Maxwell A. Fung

Light microscopic criteria for the diagnosis of early vulvar lichen sclerosus: A comparison with lichen planus

Lichen sclerosus (LS) and lichen planus (LP) are two conditions frequently affecting genital skin whose clinical and histologic distinction can be difficult. Both diseases can feature solitary genital lesions with bandlike lymphocytic infiltrates. We reviewed 68 cases of vulvar LS to find sections that contained a transition from a lichenoid interface reaction to pathognomonic LS (i.e., marked papillary dermal sclerosis or edema), and in these nine cases we studied routinely and specially stained sections, as well as sections stained with a panel of antisera to lymphoid antigens, and compared the findings with those in six cases of genital LP. We assumed that changes at the periphery of a lesion of LS mirror findings seen in early lesions. The features that we found more commonly in the inflammatory phase of LS included a psoriasiform lichenoid pattern (100% LS, 0% LP), basilar epidermotropism (78% LS, 0% LP), loss of papillary dermal elastic fibers (100% LS, 33% LP), basement membrane thickening (44% LS, 0% LP), and epidermal atrophy (33% LS, 0% LP). Features found more commonly in LP included many cytoid bodies (0% LS, 100% LP), wedge-shaped hypergranulosis (11% LS, 100% LP), basal squamatization (22% LS, 100% LP), and pointed rete ridges (11% LS, 83% LP). We did not detect any significant differences in the immunohistochemical features of the infiltrates. Taken together, these histologic features comprise light microscopic criteria for the diagnosis of early vulvar LS and its differentiation from LP.

Galectin-3 Is Critical for the Development of the Allergic Inflammatory Response in a Mouse Model of Atopic Dermatitis

Galectin-3 belongs to a family of beta-galactoside-binding animal lectins expressed in several cell types, including epithelial and immune cells. To establish the role of galectin-3 in the development of allergic skin inflammation, we compared inflammatory skin responses of galectin-3-deficient (gal3(-/-)) and wild-type (gal3(+/+)) mice to epicutaneous sensitization with ovalbumin (OVA). OVA-treated gal3(-/-) mice exhibited markedly reduced epidermal thickening, lower eosinophil infiltration, and lower serum IgE levels compared with gal3(+/+) mice. The former evoked lower interleukin-4, but higher interferon-gamma, mRNA expression at OVA-treated skin sites. Moreover, gal3(-/-) splenocytes from OVA-sensitized mice secreted more interleukin-12 compared with gal3(+/+) splenocytes. In addition, antigen presentation by gal3(-/-) dendritic cells to T cells in vitro were T helper cell (Th1)-polarized relative to presentation by gal3(+/+) dendritic cells. When exposed to OVA, recipients engrafted with T cells from gal3(-/-) OVA-specific T cell receptor transgenic mice developed significantly reduced dermatitis and a markedly lower Th2 response compared with recipients of comparable gal3(+/+) T cells. We conclude that galectin-3 is critical for the development of inflammatory Th2 responses to epicutaneously administered antigens; in its absence, mice develop a Th1-polarized response. This regulatory effect of galectin-3 on Th development is exerted at both the dendritic cell and T cell levels. Our studies suggest that galectin-3 may play an important role in the acute phase of human atopic dermatitis.

Delayed Adverse Reaction to Contrast-enhanced CT: A Prospective Single-Center Study Comparison to Control Group without Enhancement

PURPOSE To prospectively assess the incidence of delayed adverse reactions (DARs) in patients undergoing contrast material-enhanced computed tomography (CT) with the low osmolar nonionic contrast agent iohexol and compare with the incidence of DARs in patients undergoing unenhanced CT as control subjects. MATERIALS AND METHODS Institutional review board approval and informed written consent for this prospective study were obtained. The study was HIPAA compliant. Patients undergoing CT for routine indications were enrolled from a random next-available scheduling template by an on-site clinical trials monitor. All subjects received a questionnaire asking them to indicate any DAR occurring later than 1 hour after their examination. Sixteen manifestations were listed and included rash, skin redness, skin swelling, nausea, vomiting, and dizziness, among others. To ensure maximal surveillance, a clinical trials coordinator initiated direct telephone contact for further assessment. Patients suspected of having moderately severe cutaneous reactions were invited to return for a complete dermatologic clinical assessment including skin biopsy, if indicated. Statistical analysis was performed by using a two-sided Wilcoxon-Mann-Whitney test, a logistic regression utilizing a chi(2) test to adjust for sex and age, and a two-sided Fisher exact test. RESULTS A total of 539 patients (258 receiving iohexol and 281 not receiving contrast material) were enrolled. DARs were observed in 37 (14.3%) of 258 subjects receiving iohexol and in seven (2.5%) of 281 subjects in the control group (P < .0001, chi(2) test) after adjusting for sex and age. Specific manifestations of DARs that were significantly more frequent at contrast-enhanced CT were skin rash (P = .0311), skin redness (P = .0055), skin swelling (P = .0117), and headache (P = .0246). DARs involving the skin included generalized rashes of the face, neck, chest, back, and extremities and were often associated with swelling, erythema, and pruritus. CONCLUSION This study substantiates a frequent occurrence of DARs at contrast-enhanced CT compared with that in control subjects. Continued growth in the use of contrast-enhanced CT suggests a need for greater awareness and attention to prevention and management.

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream.

There are limited treatment options for metastatic melanoma, which is almost universally fatal. We report the successful treatment of 64 of 64 cutaneous and subcutaneous melanoma metastases in three patients using high-dose (22 million units per 1.2 ml) intralesional interleukin 2 (IL-2) in combination with topical imiquimod and a retinoid cream. Before intralesional therapy, all patients had been treated surgically and were no longer considered surgical candidates. Rebiopsy of 15 of the treatment sites and long-term follow-up (10, 12, and 27 months) showed regression of all treated tumors. Six months after discontinuation of therapy, one patient developed multiple new cutaneous metastases, but these were also responsive to treatment with intralesional therapy. The other two patients did not experience recurrence of their cutaneous melanoma. However, one of the two patients developed lymph node and brain metastases 18 months after initiation of intralesional therapy, but is still alive, now at 27 months. The concentration of IL-2 used for the intralesional therapy was much higher than in previously reported cases, which may explain the excellent responses that were observed. These results support intralesional high-dose IL-2 as a very effective therapy for controlling cutaneous metastatic melanoma. Additional studies are needed to determine whether this therapy is associated with a survival benefit.

Infectious eccrine hidradenitis caused by nocardia

Neutrophilic eccrine hidradenitis is a nonspecific clinical reaction pattern classified as a neutrophilic dermatosis that typically occurs in the setting of chemotherapy for hematologic malignant disease. Neutrophilic eccrine hidradenitis more rarely has been reported in association with infectious agents, including Serratia, Enterobacter, Staphylococcus, and HIV. We describe the first case of infectious eccrine hidradenitis occurring in a patient with cutaneous Nocardia infection.

Mechanical Disruption of Tumors by Iron Particles and Magnetic Field Application Results in Increased Anti-Tumor Immune Responses

The primary tumor represents a potential source of antigens for priming immune responses for disseminated disease. Current means of debulking tumors involves the use of cytoreductive conditioning that impairs immune cells or removal by surgery. We hypothesized that activation of the immune system could occur through the localized release of tumor antigens and induction of tumor death due to physical disruption of tumor architecture and destruction of the primary tumor in situ. This was accomplished by intratumor injection of magneto-rheological fluid (MRF) consisting of iron microparticles, in Balb/c mice bearing orthotopic 4T1 breast cancer, followed by local application of a magnetic field resulting in immediate coalescence of the particles, tumor cell death, slower growth of primary tumors as well as decreased tumor progression in distant sites and metastatic spread. This treatment was associated with increased activation of DCs in the draining lymph nodes and recruitment of both DCs and CD8(+)T cells to the tumor. The particles remained within the tumor and no toxicities were observed. The immune induction observed was significantly greater compared to cryoablation. Further anti-tumor effects were observed when MRF/magnet therapy was combined with systemic low dose immunotherapy. Thus, mechanical disruption of the primary tumor with MRF/magnetic field application represents a novel means to induce systemic immune activation in cancer.

Acute Generalized Exanthematous Pustulosis as a Delayed Dermatotoxic Reaction to IV-Administered Nonionic Contrast Media

OBJECTIVE Our objective was to report three delayed, generalized, and protracted cutaneous reactions in two patients that are compatible with acute generalized exanthematous pustulosis (AGEP) after contrast medium administration. CONCLUSION Radiologists and referring clinicians need to be aware of late adverse reactions to the administration of contrast media and to distinguish these from other possible causes.

Assessment of the ‘no eosinophils' rule: are eosinophils truly absent in pityriasis lichenoides, connective tissue disease, and graft‐vs.‐host disease?

Eosinophils are often present in the inflammatory infiltrate of an interface dermatitis, but the diagnostic specificity of eosinophils in interface dermatitis has not been formally evaluated. We retrospectively identified 97 examples of interface dermatitis with clinically confirmed diagnoses, including lupus erythematosus (LE), lichen planus, pityriasis lichenoides (PL), graft‐vs.‐host disease (GVHD), dermatomyositis (DM) and drug reaction. Diagnoses were clinically confirmed by at least two dermatologists. Slides were reviewed in a blinded fashion by at least two dermatopathologists. The average eosinophil count per 10 ×200 (×20 objective) fields was lowest for PL (0.2), DM (0.3), GVHD (0.4), and LE (0.5) [defined as Group 1] and was higher for lichen planus, drug reactions, erythema multiforme (major and minor) and viral exanthems [defined as Group 2]. Distinction between Group 1 and Group 2 was maximized using an eosinophil count cutoff of 1.1. In conclusion, eosinophils are usually rare to absent in PL, DM, most forms of LE and GVHD. While final interpretation requires a composite assessment of all features, our results suggest that the presence of even a single eosinophil within nine or ten ×20 fields argues against a diagnosis of PL, DM or LE.

Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts

Importance Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a “diagnosis of exclusion,” a definition not compatible with clinical decision making or inclusion for clinical trials. Objective To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum. Evidence Review Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation. Findings Delphi exercise yielded 1 major criterion—biopsy of ulcer edge demonstrating neutrophilic infiltrate—and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively. Conclusions and Relevance This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.

A Prospective Study of Acute-Onset Steroid Acne Associated with Administration of Intravenous Corticosteroids

Steroid acne (SA) may occur after the administration of topical or systemic corticosteroids. Because of several consultations of spinal injury patients with a very abrupt onset of a uniform papular eruption (i.e. days) initially misdiagnosed as a drug reaction or sepsis, we followed hospitalized patients who received intravenous corticosteroids (IVC) for the development of acute-onset SA in order to determine its incidence. Fifty-one consecutive subjects receiving IVC were followed for the duration of their hospital stay and examined for the development of acneiform lesions. Acute-onset SA occurred in 1 subject (2%). Acute spinal cord injury may represent a high-risk clinical setting for acute-onset SA.