Characterization of T-Helper Immune Phenotype in Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE) Endorses a Delayed-Type Hypersensitivity Reaction.

ABSTRACT: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug eruption with a characteristic distribution of erythema on the gluteal/inguinal region and intertriginous areas with unclear pathogenesis. In this study, we aimed to characterize the T-helper immune phenotype in SDRIFE in comparison with psoriasis and eczema to further the understanding of the pathophysiology and immune response of this rare disorder. Immunohistochemical staining was performed on 9 skin biopsies each from SDRIFE, psoriasis, and eczema using immunohistochemistry for CD3 and dual CD4/T-bet, CD4/GATA3, and CD4/RORC to quantify the percentage of Th1, Th2, and Th17 cells, respectively. A significant difference was detected in the average percentage of Th1 between all 3 groups with the highest percentage of Th1 cells seen in psoriasis, followed by SDRIFE and eczema. SDRIFE showed significantly lower Th2 expression as compared to both psoriasis and eczema. There was a trend towards a higher average percentage of Th17 in psoriasis and SDRIFE, and the ratio of Th17:Th2 was significantly higher in samples of SDRIFE compared with both eczema and psoriasis. The findings characterize SDRIFE as a Th1 and possibly Th17-driven process, which could inform future therapeutic options and substantiate the model of SDRIFE as a delayed-type hypersensitivity reaction.

Assessment of Clinical and Laboratory Use of the Cutaneous Direct Immunofluorescence Assay.

IMPORTANCE: Dermatologists submit direct immunofluorescence (DIF) biopsies on a daily basis, using an assay detecting immunoreactant deposition with a panel that has traditionally comprised immunoglobulin (Ig) G, IgA, IgM, C3, and fibrin, with or without albumin antibodies. OBJECTIVES: To evaluate and compare the frequency of immunoreactants in DIF biopsies submitted over an 8-year period and assess use by dermatologists based on clinical impression. DESIGN, SETTING, AND PARTICIPANTS: A quality improvement study was conducted in a community outreach reference laboratory associated with a large academic medical center. Results of 2050 consecutive DIF skin biopsies submitted to the laboratory between April 1, 2012, and June 12, 2020, were analyzed by final pathologic diagnosis and antibody subtype positivity, in comparison with clinical impression. Biopsies in which the submitting physician had not performed the biopsy were excluded. MAIN OUTCOMES AND MEASURES: Histopathologic findings and the results of DIF biopsies using the standard 6-antibody panel were evaluated in correlation with the submitted clinical diagnosis to assess immunoreactivity of the assay. RESULTS: Of 2050 DIF biopsies submitted, 367 (17.9%) were positive; IgG, IgA, and C3 alone identified all primary immunobullous disease cases (pemphigoid, pemphigus, linear IgA, and dermatitis herpetiformis), and IgA, C3, and fibrin antibodies alone identified all vasculitis cases. A panel of IgG, IgA, IgM, and fibrin identified all cases of lupus erythematosus. DIF results were positive in less than half of cases of hematoxylin and eosin biopsy-confirmed lupus erythematosus (23 of 47 [49%]). A total of 247 biopsies were submitted for clinical diagnoses not optimally supported on DIF: lichen planus, porphyria, and connective tissue disease. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that there is a knowledge gap among dermatologists relating to the opportunity for high-value, cost-conscious use of DIF. The practice of reflexive antibody testing using a 6-antibody panel for all DIF biopsies is likely unnecessary. DIF protocols tailored to the clinical diagnosis may enhance cost-effectiveness without loss of test sensitivity or specificity.

Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus.

High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, UVR, and immunosuppressive medications are proposed explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over 8 years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE. To investigate this clinical observation, we subjected lupus-prone MRL/lpr and control (MRL/n) mice to a skin carcinogenesis protocol. Skin tumors developed preferentially within the cutaneous lupus inflammation without scarring in MRL/lpr mice (P < 0.01). The inflammation in MRL/lpr skin was characterized by the accumulation of regulatory T cells, mast cells, M2 macrophages, and markedly elevated transforming growth factor-ß1 and IL-6 levels, which have been linked to tumor promotion. Tacrolimus treatment reduced skin inflammation and blocked cancer development in MRL/lpr mice (P = 0.0195). A similar tumor-promoting immune environment was detected in SCCs and the perilesional skin of cancer-prone DLE patients. Therefore, discoid lupus inflammation promotes skin cancer in high-risk DLE patients, and blocking the inflammation may be critical for preventing this life-threatening complication of DLE.

The ABMS MOC Part III Examination: Value, Concerns, and Alternative Formats.

This article describes the presentations and discussions at a conference co-convened by the Council on Medical Education of the American Medical Association (AMA) and by the American Board of Medical Specialties (ABMS). The conference focused on the ABMS Maintenance of Certification (MOC) Part III Examination. This article, reflecting the conference agenda, covers the value of and evidence supporting the examination, as well as concerns about the cost of the examination, and-given the current format-its relevance. In addition, the article outlines alternative formats for the examination that four ABMS member boards are currently developing or implementing. Lastly, the article presents contrasting views on the approach to professional self-regulation. One view operationalizes MOC as a high-stakes, pass-fail process while the other perspective holds MOC as an organized approach to support continuing professional development and improvement. The authors hope to begin a conversation among the AMA, the ABMS, and other professional stakeholders about how knowledge assessment in MOC might align with the MOC program's educational and quality improvement elements and best meet the future needs of both the public and the physician community.

Cytokeratin 17 is highly sensitive in discriminating cutaneous lymphadenoma (a distinct trichoblastoma variant) from basal cell carcinoma.

BACKGROUND: Cutaneous lymphadenoma (CL) is rare neoplasm that clinically and histologically resembles basal cell carcinoma (BCC). CL, composed of dermal basaloid epithelial islands with prominent admixed lymphocytes, characteristically contains cytokeratin 20 (CK20)-positive Merkel cells (MCs). However, CK20 may be of limited use because of low MC density in small samples. CK17 is expressed diffusely throughout BCC. We investigated the discriminatory utility of CK17 and CK20 in CL and BCC. METHODS: A retrospective clinicopathological review of 11 cases of CL and 14 BCC was performed. CK20-positive MCs within basaloid tumor lobules and CK17 immunohistochemical staining and pattern of expression were recorded. RESULTS: Intratumoral CK20-positive MCs were identified in 4/11 CL cases (36.4%) and 0/14 BCC cases (p = 0.012, sensitivity = 0.36). CK17 showed diffuse positive staining in all 14 BCC cases. CK17 showed a distinct patchy and peripheral rim staining in basaloid islands of 10/11 CL cases (p < 0.001, sensitivity = 0.91); one case showed patchy staining throughout tumor lobules. CONCLUSIONS: In cases with a differential diagnosis of CL and BCC, CK20 staining of intratumoral MCs has a high positive predictive value for CL but is of low sensitivity. The pattern of CK17 expression is a highly sensitive marker for distinguishing CL from BCC in small samples.

Clear cell acanthoma with changes of eccrine syringofibroadenoma: reactive change or clue to etiology?

We observed two patients with solitary lesions showing features of clear cell acanthoma with underlying eccrine syringofibroadenoma-like changes. The pathogenesis of these entities has been debated since their original descriptions, with most recent literature suggesting that both may represent reactive phenomena rather than true neoplasms. Our observation prompted us to perform a retrospective review of clear cell acanthoma cases to determine the frequency of such associated eccrine syringofibroadenoma changes. Of 47 examined cases of clear cell acanthoma, 9 (19%) showed associated changes of eccrine syringofibroadenoma. Immunohistochemical evaluation performed on a subset of cases identified similar but slightly divergent differentiation patterns within the lesions. While epithelial membrane antigen and PAS expression were similar in both components (although slightly different in intensity), the regions resembling eccrine syringofibroadenoma displayed additional immunoreactivities, supporting the presence of two distinct components. We have found that the concurrence of clear cell acanthoma with syringofibroadenomatous changes is more frequent than generally appreciated and suggest that these entities may share derivation from the eccrine apparatus.

Maintenance of Certification in dermatology: what we know, what we don't.

Participation in Maintenance of Certification is a reality for the majority of board-certified physicians in the United States. It consists of 4 parts that focus the attention of participants on knowledge assessment, practice performance, communication skills, and patient safety. This continuing medical education article reviews the development and possible future of the program, data regarding Maintenance of Certification, what is currently not known about Maintenance of Certification, and how to navigate the requirements for dermatologists.

Maintenance of Certification in dermatology: requirements for diplomates.

Since 2006, after completing a cognitive certifying or recertifying examination, dermatologists are automatically enrolled into Maintenance of Certification (MOC) and can access a personalized electronic table (at www.abderm.org) that presents the requirements over the 10-year cycle. On this web site, diplomates can also pay the annual fee and attest to completion of the various components. Clicking on hyperlinks in the table launches explanations of the requirements. A hyperlink below the table takes the reader to the various resources approved for completion of the MOC requirements. There is a login tab in the upper left corner with a login help feature below. Clicking on the MOC tab will bring up the table. The timeline is specific to the individual.

Pregnancy-associated hyperkeratosis of the nipple: a report of 25 cases.

IMPORTANCE: Reported physiologic nipple changes in pregnancy do not include hyperkeratosis and are expected to resolve or improve post partum. Hyperkeratosis of the nipple and/or areola can develop in the context of inflammatory diseases (such as atopic dermatitis), in acanthosis nigricans, as an extension of epidermal nevus, after estrogen treatment, and/or in nevoid hyperkeratosis of the nipple and areola. We performed a clinicopathologic analysis of cases of pregnancy-associated nipple hyperkeratosis. OBSERVATIONS: Twenty-five cases of pregnancy-associated nipple hyperkeratosis identified during a 5-year period (January 1, 2007, through December 31, 2012) are reported. The lesions were bilateral and involved predominantly the top of the nipple. Lesions were symptomatic in 17 patients (68%), causing tenderness or discomfort, pruritus, sensitivity to touch, and/or discomfort with breastfeeding. Nine patients (36%) experienced symptomatic aggravation only during pregnancy or breastfeeding. The lesions persisted post partum in 22 patients (88%). Histopathologic features were conspicuous orthokeratotic hyperkeratosis, with papillomatosis and acanthosis being mild or absent. CONCLUSIONS AND RELEVANCE: Pregnancy-associated hyperkeratosis of the nipple can be symptomatic and persist post partum. It may represent a physiologic change of pregnancy. The characteristic clinicopathologic features of this disorder allow differentiation from nevoid hyperkeratosis of the nipple and areola. We suggest that this distinctive clinicopathologic entity be called pregnancy-associated hyperkeratosis of the nipple.

Rapid improvement of nephrogenic systemic fibrosis with rapamycin therapy: possible role of phospho-70-ribosomal-S6 kinase.

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that occurs in some patients with renal insufficiency. Exposure to gadolinium-based contrast agents (GdCA) has been associated with the development of NSF. No uniformly effective treatment options exist. We present immunohistochemical evidence to show that the proliferating fibrocytes of NSF express phospho-70-s6 kinase (PI-3-K), a protein downstream of PI-3-K, and the target of the drug rapamycin. In our patient, use of rapamycin resulted in rapid clinical improvement marked by reduced edema, reduced skin induration, and decreased pain. This suggests a possible role for PI-3-K and rapamycin (mTOR) pathways in the pathogenesis of NSF. Drugs that inhibit these pathways may be a target for future therapy. While our patient did attribute disease onset to GdCA exposure, used on a single occasion for abdominal imaging, he was also exposed to iron, calcium, and darbepoetin alpha at the time of imaging.