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Background: COronaVIrus Disease 19 (COVID-19) is associated with a wide spectrum of skin manifestations, but SARS-CoV-2 RNA in lesional skin has been demonstrated only in few cases. Objective: To demonstrate SARS-CoV-2 presence in skin samples from patients with different COVID-19-related cutaneous phenotypes. Methods: Demographic and clinical data from 52 patients with COVID-19-associated cutaneous manifestations were collected. Immunohistochemistry and digital PCR (dPCR) were performed in all skin samples. RNA in situ hybridization (ISH) was used to confirm the presence of SARS-CoV-2 RNA. Results: Twenty out of 52 (38%) patients presented SARS-CoV-2 positivity in the skin. Among these, 10/52 (19%) patients tested positive for spike protein on immunohistochemistry, five of whom had also positive testing on dPCR. Of the latter, one tested positive both for ISH and ACE-2 on immunohistochemistry while another one tested positive for nucleocapsid protein. Twelve patients showed positivity only for nucleocapsid protein on immunohistochemistry. Conclusions: SARS-CoV-2 was detected only in 38% of patients, without any association with a specific cutaneous phenotype, suggesting that the pathophysiology of cutaneous lesions mostly depends on the activation of the immune system. The combination of spike and nucleocapsid immunohistochemistry has higher diagnostic yield than dPCR. Skin persistence of SARS-CoV-2 may depend on timing of skin lesions, viral load and immune response.

Clear cell morphology has been described in several cutaneous neoplasms either as a specific feature of some entities either as a morphological variant in the spectrum, and these two entities are frequently considered together in the differential diagnosis.We reviewed our series of cases occurred in our laboratory in order to further quantify the number of cases showing morphological features of tricholemmal differentiation and to investigate other clinical or histological difference. We retrieved 91 cases and, for each of them, all the clinical data regarding age, sex, clinical features, and clinical suspicious were collected, when available.The revision of the specimens concluded with a final diagnosis of tricholemmal carcinoma in 15 cases (17%), all the other cases were thus considered as squamous cell carcinoma with clear cell features. No statistically significant correlations were observed with the demografic or clinicopatholagical parameters such as age, sex or dimensions, but morphological revision highlighted a potentially greater "vertical" growth frequently not matched by a concomitant radial one in tricholemmal carcinoma than in squamous tumors.The debate upon the diagnostic distinction of these tumors is still ongoing with authors proposing the tricholemmal carcinoma as a variant of a squamous cell carcinoma rather than a distinct entity. Further studies are needed to confirm our data and to evaluate the reproducibility of this feature.

BACKGROUND Pemphigus is an autoimmune bullous disease mediated by autoantibodies targeting epithelial cell-cell adhesion molecules. Predictors of relapse have not yet been clearly identified. AIMS To identify factors at diagnosis and during follow-up that could be predictors of relapse. METHODS Clinical and immunopathological data at diagnosis, clinical remission and first relapse from patients with pemphigus vulgaris or foliaceus and at least a 36-month follow-up were collected retrospectively. Based on the autoantibody profile at diagnosis, three serological patient subsets were devised: (i) anti-desmoglein (Dsg)1-positive and anti-Dsg3-negative; (iii) anti-Dsg1-negative and anti-Dsg3-positive; and (iii) anti-Dsg1-positive and anti-Dsg3-positive. RESULTS Data from 143 patients were collected. No significant differences were found between relapsers (n = 90) and nonrelapsers (n = 53) for time to remission or for anti-Dsg1 and anti-Dsg3 titres at diagnosis and remission. In the analysis of all patients, a higher risk of relapse was found for a body surface area (BSA) score of 3 compared with BSA

BACKGROUND Mucous membrane pemphigoid (MMP) is an autoimmune disease characterized by scarring lesions at mucosal sites. Although the pathogenic role of specific IgG and/or IgA has been already demonstrated and the detection of these immunoglobulins is a criterion in the diagnosis of MMP, little is known about IgE role in this disease. Therefore, the main purpose of this study was to assess the presence of circulating and tissue bound IgE in patients with MMP and their possible correlations with clinical presentation and disease course. METHODS We conducted a retrospective study on 29 patients affected by MMP, recruited from a single center. Direct and indirect immunofluorescence studies were assessed to analyze the presence of specific IgE directed against the basal membrane zone. For each patient, fluorescence data were compared to clinical features. RESULTS Linear deposits of C3, IgG and IgA were present in 86.2%, 62% and 37.9% of cases respectively, while IgE linear deposits were detected in 17 out of 29 patients (58.6%) including one case with isolated IgE positivity. Circulating IgE and IgA anti-BMZ were present in 7 (24.1%) and 5 (17.2%) patients, respectively. Both the presence of circulating IgA and of tissue bound IgE deposits correlated with disease activity index (P

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. Until now, neither a systematic characterization of genetic alterations driving pcAECyTCL has been performed, nor effective therapeutic regimes for patients have been defined. Here, we present the first highresolution genetic characterization of pcAECyTCL by using wholegenome and RNA sequencing. Our study provides a comprehensive description of genetic alterations (i.e., genomic rearrangements, copy number alterations and small-scale mutations) with pathogenic relevance in this lymphoma, including events that recurrently impact genes with important roles in the cell cycle, chromatin regulation and the JAKSTAT pathway. In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL. In line with the genomic data, transcriptome analysis uncovered upregulation of the cell cycle, JAK2 signaling, NF-κB signaling and a high inflammatory response in this cancer. Functional studies confirmed oncogenicity of JAK2 fusions identified in pcAECyTCL and their sensitivity to JAK inhibitor treatment. Our findings strongly suggest that overactive JAK2 signaling is a central driver of pcAECyTCL, and consequently, patients with this neoplasm would likely benefit from therapy with JAK2 inhibitors such as Food and Drug Adminstration-approved ruxolitinib.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array-comparative genomic hybridization (a-CGH). a-CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A-CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T-cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised.

Primary cutaneous gamma delta T cell lymphomas (PCGDTCL) are a rare type of cutaneous lymphomas characterized by an heterogenous clinical and histological presentation which represents a huge challenge for diagnosis. Typically, PCGDTCL have a very bad prognosis, even if cases of cutaneous lymphomas with a gamma delta phenotype and an indolent course have been described. Based on these different reports, the last WHO classification divides PCGDTCL in epidermotropic, dermal and subcutaneous subtypes, leaving out cases with clinic and histologic features of classical mycosis fungoides and lymphomatoid papulosis. We evaluated dermo-epidermic cases of PCGDTCL from our center in Milan about clinic and phenotypic features. Nine patients were included: 2 patients with a pagetoid reticulosis-like PCGDTCL, 2 patients with peculiar pyoderma gangrenosus-like PCGDTCL and 5 patients with tumors and a previous history of MF. Neoplastic infiltrate was CD3 positive and double negative for CD4 and CD8 except for one case CD8+. Cytotoxic markers were present in all cases. Interestingly, we found that gamma-delta neoplastic cells were CD45RA positive and CD56 negative, a different expression compared the typical phenotype of subcutaneous forms. In the cases tested, the T cells expressed TCR Vd1, as expected. The subgroup of tumoral cases with a previous history of MF was the most peculiar. In these cases, the previous samples of MF had an atypical phenotype mainly CD4 positive and in two of them we could identify a partial expression of TCRdelta in the epidermotropic neoplastic cells, which probably represent a subclones. The selection of this subclones could represent the cause of the phenotypic switch in the aggressive PCGDTCL. More studies are needed to evidence the possible prognostic markers in MF cases which progressed in PCGDTCL.

Primary cutaneous acral CD8+ T-cell lymphoma (acral CD8+ TCL) is a new provisional entity characterized by acral skin lesions and an indolent course. We describe an extraordinary case characterized by relapsed nodules with CD8+ cytotoxic infiltrates on the left ear. After 35 years, the skin lesions spread to other acral sites, and a mass with the same histological features as the other skin lesions appeared on the nose. Multiple courses of chemotherapy led to stable disease. Histological examinations carried out at different times showed the gradual transformation of the neoplastic cells, with an increased proliferation index. Genomic analysis revealed losses in the regions harboring the genes involved in cell cycle control. This is the first case of an acral CD8+ TCL with a very long history of indolent nodular lesions progressing to extra-cutaneous sites.

Background Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma (CD4+ PCSM-TCL) is a rare lymphoproliferative disorder with a favorable prognosis. Distinguishing it from other cutaneous lymphomas is often a challenge. Methods We retrospectively collected CD4+PCSM-TCL cases from two centers (MD Anderson Cancer Center, USA and University of Milan, Italy) and evaluated their clinicopathological features. Array-comparative genomic hybridization (aCGH) analysis was performed on 11 cases. Results A total of 62 patients were identified. Single lesions were the most common clinical presentations (79%). Five patients (8%) showed multiple MF-like plaques. All patients' disease had an indolent course. The infiltrate was nodular and diffuse, multinodular or superficial but in all cases, it was characterized by small/medium pleomorphic CD4+/CD279(PD1+) lymphocytes grouped in clusters and ‘pseudorosettes’ around B-cells. aCGH analysis showed no significant genomic abnormalities. Single lesions were mainly treated with surgical excision (91%) and/or radiotherapy (95%) with low rate of relapse (12%). For multiple lesions, topical steroids, nitrogen mustard and phototherapy were mainly used but the rate of relapse was high (69%). Conclusions CD4+PCSM-TCL is characterized by heterogeneous clinical presentations. The arrangement of atypical cells in clusters or pseudorosettes is a useful criterion for diagnosis. The absence of significant genomic alterations is in agreement with its indolent behavior.

Summary Psoriasis is a common, inflammatory immune-mediated skin disease mainly presenting with plaques whose pathogenesis is based on the central role of the interleukin (IL)-23/IL-17 axis. However, the mechanisms acting in papular lesions of early-phase psoriasis are not fully understood. The aim of this study was to assess the involvement of autoinflammation, a state of sterile inflammation mainly driven by IL-1 over-production that has been recently hypothesized to act in the early phase of disease. Lesional skin of 10 patients with recent onset, untreated psoriasis has been investigated for expression of IL-1β, IL-17, IL-23 and other cytokines involved in the disease in comparison with normal skin of 10 healthy controls using a protein array method. Immunohistochemical phenotyping of inflammatory infiltrate and co-localization experiments with immunofluorescence confocal microscopy were conducted. IL-1β was significantly more expressed in psoriasis than in normal skin (P < 0·0001). The chemokine IL-8 was also over-expressed in psoriasis (P = 0·03) while IL-12, IL-17, IL-23, tumour necrosis factor-α and interferon-γ were only slightly more expressed in psoriasis than in normal skin, without reaching statistical significance. The inflammatory infiltrate consisted mainly of neutrophils with a relevant number of macrophages and dendritic cells and only scattered, predominantly T helper 1 lymphocytes. IL-1β co-localized mainly with CD66b, a neutrophil marker, suggesting that neutrophils were the major source of this cytokine. IL-1β over-expression in combination with low expression of cytokines that are predominant in late-phase plaque psoriasis may support the role of autoinflammation in early-phase disease, possibly paving the way to randomized trials with IL-1 antagonists.

CD10, CD271 and Nestin, which are proteins associated with tumor-initiating properties and/or progression potential, have not been specifically studied on malignant melanoma (MM) with cutaneous recurrences.We evaluated the expression of CD10, CD271 and Nestin in 27 tumor samples from 16 patients. These tumor samples corresponded to 6 primary melanomas which developed 11 ITM and 10 primary melanomas without recurrences at 10-year follow-up from specimens obtained from surgical excisions of patients referred to the Unit of Dermatology, Department of Medical-Surgical and Transplant Physiopathology, University of Milan, between 2006 and 2016.We demonstrated a higher expression of CD271 and Nestin in primary tumors which recurred than control population, Nestin was expressed with significantly higher percentages in primary tumors than recurrences, and CD10 expression was statistically significant correlated with disease-free survival: cases with a lower score recurred lately than cases with higher scores.Our preliminary results suggested that CD271 and Nestin can be considered early biomarkers for the development of ITM, Nesting can be useful in differentiating primary MM from cutaneous recurrences and CD10 is associated with a rapid disease progression and may be considered a potential prognostic marker.

Spindle or epithelioid melanocytic (Spitz) nevi usually affect children or adolescents and growth in the face or the lower extremities. Histologically, they may show cytoarchitectural atypia and mitotic figures that could represent diagnostic pitfalls with malignant melanoma. Atypical spitzoid tumors (AST) indicate lesions that microscopically show intermediate characteristics between benign nevi and malignant melanoma. Nestin expression has been evaluated in benign nevi and malignant melanoma, but no studies on its role in Spitz lesion have been elaborated so far. Our results indicate that Nestin could allow to discriminate between AST and malignant spiztoid melanoma; the typical dermoscopic pattern is also associated with benign nevi in contrast to the atypical pattern that accumunates AST and malignant spitzoid melanoma.

Cutaneous metastases represent 2% of all skin tumours. Their recognition can be challenging, as they may present with different clinical features, with consequent frequent delay and failure in diagnosis. To review our series of cutaneous metastatic lesions, analyse their frequency according to patient gender, histotype, localization of the primary tumour, and site of cutaneous metastasis, and correlate this data with clinicopathological parameters. We conducted a retrospective review of all cases of cutaneous metastases from visceral neoplasms diagnosed in our dermatopathology department from July 2003 to February 2017. We registered clinical, histological, and immunohistochemical data. Additional immunohistochemical staining panels were elaborated to confirm or identify the origin of the primary tumour, or at least to specify the histological subtype. We identified 45 histological diagnoses of cutaneous and mucocutaneous metastases. The primary tumour that was most likely to metastasize to the skin was breast cancer. Most cases of breast (89%) and lung cancer (86%) metastasized to the trunk. Of the lesions, 57.5% were nodules and 32.5% were plaques, more frequently multiple (64.4%). In 58% of cases, a metastasis was clinically suspected. Histological examination most frequently revealed an adenocarcinoma, sometimes suggestive of the site of origin. Cutaneous metastases should be primarily considered when discrete firm painless nodules emerge rapidly. Clinicians should carefully consider infiltrated lesions of the chest in women since scleroderma and erysipelas-like presentation can be a clue for undiagnosed breast cancer.

Upon T cell receptor stimulation, CD4(+) T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4(+) T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4(+) T cell proliferation and suppressed two relevant targets of miR-146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4(+) T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive malignancy derived from precursors of plasmacytoid dendritic cells. We analyzed 21 cases with array-based comparative genomic hybridization (aCGH). Complete or partial chromosomal losses largely outnumbered the gains, with common deleted regions involving 9p21.3 (CDKN2A/CDKN2B), 13q13.1-q14.3 (RB1), 12p13.2-p13.1 (CDKN1B), 13q11-q12 (LATS2), and 7p12.2 (IKZF1) regions. CDKN2A/CDKN2B deletion was confirmed by FISH. This scenario argues for disruption of cell cycle at G1/S transition, representing a genetic landmark of BPDCN, and possibly contributing to its pathogenesis. Statistical analysis of overall survival in our series highlighted an association of poor outcome with biallelic loss of locus 9p21.3. We suggest that, in the absence of reliable parameters for predicting prognosis in BPDCN other than age, tumor stage, and/or clinical presentation, simple methods, such as FISH for CDKN2A/CDKN2B, could help to identify the most aggressive cases.

SummaryPyoderma gangrenosum (PG) is a rare, immune-mediated inflammatory skin disease presenting with painful ulcers having undermined edges. Less commonly, bullous and vegetative variants exist. Histology consists of a neutrophil-rich dermal infiltrate. We characterized immunohistochemically the infiltrate in different variants of PG and in another neutrophilic dermatosis as Sweet's syndrome. We studied 21 patients with PG, eight with Sweet's syndrome and 20 controls, evaluating skin immunoreactivity for inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17], metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF). Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-α, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in both PG and Sweet's syndrome than in controls (P = 0·0001). Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome (P = 0·008–P = 0·0001). In ulcerative PG, the expression of CD3 (panT cell marker) and CD163 (macrophage marker) were significantly higher in wound edge than wound bed (P = 0·0001). In contrast, the neutrophil marker myeloperoxidase was expressed more significantly in wound bed than wound edge (P = 0·0001). Our study identifies PG as a paradigm of neutrophil-mediated inflammation, with proinflammatory cytokines/chemokines and MMPs acting as important effectors for the tissue damage, particularly in ulcerative and bullous PG where damage is stronger. In ulcerative PG, the wound bed is the site of neutrophil-recruitment, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation.

Regulatory T (Treg) cells, which represent 5% to 10% of peripheral T cells, regulate the activities of T-cell subsets by performing immunosuppressive functions and thus preventing the development of autoimmune responses. The majority of Treg cells are CD4 + , CD25 + , and FOXP3 + . Recently, it has been demonstrated that the tumor cells in adult T-cell leukemia lymphomas can function as Treg, raising the question of whether any variant of primary cutaneous T-cell lymphoma may also express a regulatory phenotype. We describe an extraordinary case of primary cutaneous T-cell lymphoma clinically characterized by protean cutaneous manifestations and histologically showing a pattern consistent with epidermotropic pleomorphic medium-/large-cell primary cutaneous T-cell lymphoma. The majority of neoplastic cells were CD4 + CD25 + T cells and strongly expressed FOXP3. With this background, the current case, characterized by an aggressive course requiring polychemotherapy, may support the existence of lymphoproliferative malignancies of Treg cells.

We describe the case of a 17-year-old Hispanic boy who had had erythroderma and diffuse lymphadenopathy for approximately 6 months. A diagnosis of Sezary syndrome was made on the basis of the histologic features of the skin; the presence of the same T-cell clone on the skin, blood, and bone marrow; and the high CD4(+) lymphocyte count with an aberrant phenotype in peripheral blood; bone marrow involvement was also present. The patient was treated with systemic gemcitabine and achieved partial remission.

Background: Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma (CD4+ PCSM-TCL) is a rare lymphoproliferative disorder with a favorable prognosis. Distinguishing it from other cutaneous lymphomas is often a challenge. Methods: We retrospectively collected CD4+PCSM-TCL cases from two centers (MD Anderson Cancer Center, USA and University of Milan, Italy) and evaluated their clinicopathological features. Array-comparative genomic hybridization (aCGH) analysis was performed on 11 cases. Results: A total of 62 patients were identified. Single lesions were the most common clinical presentations (79%). Five patients (8%) showed multiple MF-like plaques. All patients' disease had an indolent course. The infiltrate was nodular and diffuse, multinodular or superficial but in all cases, it was characterized by small/medium pleomorphic CD4+/CD279(PD1+) lymphocytes grouped in clusters and ‘pseudorosettes’ around B-cells. aCGH analysis showed no significant genomic abnormalities. Single lesions were mainly treated with surgical excision (91%) and/or radiotherapy (95%) with low rate of relapse (12%). For multiple lesions, topical steroids, nitrogen mustard and phototherapy were mainly used but the rate of relapse was high (69%). Conclusions: CD4+PCSM-TCL is characterized by heterogeneous clinical presentations. The arrangement of atypical cells in clusters or pseudorosettes is a useful criterion for diagnosis. The absence of significant genomic alterations is in agreement with its indolent behavior.

Background: Pemphigus is a severe blistering disorder caused by autoantibodies to desmogleins 1 and 3. Because some patients with pemphigus never enter into remission, new immunosuppressants are warranted. Rituximab is a chimeric monoclonal antibody binding to the CD20 antigen on B cells, which proved to be effective in recalcitrant pemphigus. Objectives: To evaluate the efficacy and safety of rituximab in refractory pemphigus and to investigate its effects on the autoantibody profile. Patients and Methods: Six patients with recalcitrant pemphigus were treated. Rituximab was administered intravenously at a dosage of 375 mg/m2 body surface once weekly for 4 weeks. Results: Three pemphigus foliaceus patients and 1 with mucocutaneous pemphigus vulgaris (PV) showed complete response over a follow-up period of up to 18 months. In one oral PV, control of the disease was achieved using pulse therapy with cyclophosphamide following rituximab withdrawal. In one PV with vegetating features, good improvement was obtained after 6 rituximab infusions. All patients tolerated the treatment well. Anti-desmoglein autoantibodies significantly decreased only in pemphigus foliaceus. Conclusions: This study highlights that rituximab is a valuable drug for refractory pemphigus, although the response of mucous membranes and cutaneous folds may be delayed.

Lymphoblastic lymphoma (LBL) is a neoplasm of precursor B- or T-lymphocytes, and primary skin involvement is uncommon. The aim of the study was to review all reported primary cutaneous (PC)-LBLs and to examine three new cases to better characterize this neoplasm. Two of our patients showed a pre-B phenotype (PC-B-LBL) and one a never-reported pre-T phenotype (PC-T-LBL). The patient with PC-T-LBL showed an aggressive course, while those with PC-B-LBL showed a complete remission (CR) after polychemotherapy. Cytogenetic analysis and gene expression profiling (GEP) were performed on one case of PC-B-LBL and on that of PC-T-LBL. A specimen of PC-B-LBL and two specimens (early and late stage) of PC-T-LBL were investigated by microarray-based comparative genomic hybridization (CGH). All specimens revealed trisomy of chromosome 4. PC-T-LBL showed a gain of 1p36.33-p22.1 in the early stage and multiple chromosome gains/losses in the late stage. Our data suggest that trisomy 4 could be detected early in LBL and gain of 1p36.33-p22.1 could be an interesting marker in PC-T-LBL. LBL is an aggressive disease but, only in B-LBL, the cutaneous presentation seems to be a favorable prognostic factor and polychemotherapy is the best therapeutic approach. We suggest that PC-LBL should be included as a provisional clinicopathologic entity in future cutaneous lymphoma classification. © 2012 Informa UK, Ltd.

Reactivities of the monoclonal antibodies (mAbs) of the 9th Human Leukocyte Differentiation Antigen Workshop, in order to define specific antigenic expression of the primary cutaneous B-cell lymphomas (PC-BCL), were analyzed by immunohistology on human tonsil and on PC-BCL, such as follicular centre B-cell lymphomas (FCL), marginal zone lymphomas (MZL) and diffuse large B-cells lymphomas leg-type (DLBL-LT). We identified some subgroups of mAbs that were exclusively or preferentially positive in one lymphoma cell type: the PC-FCL subgroup of mAbs includes PD1/CD279, GCET-1, hFCRL1/CD307a, FCRL2/CD307b, CXCR5/CD185, B7-DC/CD273, MRC/CD200, CD130, CXCR4/CD184, Siglec-5/14, CD150, on the other hand subgroup of mAbs in PC-MZL includes BTLA/CD272, BLIMP-1, hCD38. No specific subgroup of mAbs was found to label PC-DLBCL. This study may be useful to better define specific antigen profile of different PC-BCL entities leading to a correct diagnosis. © 2010 Elsevier B.V.

Extranodal natural killer/T-cell (ENK/T) lymphoma is a rare neoplasm, subcategorized into ENK/T-nasal (ENK/T-N) and ENK/T-nasal type (ENK/T-NT) lymphomas. ENK/T-NT lymphoma with initial presentation in the skin is known as primary cutaneous ENK/T-NT (PC-ENK/T-NT) lymphoma. The aim of this study was to investigate pathogenesis, genomic alterations, and prognosis of cutaneous ENK/T lymphomas to provide further insights into clinicopathologic features and genetic mechanism of lymphomagenesis. A retrospective case study of 5 white patients affected by ENK/T lymphoma (4 PC-ENK/T-NT and 1 ENK/T-N with cutaneous involvement) was performed. Most of the cases presented with multiple nodules and ulcerations localized on the extremities. A considerable percentage had disease in advanced stage with a 12-month survival rate of 40%. Genomic alterations were detected by array-based comparative genomic hybridization that showed gains of 1q, 7q and loss of 17p in the cases of PC-ENK/T-NT lymphomas and gain of 7q and loss of 9p, 12p, 12q in the case of ENK/T-N lymphoma. In conclusion, ENK/T lymphoma is a very aggressive entity, and, in our cases, the exclusively cutaneous presentation was not associated with a better prognosis. The results of our array comparative genomic hybridization analysis could be useful to better define the different ENK/T lymphoma subgroups with cutaneous involvement.

Background Bullous pemphigoid (BP) is a blistering skin disease caused by autoantibodies to hemidesmosomal proteins, with eosinophils participating in blister formation. Eosinophils are a source of tissue factor (TF), an initiator of blood coagulation. Objectives To evaluate the local and systemic activation of coagulation in BP. Methods We studied 20 patients with active BP (eight re-evaluated during remission) and 40 controls. The coagulation markers prothrombin fragment F1+2 and d-dimer were measured in the plasma of all subjects and in both plasma and blister fluid of patients with BP. TF was evaluated immunohistochemically in skin specimens from the 20 patients and in 20 normal samples. Results F1+2 and d-dimer levels were higher in plasma of patients with BP (649 +/- 96 pmol L(-1) and 18.52 +/- 3.44 nmol L(-1), respectively) than in plasma of controls (157 +/- 7 pmol L(-1) and 1.42 +/- 0.06 nmol L(-1); P = 0.0001), and were very high in blister fluid (40 449 +/- 3491 pmol L(-1) and 1532.32 +/- 262.81 nmol L(-1); P = 0.0001). Plasma and blister fluid F1+2 and d-dimer levels paralleled blood and tissue eosinophilia and disease severity. In the eight patients re-evaluated during remission, there was a marked reduction in F1+2 (from 1127 +/- 144 to 287 +/- 52 pmol L(-1); P = 0.005) and d-dimer (from 24.03 +/- 4.08 to 4.69 +/- 1.51 nmol L(-1); P = 0.029). Immunohistochemistry revealed strong TF reactivity in BP skin (P = 0.0001), and colocalization studies confirmed eosinophils as a source of TF. Conclusions The coagulation cascade is activated in BP and correlates with the severity of the disease and with eosinophilia, indicating that eosinophils play a role in coagulation activation via TF. The hypercoagulability may contribute to inflammation, tissue damage, blister formation and possibly thrombotic risk in BP.

Background: Although several cases of chronic urticaria (CU) are currently regarded as autoimmune in origin, associated with histamine-releasing autoantibodies, an activation of blood coagulation via tissue factor (TF) and a strong expression of TF in lesional skin have been described. Eosinophils, which are involved in CU skin lesions, have recently been demonstrated as the major source of TF in human blood. We assessed whether eosinophils are the cellular source of TF in CU skin lesions. Methods: Twenty patients with severe CU were studied. Skin biopsy specimens were taken from wheals. The control group consisted of specimens of perilesional normal skin from different types of skin tumours (10) and various skin disorders with non-eosinophilic infiltrates, including leukocytoclastic vasculitis (7), lichen planus (8) and mastocytosis (3). TF expression was evaluated by immunohistochemical methods using an anti-TF monoclonal antibody. Co-localization of TF and eosinophil cationic protein, a classic cell marker of eosinophils, was investigated by double-staining studies using 2 specific monoclonal antibodies in the 4 specimens showing the highest TF reactivity scores. Results: All specimens from patients with CU clearly showed TF expression that was absent in all normal control specimens (p = 0.0001) and in the skin disorders with non-eosinophilic infiltrates (p = 0.001–0.0001). The double-staining experiments for TF and eosinophil cationic protein clearly showed that the TF-positive cells were eosinophils. Conclusions: Eosinophils are the main source of TF in CU lesional skin. This finding highlights the role of these cells in the pathophysiology of CU and might pave the way for new therapeutic strategies.

Origin of basal cell carcinoma (BCC) is still unclear. We studied the cytokeratin (CK) profile in BCC using monoclonal antibodies against 12 CKs to further investigate the suggested origin of the tumor from follicular matrix cells or from follicular outer root sheath cells and to determine if BCC subtypes can be identified on the basis of their CK profiles. Cases of pilomatricoma and samples of fetal skin served as controls to establish the CK profile in matrical cells and developing follicles during intrauterine life, that of the epidermis and cutaneous adnexa in adult life having been determined in a previous study. The most significant findings were as follows: (a) CK 5 and CK 17 positivity in all the BCCs studied; (b) CK 7, CK 8, CK 18, and CK 19 positivity in 30/52, 33/52, 42/52, and 14/52 BCCs, respectively; (c) CK 14 negativity in almost all the BCCs studied; and (d) lack of CK 1 expression only in 2/2 morpheiform BCCs and 4/10 nodular BCCs. The study suggests a tumorous differentiation toward follicular outer root sheath cells and, in most cases, also toward the glandular components of the pilosebaceous-apocrine unit. No significant difference in the CK profile among the BCC subtypes studied was found. © 2008 by Lippincott Williams & Wilkins.

Summary Background The determination of clonality has proven to be a useful adjunct to the diagnosis of cutaneous lymphocytic infiltrates. It is considered particularly helpful for the distinction of mycosis fungoides (MF) and inflammatory dermatoses. Objectives To verify the sensitivity of the polymerase chain reaction (PCR)–heteroduplex analysis of T-cell receptor γ-chain gene (TCRγ) rearrangements in patients with MF and to establish whether a clinicopathological re-evaluation of lesions previously unclassified or considered to be non-neoplastic entities but found to be monoclonal allowed the recognition of additional cases of MF. Methods Included in the study were 116 patients, seen at our Institute from April 2002 to September 2003 and tested for TCRγ rearrangements. Thirty-six patients were affected by clinically and histopathologically proven MF, while the remaining 80 cases had not been classified or had been classified as non-neoplastic entities. The sensitivity of the molecular analysis was determined on the basis of the results obtained in the 36 patients with MF. The 29 cases of the second series of patients found to be monoclonal were clinically and histopathologically re-evaluated. Results Clonal rearrangements were found in 87·5% of patients with plaque stage MF and in 20% of those with patch stage MF. The clinicopathological re-evaluation allowed us to reclassify 15 of 29 monoclonal cases of the second series of patients as MF. Conclusions The study showed that the PCR–heteroduplex technique can determine a high percentage of monoclonality only in plaque stage MF. However, in spite of the low sensitivity of the method, several cases previously unrecognized could be reclassified as MF when their clinical and histopathological features were re-evaluated taking into account the clonality of the lymphocytic infiltrate.

Given the poor prognosis of patients with advanced cutaneous T-cell lymphoma and the high transplant-related mortality associated with conventional allogeneic bone marrow transplantation, we performed nonmyeloablative transplantation of allogeneic stem cells (ASCT) from HLA-identical siblings in three patients with this disease. All patients achieved full donor engraftment, clearance of clonal T cells leading to durable complete remissions but experienced high incidence of infections, which proved fatal in one case. These results suggest that nonmyeloablative ASCT is a novel and potentially curative therapy for patients with advanced T-cell lymphomas who have a histocompatible sibling.

Cutaneous leishmaniasis (CL) is an infection caused by protozoa from the genus Leishmania. The disease is transmitted by sandflies. Reservoirs are dogs, mice, wild rodents and, more rarely, humans. CL is clinically characterized by a single, polymorphous lesion, usually localized on the face or limbs. Nowadays, CL is more frequently seen among travellers returning from tropical and subtropical countries (1). Cutaneous lymphoid hyperplasia (CLH), also known as pseudolymphoma, is a reactive proliferation, probably secondary to persistent antigenic stimulation. We present here a case of CLH associated with L. panamensis infection.