Biosimilar medicines for psoriasis. Positioning of the Mexican Academy of Dermatology.

The development and marketing of biosimilars opens a new scenario in the treatment of many pathologies, including psoriasis. This article reflects the position of the Mexican Academy of Dermatology (AMD) on the use of biosimilar medicines for the treatment of psoriasis in Mexico. In summary, the AMD estates that there is sufficient evidence to accept comparability of pharmacokinetics and pharmacodynamics of some biosimilar medicines to adalimumab, infliximab and etanercept; this evidence does not sufficiently support interchangeability or indication extrapolation. It is essential to establish a close pharmacovigilance not only to guarantee compliance with the Cofepris rules in Mexico, but also to facilitate the effective monitoring of the adverse effects of biosimilar medicines. Although the goal of biotechnological drugs is to achieve substantial savings for patients and public institutions, no economic criteria should prevail over rigorous scientific criteria that guarantee maximum therapeutic efficacy and optimum safety for patients.

El desarrollo y comercialización de biocomparables abre un nuevo escenario en el tratamiento de muchas patologías, entre ellas la psoriasis. El presente artículo recoge la postura de la Academia Mexicana de Dermatología (AMD) respecto al uso de medicamentos biocomparables para el tratamiento de la psoriasis en México. En resumen, la AMD establece que existe suficiente evidencia para aceptar la comparabilidad farmacocinética y farmacodinámica entre algunos medicamentos biocomparables al adalimumab, el infliximab y el etanercept; esta evidencia no sustenta suficientemente su intercambiabilidad ni la extrapolación de indicaciones; es fundamental establecer una farmacovigilancia estrecha no solo para garantizar el cumplimiento de las reglas de la Comisión Federal para la Protección contra Riesgos Sanitarios en México, sino para facilitar un seguimiento efectivo de los efectos adversos de los medicamentos biocomparables. Si bien la meta de los medicamentos biotecnológicos es lograr un ahorro sustancial para los pacientes y las instituciones públicas, los criterios económicos no deben anteponerse a criterios científicos rigurosos que garanticen la máxima eficacia terapéutica y la óptima seguridad para los pacientes.

Approach to dermal-based lymphoid infiltrates and proliferations.

The histopathological diagnosis of dermal-based lymphoid infiltrates and proliferations is often challenging due to the vast list of biologically diverse entities that archetypally or occasionally center in the mid-dermis, especially because significant overlap exists in their clinical, histopathologic, and immunophenotypic features. The differential diagnosis includes reactive infiltrates in common and rare inflammatory dermatoses, benign conditions that may mimic lymphoid neoplasms (pseudolymphomas), and true clonal proliferations arising either primarily in the skin or rarely in extracutaneous tissues with secondary cutaneous dissemination. While numerous histopathological and immunophenotypic features have been reported to support a definitive diagnosis, no single ancillary test is sufficient for their distinction. Therefore, in this review we advocate a stepped histopathological approach for dermalbased lymphoid infiltrations, employing as key elements the general lymphocytic composition (relative B- versus T-cell ratio), coupled with the predominant cytomorphology (cell size) present. Following this strategy, the relative incidence of cutaneous involvement by each disease should always be considered, as well as the notion that a definitive diagnosis must be founded on a multiparameter approach integrating all clinical, histopathologic, immunophenotypic, and-in selected cases-molecular features.

From Classical to Unusual: Report on 5 Cases of Transient Reactive Aquagenic Pseudokeratoderma and Review of the Literature.

Transient reactive aquagenic pseudokeratoderma is characterized by transient whitish and translucent papules after water exposure in palms and soles. We report 5 additional cases and their histopathologic features. Patient 5 showed a topography that had not been reported before; this demonstrates that it is not an exclusive condition of palms and soles. Patient 2 presents very subtle clinical findings, making difficult the diagnosis. And the other 3 patients have a typical presentation. Transient reactive aquagenic pseudokeratoderma has heterogeneous clinical features; in some cases, histopathologic findings, although subtle, help to confirm the diagnosis.

Focal Epithelial Hyperplasia in Adult Patients With HIV Infection: Clearance With Topical Imiquimod.

Case 1 A 41-year-old man with human immunodeficiency virus (HIV) 1 diagnosed 16 years prior to his consultation was referred for an 8-month history of multiple painless lumps in his mouth. He had A2 status (CD4 cell count of 273 cells/mm3 and viral load of 43,000 copies/L) and was taking treatment with lamivudine/zidovudine (combivir) and efavirenz. Physical examination showed multiple small mucosal-colored and lobulated papulonodules located in the palate and lower gingiva and a whitish verrucous plaque on the lower labial mucosa (Figure 1a). The lesions were diagnosed clinically as focal epithelial hyperplasia (FEH) and further confirmed by classical histopathological findings (Figure 1b). He had previously received unspecified treatment; thus, topical 5% imiquimod cream was initiated every night. Mild erosion and ulceration developed in the upper labial mucosa, which were managed with lubrication (petrolatum ointment). After 2 weeks, all of the small lesions disappeared and the largest plaque resolved 1 week later (Figure 1c). A small residual mass in the area of biopsy, suggesting a scar, remained on the lower lip. The area was removed surgically and corresponded to fibrosis histologically, with no evidence of human papillomavirus (HPV) infection. CD4 cell count (694 cells/mm3) and viral load (<40 copies/L) did not show remarkable changes after imiquimod administration. No serious side effects were observed and the patient has remained free of disease after 1 year of follow-up.

Primary cutaneous perivascular epithelioid cell tumor: a clinicopathological and molecular reappraisal.

BACKGROUND: Perivascular epithelioid cell tumor (PEComa) is a rare neoplasm of uncertain histogenesis with a mixed myomelanocytic immunophenotype, rarely arising in the skin (primary cutaneous PEComa [pcPEComa]). OBJECTIVE: We analyzed the clinicopathological features of 8 pcPEComas, assayed for DNA copy number changes and for initiating mutations common in melanocytic neoplasms. METHODS: pcPEComas were evaluated using immunohistochemistry, comparative genomic hybridization, and DNA sequencing. RESULTS: pcPEComas were erythematous nodules, mostly in the lower extremities of women (5/8), composed of large pale-staining epithelioid cells. The patient's age range was 26 to 67 (mean 46) years. The percentages of tumors staining positively were as follows: micro-ophthalmia-associated transcription factor, NKI/C3, bcl-1, E-cadherin, and cathepsin K (100%); HMB-45, 4E-binding protein 1, and CD68 (88%); smooth muscle actin and muscle-specific actin (40%); S100 (38%); calponin (20%); desmin (13%); and melan-A, SOX10, and keratin (0%). No chromosomal copy number changes or initiating mutations were identified. LIMITATIONS: Small sample size is a limitation. CONCLUSIONS: pcPEComas have a different molecular signature than extracutaneous tumors and are unrelated to tuberous sclerosis. However, the common expression of 4E-binding protein 1 points to a role of the mTOR pathway in their pathogenesis. Because pcPEComas are diagnostically challenging, we propose that micro-ophthalmia-associated transcription factor, NKIC3, smooth muscle actin, desmin, bcl-1, cathepsin K, and 4E-binding protein 1 can be used when evaluating a possible pcPEComa.

DNA copy number changes in tumors within the spectrum of cellular, atypical, and metastasizing fibrous histiocytoma.

BACKGROUND: Cutaneous fibrous histiocytoma (FH) is a common mesenchymal neoplasm. Metastasis is rare, disproportionately occurring among the aneurysmal, cellular, atypical, and deep variants. OBJECTIVE: We determined whether DNA copy number changes occurred in atypical FH (AFH), and whether they were similar to those in metastasizing FH (MetFH) and benign cellular FH (CFH). METHODS: Five primary tumors of MetFH were evaluated by array-based comparative genomic hybridization analysis, with tissue from local recurrences and lung metastases in 2 and 2 patients, respectively. Seven indolent AFH and 5 CFH were identified for comparison. RESULTS: Substantial differences between the groups were found both in the frequency of chromosomal aberrations (higher among MetFH and absent or solitary in CFH) and array-based comparative genomic hybridization profiles (frequent gains of 7 and 8q and losses of Xq in MetFH; recurrent losses of chromosomes 9 and 22 in AFH; isolated loss of 5q and gain in chromosome 20 in 2 CFH). Fatal MetFH cases (2 of 5 cases) exhibited the highest rate of chromosomal aberrations. LIMITATIONS: This study included a small sample size with a short-term follow-up. CONCLUSIONS: Benign CFH, indolent AFH, and MetFH represent distinct biological entities within the spectrum of FH; array-based comparative genomic hybridization may be a tool in recognizing FH cases with metastatic potential and increasingly aggressive behavior.

SOX-10 expression in cutaneous myoepitheliomas and mixed tumors.

BACKGROUND: SOX-10 expression can be demonstrated by immunohistochemistry in salivary gland myoepitheliomas, but its expression in cutaneous myoepitheliomas and in cutaneous mixed tumors with prominent myoepithelial cells has not been studied. METHODS: We assessed the staining pattern of SOX-10 in five cutaneous myoepitheliomas and six cutaneous mixed tumors with a prominent myoepithelial component among both the myoepithelial cells and cells lining lumens. In addition, we examined the staining of S100, microphthalmia-associated transcription factor (MiTF), keratin cocktail, HMK903, smooth muscle actin (SMA) and epithelial membrane antigen (EMA). RESULTS: SOX-10 positivity was seen in three of five (60%) cutaneous myoepitheliomas and in the myoepithelial cells of all cutaneous mixed tumors. SOX-10 expression on the cells lining the glandular structures in mixed tumors was variable. All myoepitheliomas and mixed tumors stained positively with S100 and negatively with MiTF. Pan-keratin, HMK903, SMA and EMA showed variable expression. CONCLUSIONS: SOX-10 is a relatively reliable marker for staining cutaneous myoepitheliomas. Cutaneous myoepitheliomas are notoriously difficult to diagnose, and the addition of SOX-10 to the repertoire of stains that can label this tumor is of practical utility. These results further support that cutaneous myoepitheliomas and cutaneous mixed tumors exist on a morphologic and immunophenotypic spectrum.

Amicrobial pustulosis of the folds associated with autoimmune disorders: systemic lupus erythematosus case series and first report on the association with autoimmune hepatitis.

Amicrobial pustulosis of the folds (APF) associated with autoimmune disorders is an infrequent entity characterized by the recurrent appearance of follicular and nonfollicular sterile pustules in the context of autoimmune disease. Most reports on APF suggest systemic lupus erythematosus (SLE) as the major immunological associated disorder but the association with autoimmune hepatitis (AH) has not been previously documented. We describe the clinical and histological characteristics of 5 patients with APF: 4 with SLE and 1 with AH. As APF is an exclusion diagnosis, in order to establish an opportune diagnosis and treatment, physicians should be aware of patients with any autoimmune disease who develop a pustular dermatosis for which cultures and stains are negative. We propose the inclusion of anti-liver kidney microsome antibodies in the minor criteria for APF diagnosis.

Autoimmunity-related neutrophilic dermatosis: a newly described entity that is not exclusive of systemic lupus erythematosus.

Neutrophilic dermatoses have long been known to be associated with autoinmune systemic diseases. Recently, a small number of cases of a disorder distinct from Sweet syndrome or bullous lupus erythematosus (LE) have been described as specifically related to systemic LE under diverse terms, including nonbullous neutrophilic dermatosis, nonbullous neutrophilic LE, and Sweet-like neutrophilic dermatosis. We describe 7 patients that developed urticarial lesions in the context of a known or concurrently diagnosed autoimmune connective tissue disease. Of a total of 7 patients, 6 were afflicted by systemic LE and 1 by rheumatoid arthritis and secondary Sjögren syndrome. Histological findings in all patients included an interstitial and perivascular neutrophilic infiltrate with leukocytoclasia, vacuolar alteration along the dermal-edidermal junction, and no vasculitis. Most patients had active systemic disease at the time of the cutaneous eruption. Skin lesions resolved rapidly after the administration of immunomodulating agents. In conclusion, we provide additional evidence of the existence of a recently defined nonbullous neutrophilic dermatosis in the context of autoimmune connective tissue diseases and propose the term autoimmunity-related neutrophilic dermatosis as an appropriate designation. Furthermore, we believe that this entity should prompt physicians to screen the presence of an active systemic disorder in afflicted patients.

Association of a Proposed New Staging System for Folliculotropic Mycosis Fungoides With Prognostic Variables in a US Cohort.

Importance: A new cutaneous staging system for folliculotropic mycosis fungoides (FMF) has been purported to better estimate survival compared with the staging system for conventional mycosis fungoides. Objective: To analyze predictive variables associated with survival and evaluate the effectiveness of the newly proposed staging system for estimating overall survival and disease-specific survival (DSS) in a US cohort. Design, Setting, and Participants: This cohort study assessed 195 patients with FMF in the dermatopathology database of the University of California, San Francisco from January 1, 1990, to April 31, 2012, for eligibility. A total of 153 patients were excluded for the following reasons: (1) alternative diagnoses were favored ranging from benign dermatitides to other forms of cutaneous lymphoma; (2) technical problems with slides; and (3) lack of follow-up information. Data were analyzed from January 1, 2018, to August 31, 2020. Main Outcomes and Measures: Kaplan-Meier curves were used to estimate overall survival and DSS for the entire cohort. Possible predictive variables associated with survival were evaluated using Cox proportional hazards regression modeling. Each variable was examined separately, followed by a multiple-variable model. Kaplan-Meier curves were used to estimate overall survival and DSS by subdividing the cohort into early- and advanced-stage cutaneous disease. Results: Forty-two patients were included in the analysis (mean age at diagnosis, 55 [range, 8-89] years; 31 men [74%]). For the entire cohort, the estimated 5-year overall survival rate was 89% (95% CI, 79%-99%); 10-year rate, 78% (95% CI, 63%-92%); and 15-year rate, 58% (95% CI, 31%-85%). Estimated 5- and 10-year DSS rates were 89% (95% CI, 79%-99%); 15-year rate, 80% (95% CI, 61%-99%). For overall survival in the multiple-variable Cox proportional hazards regression model, only age was statistically significant (hazard ratio [HR] per 10-year age increase, 3.1; 95% CI, 1.4-7.2; P = .008), whereas for DSS, only cutaneous disease was statistically significant (HR, 11.4; 95% CI, 1.3-103.0; P = .03). When stage stratified, the 5-year estimated overall survival rate for early-stage disease was 96% (95% CI, 89%-103%); 10-year rate, 82% (95% CI, 65%-98%); and 15-year rate, 65% (95% CI, 33%-97%). For advanced-stage disease, the estimated 5- and 10-year overall survival rates were 70% (95% CI, 41%-98%); the 15-year rate, 53% (95% CI, 16%-89%). For early-stage cutaneous disease, the estimated 5-, 10- and 15-year DSS rates were all 96% (95% CI, 89%-103%). For advanced-stage cutaneous disease, the estimated 5- and 10-year DSS rates were 70% (95% CI, 41%-98%); the 15-year rate, 53% (95% CI, 16%-89%). Conclusions and Relevance: Cox proportional hazards regression modeling demonstrated cutaneous stage to be the only statistically significant predictive variable associated with DSS. Subdividing FMF into early and advanced cutaneous stages was associated with effective estimation of survival in this cohort. Thus, findings suggest that FMF is a heterogeneous disease with early and advanced cutaneous stages; that the new staging system is effective in estimating survival in a US cohort; and that the poor prognosis initially associated with FMF only applies to the advanced cutaneous stage.

Hypopigmented Mycosis Fungoides: Loss of Pigmentation Reflects Antitumor Immune Response in Young Patients.

Hypopigmented mycosis fungoides (HMF) is a form of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of extranodal non-Hodgkin's lymphomas. HMF has a unique set of defining features that include light colored to achromic lesions, a predilection for darker skin phototypes, an early onset of disease, and predominance of CD8+ T-cells, among others. In the current review, we detail the known pathways of molecular pathogenesis for this lymphoma and posit that an active Th1/cytotoxic antitumor immune response in part explains why this variant is primarily seen in children/adolescents and young adults, who do not exhibit signs of immunosenescence. As a result of this potent cytotoxic response, HMF patients experience mostly favorable overall prognosis, while hypopigmentation may in fact represent a useful surrogate marker of cytotoxic immunity targeting the malignant cells. Understanding the molecular processes behind the specific features that define HMF may lead to improved diagnostic accuracy, personalized prognosis by risk stratification, and improved management of HMF. Moreover, improving our knowledge of HMF may aid our further understanding of other cutaneous lymphomas.

Acral and Multicentric Pigmented Bowen's Disease in HIV-Positive Patients: Report on Two Unusual Cases.

In situ squamous cell carcinoma of the skin (SCCis or Bowen's disease) is a common intraepidermal cutaneous malignancy with a low invasive potential. Acral Bowen's disease is usually solitary, but multiple acral SCCis have been reported. Pigmented Bowen's disease is typically unilesional and characterized by a hyperpigmented plaque with a velvety of keratotic surface, which can eventually simulate melanoma clinically. We describe two HIV-positive patients who presented with multiple pigmented SCCis involving the distal extremities. In patients with immunosuppression, the presence of multiple and hyperpigmented verrucae that clinically do not respond to adequate treatment should raise the differential diagnosis of SCC in situ.

Oral and Cutaneous Lymphomas other than Mycosis Fungoides and Sézary Syndrome in a Mexican Cohort: Recategorization and Evaluation of International Geographical Disparities.

BACKGROUND: Nonmycosis fungoides/Sézary syndrome (non-MF/SS) primary cutaneous lymphomas (PCL) are currently categorized under the 2005-World Health Organization/European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for PCL. These differ in behavior from secondary cutaneous lymphomas (SCL) and to lymphomas limited to the oral cavity (primary oral lymphomas [POL]) both categorized under the 2016-WHO classification for lymphoid neoplasms. AIMS: This study aims to report the first series of non-MF/SS PCL, SCL, and POL in a Mexican cohort, examine the applicability of current classification systems and compare our findings with those from foreign cohorts. MATERIALS AND METHODS: Eighteen non-MF/SS PCL, four SCL, and two POL with available tissue for morphology and immunophenotypic assessment were reclassified according to the 2005-WHO/EORTC and 2016-WHO classifications. RESULTS: Non-MF/SS PCLs were primarily of T-cell origin (61%) where CD30+ lymphoproliferative disorders predominated, followed by Epstein-Barr virus-induced lymphomas, and peripheral T-cell lymphomas, not otherwise specified. Primary cutaneous B-cell lymphomas (BCL) were primarily of follicle center cell origin followed by postgerminal lymphomas of the diffuse large BCL variety. CONCLUSIONS: Most non-MF/SS PCL, SCL, and POL can be adequately categorized according to the 2005-WHO/EORTC and 2016-WHO classification systems, even when dealing with clinically atypical cases. The relative frequencies in our cohort hold closer similarities to Asian registries than from those of Europe/USA, supporting the concept of individual and/or racial susceptibility, and the notion of geographical variances in the rate of lymphomas. In particular, such disparity may arise from viral-induced lymphomas which might show partial geographical restriction.

Approach to Cutaneous Lymphoid Infiltrates: When to Consider Lymphoma?

Cutaneous lymphoid infiltrates (CLIs) are common in routine dermatopathology. However, differentiating a reactive CLI from a malignant lymphocytic infiltrate is often a significant challenge since many inflammatory dermatoses can clinically and/or histopathologically mimic cutaneous lymphomas, coined pseudolymphomas. We conducted a literature review from 1966 to July 1, 2015, at PubMed.gov using the search terms: Cutaneous lymphoma, cutaneous pseudolymphoma, cutaneous lymphoid hyperplasia, simulants/mimics/imitators of cutaneous lymphomas, and cutaneous lymphoid infiltrates. The diagnostic approach to CLIs and the most common differential imitators of lymphoma is discussed herein based on six predominant morphologic and immunophenotypic, histopathologic patterns: (1) Superficial dermal T-cell infiltrates (2) superficial and deep dermal perivascular and/or nodular natural killer/T-cell infiltrates (3) pan-dermal diffuse T-cell infiltrates (4) panniculitic T-cell infiltrates (5) small cell predominant B-cell infiltrates, and (6) large-cell predominant B-cell infiltrates. Since no single histopathological feature is sufficient to discern between a benign and a malignant CLI, the overall balance of clinical, histopathological, immunophenotypic, and molecular features should be considered carefully to establish a diagnosis. Despite advances in ancillary studies such as immunohistochemistry and molecular clonality, these studies often display specificity and sensitivity limitations. Therefore, proper clinicopathological correlation still remains the gold standard for the precise diagnosis of CLIs.