Utility of IL-36 immunostaining in distinguishing psoriasis from pityriasis rosea and pityriasis lichenoides.

BACKGROUND: Psoriasis is an inflammatory skin disease driven by upregulation of cytokines in the Th17 pathway, including interleukin-36 (IL-36). Previous studies have highlighted the utility of IL-36 immunostaining for psoriasis compared to spongiotic dermatitis and other psoriasiform dermatoses; however, no study has examined the role of IL-36 staining in distinguishing psoriasis from pityriasis rosea (PR) and pityriasis lichenoides (PL), known histologic mimickers of psoriasis. METHODS: We compared the immunostaining pattern of IL-36 for 21 PR cases, 22 PL cases, and 10 psoriasis cases. We graded the immunostaining as 0, negative; 1, focal weak; 2, diffuse weak; 3, focal, strong; or 4, diffuse strong. We further categorized stains as negative (0-2 score) or positive (3-4 score) and utilized Fisher's exact test to compare the immunostaining pattern of these entities. RESULTS: All psoriasis specimens were positive for IL-36, whereas all PR specimens were negative (p = 0.00000002). Twenty PL specimens were negative (p = 0.000001). Nine of 10 pityriasis lichenoides et varioliformis acuta cases were negative (p = 0.00012), and 11 of 12 cases of pityriasis lichenoides chronica were negative (p = 0.00003). CONCLUSIONS: Our findings highlight the potential role of IL-36 immunostaining in distinguishing psoriasis from other psoriasiform dermatoses, including PR and PL.

Possible role of plasmacytoid dendritic cells in pityriasis lichenoides.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) and their product, type I interferons (IFNs), have been implicated in the pathogenesis of several skin disorders characterized by an interface dermatitis (ID) pattern, such as lichen planus (LP). A type I IFN signature has previously been documented in pityriasis lichenoides (PL). Although pDCs are known to be the main source and most potent producers of local type I IFNs, their role in PL has not been investigated. AIM: To investigate the role of pDCs in PL. METHODS: In total, 20 cases of PL and 20 comparable cases of LP were immunohistochemically tested for pDC occurrence and type I IFN production using anti-blood-derived dendritic cell antigen-2 (BDCA2; a specific pDC marker) and anti-myxovirus protein A (anti-MxA) antibodies (indirect marker of pDC activity), respectively. MxA is a well-established surrogate marker for local type 1 IFN production. A semiquantitative scoring system was used. RESULTS: pDCs were present in all 40 cases with no statistically significant difference between the two groups. MxA expression was intense and diffuse in the majority of PL and LP cases. CONCLUSIONS: pDCs constitute a central component of the inflammatory infiltrate in PL, suggesting that PL shares with the other entities that exhibit an ID a common pDC-driven process through type I IFN production, which ultimately leads to the cytotoxic attack.

Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica: comparison of lesional T-cell subsets and investigation of viral associations.

BACKGROUND: Pityriasis lichenoides (PL) exhibits a broad clinical spectrum that includes both acute and chronic forms. The precise biologic mechanisms underlying PL remain unclear. OBJECTIVES: To evaluate the immunohistochemical characteristics of PL and to investigate lesional T-cell subsets and the possible role of viral infection in its pathogenesis. PATIENTS AND METHODS: Samples from 10 patients with PL et varioliformis acuta (PLEVA) and 13 with PL chronica (PLC) were analyzed immunohistochemically. Epstein-Barr virus early regions were assayed by in situ hybridization and T-cell receptor-γ (TCR-γ) gene rearrangements were assayed by polymerase chain reaction (PCR). We also utilized PCR to assay for human herpesvirus-8 (HHV-8) DNA in 51 patients with PL and in 25 controls. RESULTS: Lymphocytes expressing CD8 and T-cell intracellular antigen-1 were more abundant in patients with PLEVA than with PLC, whereas CD4+ lymphocytes and FOXP3-positive regulatory T-cells were more abundant in PLC. HHV-8 DNA was present in 11 of 51 (21.6%) PL patients and 0 of 25 controls. A clonal TCR-γ gene rearrangement was observed in only one patient with PLEVA. CONCLUSIONS: Our data suggests that PL may represent an inflammatory condition induced by various triggering agents, such as HHV-8, rather than a lymphoproliferative disorder. PLEVA, characterized by an acute course with severe symptoms, may indicate a relative lack of regulatory T-cells in comparison with PLC.

The use of synchrotron infrared microspectroscopy in the assessment of cutaneous T-cell lymphoma vs. pityriasis lichenoides chronica.

BACKGROUND: The diagnosis of cutaneous lymphomas remains a challenge for both the clinician and dermatopathologist. OBJECTIVES: To differentiate between frank malignant and premalignant lymphocytes within the skin. METHODS: This study was performed on 20 patients with a mean age of 50 years. They were divided into two groups: mycosis fungoides (MF) (stage IA, IB and IIA) and pityriasis lichenoides chronica (PLC). Immunophenotyping using antibodies CD3, CD4, CD8, CD20 and CD30 was performed. Synchrotron Fourier transform infrared microspectroscopy (S-FTIRM) was performed on cell nuclei to assess chemical differences between MF and PLC cases as a potential complementary screening tool. Dermal spectra of both MF and PLC were compared using principal components analysis (PCA) of the S-FTIRM data. RESULTS: All PLC spectra was clustered together. However, the MF spectra formed two clusters, one that grouped with the PLC and the other grouped separately. Moreover, protein and nucleic acids showed highly significant differences between MF (IIA and IB), MF (IA) and PLC. CONCLUSIONS: The malignant transformation within lymphocytes was identifiable through the spectroscopic analysis of protein, RNA and DNA with S-FTIRM, making it a promising tool for classifying the progression of cutaneous T-cell lymphoma.

Foxp3 expression in cutaneous T-cell lymphocytic infiltrates.

BACKGROUND: The primary function of regulatory T cells (Treg cells) is to regulate the function and proliferation of immunologically responsive T cells; the transcription factor Foxp3 is expressed by this cell populace and is held to be the standard marker for Treg cells. DESIGN: A variety of cutaneous T-cell lymphocytic infiltrates were evaluated for Foxp3 expression. RESULTS: Of the 95 cases, 33 (35%) were reactive, 40 (42%) were prelymphomatous cutaneous T-cell dyscrasia and 22 were (23%) T-cell lymphoma. The reactive category included dermatomyositis, lupus erythematosus, hypersensitivity reactions and graft-vs.-host disease. The prelymphomatous dyscrasia category was represented chiefly by pityriasis lichenoides chronica (PLC) and pigmented purpuric dermatosis (PPD). The Foxp3 reactivity was less than 10% for cases of dermatomyositis and lupus erythematosus, 23% for hypersensitivity cases, 0% for graft-vs.-host disease, 16% for the dyscrasias and 11% for the lymphomas. Intermediate grade and aggressive lymphomas had very few Foxp3+ cells (< 5%). There were fewer numbers of Foxp3+ T cells in the monoclonal variants of PLC and PPD. CONCLUSIONS: T-reg cells may play a role in controlling the extent of T-cell proliferations in the skin with a lack of T-regulatory function permissive to the development of various T-cell disorders.

Assessment of TCR-beta clonality in a diverse group of cutaneous T-Cell infiltrates.

While some unequivocally benign infiltrates are easy to distinguish from cutaneous T-cell lymphoma (CTCL), drug-associated lymphomatoid hypersensitivity reaction and cutaneous lesions of collagen vascular disease can show cytologic atypia, clonality and an immunophenotypic profile that closely simulates CTCL and cause diagnostics difficulties. Similar immunophenotypic and molecular abnormalities to those of malignant lymphoma can also be observed in pityriasis lichenoides chronica (PLC), large plaque parapsoriasis (LPP), pigmented purpuric dermatosis (PPD) and atypical lymphocytic lobular panniculitis leading one to consider these entities as forms of cutaneous lymphoid dyscrasia. The purpose of our study was to evaluate the distinction of these various subcategories of cutaneous T-cell infiltrates by assessment of T-cell receptor (TCR)-beta gene rearrangement. Formalin-fixed paraffin-embedded skin biopsies from 80 patients containing a T-cell dominant lymphocytic infiltrate were analyzed for TCR-beta gene rearrangement. Our findings indicate that monoclonality is a reliable characteristic of CTCL with polyclonality being very infrequent. However, some cases of drug associated lymphomatoid hypersensitivity, collagen vascular disease and the various cutaneous lymphoid dyscrasias (i.e. PLC, PPD and atypical lymphocytic lobular panniculitis) could manifest restricted molecular profiles in the context of an oligoclonal process or frank monoclonality.

Enhanced expression of human metalloelastase (MMP-12) in cutaneous granulomas and macrophage migration.

Accumulation of inflammatory cells such as macrophages may lead to degeneration of connective tissue matrix in various skin diseases. Macrophage metalloelastase, is a matrix metalloproteinase (MMP-12) capable of degrading elastin as well as various basement membrane components. To investigate the role of human macrophage metalloelastase in skin, we assessed by in situ hybridization and immunohistochemistry 66 specimens representing skin diseases characterized either by changes in elastic fibers or by pronounced infiltrations of extravasating and migrating macrophages. CD68 immunostaining was performed to identify the human macrophage metalloelastase-positive cells and Weigert's Resorcin-Fuchsin staining to reveal the status of elastic fibers. We found abundant expression of human macrophage metalloelastase mRNA in macrophages in areas devoid of normal elastic fibers in granulomatous skin diseases sarcoidosis, necrobiosis lipoidica diabeticorum, and granuloma annulare. Positive cells for human macrophage metalloelastase protein could be detected in the same regions as well as positive immunostaining for urokinase plasminogen activator. Of the other matrix metalloproteinases capable of degrading elastin, 92 kDa gelatinase colocalized with human macrophage metalloelastase, while 72 kDa gelatinase was produced by surrounding fibroblast-like cells. Furthermore, human macrophage metalloelastase was expressed by macrophages in areas with disrupted basement membrane, as assessed by type IV collagen staining, in pityriasis lichenoides and dermatitis herpetiformis. Specimens of anetoderma, acrodermatitis chronica atrophicans and pseudoxanthoma elasticum showed no signal for human macrophage metalloelastase. Matrilysin was not detected in any of the samples investigated. Our study suggests that human macrophage metalloelastase may contribute to elastin degradation occurring in granulomatous skin diseases and may aid macrophage migration through the epidermal and vascular basement membranes in inflammatory disorders.