Soluble adenylyl cyclase contributes to imiquimod-mediated inflammation and is a potential therapeutic target in psoriasis.

Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question. Adcy10-/- mice had reduced erythema, scaling and swelling in the skin and reduced CD4+ IL17+ cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. Keratinocyte-specific knock out of Adcy10 had no effect on imiquimod-induced ear swelling suggesting keratinocyte sAC has no role in imiquimod-induced inflammation. During Th17 polarization in vitro, naive T cells from Adcy10-/- mice exhibited reduced IL17 secretion and IL-17+ T-cell proliferation suggesting that differentiation into Th17 cells is suppressed without sAC activity. Interestingly, loss of sAC did not impact the expression of Th17 lineage-defining transcription factors (such as Rorc and cMaf) but rather was required for CREB-dependent gene expression, which is known to support Th17 cell gene expression. Finally, topical application of small molecule sAC inhibitors (sACi) reduced imiquimod-induced psoriasiform dermatitis and Il17 gene expression in the skin. Collectively, these findings demonstrate that sAC is important for psoriasiform dermatitis in mouse skin. sACi may provide an alternative class of topical therapeutics for Th17-mediated skin diseases.

Ethical and professionalism issues in dermatopathology: A cross-sectional survey of American Society of Dermatopathology Members.

BACKGROUND: Data regarding ethical/professional issues affecting dermatopathologists are lacking despite their importance in establishing policy priorities and educational content for dermatopathology. METHODS: A 14-item cross-sectional survey about ethical/professional issues in dermatopathology was distributed over e-mail to members of the American Society of Dermatopathology from June to September 2019. RESULTS: Two hundred sixteen surveys were completed, with a response rate of 15.3%. Respondents ranked appropriate and fair utilization of healthcare resources (n = 83 or 38.6%) as the most often encountered ethical/professional issue. Conflict of interest was ranked as the most urgent or important ethical/professional issue (n = 83 or 39.3%). One hundred thirty-three (61.6%) respondents felt "somewhat" or "not at all" well equipped to handle ethical dilemmas in practice and 47 (22.8%) respondents identified a major or extreme burden (eg, have considered resigning/retiring) due to ethical challenges. CONCLUSIONS: Areas of priority in ethics and professionalism issues can guide future policy and educational content in dermatopathology.

Investigating the histopathological findings and immunolocalization of rickettsialpox infection in skin biopsies: A case series and review of the literature.

BACKGROUND: Recognition of rickettsialpox infection on skin biopsy can be challenging. The histopathology is non-specific and inconsistently described. We assess classic histopathologic features in confirmed cases and review the literature. METHODS: We searched for cases of "rickettsialpox" diagnosed between 2006 and 2018 with positive immunostaining for Spotted Fever Group Rickettsia species. Original slides were evaluated for vacuolar alterations, granulomatous inflammation, vasculitis, necrosis, fibrin thrombi, microvesiculation, papillary dermal edema, and extravasated red blood cells. All biopsies were stained for CD3, CD20, CD68, and myeloperoxidase. RESULTS: Six biopsy specimens were compiled, three of which were sampled from vesiculopapules, one from a maculopapule, and two from eschars. Vacuolar alterations and vasculitis were present in all specimens (6/6; 100%). Granulomatous inflammation was present in five specimens (5/6; 83.3%). Fibrin thrombi and red blood cells were seen in 3/6 (50%) of specimens. The eschars showed necrosis of the epidermis and superficial dermis (2/6, 33.3%). Only one specimen showed intraepidermal vesiculation and papillary dermal edema (1/6; 16.7%). All six specimens showed perivascular infiltration with CD3+ T-cells, and low amounts of CD20+ B-cells and neutrophils. Five of the six specimens (83.3%) showed significant levels of CD68+ histiocytes. CONCLUSION: The histopathology of rickettsialpox infection is septic lymphocytic and granulomatous vasculitis.

Lichen Myxedematosus: Case Report and Review of Literature.

Lichen myxedematosus (LM) is an idiopathic cutaneous mucinosis, commonly described as localized scleromyxedema. In contrast to scleromyxedema, there is typically no systemic involvement. Treatment options are limited and spontaneous resolution has been reported. We present the case of a 66-year-old Hispanic male referred by his primary care physician for evaluation of asymptomatic dark spots on his trunk and extremities present for about one-year. Physical exam revealed smooth, brown hyperpigmented papules coalescing into plaques on the trunk. Multiple well-demarcated oval dark brown plaques measuring 3 cm in size were located on the upper back, peri-umbilical area, bilateral lower extremities, and buttocks. A diagnosis of lichen myxedematosus was made based on histologic features observed in the dermis. There are 5 subtypes of LM: a discrete papular form, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and a pure nodular form. Occasional patients with LM have atypical features or features intermediate between scleromyxedema and localized LM. We present a case of atypical LM with mixed features of the different subtypes. Herein we will review the varied clinical presentations of LM and highlight the distinguishing features of scleromyxedema. J Drugs Dermatol. 2020;19(3): 320-322 doi:10.36849/JDD.2020.4864.

Distinguishing pustular psoriasis and acute generalized exanthematous pustulosis on the basis of plasmacytoid dendritic cells and MxA protein.

BACKGROUND: Distinguishing acute generalized exanthematous pustulosis (AGEP) and pustular psoriasis (PS) can be challenging. Staining for plasmacytoid dendritic cells, or PDCs (producer of IFN-α/ß), and MxA (an IFN-α/ß inducible protein) may help discriminate these entities. METHODS: Forty-three cases of AGEP and PS were compiled from two academic institutions. All cases were examined for CD123+ PDCs, eosinophils, acanthosis, papillomatosis, suprapapillary plate thinning, tortuous dilated capillaries, single necrotic keratinocytes, papillary dermal edema, vasculitis, eosinophil exocytosis, intraepidermal pustules, and subcorneal pustules. A subset of cases (n = 26) was stained for MxA. RESULTS: Perivascular and intraepidermal PDCs, dilated tortuous vessels, and MxA expression in the dermal inflammatory infiltrate were significantly (P < 0.05) in favor of a diagnosis of PS. The absence of PDCs and presence of eosinophils favored a diagnosis of AGEP (P < 0.05). CONCLUSIONS: We found compelling evidence for the use of CD123 to highlight PDCs in these cases. The presence of PDCs and expression of MxA in dermal inflammatory infiltrate, as well as absence of eosinophils and presence of tortuous dilated capillaries favored a diagnosis of PS. Expression of MxA in the dermal infiltrate corresponds with a Th1 pathway in PS and may indicate a Th1 component in the early initial phase of AGEP.

Histological findings and pathologic diagnosis of spiradenocarcinoma: A case series and review of the literature.

BACKGROUND: Atypical spiradenoma and spiradenocarcinoma present a diagnostic challenge. We aim to assess the significance of certain histologic features, which may facilitate diagnosis of these tumors. METHODS: A natural language search for cases of "atypical spiradenoma" and "spiradenocarcinoma" diagnosed between 2009 and 2018 was performed. Original slides were retrieved and a subset of cases (n = 5) were stained for Ki-67, p53, carcinoembryonic antigen (CEA), and S100. All cases (n = 7) were assessed for overall architecture, atypical mitotic figures, abnormal cytology, necrosis, ductal proliferation, dilated vessels, and loss of dual cell population. RESULTS: All our cases showed an abrupt transition from benign to malignant morphology, nuclear atypia, atypical mitotic figures, and a monomorphic loss of the dual cell population (7/7; 100%). The majority also had dilated vessels (6/7; 85.7%), and ductal dilation or proliferation (5/7; 71.4%). Fewer cases showed tumor encapsulation (3/7; 43%), massive necrosis (3/7; 43%), and focal cellular necrosis (1/7; 14%). All cases showed a relatively increased Ki-67 proliferation index at the transitional interface (5/5; 100%). Almost all cases stained positively for p53 (4/5; 80%). Malignant areas of tumor or at the transitional interface showed more intense S100 staining (3/5; 60%). All cases were negative for CEA. CONCLUSION: Histologic features that strongly favor atypical spiradenoma or spiradenocarcinoma include abrupt transition to malignant foci, atypical mitotic figures, and monomorphic loss of the dual cell population. Ki-67, p53, and S100 may help delineate areas of atypical or malignant transformation in spiradenomas.

Observational Study Examining the Diagnostic Practice of Ki67 Staining for Melanocytic Lesions.

BACKGROUND: Dermatopathologists routinely use Ki67 immunostaining to assess atypical melanocytic lesions with a dermal component to determine whether an ambiguous tumor is melanoma. However, there is no universal standard of use for Ki67 in melanocytic neoplasms. We sought to observe the real-world use of Ki67 in the diagnosis of melanocytic lesions and establish a best practice recommendation. METHODS: We searched dermatopathology reports from 2 academic practices for melanocytic lesions in which Ki67 staining was used for diagnosis. The proliferation rate was compared between cases diagnosed as benign (not requiring re-excision), moderate to severely dysplastic or atypical Spitz nevi (requiring re-excision), and malignant melanoma. The use of other melanocytic markers and consensus review was also recorded and compared between institutions. RESULTS: Pathology reports for 106 cases were reviewed. A high Ki67 proliferation rate (n = 18) favored a diagnosis of melanoma or nevi requiring re-excision (15/18, 83.3%) versus a benign nevus (3/18, 16.67%). A high Ki67 rate was 71.4%-90.9% sensitive and 40%-56% specific for the diagnosis of nevus requiring re-excision or melanoma. Institutional practices differed in regard to reporting of Ki67 staining, the use of multiple markers in the workup of atypical melanocytic lesions (HMB45, Melan-A, Ki67 being most common), and consensus review. CONCLUSIONS: A negative or low Ki67 proliferation rate correlates well with rendering of a benign diagnosis. However, a low proliferation rate does not preclude the diagnosis of melanoma. Ki67 staining is most commonly used as an ancillary test to support a diagnosis after other factors have been considered, such as histopathologic morphology and results of additional concurrently used stains.

Congenital Ichthyosiform Erythroderma Superimposed with Chronic Dermatophytosis: A Report of Three Siblings.

Congenital ichthyosiform erythroderma is an autosomal recessive ichthyosis characterized by severe scaling and erythroderma. We report a family of three siblings who were all born with a collodion membrane and presented with diffuse scaling and pruritus. All three children subsequently developed chronic cutaneous dermatophyte infections requiring oral antifungals. One child developed superinfection with methicillin-resistant Staphylococcus aureus requiring antibiotics.

Role of histological findings and pathologic diagnosis for detection of human papillomavirus infection in men.

Early HPV infection in males is difficult to detect clinically and pathologically. This study assessed histopathology in diagnosing male genital HPV. External genital lesions (n = 352) were biopsied, diagnosed by a dermatopathologist, and HPV genotyped. A subset (n = 167) was diagnosed independently by a second dermatopathologist and also re-evaluated in detail, tabulating the presence of a set of histopathologic characteristics related to HPV infection. Cases that received discrepant diagnoses or HPV-related diagnoses were evaluated by a third dermatopathologist (n = 163). Across dermatopathologists, three-way concordance was fair (k = 0.30). Pairwise concordance for condyloma was fair to good (k = 0.30-0.67) and poor to moderate for penile intraepithelial neoplasia (k = -0.05 to 0.42). Diagnoses were 44-47% sensitive and 65-72% specific for HPV 6/11-containing lesions, and 20-37% sensitive and 98-99% specific for HPV 16/18. Presence of HPV 6/11 was 75-79% sensitive and 35% specific for predicting pathologic diagnosis of condyloma. For diagnosis of penile intraepithelial neoplasia, HPV 16/18 was 95-96% specific but only 40-64% sensitive. Rounded papillomatosis, hypergranulosis, and dilated vessels were significantly (P < 0.05) associated with HPV 6/11. Dysplasia was significantly (P = 0.001) associated with HPV 16/18. Dermatopathologists' diagnoses of early male genital HPV-related lesions appear discordant with low sensitivity, while genotyping may overestimate clinically significant HPV-related disease. Rounded papillomatosis, hypergranulosis, and dilated vessels may help establish diagnosis of early condyloma.

B7-H3 drives immunosuppression and Co-targeting with CD47 is a new therapeutic strategy in ß-catenin activated melanomas.

In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T-cell non-inflamed tumors (cold tumors) are associated with tumor cell-intrinsic Wnt/ß-catenin activation, and are typically resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the 'cold tumor' phenotype and identifying new effective immunotherapies are challenges. We sought to investigate the role of a newer immunotherapy agent, B7-H3, in this setting. RNA sequencing was used to identify co-targeting strategies upon B7-H3 inhibition in a well-defined preclinical melanoma model driven by ß-catenin. We found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and innate immunity. B7-H3 inhibition led to an inflamed microenvironment, up-regulation of CD47/SIRPa signaling, and together with blockade of the macrophage checkpoint CD47 resulted in additive antitumor responses. We found that the antitumor effects of the B7-H3/CD47 antibody combination were dependent on cytokine signaling pathways (CCR5/CCL5 and IL4).

MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping.

MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic T cells, characteristics consistent with a compromised anti-tumour response. Single cell and spatial transcriptomics identify increased dedifferentiation along the neural crest lineage of the tumour compartment and increased frequency and activation of cancer-associated fibroblasts following macroH2A loss. Mechanistically, macroH2A-deficient cancer-associated fibroblasts display increased myeloid chemoattractant activity as a consequence of hyperinducible expression of inflammatory genes, which is enforced by increased chromatin looping of their promoters to enhancers that gain H3K27ac. In summary, we reveal a tumour suppressive role for macroH2A variants through the regulation of chromatin architecture in the tumour stroma with potential implications for human melanoma.

Unilateral Verrucous Psoriasis.

Verrucous psoriasis is a variant of psoriasis that presents with wartlike clinical features and overlapping histologic features of verruca and psoriasis. The disease typically arises in patients with established psoriasis but can occur de novo. We report the case of an 80-year-old man with a history of hypertension and coronary artery disease who presented with a rash characterized by multiple asymptomatic plaques with overlying verrucous nodules on the left side of the body. The lesions appeared shortly after coronary artery bypass surgery with a saphenous vein graft.

Comparing whole slide digital images versus traditional glass slides in the detection of common microscopic features seen in dermatitis.

BACKGROUND: The quality and limitations of digital slides are not fully known. We aimed to estimate intrapathologist discrepancy in detecting specific microscopic features on glass slides and digital slides created by scanning at ×20. METHODS: Hematoxylin and eosin and periodic acid-Schiff glass slides were digitized using the Mirax Scan (Carl Zeiss Inc., Germany). Six pathologists assessed 50-71 digital slides. We recorded objective magnification, total time, and detection of the following: Mast cells; eosinophils; plasma cells; pigmented macrophages; melanin in the epidermis; fungal bodies; neutrophils; civatte bodies; parakeratosis; and sebocytes. This process was repeated using the corresponding glass slides after 3 weeks. The diagnosis was not required. RESULTS: The mean time to assess digital slides was 176.77 s and 137.61 s for glass slides (P < 0.001, 99% confidence interval [CI]). The mean objective magnification used to detect features using digital slides was 18.28 and 14.07 for glass slides (P < 0.001, 99.99% CI). Parakeratosis, civatte bodies, pigmented macrophages, melanin in the epidermis, mast cells, eosinophils, plasma cells, and neutrophils, were identified at lower objectives on glass slides (P = 0.023-0.001, 95% CI). Average intraobserver concordance ranged from κ = 0.30 to κ = 0.78. Features with poor to fair average concordance were: Melanin in the epidermis (κ = 0.15-0.58); plasma cells (κ = 0.15-0.49); and neutrophils (κ = 0.12-0.48). Features with moderate average intrapathologist concordance were: parakeratosis (κ = 0.21-0.61); civatte bodies (κ = 0.21-0.71); pigment-laden macrophages (κ = 0.34-0.66); mast cells (κ = 0.29-0.78); and eosinophils (κ = 0.31-0.79). The average intrapathologist concordance was good for sebocytes (κ = 0.51-1.00) and fungal bodies (κ = 0.47-0.76). CONCLUSIONS: Telepathology using digital slides scanned at ×20 is sufficient for detection of histopathologic features routinely encountered in dermatitis cases, though less efficient than glass slides.

Autologous, Noncultured Epidermal Cell Suspension Grafting in the Management of Mechanically and Chemically Induced Leukodermic Scars.

BACKGROUND: Melanocyte-keratinocyte transplant procedure (MKTP) successfully repigments postburn leukodermic scars. OBJECTIVE: To further investigate the efficacy and limitations of MKTP for treatment of mechanically and chemically induced leukodermic scars. METHODS: Ten patients with mechanically or chemically induced, depigmented or hypopigmented scars were preoperatively evaluated with Wood's light examination, treated with MKTP, and followed for at least 6 months, with monitoring of repigmentation and colour matching. RESULTS: Nine patients attended at least 6 months of follow-up. Six patients showed no fluorescence of scars under Wood's lamp. All patients whose lesions didn't fluoresce displayed less than 50% repigmentation, with 5 of 6 attaining 0% to 24%. Of the 3 patients displaying bright or some fluorescence, more than 95% repigmentation was achieved in 2 patients (skin phototypes V and VI), while less than 24% was attained for the third (skin phototype II). CONCLUSIONS: In this small case series, lack of fluorescence in leukodermic scars may be a useful negative prognostic indicator for MKTP, but additional trials are needed to verify that this is not due to melanocompetency.

Sodium thiosulfate in the treatment of calciphylaxis.

The authors review the presentation, diagnosis, and treatment of calciphylaxis and also describe applications of a novel therapeutic option, sodium thiosulfate. Two cases of advanced uremic calciphylaxis from both clinic and hospital settings are presented. One patient, a 57-year-old woman with end-stage renal disease, was treated with surgical debridement and sodium thiosulfate 25g three times a week. After introducing sodium thiosulfate treatment, the affected sites continue to heal with encouraging improvement of ulcer depth. Sodium thiosulfate was well-tolerated and facilitated wound healing. The patient did not develop sepsis. Sodium thiosulfate appears to be a viable first-line treatment for calciphylaxis and should be seriously considered early in the course of treatment.