Melanocytic nevi with Spitz differentiation: diagnosis and management.

OBJECTIVES: Melanocytic proliferations with Spitz differentiation present a difficult clinicopathologic dilemma, as their spectrum ranges from benign to malignant. Distinct entities include Spitz nevus, atypical Spitz nevus, and Spitzoid melanoma. Their histopathologic differentiation can be challenging, and cases of Spitzoid melanoma initially diagnosed as benign Spitz nevi are reported in the literature. The goal of this article is to discuss the diagnostic tools (including comparative genomic hybridization), which may be helpful in differentiating benign Spitz nevi from malignant melanoma with Spitzoid features, and to propose an appropriate management strategy for each entity. STUDY DESIGN: Retrospective case reports. METHODS: Medical records of patients referred for suspicious nevi were reviewed. Data regarding demographics, site, pathology reports, and treatment were reviewed. RESULTS: Four patients with three distinct diagnoses involving Spitz differentiation were identified. The pathologic interpretation of these biopsies was difficult and multiple dermatopathologists were involved. All four patients underwent excision with or without sentinel node biopsy. CONCLUSIONS: Otolaryngologists, plastic surgeons and dermatopathologists will encounter patients who have melanocytic lesions with Spitz differentiation at some point in their career. The management of these patients is significantly impacted by the histopathologic diagnosis, and should not be undertaken until it is confirmed, possibly with comparative genomic hybridization. In our experience, it is not unusual to have multiple independent pathologic examinations. We believe that a team approach between the surgeon and the dermatopathologist is crucial when diagnosing and managing patients with Spitz lesions.

An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis.

Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-gamma) and chemokines (IL-8, IFN-gamma-inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-alpha levels and infiltrating T cells were observed in high responders (improvement in clinical score, > or =75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF-alpha significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.

A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis.

The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.