PRAME immunohistochemistry is useful in differentiating oral melanomas from nevi and melanotic macules.

BACKGROUND: Oral melanocytic neoplasms pose a diagnostic challenge to pathologists owing to their rarity relative to those in the skin. The utility of PRAME in distinguishing nevi from melanomas has been established in the skin, but limited information exists regarding its usefulness in the oral cavity. METHODS: Thirty-five previously diagnosed pigmented oral lesions were retrospectively evaluated with PRAME. The lesions consisted of 16 oral nevi, 10 melanomas, and 10 melanotic macules. RESULTS: Strong and diffuse nuclear PRAME staining was observed in all but one of the oral melanomas, which showed no staining. No nuclear PRAME staining was observed in any of the oral nevi or melanotic macules. CONCLUSIONS: PRAME is a useful tool in the evaluation of oral melanocytic neoplasms. Our data indicate that PRAME is a highly specific but incompletely sensitive marker of oral melanoma. Larger studies could further illuminate the diagnostic value of PRAME in oral lesions.

Small plaque psoriasis re-visited: A type of psoriasis mediated by a type-I interferon pathway.

TNFα-inhibitor-induced psoriasis is mediated by the type-I interferon pathway, of which IFNα, LL37 and IL-36γ are major players. A subset of patients treated with TNFα inhibitors develop small plaque psoriatic lesions. Small plaque psoriasis is similarly observed in patients on immune checkpoint inhibitors (ICI), and with concurrent systemic lupus erythematosus (SLE) or positive antinuclear antibody (ANA). Small plaque psoriasis is also the predominant phenotype in Asian populations. The association between small plaque psoriasis morphology in various clinical scenarios and the type-I interferon pathway has not been previously studied. A cross-sectional study was conducted of patients who developed small plaque psoriasis and had a biopsy for diagnostic clarification between 2009 and 2017. We obtained skin specimens from 14 adults with small plaque psoriasis: four patients taking anti-TNFα treatment, four patients with antecedent SLE, three patients with concurrent ANA positivity and three patients taking ICI. Controls included three patients with chronic plaque psoriasis. Histology confirmed psoriasiform epidermal hyperplasia with focal lichenoid and spongiotic features. Immunohistochemical analysis revealed higher expression of IFNα-induced MXA, LL37 and IL-36γ in all clinical scenarios of small plaque psoriasis compared to chronic plaque psoriasis. There was decreased CD8 T-cell migration to the epidermis and variability in the number of LAMP3+ cytoplasmic dendritic cells in the dermis of small plaque psoriasis. The findings suggest that small plaque psoriasis is a unique type of psoriasis with a distinct morphology and immune-phenotype, primarily mediated by the type-I interferon pathway. Associating morphology and disease pathogenesis may help identify therapeutic targets for better disease control.

Population-based assessment of sentinel lymph node biopsy in the management of cutaneous melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) for melanoma plays a central role in determining prognosis and guiding treatment and surveillance strategies. Despite widely published guidelines for SLNB, variation exists in its use. We aimed to determine the frequency of and predictive factors for SLNB in patients with clinically node-negative melanoma in British Columbia. METHODS: A retrospective review was performed of patients with clinically node-negative melanoma diagnosed between January 2015 and December 2017. Patients included had a Breslow depth greater than 0.75 mm or a Breslow depth less than or equal to 0.75 mm with ulceration, or a mitotic rate greater than or equal to 1/mm2. SLNB was considered to be indicated for clinical stages IB to IIC (American Joint Committee on Cancer's AJCC Cancer Staging Manual, seventh edition). RESULTS: A total of 759 patients were included. SLNB was performed in 54.8% (363/662) of patients when indicated. SLNB was more likely to be performed for tumours with a Breslow depth greater than 1.0 mm or a mitotic rate greater than or equal to 1/mm2. SLNB was less likely to be performed in patients older than 75 years and with a nonextremity tumour location. Compliance with SLNB guidelines decreased distant recurrence but did not significantly affect regional recurrence, nor did it have a significant impact on overall survival among patients aged 75 years and younger. CONCLUSION: SLNB is being underutilized in British Columbia. These results are concerning and highly relevant given the rapidly evolving field of adjuvant systemic therapy for high-risk patients and the increased proportion of patients who should be considered for SLNB on the basis of the eighth edition of the AJCC Cancer Staging Manual and current guidelines. Efforts should be made to increase the use of SLNB in appropriate patients.

Case Series: A Kindred With Eruptive Vellus Hair Cysts and Systemic Features.

Eruptive vellus hair cysts (EVHCs) often occur on the trunk and limbs. Facial involvement is uncommon. Autosomal dominant inheritance has been described, but associated extracutaneous anomalies have not. We describe a 4-patient kindred presenting with multiple facial EVHCs and an association of preauricular pits, lipomas, joint hypermobility, and cardiac defects. Histopathologic examination confirmed the diagnosis of EVHCs in 3 affected individuals. We propose that facial EVHCs may indicate the presence of an inherited autosomal dominant disorder with extracutaneous manifestations. Extracutaneous manifestations noted in the kindred have been sporadically described in association with steatocystoma multiplex (SM), a condition occasionally noted in the presence of EVHCs, further supporting an association between these disorders.

Prognostic significance of KAI1/CD82 in human melanoma and its role in cell migration and invasion through the regulation of ING4.

KAI1/CD82 is a member of the transmembrane 4 superfamily, which was first identified as a metastasis suppressor for prostate cancer. The expression of KAI1 was found to be reduced in many types of cancers, including prostate, breast, ovarian, cervical and endometrial cancer. However, the role of KAI1 in melanoma pathogenesis is not known. In this study, we investigated the expression level of KAI1 in a large set of melanocytic lesions at different stages. We found that the expression of KAI1 is significantly decreased during melanoma progression. In fact, KAI1 expression is drastically reduced in primary melanoma compared with dysplastic nevi (P = 1.8×10(-4)) and further reduced in metastatic melanoma compared with primary melanoma (P = 9.4 × 10(-15)). Furthermore, decreased KAI1 staining is strongly correlated with a worse 5 year and 10 year patient survival. Multivariate Cox regression analysis showed that KAI1 is also an independent prognostic factor for both 5 year and 10 year survival. Moreover, we found that overexpression of KAI1 significantly inhibited melanoma cell migration through suppression of Rho-associated kinase-mediated formation of stress fiber. Our data also suggested that overexpression of KAI1 significantly inhibited melanoma cell invasion by reducing the activity of metalloproteinase-2. In addition, we found that suppression of melanoma cell migration by KAI1 is mediated by another tumor-suppressor protein called inhibitor of growth 4 through the regulation of p65. Taken together, our data suggest that KAI1 may be used as a promising prognostic marker and a possible therapeutic target for human melanoma.

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival.

Deleted in Liver Cancer-1 (DLC1) is a Rho-GTPase-activating protein known to be downregulated and function as a tumor suppressor in numerous solid and hematological cancers. Its expression status in melanoma is currently unknown however, prompting us to examine this. Using immunohistochemistry and tissue microarrays containing a large set of melanocytic lesions (n=539), we examined the expression profile of DLC1 in melanoma progression, as well as the association between DLC1 and patient survival. We detected both cytoplasmic and nuclear DLC1 expression, and found that whereas cytoplasmic DLC1 was significantly downregulated in metastatic melanoma compared with nevi and primary melanoma, nuclear DLC1 expression was significantly down in primary melanoma compared with nevi, and then further down in metastatic melanoma. Loss of cytoplasmic DLC1 was significantly associated with poorer overall and disease-specific 5-year survival rates of all melanoma (P<0.001 and P=0.001, respectively) and metastatic melanoma patients (P=0.020 and 0.008, respectively), and similar results were seen for nuclear DLC1 (P<0.001 for both overall and disease-specific survival for all melanoma patients, and P=0.004 for metastatic melanoma patients). Next, we examined the correlation between cytoplasmic and nuclear DLC1 and found that concomitant loss of both forms was associated with the worst outcome for metastatic melanoma patients (P=0.013 and P=0.008 for overall and disease-specific 5-year survival, respectively). Finally, multivariate Cox regression analysis determined that strong cytoplasmic and nuclear DLC1 expression was a favorable independent prognostic factor for all melanoma (HR, 0.61; 95% CI, 0.42-0.88; P=0.008) and metastatic melanoma patients (HR, 0.42; 95% CI, 0.23-0.77; P=0.005). Although more research still needs to be done on the topic, these preliminary results support the hypothesis that DLC1 is a tumor suppressor in melanoma.

A combination of p300 and Braf expression in the diagnosis and prognosis of melanoma.

BACKGROUND: To date only a handful of drugs are available for the treatment of melanoma. Among them vemurafenib, a BrafV600E specific inhibitor, showed promising results in terms of response rate and increase in median survival time. However, its effectiveness is limited by development of resistance and the search for additional drugs for melanoma treatment is ongoing. The present study was performed to analyze the correlation between Braf expression and the expression of p300, a known down stream target of the mitogen activated protein kinase (MAPK) pathway, which was recently shown by us to be a prognostic marker for melanoma progression and patient survival. METHODS: The expression of Braf and p300 expression were correlated and analyzed by Chi-square test. A total of 327 melanoma patient cases (193 primary melanoma and 134 metastatic melanoma) were used for the study. Classification & regression tree (CRT), Kaplan-Meier, and multivariate Cox regression analysis were used to elucidate the significance of the combination of Braf and p300 expression in the diagnosis and prognosis of melanoma. RESULTS: Our results demonstrate that Braf expression is inversely correlated with nuclear p300 and positively correlated with cytoplasmic p300 expression. Braf and cytoplasmic p300 were found to be associated with melanoma progression, tumor size and ulceration status. CRT analysis revealed that a combination of Braf and p300 expression (nuclear and cytoplasmic), could be used to distinguish between nevi and melanoma, and primary from metastatic melanoma lesions. The combination of Braf and nuclear p300 was significantly associated with patient survival and nuclear p300 was found to be an independent predictor of patient survival. CONCLUSION: Our results indicate a cross-talk between Braf and p300 in melanoma and demonstrate the importance Braf and p300 expression in the diagnosis and prognosis of melanoma.

The significance of Melan-A-positive pagetoid melanocytosis in dysplastic nevi.

Dysplastic nevi may occasionally display alarming histological features. One of these features is the presence of upward spread of melanocytes (pagetoid melanocytosis), identified either on routine histologic sections or after immunohistochemistry using one of the melanocytic markers. Forty-three cases of dysplastic nevi with mild to moderate atypia were selected and retrieved, and Melan-A staining was performed. Melan-A-positive cells with pagetoid architecture were present in 27 cases (63%). Of these, only 5 cases demonstrated pagetoid architecture on routine staining. It is concluded that Melan-A staining should be used only with caution as an adjunct to routine histology in the evaluation of dysplastic nevi with mild to moderate atypia because the identification of pagetoid melanocytosis using this technique has the potential to lead to an erroneous diagnosis of melanoma.

JWA inhibits melanoma angiogenesis by suppressing ILK signaling and is an independent prognostic biomarker for melanoma.

Melanoma is the deadliest cutaneous malignancy because of its high incidence of metastasis. Melanoma growth and metastasis relies on sustained angiogenesis; therefore, inhibiting angiogenesis is a promising approach to treat metastatic melanoma. JWA is a novel microtubule-associated protein and our previous work revealed that JWA inhibited melanoma cell invasion and metastasis. However, the role of JWA in melanoma angiogenesis and the prognostic value are still unknown. Here, we report that JWA in melanoma cells significantly inhibited the tube formation of endothelial cells. In addition, JWA regulated integrin-linked kinase (ILK) through integrin αVß3 and such regulation was achieved through the transcription factor Sp1. Notably, both in vitro and in vivo angiogenesis assays revealed that JWA dramatically suppressed melanoma angiogenesis by inhibiting ILK signaling. Furthermore, we examined the expression of JWA protein in a large set of melanocytic lesions (n = 505) at different stages by tissue microarray and found an inverse correlation between JWA expression and melanoma progression (P = 5 × 10(-6)). Importantly, reduced JWA expression was correlated with a poorer overall, and disease-specific 5 year survival of patients (P = 0.001 and 0.007, respectively). Multivariate Cox regression analyses indicated that JWA was an independent prognostic marker for melanoma patients. Moreover, we found a significant negative correlation between JWA and ILK in melanoma biopsies, and their concomitant expression was closely correlated with melanoma patient survival (P = 0.004), further indicating the regulation of ILK expression by JWA is critical in melanoma. Taken together, our data highlight the function of JWA in melanoma angiogenesis and reveal the clinical prognostic value of JWA.

Expression of the RNase III enzyme DROSHA is reduced during progression of human cutaneous melanoma.

Aberrant expression of microRNAs (miRNAs) and their biogenesis factors has been frequently observed in different types of cancer. We recently reported that expression of DICER1 is reduced in metastatic melanoma. Nevertheless, so far very little is known about the expression pattern of other miRNA biogenesis factors in this type of malignancy. Here, we investigated the expression pattern of DROSHA in a large set of melanocytic lesions (n=409) by tissue microarray and immunohistochemistry. We found that nuclear expression of DROSHA is markedly reduced in the early stages of melanoma progression (P=0.0001) and is inversely correlated with melanoma thickness (P=0.0001), AJCC stages (P=0.0001), and ulceration status (P=0.002). We also confirmed the reduced expression of nuclear DROSHA by a second specific antibody raised against a different region of the DROSHA protein. In addition, we observed that the reduced nuclear expression of DROSHA during melanoma progression is accompanied by an increased cytoplasmic expression of this protein (P=0.0001). Finally, we found that expression pattern of DROSHA varies from that of DICER1 and concomitant loss of expression of both DICER1 and DROSHA confers the worse outcome for melanoma patients. Our results demonstrate a reduced nuclear expression of DROSHA, which further highlights a perturbed miRNA biogenesis pathway in melanoma. In addition, the aberrant subcellular localization of DROSHA indicates possible deregulation in the mechanisms responsible for its proper localization in the nucleus.

Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells.

Studies in mice have shown that proinflammatory Th17 cells can cause acute graft-versus-host disease (aGVHD) related tissue damage; however, whether they play a role in human aGVHD remains unclear. In a prospective study, we measured the proportion of Th17 cells in the blood and skin of patients at the onset of aGVHD. We found no difference in the proportion or amount of IL-17 produced by T cells in the blood of patients with aGVHD (n = 20) compared with time-matched patients without GVHD (n = 14). Moreover, Th17 cells were not increased in the skin of patients with cutaneous aGVHD (n = 7) compared with healthy controls (n = 10). In contrast, we found significantly more interferon-γ-producing T cells in the skin of patients with aGVHD compared with controls. These data support the long-standing paradigm that tissue localized interferon-γ-producing cells are the perpetrators of aGVHD.

Prognostic significance of RUNX3 expression in human melanoma.

BACKGROUND: RUNX3 is a tumor suppressor that plays important roles in cell proliferation, apoptosis, and metastasis. The authors investigated the role of RUNX3 in melanoma pathogenesis and analyzed the prognostic impact of RUNX3 expression in a large series of melanoma patients. METHODS: Two sets of tissue microarrays were constructed, including 440 cases of melanomas (202 for the training set and 238 for the validation set) and 88 cases of nevi (25 normal nevi and 63 dysplastic nevi). RUNX3 expression was evaluated by immunohistochemistry. RESULTS: Positive RUNX3 expression was observed in 56%, 54%, 33%, and 24% of the biopsies in normal nevi, dysplastic nevi, primary melanoma, and melanoma metastases, respectively. Significant differences for positive nuclear RUNX3 staining were observed between dysplastic nevi and primary melanomas (P = .002, chi-square test), between dysplastic nevi and melanoma metastases (P < .001, chi-square test), and between primary melanoma and melanoma metastases (P = .045, chi-square test). Loss of RUNX3 expression was correlated with a worse 5-year survival of melanoma patients in both training and validation sets. Furthermore, loss of RUNX3 expression was also correlated with a poor 5-year disease-specific survival in primary melanoma (P = .001) and metastatic melanoma patients (P = .008). Multivariate Cox regression analysis revealed that positive RUNX3 expression is an independent prognostic factor to predict melanoma patient outcome. CONCLUSIONS: Our findings indicate that RUNX3 plays an important role in melanoma pathogenesis and may serve as a promising prognostic marker for melanoma.

Prognostic significance of Sox4 expression in human cutaneous melanoma and its role in cell migration and invasion.

The Sox4 transcription factor is involved in various cellular processes, such as embryonic development and differentiation. Deregulated expression of Sox4 in several human cancers has been reported to date, but its role in melanoma is unknown. We explored the role of Sox4 in melanoma pathogenesis in vivo and in vitro. Using tissue microarray, we evaluated Sox4 expression in 180 melanocytic lesions and investigated its role in melanoma cell migration and invasion. Sox4 expression was remarkably reduced in metastatic melanoma compared with dysplastic nevi (P < 0.05) and primary melanoma (P < 0.01). This reduction was correlated with a poorer disease-specific survival of melanoma patients (P = 0.039). Multivariate Cox regression analysis revealed that reduced Sox4 expression is an independent prognostic factor (P = 0.049). Knockdown of Sox4 enhanced melanoma cell invasion, migration, and stress fiber formation. The increased migration and invasion on Sox4 knockdown depends on the presence of nuclear factor (NF)-κB p50 and is abrogated when p50 is knocked down. We further observed inhibition of NF-κB p50 transcription by Sox4, in addition to a reverse pattern of expression of Sox4 and NF-κB p50 in different stages of melanocytic lesions. Our results suggest that Sox4 regulates melanoma cell migration and invasion in an NF-κB p50-dependent manner and may serve as a prognostic marker and potential therapeutic target for human melanoma.

Immunohistochemistry analysis reveals lysyl oxidase-like 3 as a novel prognostic marker for primary melanoma.

Lysyl oxidase-like 3 (LOXL3) is an extracellular enzyme involved in the synthesis of collagen and elastin, and it has been reported to promote melanoma cell proliferation and invasion in vitro. However, the expression level of LOXL3 at different stages of melanocytic lesions and the role of LOXL3 in melanoma pathogenesis remain unknown. Immunohistochemical staining of LOXL3 in a tissue microarray of 373 biopsies at different melanocytic stages was conducted. The correlation between LOXL3 expression and patient survival was examined using Kaplan-Meier survival analysis. Univariate and multivariate Cox regression analyses were conducted to study the hazard ratios. The tissue microarray study revealed that stronger expression of LOXL3 protein was found at more advanced melanocytic stages (P < 0.0001; χ2 test). Increased LOXL3 expression was associated with enhanced tumor thickness and mitosis. Survival analysis showed significantly worsened prognosis in primary melanoma patients when the LOXL3 expression level was higher (P = 0.043; log-rank test). Multivariate Cox regression analysis further showed that LOXL3 expression is a prognostic factor for primary melanoma patient survival (P = 0.04). LOXL3 expression is positively correlated with tumor progression and invasion, and its overexpression is associated with worse prognosis of primary melanoma patients. LOXL3 can serve as a prognostic marker to help identify primary melanoma patients at higher risks of death.

Role of ING4 in human melanoma cell migration, invasion and patient survival.

Inhibitor of growth (ING) 4 has been reported as a tumor suppressor and shown to diminish colony-forming efficiency, induce p53-dependent apoptosis and arrest cell cycle at G(2)-M phase. In this study, we investigated the role of ING4 in human melanoma pathogenesis. Using the tissue microarray technology, we found that ING4 expression is significantly decreased in malignant melanoma compared with dysplastic nevi (P < 0.0001, chi(2) test) and reduced ING4 staining is associated with melanoma thickness, ulceration (P = 0.034 and 0.002, respectively, chi(2) test) as well as poor overall and disease-specific 5-year survival of primary melanoma patients (P = 0.0002 and 0.001, respectively, chi(2) test). Cox regression analysis revealed that reduced ING4 staining is an independent factor for the poor prognosis of patients with primary melanomas. Furthermore, we found that overexpression of ING4 suppressed cell migration by 63% and inhibited the activity of Ras homolog gene family member A (RhoA) small GTPase protein and Rho-associated kinase (ROCK)-mediated formation of stress fiber in melanoma cells. Moreover, our data showed that overexpression of ING4 inhibited melanoma cell invasion by 43% compared with the control (P = 0.006, t-test) and ING4-overexpressing melanoma cells showed significantly reduced activity of matrix metalloproteinase (MMP)-2 and MMP-9. Taken together, this study highlights the importance of ING4 in melanoma pathogenesis and ING4 may serve as a promising prognostic marker and a potential therapeutic target for human melanoma.

Myeloid leukemia-1 expression in benign and malignant melanocytic lesions.

Myeloid leukemia-1 (Mcl-1) is an anti-apoptotic protein implicated in tumor progression. Its expression was found to be elevated in many types of human cancers and is correlated with tumor progression. The expression of Mcl-1 in melanoma is not fully understood. We investigated the expression of Mcl-1 in normal nevi, dysplastic nevi, primary melanoma and melanoma metastases by tissue microarray and immunohistochemistry. We found that Mcl-1 expression was significantly increased in dysplastic nevi, primary melanoma and melanoma metastases when compared to normal nevi, though the expression of Mcl-1 was decreased in metastatic melanoma when compared to dysplastic nevi. We did not find any correlation between Mcl-1 expression and melanoma patient survival. Our data suggest that Mcl-1 may play a critical role in the initiation of melanoma development.

Prognostic significance of nuclear ING3 expression in human cutaneous melanoma.

PURPOSE: The novel tumor-suppressor ING3 has been shown to modulate transcription, cell cycle control, and apoptosis. Our previous study showed that ING3 promotes UV-induced apoptosis via the Fas/caspase-8-dependent pathway in melanoma cells. To investigate the putative role of ING3 in the development of melanoma, we examined the expression of ING3 in melanocytic lesions at different stages and analyzed the correlation between ING3 expression and clinicopathologic variables and patient survival. EXPERIMENTAL DESIGN: Using tissue microarray and immunohistochemistry, we evaluated nuclear and cytoplasmic ING3 staining in 58 dysplastic nevi, 114 primary melanomas, and 50 metastatic melanomas. RESULTS: Nuclear ING3 expression was remarkably reduced in malignant melanomas compared with dysplastic nevi (P<0.001), which was significantly correlated with the increased ING3 level in cytoplasm (P<0.05). Furthermore, the reduced nuclear ING3 expression was significantly correlated with a poorer disease-specific 5-year survival of patients with primary melanoma, especially for the high-risk melanomas (thickness >or=2.0 mm) with the survival rate reducing from 93% for patients with strong nuclear ING3 staining in their tumor biopsies to 44% for those with negative-to-moderate nuclear ING3 staining (P=0.004). Strikingly, our multivariate Cox regression analysis revealed that reduced nuclear ING3 expression is an independent prognostic factor to predict patient outcome in primary melanomas (P=0.038). CONCLUSIONS: Our data indicate that ING3 may be an important marker for human melanoma progression and prognosis as well as a potential therapeutic target.

Cytoplasmic Pin1 expression is increased in human cutaneous melanoma and predicts poor prognosis.

The prolyl isomerase Pin1 is widely over-expressed or over-activated in cancers and promotes tumorigenesis. The authors investigated the expression level of Pin1 and analyzed the prognostic value of Pin1 expression using a large-scale melanoma tissue microarray study. Two independent sets of tissue microarrays were employed, including 114 melanoma cases in the discovery set and 424 in the validation set (538 cases in total), 32 normal nevi and 86 dysplastic nevi 118 cases of nevi. The subcellular Pin1 expression in different stages of melanocytic lesions and its prognostic significance were studied. High expression (IRS 0-8) of cytoplasmic Pin1 was observed in 3.13%, 8.33%, 16.49% and 22.76% of the biopsies in normal nevi, dysplastic nevi, primary melanoma and metastatic melanoma, respectively. Significant differences for cytoplasmic Pin1 staining were observed between normal nevi and metastatic melanoma (P = 0.011, χ2 test), between dysplastic nevi and primary melanoma (P = 0.046, χ2 test) and between dysplastic nevi and metastatic melanoma (P = 0.016, χ2 test). Kaplan-Meier survival analysis showed that increased cytoplasmic Pin1 expression was associated with a worse 5-year melanoma-specific survival of melanoma (P < 0.001) and metastatic melanoma patients (P = 0.004). Multivariate Cox regression analysis showed that cytoplasmic Pin1 expression is an independent prognostic factor in melanoma. Our data indicate that cytoplasmic Pin1 plays an important role in melanoma pathogenesis and progression, and serve as a potential prognostic marker for melanoma.

Treatment of atypical nevi with imiquimod 5% cream.

BACKGROUND: 5% Imiquimod cream is a topical immune response modifier that has been used off-label to treat malignant melanocytic proliferations such as lentigo maligna. To our knowledge, imiquimod has not been previously used to treat atypical nevi (AN). OBSERVATIONS: Three patients each with 1 selected clinically AN were treated with imiquimod 5 nights per week for 12 weeks. The lesions were subsequently excised and sent for routine histologic and immunohistochemical analysis. None of the lesions cleared. Two were consistent with atypical compound nevus on excisional biopsy and demonstrated inflammation, while the third showed congenital features and demonstrated minimal inflammation. The AN were initially interpreted as displaying more severe histologic atypia on excisional biopsy than was present at baseline. Immunohistochemical studies revealed that the AN but not the congenital-like nevus exhibited increased staining for CD4(+) and CD8(+) cells and for a surrogate marker of interferon alpha expression. CONCLUSIONS: Twelve weeks of imiquimod treatment failed to cause lesional resolution. A differential inflammatory response was observed between the AN and the congenital-like nevus. The character of the inflammatory infiltrate was similar to that observed with halo nevi. Uncertainties remain concerning imiquimod use for chemoprevention of AN, and the posttreatment histologic features may be misinterpreted as severe melanocytic atypia or melanoma.

Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients with rheumatologic conditions.

BACKGROUND: New onset or worsening of psoriasis has been reported in patients treated with tumor necrosis factor alpha (TNF-alpha) inhibitors for a variety of rheumatologic conditions. There is mounting evidence that a key innate immune pathway for triggering common human autoimmune disease, including psoriasis, involves plasmacytoid dendritic cell precursors (PDCs) and type 1 interferon (IFN) production. We present herein a case series with clinical and histopathologic evidence of psoriasis in patients with rheumatologic disease treated with TNF-alpha inhibitors. We propose that the cross regulation between TNF-alpha and IFN may have a role in the pathogenesis of this reaction. OBSERVATIONS: We observed new-onset psoriasis (n = 13) or severe exacerbation of psoriasis (n = 2) in 15 patients with a variety of rheumatologic conditions-rheumatoid arthritis (n = 13), psoriatic arthritis (n = 1), and seronegative arthritis (n = 1)-during treatment with etanercept (n = 6), infliximab (n = 5), and adalimumab (n = 4). Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (MxA, a surrogate marker for lesional type 1 IFN activity) showed increased staining in TNF-alpha inhibitor-induced psoriasis compared with psoriasis vulgaris. CONCLUSIONS: New onset or severe exacerbation of psoriasis is a rare complication of TNF-alpha inhibitor therapy. The finding of increased production of IFN-alpha in TNF-alpha inhibitor-induced psoriasis is a possible pathophysiologic explanation for this reaction.