T-Cell Monoclonality in the Blood and the Skin Correlates With Poor Response to Treatment in Mycosis Fungoides.

BACKGROUND: The prognostic value of skin and blood T-cell receptor clonality in mycosis fungoides is a matter of debate. Our aim was to ascertain the relation between the presence of a monoclonal T-cell population in the blood and in the skin with response to treatment in patients with mycosis fungoides. PATIENTS AND METHODS: Clinical features and follow-up data were retrospectively collected and analyzed in 94 patients with mycosis fungoides seen at a cutaneous lymphoma clinic in a single tertiary center. All patients had results of polymerase chain reaction analysis of T-cell receptor gamma gene rearrangement in lesional skin and in peripheral blood at time of diagnosis. Association of response to treatment with clonality in the tissue and in the blood was assessed. RESULTS: T-cell monoclonality was detected in the skin in 30 of 94 patients, in the blood in 12 of 94 cases and the same clone was found in both tissues in 6 of 94 patients. The presence of a polyclonal T-cell population in the circulation was associated with complete response (P = .006). Lack of response to treatment (stable disease or progression of disease) was associated with T-cell clonality in skin (P = .009), in blood (P = .002) and in both tissues (P < .001). A multivariate analysis showed that T-cell monoclonality in the skin is independently associated with lack of response of mycosis fungoides to therapy. CONCLUSION: Blood and skin should be studied for T-cell clonality as part of the routine initial workup, even in patients with early-stage disease.

CRP Levels as a Prognostic Factor in Mycosis Fungoides.

Mycosis Fungoides (MF) and Sézary syndrome (SS) are the most common forms of cutaneous T-cell lymphomas. Few validated prognostic factors have been reported in MF/SS, especially when compared with non-cutaneous lymphomas. Increased C-reactive protein (CRP) levels have recently been associated with poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of serum CRP levels at diagnosis in patients with MF/SS. This retrospective study included 76 patients with MF/SS. Stage was assigned according to the ISCL/EORTC guidelines. The follow-up period was 24 months or more. Disease course and response to treatment were determined using quantitative scales. Wilcoxon's rank test and multivariate regression analysis were used to analyze the data. Increased CRP levels correlated significantly with advanced stages (Wilcoxon's test, P>0.0001). Furthermore, increased CRP levels were associated with a lower treatment response rate (Wilcoxon's test, P=0.0012). Multivariate regression analysis showed that CRP is an independent predictor of advanced clinical stage at diagnosis.The present data suggest that elevated CRP levels could serve as a useful prognostic factor in MF/SS and may assist in guiding treatment choices.

An Uncommon Presentation of Darier-White Disease with Hystrix-like Palmoplantar Keratoderma.

Darier-White disease is a relatively common autosomal dominant genodermatosis caused by mutation in the ATP2A2 gene. It is characterized by multiple warty papules coalescing into plaques in the seborrheic areas and by specific histological skin changes. Palm and sole involvement in Darier-White disease is usually mild, mainly featuring discrete and small keratotic papules. We present a unique case of Darier-White disease presenting with a diffuse, mutilating hystrix-like palmoplantar keratoderma.

FOXP3 Predicts Response to Treatment in Mycosis Fungoides.

BACKGROUND: The role of the T-regulatory cells (Tregs) marker forkhead box Protein 3 (FOXP3) in mycoses fungoides (MF) pathogenesis is unclear and the results of previous studies are inconclusive. OBJECTIVE: We aimed at ascertaining the possibility that FOXP3 expression may serve to predict MF stage and response to therapy. PATIENTS AND METHODS: Immunohistochemistry staining for FOXP3 was performed on 30 skin biopsies from patients with MF, and FOXP3 expression level was quantitatively graded. Disease stage, progression, and response to treatment were determined based on clinical and imaging evidence, and association with FOXP3 expression was assessed. RESULTS: FOXP3 expression in the dermis correlated with poor response to treatment (P=0.047). A negative non-significant relationship between epidermal FOXP3 expression and clinical stage severity was observed (P=0.17). CONCLUSIONS: Dermal FOXP3 expression in MF lesions could be used to predict response to treatment in patients with MF.

Primary Cutaneous B-Cell Lymphomas in Children and Adolescents: A SEER Population-Based Study.

BACKGROUND: Although primary cutaneous B-cell lymphomas (PCBCL) comprise 25% of all cutaneous lymphomas, their incidence in the pediatric population is unknown, and the information on pediatric PCBCL has mostly been gathered from individual case reports or series from single centers. PATIENTS AND METHODS: This was a population-based, retrospective cohort study of patients in 18 cancer registries in the United States diagnosed between 2000 to 2016 through the Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted incidence rates were calculated for PCBCL in pediatric (<20 years) and adult (≥20 years) populations. Demographic, clinical, and pathological characteristics of PCBCL were compared between the two groups. RESULTS: A total of 48 pediatric and 5128 adult PCBCL cases were included. Median age at diagnosis was 16.5 years and 65 years in the two groups, respectively. The major histologic subtypes of pediatric cases were marginal zone lymphoma (77.1%), followed by diffuse large B-cell lymphoma (12.5%) and follicle center lymphoma (10.4%), which were equally distributed in adults. The age-adjusted pediatric PCBCL incidence rate (per 1,000,000 person-years) was 0.12 (95% CI 0.09-0.16). The incidence in the adult population was approximately 40-fold higher than the one observed in the pediatric group (IRR 41.4, 95% CI 31.2-56.2). All 48 pediatric cases were alive during a median follow-up time of 48 months. CONCLUSIONS: Pediatric PCBCL is a very rare disease affecting mostly adolescents of both sexes. The major histologic subtype is marginal zone lymphoma, and the prognosis is favorable.

[LINEAR MYCOSIS FUNGOIDES IN A BLASCHKOID DISTRIBUTION].

INTRODUCTION: Mycosis fungoides (MF) is the most common type of primary cutaneous T cell lymphoma. Many clinicopathological variants of MF have been described in the literature, though only a few presented in a segmental pattern. There are several unique patterns of distribution of skin diseases, one of which is the Blaschko Lines. Congenital skin diseases develop in a Blaschkoid pattern due to mosaicism. In contrast, according to Happle, the development of acquired skin diseases in a similar pattern is explained by superimposed segmental manifestation - a process which involves mosaicism overlapping a preexisting congenital mutation. The theories by which previous case reports explained the segmental appearance of MF did not cover the molecular basis for their development. We report a case of a patient who presented with MF in a unique segmental distribution consistent with the Blaschko lines. The patient was found to have an acquired mosaic mutation in GNAS gene exclusively in the involved skin which represents a superimposed segmental manifestation according to Happle's theory. This case demonstrates the hidden potential of these rare cases which allows a better understanding of the pathogenesis by which acquired diseases develop. This is a basis for further research that could help identify new therapeutic targets for MF and other diseases that share its genetic etiology.

Comparative Study of Frozen and Paraffin-Embedded Sections: Evaluation of Inflammatory Dermatoses.

BACKGROUND: Frozen section (FS) is often performed when histopathological evaluations are urgently required for implementation of therapeutic measures. In dermatology, this method is most commonly used to evaluate excision margins of tumors. FS are also routinely employed to differentiate toxic epidermal necrolysis from staphylococcal scalded skin syndrome. However, little is currently known about the performance of FS in the diagnosis of inflammatory dermatoses. OBJECTIVES: To compare histopathological diagnoses in a series of patients with a clinical diagnosis of an inflammatory dermatosis for which FS and paraffin-section (PS) specimens were obtained on the same day. METHODS: We conducted a single-center retrospective analysis of 43 cases. All histological slides were reviewed by a single dermato-pathologist. Concordance was calculated between FS and PS. RESULTS: Patients were divided into three groups according to diagnosis: papulosquamous diseases (group I), drug eruptions (group II), and a heterogeneous group (group III) that included cases of bullous vasculitis and Sweet syndrome. Among the three groups, the results of FS and of PS were discordant only in five cases (5/43, 11.6%). Compared to PS, FS had a sensitivity of 92.9% [95% confidence interval (95%CI) 64.17-99.63%] and a specificity of 100% in group I, sensitivity of 90.9% (95%CI 57.12-99.52%) and specificity of 100% in group II, and sensitivity of 83.33% (95%CI 60.78-94.16%) and specificity of 100% in group III. The degree of agreement between the results of the FS and of the PS was almost perfect (kappa = 0.95, 0.93 and 0.85 respectively). CONCLUSIONS: This study suggests that FS is a valid approach for the rapid diagnosis of inflammatory dermatoses. This method is as specific as PS, although it is less sensitive.

Occupational mycosis fungoides - a case series.

BACKGROUND: Mycosis fungoides (MF) is the most frequent type of cutaneous T-cell lymphoma. MF has long been considered to develop as the result of a combination of genetic defects and exogenous triggers. Although no specific MF-associated environmental trigger has been established to date, some studies have suggested that occupational exposures may occasionally trigger the onset of MF. OBJECTIVE: In this observational study, we aimed at underscoring the potential association between occupational exposure and MF. METHODS: We ascertained a cohort of 150 MF patients for possible occupational exposure. RESULTS: Five MF patients with occupational exposure were identified in our cohort. Three patients had intensive contact with aromatic hydrocarbons; two of them were working in the same plant and in the same unit for more than 30 years. The third patient had been in contact with aromatic hydrocarbons for a total of 8 years. Patient 4 had additional contact for 12 years with hydrazine, and patient 5 had been exposed for 3 years to formaldehyde. CONCLUSION: The clustering of two cases of MF, an exceptionally rare disease, in the same plant unit, as well as the long-term, intense occupational exposure in other cases, substantiates the notion that occupational exposures may contribute to the pathogenesis of MF.

Assessment of the effectiveness of topical propranolol 4% gel for infantile hemangiomas.

BACKGROUND: Infantile hemangiomas (IHs) are the most common vascular tumors in children. Because of their benign character and natural involution, the vast majority of IHs do not require any treatment. In the past few years, topical beta blockers have been reported to be an effective treatment of superficial IHs. OBJECTIVE: We sought to evaluate the clinical effectiveness and safety profile of topical propranolol 4% gel for the treatment of IHs. METHODS: A retrospective study of all cases of IHs treated with topical propranolol 4% gel between 2013 and 2015 was performed. All patients were evaluated in a pediatric dermatology unit of a tertiary medical center. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. RESULTS: The study included 63 patients with a total of 75 IHs. Of the total number of IHs, 43 (57.3%) showed a good response to treatment, 19 (25.3%) a partial response, and 13 (17.33%) poor or no response, thus 62 (82.6%) had good or partial response to treatment. Age at treatment initiation, treatment time, thickness of the superficial component, and size of the lesions were shown to predict response to therapy. Out of the entire examined group, only two patients reported minor local side effects manifested by irritation, redness, and scaling of the treated area. No systemic adverse effects were reported. LIMITATIONS: This is an uncontrolled retrospective study. CONCLUSION: Propranolol 4% gel is a safe and efficient topical therapy for IH.

Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.

Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Mycosis Fungoides Associated with Kaposi's Sarcoma, T-cell Rich B-cell Lymphoma, and T-cell Lymphoma with Angioimmunoblastic Features.

A patient with mycosis fungoides (MF), Kaposi's sarcoma, T-cell rich B-cell lymphoma, and T-cell lymphoma with angioimmunoblastic features is described. The appearance of multiple malignancies in this patient may have been caused by previous exposure to radiation in the Chernobyl accident and/or systemic chemotherapy for the initial T-cell rich B-cell lymphoma which he underwent.

Clinical considerations and key issues in the management of patients with Erdheim-Chester Disease: a seven case series.

BACKGROUND: Erdheim-Chester Disease (ECD), a non Langerhans' cell histiocytosis of orphan nature and propensity for multi-systemic presentations, comprises an intricate medical challenge in terms of diagnosis, treatment and complication management. OBJECTIVES: The objectives are to report the clinical, radiological and pathological characteristics, as well as cardinal therapeutic approaches to ECD patients and to provide clinical analyses of the medical chronicles of these complex patients. METHODS: Patients with biopsy proven ECD were audited by a multi-disciplinary team of specialists who formed a coherent timeline of all the substantial clinical events in the evolution of their patients' illness. RESULTS: Seven patients (five men, two women) were recruited to the study. The median age at presentation was 53 years (range: 39 to 62 years). The median follow-up time was 36 months (range: 1 to 72 months). Notable ECD involvement sites included the skeleton (seven), pituitary gland (seven), retroperitoneum (five), central nervous system (four), skin (four), lungs and pleura (four), orbits (three), heart and great vessels (three) and retinae (one). Prominent signs and symptoms were fever (seven), polyuria and polydipsia (six), ataxia and dysarthria (four), bone pain (four), exophthalmos (three), renovascular hypertension (one) and dyspnea (one). The V600E BRAF mutation was verified in three of six patients tested. Interferon-α treatment was beneficial in three of six patients treated. Vemurafenib yielded dramatic neurological improvement in a BRAF mutated patient. Infliximab facilitated pericardial effusion volume reduction. Cladribine improved cerebral blood flow originally compromised by perivenous lesions. CONCLUSIONS: ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

Concomitant occurrence of pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease.

Erythema nodosum and pyoderma gangrenosum are common skin manifestations in inflammatory bowel diseases. Curiously, these two cutaneous features have seldom been reported to occur simultaneously. We present three patients affected with inflammatory bowel disease with concomitant erythema nodosum and pyoderma gangrenosum.

[Parapsoriasis--to be or not be (mycosis fungoides)].

Mycosis fungoides (MF) is the most prevalent cutaneous lymphoma, characterized by uncontrolled growth of T cells within the skin. The diagnosis in the early stages may be difficult, since, in these stages, the disease can imitate benign inflammatory processes, both clinically and histologically. One of the difficulties in determining diagnostic criteria for early MF is the existing terminology of parapsoriasis. There is disagreement concerning the exact definition and whether it is a chronic benign condition with similar clinical and histological characteristics as MF, or rather it is part of the disease spectrum itself. There is a need for uniformity in the definition for treatment decisions, for epidemiological purposes and for clinical and experimental research. This article reviews the different approaches to parapsoriasis as part of MF over the years.

Expression of vinculin in autoimmune cutaneous diseases.

BACKGROUND: Reports have appeared that sera of patients with systemic autoimmune disorders have demonstrated autoantibodies to vinculin. OBJECTIVE: To determine the presence and distribution of vinculin in the skin of patients with cutaneous autoimmune disorders. METHODS: Semiquantitative immunohistochemistry investigations for presence of vinculin were conducted on skin biopsy specimens from patients with pemphigus vulgaris (PV), bullous pemphigoid (BP), and various collagen vascular diseases, and from healthy controls. RESULTS: Results of staining for vinculin were positive in 2 of 7 PV patients, 6 of 9 BP patients, and all 6 cutaneous autoimmune patients. Staining results were negative in all controls. Strong immunostaining to vinculin was found in 3 of 6 vinculin-positive BP patients and 5 of 6 vinculin-positive cutaneous autoimmune patients. CONCLUSIONS: The expression and distribution of vinculin are accentuated in patients with various skin autoimmune diseases and appear to be stronger in diseases involving the basement membrane, where it is thought to be relatively more important than in other skin disorders.

Chlorpyrifos exacerbating pemphigus vulgaris: a preliminary report and suggested in vitro immunologic evaluation model.

BACKGROUND: There is accumulating evidence on the role of pesticides in the etiology of pemphigus vulgaris (PV). OBJECTIVE: To determine whether chlorpyrifos, an organophosphate pesticide, is involved in the immunopathology of PV. METHODS: Normal human skin biopsy specimens incubated with progressively diluted chlorpyrifos solutions were used as indirect immunofluorescence substrates for sera from two PV patients previously exposed to the agent and from healthy controls. Involvement of T-cell lymphocytes was assessed by release of interferon-g in the presence of chlorpyrifos. RESULTS: In one PV patient, immunofluorescence was strongly positive for the specimen incubated with the pesticide and weakly positive for the specimen incubated with medium alone. Immunofluorescence was negative in the patient under immunosuppression with prednisolone and in all controls. Both patients tested positive on interferon-g assay; controls tested negative. CONCLUSIONS: Findings suggest an immunopathogenic role of chlorpyrifos in PV. Interferon-g cytokine assay with the pesticide combined with immunofluorescence tests may provide an in vitro diagnostic tool in suspected pesticide-induced/exacerbated pemphigus.

A possible mechanism for phenol-induced pemphigus.

A possible mechanism for phenol-induced pemphigus lesions in genetically predisposed individuals is proposed that accounts for in vitro observations and cases of biochemical acantholysis, as well as the in vivo acantholysis in pemphigus induced by phenols. The mechanism involves the induction of interleukin-1a and tumor necrosis factor-a release by keratinocytes. These cytokines in turn have been shown to be involved in the regulation and synthesis of complement and proteases like plasminogen activator, which have been implicated in the pathogenesis of acantholysis in pemphigus vulgaris.