A Novel Actinic Keratosis Field Assessment Scale for Grading Actinic Keratosis Disease Severity.

Actinic keratosis (AK) lesions are surrounded by field cancerization (areas of subclinical, non-visible sun damage). Existing AK grading tools rely on AK counts, which are not reproducible. An Actinic Keratosis Field Assessment Scale (AK-FAS) for grading the severity of AK/field was developed. Standardized photographs of patients representing the full range of AK severity were collected. Six investigators independently rated each photograph according to 3 criteria: AK area (total skin area affected by AK lesions), hyperkeratosis and sun damage. Inter-rater reproducibility was good for all 3 criteria. Validation of the AK-FAS showed good reproducibility for AK area and hyperkeratosis, even for dermatologists untrained on use of the scale. In conclusion, the AK-FAS is objective, easy to use and implement, and reproducible. It incorporates assessment of the entire field affected by AK instead of relying on lesion counts. Use of the AK-FAS may standardize AK diagnosis, making it relevant to routine clinical practice.

Prior knowledge of the clinical picture does not introduce bias in the histopathologic diagnosis of melanocytic skin lesions.

A common debate among dermatopathologists is that prior knowledge of the clinical picture of melanocytic skin neoplasms may introduce a potential bias in the histopathologic examination. Histologic slides from 99 melanocytic skin neoplasms were circulated among 10 clinical dermatologists, all of them formally trained and board-certified dermatopathologists: 5 dermatopathologists had clinical images available after a 'blind' examination (Group 1); the other 5 had clinical images available before microscopic examination (Group 2). Data from the two groups were compared regarding 'consensus' (a diagnosis in agreement by ≥4 dermatopathologists/group), chance-corrected interobserver agreement (Fleiss' k) and level of diagnostic confidence (LDC: a 1-5 arbitrary scale indicating 'increasing reliability' of any given diagnosis). Compared with Group 1 dermatopathologists, Group 2 achieved a lower number of consensus (84 vs. 90) but a higher k value (0.74 vs. 0.69) and a greater mean LDC value (4.57 vs. 4.32). The same consensus was achieved by the two groups in 81/99 cases. Spitzoid neoplasms were most frequently controversial for both groups. The histopathologic interpretation of melanocytic neoplasms seems to be not biased by the knowledge of the clinical picture before histopathologic examination.

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC. To investigate the apparent association between deletion within PTPRD and cSCC metastasis, a series of 74 formalin-fixed paraffin-embedded tumors from 31 patients was analyzed using a custom Illumina 384 SNP microarray. Deletions were found in 37% of patients with metastatic cSCC and were strongly associated with metastatic tumors when compared to those that had not metastasized (p = 0.007). Subsequent mutation analysis revealed a higher mutation rate for PTPRD than has been reported in any other cancer type, with 37% of tumors harboring a somatic mutation. Conversely, bisulfite sequencing showed that methylation was not a mechanism of PTPRD disruption in cSCC. This is the first report to observe an association between deletion within PTPRD and metastatic disease and highlights the potential use of these deletions as a diagnostic biomarker for tumor progression. Combined with the high mutation rate observed in our study, PTPRD is one of the most commonly altered genes in cSCC and warrants further investigation to determine its significance for metastasis in other tumor types.

Cutaneous mucinous carcinoma arising in extramammary Paget disease of the perineum.

We present the case of a 74-year-old woman with a 7-year history of an expanding vulval and perianal erythematous plaque, which failed to respond to topical treatments in the community. Biopsy of the affected skin showed typical features of extramammary Paget disease. No underlying associated malignancy was identified. After 2 months of treatment with 5% topical imiquimod, the patient developed a new tender nodule in the perineal region. Histological examination revealed a mucinous carcinoma, which, after careful clinical assessment, was deemed to be a primary cutaneous mucinous carcinoma. This is the second reported case of a primary cutaneous mucinous carcinoma arising on a background of extramammary Paget disease of the vulva and perineum.

Influence of evaluation of clinical pictures on the histopathologic diagnosis of inflammatory skin disorders.

BACKGROUND: Clinical information on histologic referral sheets is usually very limited, and particularly for inflammatory skin disorders, dermatopathologists often ask referring physicians for clinical correlation. OBJECTIVE: In this study we tested the value of clinicopathologic correlation in the histopathologic diagnosis of inflammatory skin disorders. METHODS: One-hundred biopsy specimens were digitalized and stored on 3 DVDs along with the clinical images. All cases were evaluated by 9 independent full-time dermatopathologists, initially without looking at the clinical pictures and subsequently after checking them. All diagnoses were finally compared with the "reference" diagnosis established in Graz, Austria, and the results were statistically analyzed. RESULTS: After evaluation of the clinical images, the number of dermatopathologists making a correct diagnosis was increased in 70 cases, unchanged in 25 cases, and decreased in 5 cases. The total number of correct diagnoses increased from 332 (diagnoses before evaluation of clinical pictures) to 481 (diagnoses after evaluation of clinical pictures), with a 16.6% increase in the total. LIMITATIONS: The computerized setting is different from real-life dermatopathology and physical examination of patients. CONCLUSION: Our study clearly shows that clinical pictures should be added to biopsy request slips of inflammatory skin disorders whenever possible, as they allow a better interpretation of histopathologic findings.

Mechanism of action and clinical benefits of colloidal oatmeal for dermatologic practice.

Colloidal oatmeal has a long history of beneficial use in dermatology. It is a natural product that has an excellent safety record and has demonstrated efficacy for the treatment of atopic dermatitis, psoriasis, drug-induced rash and other conditions. In recent years, in vitro and in vivo studies have begun to elucidate the multiple mechanisms of action of naturally derived colloidal oatmeal. Evidence now describes its molecular mechanisms of anti-inflammatory and antihistaminic activity. The avenanthramides, a recently described component of whole oat grain, are responsible for many of these effects. Studies have demonstrated that avenanthramides can inhibit the activity of nuclear factor kappaB and the release of proinflammatory cytokines and histamine, well known key mechanisms in the pathophysiology of inflammatory dermatoses. Topical formulations of natural colloidal oatmeal should be considered an important component of therapy for atopic dermatitis and other conditions and may allow for reduced use of corticosteroids and calcineurin inhibitors.

Paraneoplastic Acanthosis Nigricans: The importance of exhaustive and repeated malignancy screening.

Paraneoplastic acanthosis nigricans (P-AN) characteristically has a sudden onset, rapid progression, and extensive cutaneous involvement. The association between P-AN and internal malignancy is well established and the most common association is with adenocarcinoma of gastrointestinal origin. We present the case of an 81-year-old man with a 12-month history of anorexia, weight loss, and clinical evidence of extensive acanthosis nigricans. After exhaustive and repeated investigations a papillary thyroid carcinoma and a follicular adenoma were identified and he improved upon its resection. To our knowledge, P-AN in association with thyroid neoplasm has been reported on only one previous occasion.

Palisaded neutrophilic granulomatous dermatitis associated with systemic lupus erythematosus presenting with the burning rope sign.

Palisaded neutrophilic granulomatous dermatitis is a rare but increasingly recognized cutaneous manifestation of connective tissue disorders. It is reported most commonly with rheumatoid arthritis but also occasionally in association with systemic lupus erythematosus, inflammatory bowel disease, lymphoproliferative disorders, and systemic vasculitides. The clinicopathological presentation is highly variable, which has led to suggestions that it encompasses a number of distinct diseases. Most previous cases have reported only a single clinical and histologic manifestation of the condition within an individual. Here, we present a case of systemic lupus erythematosus-associated palisaded neutrophilic granulomatous dermatitis in which a striking evolution of both clinical and histologic features was observed during the course of 7 years, providing compelling evidence for the proposal that palisaded neutrophilic granulomatous dermatitis represents a disease spectrum rather than separate disease entities.

Clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series.

BACKGROUND: Non-melanoma skin cancers (NMSCs) are increased in organ transplant recipients, but transplant and immunocompetent squamous and basal cell carcinomas (SCCs, BCCs) have not been compared previously in a single-center study. OBJECTIVE: To compare clinicopathologic features of transplant and immunocompetent NMSCs. METHODS: Consecutive transplant NMSCs (60 SCCs, 100 BCCs) and immunocompetent NMSCs (40 SCCs, 125 BCCs) presenting between 1995-1997. RESULTS: Transplant patients were 15 years younger at time of NMSC diagnosis compared with immunocompetent individuals, and transplant tumors were often more multiple and extracephalic. Spindle cell morphology was more common in transplant SCCs, a superficial component was more common in transplant BCCs, and histologic features of HPV infection were overrepresented in transplant tumors. Outcome was worse for transplant SCCs but not transplant BCCs. LIMITATIONS: Histologic features required to identify HPV infection have not been validated. CONCLUSIONS: These findings have direct implications for clinical care. The increased frequency and distribution of transplant NMSCs underscore the importance of whole-body surveillance. Transplant SCCs, particularly those with diffuse spindle cell change, may require more aggressive management, whereas transplant BCCs do not. Finally, our data support differences in the pathogenesis of transplant NMSC, which may influence future preventive and therapeutic strategies.

Adherence to topical therapies in actinic keratosis: A literature review.

BACKGROUND: Actinic keratosis (AK) is a common skin condition, for which topical therapies are frequently prescribed. This review summarises current understanding of patient adherence and persistence to topical AK treatment by identifying literature relating to measures of adherence and persistence and influencing factors. METHODS: A multi-database literature search was conducted (2004-2015) using key search terms. Supplementary searches of pivotal clinical trials and reference lists of eligible papers were also conducted. RESULTS: Non-adherence and non-persistence rates varied between real-world studies (10-63% and 23-31%, respectively), with combined non-adherence and non-persistence reported as high as 88%. Methods to calculate adherence and persistence differed between studies. Adherence and persistence were generally higher in clinical trials than clinical practice. Key contributing factors to non-adherence and non-persistence to AK treatment were identified as: treatment duration, severity and persistence of local skin responses and patient confusion over treatment regimens. CONCLUSION: The review highlighted a significant evidence gap regarding adherence and persistence to topical AK therapies. Combined, non-adherence and non-persistence may be as high as 88% in clinical practice, highlighting the importance of incorporating contributing factors to patient non-adherence into treatment decisions.

Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of 5% imiquimod cream for cutaneous dysplasia in high-risk renal transplant recipients. DESIGN: A randomized, blinded, placebo-controlled study comparing treated with control skin. SETTING: A specialist organ transplant dermatology clinic. PATIENTS: Twenty-one high-risk patients with skin cancer with comparable areas of clinically atypical skin on dorsal hands or forearms. INTERVENTIONS: Imiquimod or placebo (randomly assigned) applied 3 times a week for 16 weeks to 1 dorsal hand or forearm, with 8 months of follow-up. At week 16, biopsy samples were collected from pre-assigned sites in the treatment and control areas and were examined for dysplasia. MAIN OUTCOME MEASURES: The proportion of patients showing reduced numbers of viral and keratotic lesions and reduced histological severity of dysplasia in the treatment vs control areas at week 16, serum creatinine levels, and tumors developing in the study sites. RESULTS: Fourteen patients receiving imiquimod and 6 receiving placebo completed the study. Seven patients using imiquimod (1 taking placebo) had reduced skin atypia, 7 using imiquimod (none taking placebo) had reduced viral warts, and 5 using imiquimod (1 taking placebo) showed less dysplasia histologically. In 1 year, fewer squamous skin tumors arose in imiquimod-treated skin than in control areas. Renal function was not adversely affected. CONCLUSIONS: Topical 5% imiquimod cream seems to be safe on skin areas up to 60 cm2 in renal transplant recipients. It may be effective in reducing cutaneous dysplasia and the frequency of squamous tumors developing in high-risk patients. Larger studies are required to confirm these results.

Successful treatment of a patient with severe atopic dermatitis and severe asthma by centrifugal therapeutic plasma exchange.

This is a case of a 42-year-old atopic man with severe atopic dermatitis and asthma who despite long-term immunosuppression was not well controlled. He had a very high IgE at 7897 Iu/mL prior to treatment. He underwent two therapeutic plasma exchanges (TPEs) through two peripheral lines in our outpatient department, which led to an absolute decrease of 44.1% and 37% in his plasma IgE for each exchange, and immediate sustained improvement in shortness of breath, and atopic dermatitis, and hence led to a vast improvement in his quality of life. TPE offers a new exciting adjunctive treatment option for severe atopic individuals, where it may provide a novel role to reduce health burden and improve clinical symptoms. Further studies need to be performed to establish an optimal protocol and potential maintenance with recently available targeted anti-IgE biologics.

A consensus approach to improving patient adherence and persistence with topical treatment for actinic keratosis.

BACKGROUND: Topical therapy is important in the treatment of actinic keratosis, but guidance for improving adherence/persistence during topical therapy is still lacking. OBJECTIVES: To utilize expert consensus to generate a list of recommendations to improve real-world efficacy when prescribing topical therapy for actinic keratosis. METHODS: An expert panel of eight dermatologists was convened to generate recommendations based on facilitated discussion and consensus generation using a modified Delphi session. The recommendations were ratified with the expert panel. RESULTS: Facilitated discussion generated 31 issues within five themes, which were prioritized using expert voting. Consensus was achieved on the importance of short and simple treatment regimens for maximizing patient compliance, physician awareness of the progression of actinic keratosis to squamous cell carcinoma, provision of appropriate patient information, and the use of effective communication strategies to educate physicians about actinic keratosis. Based on these key findings, eight recommendations were generated. CONCLUSIONS: The recommendations will assist physicians when prescribing topical actinic keratosis therapy. Further research should focus on the types of patient outcomes that are influenced by the characteristics of topical field therapy.

Autoimmune subepidermal bullous skin diseases: the impact of recent findings for the dermatopathologist.

In recent years improved knowledge of the mechanisms of intercellular and cell-matrix adhesion has led to better understanding of the blistering process in many bullous dermatoses. The wide characterisation of adhesion molecules has partially changed some traditional views and invariably has made the routine work of the pathologist more complex. If understanding cell-cell cohesion structures such as desmosomes and adherens junctions is complex enough, the cell-matrix adhesion structures, such as hemidesmosomes and their structural analogues on the basement membrane and superficial dermis, are even more complex. Defects of such structures cause the subepidermal bullous diseases in which there has been most characterisation of the adhesion molecules and has also led to the discovery of new diseases (e.g. p200 pemphigoid). Most of the antigens are also the targets for mutations seen in patients with the inherited type of epidermolysis bullosa, a group of rare blistering genodermatoses. Another important aspect of bullous skin conditions is the more accurate definition of the role of the different inflammatory cells involved in triggering, development and maintenance of these diseases. Recent studies have outlined the important role of T-cell lymphocytes and their cytokines in their pathogenesis. All these studies, based mainly on highly sophisticated ultrastructural and molecular biology techniques, have updated our knowledge of the pathogenesis of blistering diseases. Nevertheless, the diagnostic characterisation of bullous diseases remains sometimes difficult, and some pathological features and mechanisms still represent an enigma. Diseases such as bullous pemphigoid and cicatricial pemphigoid, or anti-laminin cicatricial pemphigoid and acquired bullous epidermolysis share the same molecular target but have very different clinical manifestations. Explaining this phenomenon, probably linked to different expressions of MHC, is one of the challenges for the future.

Development and testing of new candidate psoriatic arthritis screening questionnaires combining optimal questions from existing tools.

OBJECTIVE: Several questionnaires have been developed to screen for psoriatic arthritis (PsA), but head-to-head studies have found limitations. This study aimed to develop new questionnaires encompassing the most discriminative questions from existing instruments. METHODS: Data from the CONTEST study, a head-to-head comparison of 3 existing questionnaires, were used to identify items with a Youden index score of ≥0.1. These were combined using 4 approaches: CONTEST (simple additions of questions), CONTESTw (weighting using logistic regression), CONTESTjt (addition of a joint manikin), and CONTESTtree (additional questions identified by classification and regression tree [CART] analysis). These candidate questionnaires were tested in independent data sets. RESULTS: Twelve individual questions with a Youden index score of ≥0.1 were identified, but 4 of these were excluded due to duplication and redundancy. Weighting for 2 of these questions was included in CONTESTw. Receiver operating characteristic (ROC) curve analysis showed that involvement in 6 joint areas on the manikin was predictive of PsA for inclusion in CONTESTjt. CART analysis identified a further 5 questions for inclusion in CONTESTtree. CONTESTtree was not significant on ROC curve analysis and discarded. The other 3 questionnaires were significant in all data sets, although CONTESTw was slightly inferior to the others in the validation data sets. Potential cut points for referral were also discussed. CONCLUSION: Of 4 candidate questionnaires combining existing discriminatory items to identify PsA in people with psoriasis, 3 were found to be significant on ROC curve analysis. Testing in independent data sets identified 2 questionnaires (CONTEST and CONTESTjt) that should be pursued for further prospective testing.

Prospective study of sentinel lymph node biopsy for conjunctival melanoma.

BACKGROUND: To report our experience with sentinel lymph node biopsy for staging patients with conjunctival melanoma. METHODS: A prospective review of patients with conjunctival melanoma who underwent sentinel lymph node biopsy at St Bartholomew's Hospital from May 2008 to May 2012. The selection criterion for sentinel node biopsy depended on the tumour thickness (≥2 mm) and location of the conjunctival melanoma. The main outcome measures were the incidence of sentinel lymph node positivity and the procedure-related complications. RESULTS: In 4 years, 26 out of 70 patients met the selection criteria for sentinel lymph node biopsy. 4 patients declined and 22 patients consented for the procedure. Technetium-99m failed to identify a sentinel lymph node in four of the 22 patients (18%). Of the remaining 18 patients, two were found to have subclinical micrometastasis in regional lymph nodes. Median follow-up was 20 months (range 6-36 months). No false-negative events were observed. Complications of the procedure included transient blue staining of the epibulbar surface in five patients and transient facial nerve palsy in one patient. CONCLUSIONS: Sentinel lymph node biopsy is a safe procedure with minimal complications. It should be considered for the staging of conjunctival melanomas, especially melanomas in non-limbal location or conjunctival melanomas ≥2 mm thick.