Summary Background Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic ...diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. Methods In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov , NCT02260986. Findings Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% 125 patients who received dupilumab plus topical corticosteroids qw and 39% 41 patients who received dupilumab q2w plus topical corticosteroids vs 12% 39 patients who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% 204 and 69% 73 vs 23% 73; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. Interpretation Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. Funding Sanofi and Regeneron Pharmaceuticals Inc.
Background Primary cutaneous marginal zone B-cell lymphomas are low-grade lymphomas running an indolent course. Skin relapses have been frequently reported but little information about disease-free ...survival (DFS) is available. Objective We sought to evaluate relapse rate and DFS in patients with primary cutaneous marginal zone B-cell lymphomas. Methods Clinical features, European Organization for Research and Treatment of Cancer/International Society for Cutaneous Lymphomas stage, light chain restriction, clonality, treatments, skin relapses, DFS, stage progression, extracutaneous disease, and outcome are analyzed in a series of 137 patients. Results Patients were classified as solitary lesion (T1) (n = 70; 51%), regional skin involvement (T2) (n = 40; 29%), and generalized skin lesions (T3) (n = 27; 20%). Surgical excision, local radiotherapy, or a combination were the initial treatment in 118 patients (86%). In 121 of 137 patients (88%) a complete remission was observed after initial treatment, including 99 of 106 patients (93%) with solitary or localized disease and 22 of 31 patients (71%) with multifocal lesions. Cutaneous relapses were observed in 53 patients (44%). Median DFS was 47 months. Patients with multifocal lesions or T3 disease showed higher relapse rate and shorter DFS. No significant differences were observed between surgery and radiotherapy, but surgery alone was associated with more recurrences at initial site. Overall survival at 5 and 10 years was 93%. Six patients (4%) developed extracutaneous disease during follow-up. Limitations This was a case series retrospective study. Conclusion Our results support long-term follow-up in patients with primary cutaneous marginal zone B-cell lymphomas. Disseminated skin lesions have higher relapse rate and shorter DFS suggesting further investigation on systemic therapies in such a group of patients.
Background Data about special phenotypes, natural course, and prognostic variables of patients with acquired cold urticaria (ACU) are scarce. Objectives We sought to describe the clinical features ...and disease course of patients with ACU, with special attention paid to particular phenotypes, and to examine possible parameters that could predict the evolution of the disease. Methods This study was a retrospective chart review of 74 patients with ACU who visited a tertiary referral center of urticaria between 2005 and 2015. Results Fourteen patients (18.9%) presented with life-threatening reactions after cold exposure, and 21 (28.4%) showed negative results after cold stimulation tests (classified as atypical ACU). Nineteen patients (25.7%) achieved complete symptoms resolution at the end of the surveillance period and had no subsequent recurrences. Higher rates of atypical ACU along with a lower likelihood of achieving complete symptom resolution was observed in patients who had an onset of symptoms during childhood ( P < .05). In patients with atypical ACU, shorter disease duration and lower doses of antihistamines required for achieving disease control were detected ( P < .05). Age at disease onset, symptom severity, and cold urticaria threshold values were found to be related to disease evolution ( P < .05). Limitations This study was limited by its retrospective nature. Conclusions The knowledge of the clinical predictors of the disease evolution along with the clinical features of ACU phenotypes would allow for the establishment of an early and proper therapeutic strategy.
Background Folliculotropic mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma in which the neoplastic T lymphocytes display tropism for the follicular epithelium. Objectives To ...better categorize this rare form of cutaneous T-cell lymphoma we evaluated the clinical, pathological, and immunophenotypic findings, and the response to therapy and course of the disease. Methods Folliculotropic MF cases were selected from the registry of the Thematic Network of Cutaneous Lymphoma of Barcelona (Spain) from 1988 to 2007. Results Twenty patients (11 male, 9 female) with a mean age of 54 years were included. Mean follow-up time was 43 months. The most common sites of involvement were the head and neck (80%), upper extremities, and thorax. Infiltrated plaques (55%), acneiform lesions (comedo-like and epidermal cysts) (45%), and follicular keratosis-pilaris–like lesions (45%) were the more prominent features. Histopathological findings included selective infiltration of the follicular epithelium by atypical lymphocytes in all cases. Mucinous degeneration of the follicular epithelium occurred in 60% of cases. Psoralen plus ultraviolet A therapy was the treatment of choice in the majority of patients, but these patients did not respond as well as patients with classic MF. Radiotherapy (local or total skin electron beam) was found to be the most effective treatment. A good response to bexarotene was seen in some patients. Limitation This was a case series descriptive study. Conclusions Folliculotropic MF is a rare but well-defined clinicopathological variant of MF. Although refractory to standard therapies used in classic MF, most of our patients showed only slow disease progression.
Background Approximately 4% of cutaneous squamous cell carcinomas (cSCCs) develop lymphatic metastases. The value of lymphatic endothelial markers to enhance the detection of lymphatic tumor invasion ...in cSCC has not been assessed previously. Objective We sought to evaluate the use of the antibody D2-40, a podoplanin immunohistochemical marker, to identify tumor lymph vessel invasion in cSCC and to assess its expression in tumor cells. Methods This was a retrospective case-control study. A series of 101 cSCC, including 51 cases that developed lymphatic metastatic spread (metastasizing cSCC MSCC) and 50 cases that resolved definitely after surgical excision (non-MSCC) were included in the study. Lymph vessel invasion using D2-40 was evaluated on all primary biopsy specimens. The percentage of tumor cells showing D2-40 positivity and intensity scoring were recorded. All the immunohistochemical findings were correlated with the clinicopathological features. Results Lymph vessel invasion was observed in 8% of non-MSCCs and in 25.5% of MSCCs ( P = .031). D2-40 expression was significantly increased, both in intensity (odds ratio 4.42 for intensity ++/+++) and in area (odds ratio 2.29 for area >10%), in MSCC when compared with non-MSCC. Interestingly, almost half (49%) of the MSCC had moderate to intense D2-40 positivity compared with 16% of non-MSCC. D2-40 immunohistochemical expression was increased in tumors with an infiltrative pattern of extension. In the multivariate analysis, histologically poorly differentiated tumors, recurrent lesions, and cSCC showing D2-40 overexpression (in intensity) were significantly associated with lymphatic metastases development (odds ratios 15.67, 14.72, and 6.07, respectively). Limitations This was a retrospective study. Conclusion The expression of podoplanin associates with high metastatic risk in cSCC.
Summary To study the different patterns of Treponema pallidum distribution in primary and secondary syphilis, 34 biopsy specimens of 8 patients with primary and 26 with secondary syphilis were ...assessed. Histopathological features, silver stain, and immunohistochemical T pallidum polyclonal antibody expression were investigated. The number and distribution of spirochetes were evaluated, and ultrastructural studies were performed. Spirochetes were identified with Warthin-Starry stain in 17 specimens (4/8 primary and 13/26 secondary syphilis), whereas immunohistochemical analysis disclosed spirochetes in 29 (8/8 primary and 21/26 secondary syphilis). In secondary syphilis, an epitheliotropic pattern characterized by abundant spirochetes in the lower mucosa/epidermis in an intercellular distribution was observed. In contrast, primary syphilis exhibited a mixed epitheliotropic and vasculotropic pattern further manifested by treponemes surrounding the vascular walls. These differences were statistically significant. Ultrastructural examination confirmed these results. Immunohistochemistry shows greater sensitivity when compared with Warthin-Starry staining. The immunohistochemical pattern of T pallidum distribution may permit the diagnostic differentiation of primary from secondary syphilis.
Background Erythema induratum of Bazin is a mostly lobular panniculitis. There is considerable controversy in the literature about whether or not vasculitis is a histopathologic requirement to ...establish the diagnosis of erythema induratum of Bazin. Even accepting vasculitis as a histopathologic criterion, there is no agreement about the nature and size of the involved vessels. Objective The main goal of our study was to investigate whether or not vasculitis was present in a large series of cases of erythema induratum of Bazin and, when vasculitis was found, to determine the nature and localization of the involved vessels. Methods We studied 101 skin biopsy specimens from 86 patients with clinicopathologic diagnosis of erythema induratum of Bazin. Histopathologic criteria required in each case to be included in this study were: (1) a mostly lobular panniculitis with necrotic adipocytes at the center of the fat lobule; (2) inflammatory infiltrate within the fat lobule mostly composed of neutrophils in early lesions and granulomatous infiltrate in fully developed lesions; (3) significant fat necrosis; and (4) absence of other histopathologic findings that allow a specific diagnosis of other lobular panniculitis different from erythema induratum of Bazin. We also recorded the nature of the inflammatory cells involving the fat lobule, and the lesions were classified into two main categories: (1) early lesions, when the inflammatory infiltrate was mainly composed of neutrophils, with or without leukocytoclasis; and (2) fully developed lesions, when histiocytes and lipophages were the predominant inflammatory cells within the involved fat lobule. Results Some type of vasculitis was evident in 91 cases (90.09%). A total of 47 biopsy specimens (46.5%) showed a mostly lobular panniculitis with necrotizing vasculitis involving the small vessels, probably venules, of the center of the fat lobule. Thirteen biopsy specimens (12.8%) showed a mostly lobular panniculitis with vasculitis involving both large septal veins and small vessels, probably venules, of the center of the fat lobule. Twelve biopsy specimens (11.8%) showed a mostly lobular panniculitis with vasculitis involving large septal veins, with no involvement or other septal or lobular vessels. Ten biopsy specimens (9.9%) showed a mostly lobular panniculitis with vasculitis involving large septal vessels, both arteries and veins, and necrotizing vasculitis involving the small vessels, probably venules, of the center of the fat lobule. Nine biopsy specimens (8.9%) showed a mostly lobular panniculitis with vasculitis involving large septal vessels, both arteries and veins, but with no involvement of the small blood vessels of the center of the fat lobule. Finally, 10 biopsy specimens (9.9%) showed a mostly lobular panniculitis without evidence of septal or lobular vasculitis in serial sections. Associated diseases included history of extracutaneous tuberculosis (including tuberculosis of the lung, lymph nodes, kidney, or bowel) in 12 cases (13.95%), previous episodes of superficial thrombophlebitis of the lower legs in 3 cases (3.72%), rheumatoid arthritis in one case (1.16%), Crohn disease in one case (1.16%), chronic lymphocytic leukemia in two cases (2.32%), hypothyroidism in two cases (2.32%), and positive serology for hepatitis B virus in 4 cases (4.65%) and for hepatitis C virus in 5 cases (5.81%). Limitations Serial sections were not performed in all cases. At least 10 sections were studied in each case. When vasculitis was evident in some of these first 10 sections, no further sections were cut, but when histopathologic features of vasculitis were not found in the first 10 sections, serial sections throughout the specimen were performed looking for vasculitis. Because some type of vasculitis was evident in the first 10 sections of 91 cases, serial sections were performed only in the remaining 10 cases and they failed to demonstrate clear-cut histopathologic features of vasculitis. On the other hand, this is a retrospective study that was performed from the histopathologic slides of our files, and only the clinical information contained in the report accompanying the biopsy specimen could be recorded. Conclusions In our experience, vasculitis is present in most lesions of erythema induratum of Bazin, and the nature, location, and size of the involved vessels is, from more to less frequent, as follows: (1) small venules of the fat lobule; (2) both veins of the connective tissue septa and venules of the fat lobule; (3) only veins of the connective tissue septa; (4) veins and arteries of the connective tissue septa and venules of the fat lobule; and (5) veins and arteries of the connective tissue septa. However, in some cases with all clinicopathologic features of erythema induratum of Bazin vasculitis could not be demonstrated with serial sections throughout the specimen and, therefore, the presence of vasculitis should be not considered as a criterion sine qua non for histopathologic diagnosis of erythema induratum of Bazin.
Summary Dermatofibrosarcoma protuberans is genetically characterized by the translocation t(17;22)(q22;q13) resulting in the PDGFB/COL1A1 fusion gene. Fluorescence in situ hybridization with specific ...probes enables a rapid detection of this gene. In this study, the presence of the translocation t(17;22)(q22;q13) by fluorescence in situ hybridization in paraffin-embedded tissue microarrays was analyzed. Two tissue microarrays including 40 cases of dermatofibrosarcoma protuberans and 20 dermatofibromas were evaluated. Fluorescence in situ hybridization analyses were performed using a dual-color dual-fusion noncommercial probe. Clinical and histopathologic features were examined, and the association with fluorescence in situ hybridization results was assessed. A total of 29 samples of dermatofibrosarcoma protuberans and 16 of dermatofibromas were successfully evaluated. Twenty-five (86%) dermatofibrosarcoma protuberans samples were positive for the translocation, which was absent in all samples of dermatofibromas. Two of the negative dermatofibrosarcoma protuberans showed unusual, hypercellular areas with marked cytologic atypia, whereas 1 case exhibited overlap features with dermatofibroma. Tumors with fibrosarcomatous areas seemed to have a higher percentage of positive cells and the number of copies of the COL1A1/PDFGB gene. In conclusion, the COL1A1/PDGFB fusion gene was present in most of the dermatofibrosarcoma protuberans tissue samples. The detection of the translocation may be an additional diagnostic tool in cases of dermatofibrosarcoma protuberans showing nonconclusive histologic features.
Background Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg type can eventually disseminate to extracutaneous sites including testes. In addition, patients with testicular lymphoma can ...develop specific skin involvement. Objective We sought to describe similarities between PCDLBCL, leg type and testicular B-cell lymphoma affecting the skin. Methods We report two cases with typical clinicopathological and immunophenotypical features of leg type lymphoma occurring simultaneously with a testicular B-cell lymphoma. We also report an additional case of PCDLBCL, leg type with secondary testicular involvement. Results All cases presented with typical red tumors exclusively located on the legs. Histologically, all cases showed a diffuse nonepidermotropic infiltrate composed of large blastic cells mainly centroblastic type. Phenotype showed strong positivity for Bcl-2, MUM-1, and FOXP1. Epstein-Barr virus stains and CD30 were negative in the 3 cases. In all cases the testicular infiltration showed the same pathological and phenotypical changes to those observed in the skin. Limitations This was a retrospective case series study. Conclusion Skin involvement by testicular B-cell lymphomas and PCDLBCL, leg type are indistinguishable on the basis of pathologic and immunophenotypical features, therefore specific investigation and clinic correlation are needed.
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