists. Cronbach alpha index ≥0.7 was used as a measure of homogeneity in the responses among questions related to the same topic. RESULTS: Overall, there was a high homogeneity among responders (0.78). On specific topics, the highest grade was observed for technical items (0.8) followed by indications for early (0.73) and advanced stages (0.7). CONCLUSIONS: Items related to the most canonical indications of phototherapy and to treatment schedules showed the highest agreements rates. There is consensus about the use of standardized treatment schedules for the induction and consolidation phases for NB-UVB and PUVA in MF.

Profiling Cancer-Associated Fibroblasts in Melanoma.

Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma-fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF-melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.

NTRK Gene Fusion Detection in Atypical Spitz Tumors.

Atypical Spitz tumors (AST) deviate from stereotypical Spitz nevi for one or more atypical features and are now regarded as an intermediate category of melanocytic tumors with uncertain malignant potential. Activating NTRK1/NTRK3 fusions elicit oncogenic events in Spitz lesions and are targetable with kinase inhibitors. However, their prevalence among ASTs and the optimal approach for their detection is yet to be determined. A series of 180 ASTs were screened with pan-TRK immunohistochemistry and the presence of NTRK fusions was confirmed using FISH, two different RNA-based NGS panels for solid tumors, and a specific real time RT-PCR panel. Overall, 26 ASTs showed pan-TRK immunostaining. NTRK1 fusions were detected in 15 of these cases showing cytoplasmic immunoreaction, whereas NTRK3 was detected in one case showing nuclear immunoreaction. Molecular tests resulted all positive in only two ASTs (included the NTRK3 translocated), RNA-based NGS and real time RT-PCR were both positive in three cases, and FISH and real time RT-PCR in another two cases. In seven ASTs NTRK1 fusions were detected only by FISH and in two cases only by real time RT-PCR. The frequency of NTRK fusions in ASTs is 9%, with a clear prevalence of NTRK1 compared to NTRK3 alterations. Pan-TRK immunohistochemistry is an excellent screening test. Confirmation of NTRK fusions may require the use of different molecular techniques.

Adipose tissue stromal vascular fraction and adipose tissue stromal vascular fraction plus platelet-rich plasma grafting: New regenerative perspectives in genital lichen sclerosus.

Lichen sclerosus (LS) is a chronic relapsing, inflammatory skin disorder usually involving the anogenital region of both sexes lacking a resolutive therapy. This study compared adipose tissue derived-stromal vascular fraction (AD-SVF) and AD-SVF-enriched platelet-rich plasma (PRP) therapy in the management of genital LS patients. Additionally, in vitro evaluation of cells and growth factors contained in the injected SVF has been evaluated as possible predictive factors for treatment outcome. The study population was 40 patients diagnosed with LS who were symptomatic despite medical treatment. Patients (age 43-78 years) randomized into two groups using a 1:1 allocation ratio, were evaluated clinically and assessing dermatology life quality index (DLQI) before and 6 months after treatment. Both procedures demonstrated a strong safety profile with no complications linked to the therapy. After 6 months, both treatments allowed for a significant improvement respect to baseline. Combinatory therapy demonstrated decreased efficacy in late stage patients. No correlations have been found between clinical and biological findings. AD-SVF and AD-SVF plus PRP are safe and effective regenerative approaches for genital LS patients. Clinical results support the preferential use of combinatory therapy for early stage patients confirming a synergic effect of AD-SVF and PRP. In contrast, AD-SVF plus PRP is discouraged for late stage patients.

Clinical management of very small pigmented lesions: Improved clinical outcome through dermoscopy and reflectance confocal microscopy combination.

INTRODUCTION: Small-sized pigmented lesions (SSPL) <3 mm in diameter are common pitfall in the daily dermatology practice. Dermoscopy alone is hampered by the lack of specific features inversely proportional to the diameter of the lesions and its performance is highly operator-dependent. Reflectance confocal microscopy (RCM) has been demonstrated to be effective in the diagnosis of several difficult lesions where dermoscopy lacks to provide conclusive information. MATERIALS AND METHODS: A total of 179 lesions with uncertain or equivocal clinical and dermoscopy appearance were selected. Dermoscopist has been requested to express a diagnostic suspect when possible. Equivocal lesions underwent RCM performed by expert for second-level evaluation before surgical excision for histological diagnosis. Results have been later statistically analysed. RESULTS: Dermoscopy was not diagnostic in large number of lesions with low concordance histology (39.1%) instead of a much high concordance when combined with RCM (93.9%). CONCLUSIONS: Small-sized pigmented lesions were more likely to be located on the face area. Diagnosis of pigmented BCC was relatively easy on dermoscopy and also in the case of small lesions showing typical signs of BCC. LM and MM have been seen to be particularly difficult to be diagnosed using only dermoscopy. The combination of digital dermoscopy and RCM represents the correct approach of SSPL.

Incidental Acantholysis in Hailey-Hailey Disease (Microscopic Nikolsky Sign): An Underappreciated Histologic Sign.

Identification of subtle disease-specific histologic changes may be of significant help in early diagnosis of acantholytic skin diseases. Hailey-Hailey disease (HHD) is an autosomal dominant genodermatosis characterized by vesiculoerosive lesions favoring the intertriginous areas. Histologically, HHD is characterized by full-thickness acantholysis of the spinous layer in association with dyskeratosis of individual keratinocytes; a pemphigus vulgaris-like suprabasal pattern of acantholysis may be observed in the earliest stages of disease. HHD is characterized by highly variable expressivity regarding the age at onset and severity of the disease. Patients may present with late-onset and/or only mild disease. We report the recurrent presence of incidental foci of variably extensive, subclinical acantholysis in multiple bioptic specimens taken from a patient with known HHD for dermatologic conditions other than HHD. Such histologic finding has gone underappreciated in the literature, despite being a likely frequent occurrence in skin biopsies from HHD patients; recognition of this finding might represent a valuable diagnostic clue in selected cases of HHD.

Diffuse (Generalized) Plane Xanthoma Misdiagnosed as Carotenoderma: Usefulness of Reflectance Confocal Microscopy.

Diffuse (generalized) plane xanthoma is a rare normolipemic xanthomatosis, frequently associated with multiple myeloma and monoclonal gammopathy. Its clinical presentation is well described, and in most cases, clinical suspicion is immediate. Rarely, it can clinically present with a diffuse and uniform yellowish discoloration, and in this context, several investigations are required to identify the correct diagnosis. We describe a case characterized by progressive diffuse yellow-orange discoloration lasting about 3 years and classified as carotenoderma in which reflectance confocal microscopy addressed the diagnosis and drove the correct selection of the biopsy site. Definitive diagnosis of diffuse (generalized) plane xanthoma was confirmed later by histological examination.

Alveolar Soft-Part Sarcoma of the Tongue.

Alveolar soft-part sarcoma is a rare neoplasm of unknown histogenesis that accounts for less than 1% of all soft-tissue sarcomas. The tumor is highly vascularized with small vascular spaces separating nests of cells, and from cytogenetic point of view, is characterized by chromosome rearrangement der(17)t(X:17)(p11:q25) that results in the ASPL-TFE3 translocation. It can occur at any age, but it is most common between 15 and 35 years of age. The prognosis is poor, despite the relatively slow growth of the tumor. We present here an atypical case of alveolar soft-part sarcoma in which the age of the patient, the location, and the histopathologic characteristics of the lesion represented a diagnostic challenge.

Uncommon Histopathological Variants of Malignant Melanoma: Part 1.

Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinicopathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma.

Pathogenesis of Leprosy: An Insight Into B Lymphocytes and Plasma Cells.

The pathogenesis of leprosy is still not fully understood. Several studies have been performed on the involvement of T cells in leprosy and more recently have focused on genetic factors and innate immune response. There are still only few reports about the role of B cells in active leprosy lesions in different spectral forms of the disease. The literature on tuberculosis suggests that B cells play an important role in the regulation of the granulomas, in cytokine production, T-cell response, and antigen presentation. Only few studies investigated the role of B cell in leprosy. We investigated the distribution of B cells in 85 leprosy biopsies covering all forms of the disease and compared results with 13 biopsies of tuberculosis and atypical mycobacteriosis, expanding the previous experiences. A statistically significant difference in the number of CD20 (P = 0.014) and CD138+ (P = 0.01) cells between the different forms of leprosy was observed. A remarkable amount of CD138+ cells could also be detected in borderline tuberculoid. The median of the CD20 cells decreased from the bacilloscopy-negative samples to the bacilloscopy-positive samples by 50% (P = 0.004). Contrarily, the median of CD138+ cells showed an increase from bacilloscopy-negative to bacilloscopy-positive samples of 966.67% (P = 0.001). In our experience, tuberculoid leprosy showed more B cells and less plasma cells than lepromatous leprosy. Our results show that B cells might be implicated in leprosy pathogenesis, not only in the lepromatous pole as previously postulated, but also in tuberculoid granuloma formation and type 1 reactions.

Uncommon Histopathological Variants of Malignant Melanoma. Part 2.

Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinico-pathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma.

Cutaneous hemophagocytosis: Clinicopathologic features of 21 cases.

BACKGROUND: Hemophagocytosis is well known in cytotoxic cutaneous T-cell lymphomas (CTCLs), in which it may represent a sign of hemophagocytic lymphohistiocytosis syndrome (HLHS), and is also typical of cutaneous Rosai-Dorfman disease (cRDD) (without prognostic relevance). Only rarely, has cutaneous hemophagocytosis (CH) been described in other skin conditions. OBJECTIVE: To characterize the clinicopathologic features of CH in skin biopsy specimens from patients with conditions other than CTCL or cRDD. METHODS: Case series analyzing clinicopathologic features and follow-up data on patients presenting with histopathologic signs of CH. RESULTS: Biopsy specimens from 21 patients were included. None of the patients had HLHS. The majority (n = 11) presented with leukocytoclastic vasculitis. Other associated diseases were lupus erythematous (n = 2), arthropod bite reaction (n = 2), erysipelas (n = 1), acne conglobata (n = 1), and Sweet syndrome (n = 1). Three patients had a nonspecific rash concomitant with Chlamydia pneumonia, middle ear infection, and pharyngitis, respectively. LIMITATIONS: This was a single-center, retrospective study. CONCLUSION: Isolated CH in conditions other than CTCL and cRDD is a histopathologic finding related mostly to leukocytoclastic vasculitis. Extensive investigations should be performed only if patients have other signs or symptoms of HLHS.

The Histopathological Spectrum of Pseudolymphomatous Infiltrates in Cutaneous Lupus Erythematosus.

The occurrence of pseudolymphomatous infiltrates in cutaneous lupus erythematosus (cLE) is described mainly in lupus panniculitis and lupus tumidus/lymphocytic infiltration of the skin (Jessner-Kanof). We collected 15 cases of pseudolymphomatous cLE other than lupus panniculitis and lupus tumidus (M:F = 4:11; age range: 23-79 years; mean age: 50.9 years; median age: 57 years). Of the 15 cases, 9 (60%) were characterized by dense nodular infiltrates. Three cases (20%) showed an angiocentric pattern with cytological atypia of lymphoid cells; 2 cases (13.3%) showed a band-like infiltrate mimicking mycosis fungoides, and 1 case had mixed features of the band-like and angiocentric patterns. Clues to the histopathological diagnosis of cLE were presence of interface dermatitis, clusters of plasmacytoid dendritic cells, and dermal mucin deposition. Our study shows that the spectrum of pseudolymphomatous presentations of cLE is broader than previously described, including band-like cases that may be misconstrued as mycosis fungoides, and angiocentric cases that may be misinterpreted as an aggressive lymphoma. Recognition of such cases is possible only on careful clinicopathologic correlation and requires a high level of histopathological suspicion to allow a correct diagnosis and the proper management of the patients.

Male and female genital lichen sclerosus. Clinical and functional classification criteria.

INTRODUCTION: Lichen sclerosus (LS) is a chronic inflammatory disease affecting mainly the genital mucous membranes in both sexes. In the past, different terms were used to describe the disease, rendering a unique and specific clinical classification impossible. AIM: New therapeutic approaches are being defined, which may contribute to a proper clinical management, however, a stage classification is essential to better define appropriate treatment for every stage of the disease. MATERIAL AND METHODS: One hundred and fifteen patients (50 women and 65 men) with a diagnosis of LS were enrolled between January 2014 and September 2016. All patients underwent cutaneous biopsy to confirm the clinical diagnosis of LS. Clinical and symptomatological parameters were used in order to put the patients into the correct stage of LS. The Dermatology Life Quality Index (DLQI) was used to classify patients based on subjective symptoms. Different cutaneous alterations and structural modifications of the genital mucosa were also taken into consideration in order to assign every patient to a specific stage. CONCLUSIONS: Lichen sclerosus is clinically described differently in females and in males and every form of LS is put into one of two stages according to the degree of severity: early and late stages. Within the clinical practice, it is useful to screen patients for groups of early or late forms of the disease in order to obtain a uniform subdivision of patients: those who may benefit from localized treatments, require a systemic drug and must undergo physical treatments (surgical, stem cells infiltrations).