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Competing Interests: The authors declare no conflicts of interest.

Vulvovaginal melanoma (VVM) is a rare but deadly disease, accounting for 5% of all vulvar malignancies, with a 5-yr survival rate of only 47% for all stages of the disease. VVM is a distinct subset of melanoma, with a unique genomic profile and underlying pathogenesis unassociated with sun exposure. Distinguishing these rare malignancies from very common pigmented lesions of the vulva and vagina is challenging as histologic features often overlap between entities. PReferentially expressed Antigen in MElanoma (PRAME) is a melanoma-associated protein, and immunohistochemistry (IHC) for PRAME distinguishes cutaneous, oral mucosal, and retinal melanoma from atypical nevi. Given the biological differences between VVM and cutaneous melanoma, the utility of PRAME IHC for the diagnosis of VVM is unknown. We accrued a cohort of 20 VVM and 21 benign vulvar melanocytic nevi. We found that nuclear PRAME IHC staining with 4+ intensity was present in 85% of the VVM and 0% of the nevi. With the assistance of PRAME IHC, we found evidence of close or positive margin involvement in 3 of 10 cases where margins were originally diagnosed as negative for melanoma in situ. Our study is the first to assess PRAME IHC in a cohort of VVM cases and provides confidence for using PRAME IHC to assist with diagnosis and margin assessment in this rare disease., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization in vitro revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity., Competing Interests: DG is a co-founder and serves as a Chief Scientific Officer and consultant for viDA Therapeutics, Inc. However, no viDA products or reagents were used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Richardson, Aubert, Turner, Nabai, Hiroyasu, Pawluk, Cederberg, Zhao, Jung, Burleigh, Crawford and Granville.)

Background: Psoralen + ultraviolet-A (PUVA) is associated with photocarcinogenesis. However, carcinogenic risk with other ultraviolet phototherapies remains unclear., Objective: Evaluate whether phototherapy without psoralens increases skin cancer risk., Methods: Retrospective cohort study of patients treated at a teaching-hospital phototherapy center (1977-2018). Skin cancer records were validated against pathology reports. Age-standardized incidence rates (ASIRs) of skin cancer were evaluated for gender, skin phototype, diagnosis, ultraviolet modality, anatomical site; and compared to provincial population incidence rates (2003)., Results: In total, 3506 patients treated with broadband-ultraviolet-B, narrowband-UVB and/or combined UVAB were assessed with a mean follow-up of 7.3 years. Majority of patients had psoriasis (60.9%) or eczema (26.4%). Median number of treatments was 43 (1-3598). Overall, 170 skin cancers (17 melanoma, 33 squamous cell carcinoma and 120 basal cell carcinoma) occurred in 79 patients. Patient-based and tumor-based ASIR of skin cancer was 149 (95% CI: 112-187)/100,000 and 264 (219-309)/100,000 person-years, respectively. There was no significant difference between tumor-based ASIRs for melanoma, squamous cell carcinoma, and basal cell carcinoma compared to the general population; or in phototherapy patients with-psoriasis or eczema; or immunosuppressants. No cumulative dose-response correlation between UVB and skin cancer was seen., Limitations: Treatment and follow-up duration., Conclusion: No increased risk of melanoma and keratinocyte cancer was found with phototherapy., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Abstract: The human progenitor-cell antigen CD34 is expressed in dermal dendritic cells and is lost in several disorders affecting dermal collagen. The loss of CD34 immunohistochemical staining has been demonstrated to be helpful in the histologic diagnosis of morphea, lichen sclerosus, and the classic pattern of granuloma annulare. This study characterized CD34 expression in 2 sclerosing disorders affecting the subcutis: lipodermatosclerosis (LDS) and the sclerodermoid form of chronic graft-versus-host disease (ScGVHD). In addition, we applied CD34 staining to the interstitial pattern of granuloma annulare (IGA), which is a diagnostically challenging entity with subtle amounts of dermal collagen degeneration. Fifteen cases of LDS, 6 cases of ScGVHD, and 4 cases of IGA were identified and stained with CD34. All cases of LDS showed loss of CD34 within subcutaneous septa, and 9 cases (60%) also exhibited full-thickness dermal loss of interstitial staining. All 6 cases of ScGVHD showed varying degrees of CD34 loss within the dermis and/or subcutaneous septa. The normal subcutis showed diffuse septal staining with CD34, with a density equal to that seen in the dermis. CD34 staining was lost in areas of dermal inflammation in half of the IGA cases. We conclude that CD34 staining is a useful ancillary test in disease processes affecting the subcutaneous collagen such as LDS and ScGVHD. Its utility also extends to diagnostically challenging disorders of dermal collagen degeneration such as IGA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Differentiated vulvar intraepithelial neoplasia (dVIN), the precursor lesion to human papillomavirus-independent vulvar squamous cell carcinoma (VSCC), can be difficult to distinguish from vulvar inflammatory dermatoses. Our goal was to determine if p53 could be a useful biomarker for dVIN, by characterizing p53 percentage, intensity and patterns of staining in dVIN and its histological mimics., Methods and Results: We studied p53 immunohistochemical staining patterns in 16 dVIN cases and 46 vulvar non-neoplastic squamous lesions [12 lichen sclerosus (LS); seven lichen simplex chronicus; three lichen planus (LP); six psoriasis; 13 spongiotic dermatitis (SPO); and five candidiasis]. dVIN cases were adjacent to a p16-negative invasive VSCC in resection specimens. All dVIN cases showed null-type or moderate to strong uniform p53 staining in >70% of basal cells, with moderate to strong continuous parabasal staining extending to two-thirds of the epidermis. This was in contrast to weak or weak to moderate patchy p53 staining in the majority of other lesions. Moderate to strong and increased basal p53 staining (≥70%) was also observed in a subset of LS cases (5/12, 42%), LP cases (1/3, 33%), and SPO cases (36%, 4/11); however, in all categories, this was limited to the basal layer, and any staining in the parabasal layers was patchy., Conclusion: Strong and uniform p53 staining of basal cells, extending into the parabasal layers, and a complete absence of staining (null type) is useful in distinguishing dVIN from other mimics in the vulva. p53 staining of lesser intensity or quantity, particularly basal overexpression only, overlaps with that in vulvar inflammatory lesions., (© 2020 John Wiley & Sons Ltd.)

Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

Background: Ki-67 is an immunohistochemical stain used as a nuclear proliferation marker. It is nonspecific, and is expressed in all active phases of the cell cycle. Vulvar vestibular papules in women and pearly penile papules in men are benign fibrous papules on the genitals, are noninfectious, and do not require treatment. However, these lesions can be clinically confused with condylomata acuminata induced by human papillomavirus (HPV), which have medical and social implications., Objective: Because HPV infection is known to induce expression of proliferation markers, we propose that Ki-67 be used to differentiate condylomata acuminata from vulvar vestibular papules or pearly penile papules on pathologic examination., Methods: We reviewed a total of 26 lesions from 18 patients of previously pathologically diagnosed lesions, including condylomata acuminata (11 lesions), vulvar vestibular papules (10 lesions), and pearly penile papules (5 lesions). All slides were stained with Ki-67, reviewed, and categorized as positive or negative for Ki-67 staining by 1 investigator who was unaware of the original diagnosis., Results: Eleven out of 11 cases of condylomata acuminata were identified as positive for Ki-67 staining. Ten out of 10 cases of vulvar vestibular papules were negative for Ki-67. Five out of 5 cases of pearly penile papules were negative for Ki-67., Conclusion: Ki-67 is a reliable marker to pathologically distinguish benign vulvar vestibular papules in women, or pearly penile papules in men, from HPV-induced condylomata acuminata.

Background: Bullous pemphigoid (BP) is the most common subepidermal autoimmune disorder characterized by tense bullae. It is associated with circulating autoantibodies against BP antigen-1 and BP antigen-2. Diagnosis is based upon clinical, histopathologic, and immunopathologic examination. Direct immunofluorescence (DIF) of perilesional skin highlights C3 with or without IgG in a linear pattern along the basement membrane., Objectives: We hypothesized that repeat biopsies may be required for a definitive DIF diagnosis of BP, as initial DIF evaluation may result in a false-negative result., Methods: A retrospective chart review was conducted on 1143 specimens collected for evaluation for BP. Cases from 2 Vancouver Coastal Health Authority laboratories from 2006 to 2016 were reviewed. Results were interpreted as positive, negative, or indeterminate based on pathologic description and specimen quality., Results: After meeting the inclusion criteria, 739 specimens were further evaluated. There were 289 cases of BP in the 10-year period. Five patients (1.73%; 95% confidence interval [CI], 1.50-1.96) required a second biopsy to support a BP diagnosis, and within this group, 1.04% of the 289 (95% CI, 0.811-1.27) were true successive negative-to-positive DIF results., Conclusions: DIF is the most reliable test used to diagnose BP; however, a small percentage of patients will initially have a negative result. False-negative or indeterminate results may be due to specimen sampling from lesional skin or due to a subthreshold quantity of immune complexes in the skin. Repeat biopsy is warranted despite an initial negative DIF if BP is clinically suspected.

In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach.

Background: It has been postulated that periodic acid-Schiff staining of basement membrane can predict direct immunofluorescence patterns seen in epidermolysis bullosa acquisita and bullous pemphigoid. It has also been suggested that the type of inflammatory infiltrate or presence of fraying of basal keratinocytes may differentiate these two conditions., Objective: In this study, we aimed to confirm these observations., Methods: We reviewed 13 cases of direct immunofluorescence-confirmed epidermolysis bullosa acquisita and 19 cases of direct immunofluorescence-confirmed bullous pemphigoid, all with a subepidermal blister in the routinely processed specimen. The gold standard for diagnosis of epidermolysis bullosa acquisita vs bullous pemphigoid was taken to be identification of immune deposits on the dermal side ('floor' for epidermolysis bullosa acquisita) or the epidermal side ('roof' for bullous pemphigoid) of the salt-split direct immunofluorescence specimen. Our tests to distinguish epidermolysis bullosa acquisita from bullous pemphigoid on the routinely processed biopsy included periodic acid-Schiff basement membrane on the blister roof, neutrophilic infiltrate, lack of eosinophilic infiltrate, and absence of keratinocyte fraying., Results: Sensitivity and specificity for each test were as follows: periodic acid-Schiff staining of roof (sensitivity 25%, specificity 95%), neutrophilic infiltrate (sensitivity 54%, specificity 74%), lack of eosinophilic infiltrate (sensitivity 92%, specificity 68%), and absence of keratinocyte fraying (sensitivity 62%, specificity 58%)., Conclusions: Features in the routinely processed biopsy were unable to reliably distinguish between epidermolysis bullosa acquisita and bullous pemphigoid. Direct immunofluorescence on salt-split skin remains the standard for differentiation.

Amelanotic lentigo maligna melanoma represents <2% of melanomas. Diagnosis is delayed owing to the lack of lesion pigmentation and advanced disease at presentation. Excision with appropriate margins is the treatment standard, but the starting point for such margins is often unclear. We describe 2 patients with amelanotic melanoma treated by Mohs micrographic surgery (MMS) that would not have been cleared by wide local excision alone and provide an extensive review of the literature. Both patients presented with histologic diagnoses of malignant melanoma, one with a barely perceptible biopsy site scar on the left infraorbital cheek/lower eyelid (Breslow 1.8 mm) and the second with an amelanotic tumour on the right helix (Breslow 10 mm). Due to location, aggressive histology, amelanotic appearance, and no apparent surrounding skin surface changes, MMS was elected to maximise margin control. For patient 1, invasive and in situ tumour was found at the American Joint Committee on Cancer-recommended margin of 1.5 cm, and the final defect measured 8.5 × 4.8 cm. Patient 2 had a significant invasive and amelanotic lentigo maligna component, resulting in a 9.0 × 6.5-cm defect. MMS allows for immediate histologic feedback on tumour margins of a clinically invisible tumour and thus offers the most definitive treatment.

Background: Cytomegalovirus (CMV) is a highly prevalent herpesvirus that can present with cutaneous disease in immunocompromised individuals. This may reflect systemic involvement, which is associated with significant morbidity and mortality., Objective: To report a case of cutaneous CMV in an immunocompromised patient and to discuss the differential diagnosis of genital ulcers., Methods: A medical chart review was conducted on a patient who presented with a scrotal ulcer after renal transplantation. A review of the literature on cutaneous CMV disease was also completed., Results: Biopsy of the scrotal ulcer revealed classic findings of CMV disease. The patient also developed CMV viremia. Treatment with valganciclovir resolved his scrotal ulcer and viremia., Conclusion: The differential diagnosis for genital ulcers is broad, especially in the immunocompromised patient. Cutaneous CMV disease should be ruled out with biopsy and immunohistochemical examination in immunocompromised patients, as it may reflect systemic involvement and significantly affect patient care., (© The Author(s) 2016.)

Background: The incidence of melanoma is increasing annually in Canada., Objectives: This retrospective study was designed to assess the ability of physicians of different specialties to accurately recognize melanoma., Methods: Pathology reports of biopsies submitted to Vancouver Coastal Health with clinical diagnoses of melanoma were reviewed (January to July 2013). The clinical diagnoses made by dermatologists, general practitioners and family physicians, and all other specialists were correlated with the final histopathologic diagnoses., Results: The dermatologists, general practitioners and family physicians, and all other specialists achieved diagnostic accuracies of 24.75%, 3.52%, and 12.75%, respectively., Conclusions: Although the diagnostic accuracy of dermatologists was significantly better than that the other practitioners, the majority of patients with suspicious skin lesions present to family physicians or general practitioners first. Thus, there is considerable value in providing more training and education to nondermatologists, because it can have a meaningful impact on patient care., (© The Author(s) 2015.)

The diagnosis of panniculitis is a relatively rare occurrence for many practising pathologists. The smaller subset of lymphocyte-predominant panniculitis is further complicated by the diagnostic consideration of T cell lymphoma involving the subcutaneous tissue, mimicking inflammatory causes of panniculitis. Accurate classification of the panniculitis is crucial to direct clinical management as treatment options may vary from non-medical therapy to immunosuppressive agents to aggressive chemotherapy. Many diseases show significant overlap in clinical and histological features, making the process of determining a specific diagnosis very challenging. However, with an adequate biopsy including skin and deep subcutaneous tissue, a collaborative effort between clinician and pathologist can often lead to a specific diagnosis. This review provides an algorithmic approach to the diagnosis of lymphocyte-predominant panniculitis, including entities of septal-predominant pattern panniculitis (erythema nodosum, deep necrobiosis lipoidica, morphea profunda and sclerosing panniculitis) and lobular-predominant pattern panniculitis (lupus erythematous panniculitis/lupus profundus, subcutaneous panniculitis-like T cell lymphoma, cutaneous γ-δ T cell lymphoma, Borrelia infection and cold panniculitis)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Tophaceous gout is the nonarticular deposition of monosodium urate resulting from a disorder in purine metabolism that causes an elevation of serum uric acid. Cutaneous variants of tophaceous gout include papular, nodular, ulcerative, and pustular forms., Objective: We present a case of a 67-year-old man who presented with multiple cutaneous creamy white papules and nodules. A biopsy was taken, and a diagnosis of cutaneous tophaceous gout was made. The treatment and pathophysiology are discussed., Conclusion: Miliarial gout is a rare form of cutaneous tophaceous gout that is treated using xanthine oxidase inhibitors such as allopurinol and febuxostat or uricosurics such as probenecid., (© 2014 Canadian Dermatology Association.)

Background: Recent advances in biomedical optics have enabled dermal and epidermal components to be visualized at subcellular resolution and assessed noninvasively. Multiphoton microscopy (MPM) and reflectance confocal microscopy (RCM) are noninvasive imaging modalities that have demonstrated promising results in imaging skin micromorphology, and which provide complementary information regarding skin components. This study assesses whether combined MPM/RCM can visualize intracellular and extracellular melanin granules in the epidermis and dermis of normal human skin., Methods: We perform MPM and RCM imaging of in vivo and ex vivo skin in the infrared domain. The inherent three-dimensional optical sectioning capability of MPM/RCM is used to image high-contrast granular features across skin depths ranging from 50 to 90 μm. The optical images thus obtained were correlated with conventional histologic examination including melanin-specific staining of ex vivo specimens., Results: MPM revealed highly fluorescent granular structures below the dermal-epidermal junction (DEJ) region. Histochemical staining also demonstrated melanin-containing granules that correlate well in size and location with the granular fluorescent structures observed in MPM. Furthermore, the MPM fluorescence excitation wavelength and RCM reflectance of cell culture-derived melanin were equivalent to those of the granules., Conclusion: This study suggests that MPM can noninvasively visualize and quantify subepidermal melanin in situ., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Trichodysplasia spinulosa (TS) is a rare, striking, folliculocentric papular eruption seen exclusively in immunosuppressed patients. The eruption can be disfiguring, associated with leonine faces and alopecia. TS is caused by a polyomavirus, identified as trichodysplasia spinulosa polyomavirus (TSPyV). Few reports exist in the literature, and support for treatment options is sparse., Method and Results: We report a patient with TS with underlying lupus nephropathy and renal transplant-associated immunosuppression. Diagnosis was confirmed by biopsy and pathognomonic histologic findings in the context of her extensive, spiculated monomorphous papules. With a biopsy-confirmed diagnosis, oral valganciclovir was prescribed, and the patient showed marked skin texture improvement and hair regrowth., Conclusion: The continued reporting of cases of TS will improve clinical identification of this condition and provide better information regarding treatment and long-term consequences.

Background: Bullous pemphigoid (BP) is an autoimmune polymorphic skin disease characterized by erythematous papules and plaques and tense bullae. A skin biopsy for direct immunofluorescence (DIF) is used to detect autoantibodies and complement proteins., Objective: We sought to determine which location would provide the highest probability of obtaining a positive DIF result., Method: We undertook a retrospective chart review of 1,423 DIF biopsies. Biopsies with a clinical suspicion of BP were designated as either lesional, perilesional, or indeterminate., Results: Fifty percent of lesional DIF biopsies were positive, whereas 22% of perilesional and 12% of indeterminate biopsies had a positive DIF result. The odds ratio of a positive DIF from a lesional versus perilesional biopsy site was found to be 3.45 (95% CI 1.44-8.29)., Conclusion: Clinicians are more likely to obtain a positive DIF result from a lesional nonbullous skin biopsy than from a perilesional or normal skin biopsy.

Context: Biopsy of the face is rarely done for inflammatory skin diseases, unless the entire process is confined to the face., Objective: We hypothesized that facial dermatitis has a differential diagnosis that is more limited than the differential diagnosis of inflammatory skin diseases that affect other parts of the body. To our knowledge, the classification of inflammatory skin diseases occurring on the face has never been conducted before in the English literature., Design: The most-recent 100 facial biopsies of inflammatory skin conditions were retrieved from our files, and the cases were categorized into the main inflammatory skin patterns., Results: Forty-seven cases (47%) were categorized as interface dermatitis, 2 cases (2%) as psoriasiform dermatitis, 11 cases (11%) as spongiotic dermatitis, 16 cases (16%) as diffuse and nodular dermatitis, 8 cases (8%) as perivascular dermatitis, 14 cases (14%) as folliculitis and perifolliculitis, 1 case (1%) as panniculitis, and 1 case (1%) as fibrosing dermatitis. The number of diagnostic entities represented within each of these patterns was small., Conclusions: We believe that facial dermatitis should have its own more-circumscribed differential diagnosis. From a practical viewpoint, many of the inflammatory skin diseases that affect other parts of the body should be excluded from the differential diagnosis after the tissue is determined to be from a facial skin biopsy, and others should not be considered unless the biopsy is from the face.

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.

Background: Acquired hemophilia (AH) is a rare autoimmune disease with an annual incidence of one per million and has a mortality rate of up to 22%. It is caused by the development of autoantibodies against factor VIII. Approximately half of the reported cases are associated with autoimmune disorders, pregnancy, malignancies, and adverse drug reactions. Autoimmune diseases are the most frequently associated disorders and include rheumatoid arthritis, systemic lupus erythematosus, cryoglobulinemia, pemphigus vulgaris, and bullous pemphigoid. There are a few reports of acquired hemophilia and bullous pemphigoid in the literature., Method: We report a 73-year-old male who presented with cutaneous blistering, upper gastrointestinal bleeding, and hemoptysis. He later developed right flank pain secondary to a retroperitoneal hematoma. He had a prolonged partial thromboplastin time, a low factor VIII level, and a high factor VIII inhibitor level, all consistent with acquired hemophilia. Skin biopsies were diagnostic for bullous pemphigoid., Results: He was treated successfully with prednisone, cyclophosphamide, rituximab, and intravenous immunoglobulin.

Background: Sarcoidosis is a systemic inflammatory disorder with cutaneous involvement present in 25% of cases. The presence of naked granulomas histologically is the hallmark of sarcoidosis. The presence of necrotizing granulomas is highly suggestive of other granulomatous conditions and leads the clinician to pursue other diagnoses, such as infectious causes., Objectives: We describe two cases of sarcoidosis in which necrotizing granulomas were present on biopsy. Both patients had ulcerated cutaneous lesions of sarcoidosis. In one case, the presence of these atypical histologic features led to a delay in diagnosis of almost 10 years. We review the various histopathologic findings associated with cutaneous sarcoidosis and discuss a potential connection between ulcerated sarcoidosis and atypical histologic findings., Conclusion: When atypical histopathologic features are present, the differential diagnosis of sarcoidosis should not be excluded.

Background: Intralesional Candida antigen has been used as immunotherapy to treat refractory warts in the immunocompetent pediatric and adult populations but has not been reported in individuals with human immunodeficiency virus (HIV)., Purpose: To examine if Candida antigen resulted in clearance of medically refractory, long-standing common warts in a series of HIV patients., Method: At a hospital-based, adult, outpatient dermatology clinic, seven patients with HIV with common warts of the hands and feet were treated with intralesional Candida antigen. The warts had been resistant to standard patient- and physician-applied modalities., Results: Clearance was achieved in three of seven patients, whereas four of seven did not respond due to a lack of effectiveness or an inability to tolerate treatment. Adverse events included injection-site redness, pruritus, and pain., Conclusion: This is the first reported case series using Candida antigen for warts in individuals with HIV. The use of Candida antigen represents a simple and novel approach to the management of treatment-refractory warts in those with HIV. This case series provides a foundation for future larger, randomized trials.

Background: Pagetoid dyskeratosis (PD) is characterized by pale cells within the epidermis resembling those of Paget disease. These cells have been seen as an incidental finding in a variety of benign papules most commonly located in intertriginous areas. The lesion is considered a reactive process in which a small proportion of the normal population of keratinocytes is altered. Among the triggers for this lesion, friction has been suggested; however, a direct cause-and-effect relationship has not yet been reported., Results: We confirmed the relationship between PD and friction in a biopsy taken from a 19-year-old woman who presented with clinical features indicating exogenously induced bullae and erosions and consented to a biopsy of a lesion immediately after its induction, demonstrating combined features of PD and friction bulla.

Helicobacter bilis, an unusual cause of chronic infections in patients with X-linked agammaglobulinemia (XLA), is notoriously difficult to diagnose and eradicate. Based on the limited number of cases reported worldwide, we highlight the typical features of H. bilis infection in XLA and provide a rational and successful approach to diagnosis and treatment of this challenging infection.

Only one description of trichoblastic sarcoma exists in the literature. Here, we present the first case of trichoblastic sarcoma with heterologous osteosarcomatous differentiation. Biospy 1 demonstrated an intermediate-grade trichoblastic sarcoma with pleomorphic cells and atypical mitotic figures observed only in the stroma. The epithelium contained no malignant cells. The histologic morphology was reminiscent of an intermediate-grade phyllodes tumor of the breast. Biopsy 2, an excisional biopsy taken 7 months later, showed a high-grade sarcoma with osteosarcomatous differentiation. Immunohistochemistry performed on both specimens showed positive CD10 and bcl-2 staining in the sarcomatous component; p63 was positive in the benign epithelium only. p53 was negative in both the benign epithelium and the malignant stroma. Ki-67 labeling was approximately 10% in both components. Specimen 3, a complete rhinectomy performed 3 months later, showed a poorly differentiated sarcoma. Six months following his rhinectomy procedure, multiple pulmonary nodules consistent with metastatic disease were detected on chest computed tomography. This is the first case report documenting the evolution of an intermediate-grade trichoblastic sarcoma to a high-grade lesion with osteosarcomatous differentiation, to a poorly differentiated sarcoma. The tumor morphologically resembles malignant phyllodes tumor of the breast. Our case is the first to show negative p53 and positive bcl-2 staining in a trichoblastic sarcoma. We propose that cutaneous trichoblastic sarcoma is pathogenetically analogous to phyllodes tumors of the breast, adenosarcoma of the uterus, or ameloblastoma of the oral cavity.

Mucoepidermoid carcinoma is a relatively common neoplasm of the major and minor salivary glands that can secondarily involve skin. In the vicinity of the ear lobe, mimicry of a benign cyst, both clinically and histopathologically is a diagnostic pitfall to avoid. The clinical manifestations, diagnostic histopathology, and clinical course of mucoepidermoid carcinoma of the parotid gland presenting as a clinically benign periauricular cystic nodule in four patients ranging in age from 11 to 63 years, are analyzed in the present report. Illustrating the challenge of accurate diagnosis, three of the four cases were initially misinterpreted on biopsy as benign cystic lesions. Multiple biopsies displayed foamy histiocytes around mucinous extravasations into dermis that mimicked ruptured epithelial cysts in two cases before malignancy was ascertained. This series demonstrates the need to include parotid tumor in the differential diagnosis of odd periauricular cyst-like expansions and adenosquamous proliferations. Mucoepidermoid carcinoma in particular can explain indolent, infra-auricular 'mucinous cysts'. Familiarity with this syndrome should arouse suspicion of parotid carcinoma when a 'cyst' or nodule is located near the earlobe. Delay in diagnosis results in larger surgical procedures than are otherwise necessary., (Copyright © 2012 John Wiley & Sons A/S.)

Background: Calcific uraemic arteriolopathy (CUA), previously known as calciphylaxis, is a condition of microvascular calcification and thrombosis with resultant tissue necrosis. Due to the rarity of this disease, our understanding of its pathogenesis remains speculative. Iron has emerged as a potential pathogenic contributor to the development of CUA, but investigation into this link is lacking. The purpose of our study was to explore the clinical characteristics of patients diagnosed with CUA at our institution to allow for comparison to available literature. In addition, we wanted to pursue the possibility of iron being a pathogenic contributor to CUA development. We hypothesized that iron would have to be present in areas of microvascular calcification in order to play a contributing pathogenic role and, therefore, wished to establish whether iron deposition was present within available diagnostic CUA skin biopsy specimens., Methods: This study included all patients diagnosed with CUA at our institution between 1997 and 2009 whose tissue was available for further analysis. All available diagnostic skin biopsy specimens were reviewed and further analysed by a dermatopathologist. As the goal was to explore the potential pathogenic role of iron, staining for iron deposition within biopsy specimens was undertaken. All available medical and biochemical information about patients was also collated for analytic purposes and related to the biopsy specimen findings., Results: Tissue blocks from 12 patients diagnosed with CUA at our institution were available for further analysis. In this CUA cohort, the average age at diagnosis was 61 years (range, 36-83 years), with six (50%) patients being female. Of these patients, 8 (67%) had diabetes, 8 (67%) had coronary artery disease and 10 (83%) had dyslipidaemia. At the time of diagnosis, eight (67%) were on peritoneal dialysis, two (17%) on haemodialysis and two (17%) were pre-dialysis. Our patients had short dialysis vintage times prior to diagnosis (average, 2.1 years). Iron deposition was detected in areas of microvascular calcification in all diagnostic specimens and was absent in unaffected microvasculature within the same biopsy specimens., Conclusions: The findings of iron deposition in affected microvasculature lend support to the potential role of iron in the complex pathophysiologic cascade of CUA. The implications for iron therapy in high-risk patients and the possible rationale for the use of sodium thiosulphate, a metal chelator, in the treatment of CUA are explored.

Background: Necrobiosis lipoidica (NL) presents clinically as waxy yellow-brown plaques, commonly on the shins. Venous insufficiency also involves the legs; however, it has distinct clinical and pathologic features., Objective: We present a series of eight patients who had lesions that clinically resembled NL but on pathology showed features resembling venous insufficiency., Methods: Between 1997 and 2008, eight patients were identified at St. Paul's Hospital, Vancouver, to have had skin lesions clinically diagnosed as NL, or a similar morphologic entity, but showing histopathologic features resembling venous insufficiency on biopsy. The clinical records and pathology reports of these patients were reviewed., Results: The patients' ages ranged from 39 to 73 years. Only one patient was female. Members of the group held diagnoses of diabetes, renal failure, or venous or arterial disease. All patients had lesions on the legs, most on the anterior aspect. The clinical diagnosis was generally NL; other clinical impressions included lichen planus, morphea, and Kaposi sarcoma. All patients had features on pathology resembling venous insufficiency and no features of NL., Conclusion: We propose that this unique combination of clinical features of NL and histopathologic features resembling venous insufficiency represents a novel entity for which we propose the name pretibial angioplasia.

Background: Progressive mucinous histiocytosis (PMH) is a benign, non-Langerhans cell histiocytosis with characteristic ultrastructural features that can be used for diagnosis. Once an important tool in dermatologic diagnosis, electron microscopy has been largely replaced by immunohistochemistry and immunofluorescence techniques today. However, electron microscopy occasionally still plays a crucial role in the diagnosis of dermatologic conditions. We report a case of PMH as an example of a dermatologic disorder that requires electron microscopy for its diagnosis., Methods: A 60-year-old woman presented to our clinic with a history of small, sharply demarcated, skin-colored papules ranging from 2 to 5 mm in diameter distributed over the arms, forearms, and dorsal hands. The results of light microscopy, immunohistochemical studies, and clinical examination were inconclusive. Another biopsy for electron microscopy showed the characteristic features of PMH., Conclusion: This case demonstrates that a dermatopathology service still needs to have access to electron microscopy for diagnostic purposes to successfully diagnose a small number of rare conditions.

Background: Melanoma in situ is a rare malignant lesion of the vulva. The standard treatment is surgical excision., Case: We describe a case of melanoma in situ of the vulva in a 72-year-old woman that reoccurred after surgical excision and was treated successfully with topical 5% imiquimod., Conclusion: There may be a role for imiquimod in treating melanoma in situ of the vulva.

Background: Elastosis perforans serpiginosa (EPS) is a rare skin disease in which abnormal elastic tissue fibers, other connective tissue elements, and cellular debris are expelled from the papillary dermis via transepithelial elimination. It is characterized by an eruption of small grouped hyperkeratotic papules in a serpiginous arrangement. This condition presents a therapeutic challenge as many treatments have been reported with inconsistent efficacy., Methods: This article reports a case of a 13-year-old male who presented to our outpatient clinic with a 1-year history of facial lesions showing multiple annular keratotic plaques with slight central atrophy., Conclusion: We report a case of EPS treated successfully with liquid nitrogen cryotherapy. Liquid nitrogen cryotherapy is well tolerated, with few side effects, and can be considered in the management of EPS.

Drug-induced cutaneous eruptions are named among the most common side effects of many medications. Thus, cutaneous drug eruptions are a common cause of morbidity and mortality, especially in hospital settings. The present article reviews different presentations of drug-induced cutaneous eruptions, with a focus on eruptions reported secondary to the use of interferon and ribavirin. Presentations include injection site reactions, psoriasis, eczematous drug reactions, alopecia, sarcoidosis, lupus, fixed drug eruptions, pigmentary changes and lichenoid eruptions. Also reviewed are findings regarding life-threatening systemic drug reactions.

The brain gumma is a rare manifestation of the tertiary stage of syphilis. A case of neurosyphilitic gumma was confirmed by the Treponema pallidum polymerase chain reaction in a 46-year-old HIV-positive homosexual man. The patient presented with a severe headache and was hospitalized. A computed tomography scan was performed which revealed a left frontal lobe mass. Lymphoma was suspected. However, infectious disease diagnostics were performed on the cerebrospinal fluid that included investigations for syphilis and other microbiological agents such as Toxoplasma gondii. This revealed a reactive venereal disease research laboratory test, a reactive syphilis rapid plasma reagin and a reactive T. pallidum particle agglutination test. The patient was treated for syphilis till complete recovery.

Background: Drug use patterns and serious bloodborne infections commonly have dermatologic manifestations among illicit injection-drug users (IDUs)., Objective: To assess how self-reported skin conditions of IDUs may correlate with underlying infectious diseases after adjustment for drug use patterns., Methods: Prospective analysis of factors associated with self-reports of skin rashes, cellulitis, oral lesions, and lymphadenopathy obtained from 1,065 IDUs enrolled in a large cohort study. Variables potentially associated with each outcome were evaluated using multivariate generalized estimating equations., Results: In multivariate analyses, drug use patterns were associated with cellulitis, whereas human immunodeficiency virus (HIV) infection and hepatitis C (HCV) were not. HCV infection was independently associated with skin rashes (odds ratio [OR] 1.85; 95% CI 1.17-2.94). HIV infection was independently associated with lymphadenopathy (OR 2.00; 95% CI 1.52-2.63), skin rash (OR 2.12; 95% CI 1.57-2.86), and oral lesions (OR 14.95; 95% CI 9.41-23.76)., Conclusions: Self-reports of IDUs, which could easily be obtained as part of a functional inquiry in a clinical setting, correlate with specific drug use patterns and underlying bloodborne infections.

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.

Background: Acne vulgaris may occur as part of immune reconstitution in human immunodeficiency virus (HIV)-seropositive patients on highly active antiretroviral therapy (HAART). Tetracyclines are a common acne treatment. Hypertriglyceridemia has not been reported as a side effect of this drug class., Objective: We report a case of an HIV-seropositive man on HAART (CD4 count 450 cells/microL) who developed isolated hypertriglyceridemia (> 13 mmol/L) after three separate challenges with minocycline or tetracycline, improving each time therapy was discontinued., Results: Based on a review of the literature, this is the first reported case of hypertriglyceridemia with minocycline or tetracycline therapy. No published reports have examined the safety of tetracyclines in the setting of HIV or HAART., Conclusion: A strong temporal association between tetracycline use and hypertriglyceridemia was found without an alternate explanation for the observed lipid profile. Given the common use of tetracyclines in dermatology, we feel that this is an important observation to report.

Objective: The purpose of this study was to characterize the number and distribution of epidermal Langerhans cells in different clinical forms of dry-type cutaneous leishmaniasis (CL)., Methods: Sixteen cases of dry-type cutaneous leishmaniasis caused by Leishmania tropica were studied. These cases were classified clinically as five cases of acute leishmaniasis with indurated papules, nodules and plaques with central crust formation and duration < 2 years, six cases of lupoid leishmaniasis with characteristic papules around previous scars of cutaneous leishmaniasis with duration > 2 years, and five cases of chronic nonlupoid type with nonhealing lesions of duration > 2 years. Paraffin-embedded blocks were stained with hematoxylin and eosin (H&E) and stained immunohistochemically for CD1a., Results: The number of Langerhans cells per millimeter length of epidermis was increased in acute cases compared to chronic and lupoid cases., Conclusions: Lesions of acute leishmaniasis contain the greatest amounts of antigen for presentation, so Langerhans cells increase in number and in trafficking to present antigens derived from Leishman bodies to the cellular immune system. In chronic leishmaniasis, the Langerhans cell population is reduced, perhaps because of exhaustion of the source of Langerhans cells, or because of reduced response to modified antigen.