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Cutaneous B cell pseudolymphoma (CBPL), or cutaneous lymphoid hyperplasia, is the most common pseudolymphoma. It typically responds well to local treatment and follows a benign course. Herein, we describe the unique case of a patient with CBPL that was refractory to a variety of treatments, with subsequent response to rituximab followed by methotrexate. This case explores the complex interplay of T and B lymphocytes, and the potential role of perifollicular T cells in treatment resistant CBPL. Further, it describes the additive therapeutic effect of rituximab and methotrexate to target both B cell and T cell populations in CBPL, a strategy already employed in a number of other conditions.

Background: Severe pretibial myxedema (PTM) can be difficult to manage, highlighting the need to investigate newer therapies. Rituximab (RTX) and intravenous immunoglobulin (IVIg) have been tried in Graves' orbitopathy. Since PTM and orbitopathy share a similar underlying pathophysiology, this study aimed to explore these therapies for progressive PTM. Methods: The electronic database was screened for PTM patients evaluated at the Mayo Clinic, Rochester, from 2002 to 2016, and three patients who received IVIg and five who received RTX are reported. PTM pattern was classified as non-pitting edema, plaque and induration, nodular/nummular, and elephantiasis. PTM was confirmed by biopsy in six patients. Results: The patients' median age was 53.8 years, 75% were female, and all but one patient were either active or former smokers. All patients were euthyroid and had progressed despite various therapies prior to starting these agents. Six patients had a plaque and induration pattern, and two had a nodular pattern with elephantiasis. After therapy, six (75%) patients had PTM stability or improvement both subjectively and objectively (80% with RTX and 66% with IVIg). The three patients (one in the IVIg group and two in the RTX group) who had subjective improvement had a plaque pattern. One patient with elephantiasis had a transient response to IVIg and another had stability after RTX. Thyrotropin receptor antibody values and orbitopathy also improved in patients who demonstrated PTM improvement. No serious adverse events were reported, but one patient each had transient hypertension and injection-site thrombophlebitis after IVIg. Conclusions: Immunomodulation therapy was followed by PTM improvement or stability in most patients, with a slightly better response after RTX compared to IVIg. A validated response assessment instrument and larger series of patients are required to determine if the underlying disease process could be curtailed with these agents.

BACKGROUND Little research has been done in teledermatology to examine the effects of standardized templates and subject-specific learning modules. METHODS We performed a prospective study examining the effects of standardized templates and standardized cutaneous oncology learning modules on teledermatology referrals at Mayo Clinic. This data was then compared to previous teledermatology referrals before standardized templates were adopted. RESULTS A total of 42 teledermatology consultations were performed during the 4-month study period. The use of standardized templates resulted in an absolute reduction in face-to-face referrals. Teledermatology consultation increased the absolute diagnostic and management concordance by 26.2% (P = 0.02) and 33.3% (P < 0.01), respectively, and decreased the absolute diagnostic and management discordance by 19.1% (P = 0.03) and 31.0% (P < 0.01), respectively. The largest knowledge gaps were identified in cutaneous oncology. Educational intervention improved theoretical referral rates and confidence in diagnosis and management overall. CONCLUSION The implementation of standardized intake templates reduces the rate of face-to-face referrals. Teledermatology improves primary care-based dermatological care and reduces theoretical referral rates.

PURPOSE: Patients with stage I/IIA cutaneous melanoma (CM) are currently not eligible for adjuvant therapies despite uncertainty in relapse risk. Here, we studied the ability of a recently developed model which combines clinicopathologic and gene expression variables (CP-GEP) to identify stage I/IIA melanoma patients who have a high risk for disease relapse. PATIENTS AND METHODS: Archival specimens from a cohort of 837 consecutive primary cutaneous melanomas were used for assessing the prognostic performance of CP-GEP. The CP-GEP model combines Breslow thickness and patient age, with the expression of eight genes in the primary tumor. Our specific patient group, represented by 580 stage I/IIA patients, was stratified according to their risk of relapse: CP-GEP High Risk and CP-GEP Low Risk. The main clinical endpoint of this study was five-year relapse free survival (RFS). RESULTS: Within the stage I/IIA melanoma group, CP-GEP identified a high-risk patient group (47% of total stage I/IIA patients) which had a considerably worse five-year RFS than the low-risk patient group; 74% (95% CI: 67% − 80%) vs. 89% (95% CI: 84% − 93%); HR 2.98 (95% CI: 1.78 − 4.98); P < 0.0001. Of patients in the high-risk group, those who relapsed were most likely to do so within the first 3 years. CONCLUSION: The CP-GEP model can be used to identify stage I/IIA patients who have a high risk for disease relapse. These patients may benefit from adjuvant therapy.

Background Classic Sezary syndrome (SS) is defined by erythroderma, generalized lymphadenopathy, and leukemic blood involvement. Clinical observations suggest that SS begins as a nonerythrodermic disease. Objective To describe the early clinical characteristics of patients with SS. Methods A retrospective, multicenter chart review was performed for 263 confirmed cases of SS diagnosed during 1976-2015. Results Erythroderma was the earliest recorded skin sign of SS in only 25.5% of cases, although most patients (86.3%) eventually developed erythroderma. In patients without erythroderma during their initial visit, the first cutaneous signs of SS were nonspecific dermatitis (49%), atopic dermatitis-like eruption (4.9%), or patches and plaques of mycosis fungoides (10.6%). The mean diagnostic delay was 4.2 years overall, 2.2 years for cases involving erythroderma at the initial presentation, and 5.0 years for cases not involving erythroderma at the initial presentation. Limitations This study is retrospective. Conclusion Erythroderma is uncommon as an initial sign of SS. Early SS should be considered in cases of nonerythrodermic dermatitis that is refractory to conventional treatments. In these cases, examination of the blood by PCR for monoclonal T-cell receptor rearrangement and by flow cytometry to identify an expanded or aberrant T-cell population should be considered.

Introduction: Access to dermatologic care is a major issue in the United States, especially within the un- and underinsured populations; technology, including teledermatology, will pay a role in improving access to care. Methods: We performed a prospective study between November 2016 and September 2017. We leveraged a partnership between Mayo Clinic and Mountain Park Health Clinic, a community clinic that primarily serves un- and underinsured populations. We implemented a mobile phone-based store and forward (SAF) teledermatology service, which integrated an external community health clinic to an existing electronic health record (EHR) using standardized data capture forms, real-time support, and simple workflows. Results: Thirty-seven patients were enrolled in the study, 65% female and 35% male with an average age of 47.9 (SD = 15.9). The ethnic breakdown was: 81.1% Hispanic, 13.5% Caucasian, and 5.4% African American. The majority, 62.2%, did not have a high school education, 45.9% were unemployed, and 51.4% were uninsured. 64.9% earned less than $25,000 for annual household income. Teledermatology consultation increased the absolute diagnostic and management concordance by 36.6% (p = 0.01, 95% CI 12.2%–61.0%) and 34.2% (p < 0.01, 95% CI 11%–57%), respectively. Primary care providers had a significant increase in mean confidence in the diagnosis and management of dermatology conditions pre and poststudy (3.60 vs. 3.70 and 3.21 vs. 3.60, respectively; p < 0.01). Ninety-six percent of the primary care providers agreed (52.0%) and strongly agreed (44.0%) that they would send another patient for teleconsultation. Conclusion: We successfully implemented a SAF teledermatology consultative service in a community health clinic outside our EHR. A similar approach can be used by other large health care organizations to provide integrated, high-quality consultation to clinics with rural, un- and underinsured populations.

Background Granuloma annulare (GA) and the related annular elastolytic giant cell granuloma (AEGCG) and interstitial granulomatous dermatitis (IGD) are idiopathic histiocytic inflammatory disorders, which are frequently recalcitrant to treatment. Objectives Evaluate the efficacy of sulphasalazine in treating GA, AEGCG and IGD. Methods Sixteen patients were identified with granulomatous disease who were treated with sulphasalazine between September 2015 and September 2019. Outcomes were based on patients' and providers' subjective evaluations. Results Sixteen patients were included in the study (ages 56-89, four male and twelve female). Previous treatments were attempted in fifteen patients. Clinical improvement was seen in fourteen patients (87.5%). Initial improvement was noted within a mean (SD) of 66.4 (35.1) days after starting therapy, with increasing benefits over time. Ten patients (62.5%) reported complete or near-complete clearance, three patients (18.8%) reported significant improvement, and one (6.3%) reported partial improvement. Twelve patients elected to stop or reduce therapy, resulting in relapse or worsening in five patients. Conclusions Sulphasalazine may be considered as treatment for GA and GA-related conditions.

Background Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. Objective To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. Methods We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. Results Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). Limitations This is a multicenter but single institution study of a white population. Conclusion Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.

Key Points Question In patients with Raynaud phenomenon, what is the microvascular complication risk of calcitonin gene-related peptide (CGRP) antagonist use? Findings In this cohort study of 169 adults with Raynaud phenomenon, 9 patients had microvascular complications after CGRP antagonist use. Two of the 9 patients had severe adverse events, including digital autonecrosis that required distal amputation. Meaning This study suggests that microvascular complications are uncommon in patients with Raynaud phenomenon who are taking CGRP antagonists; however, the incidence of adverse microvascular events with high morbidity warrants caution in prescribing CGRP antagonists in these patients., Importance Calcitonin gene-related peptide (CGRP) antagonists have demonstrated tremendous promise in migraine management. However, these medications decrease reflex vasodilatory response, which may lead to exacerbation of microvascular disease in susceptible patients, such as patients with Raynaud phenomenon (RP). Objective To investigate the microvascular complications of CGRP antagonists in patients with underlying RP. Design, Setting, and Participants This retrospective cohort study was performed from May 18, 2018, to September 15, 2020, in Mayo Clinic Health System patients with Raynaud phenomenon while undergoing CGRP antagonist therapy to treat migraine. Inclusion criteria were age older than 18 years, history of migraine, past or current treatment with CGRP antagonists, and diagnosis of primary or secondary RP. Exposure Treatment with CGRP antagonists. Main Outcomes and Measures The main outcome measure was microvascular complications (eg, worsening RP, digital ulcerations, and gangrenous necrosis) after initiation of treatment with a CGRP antagonist. Patient demographic and clinical characteristics were compared between those who experienced complications and those who did not. Results A total of 169 patients (163 [96.4%] female; 151 [89.3%] non-Hispanic White; mean [SD] age, 46 [13] years) were identified. Of the 169 patients, 9 (5.3%) exhibited microvascular complications, ranging from worsening RP to gangrene and autonecrosis that required distal digit amputation. Comparative analysis did not find statistically significant differences in demographic or clinical characteristics between the 2 cohorts. All 9 patients with complications were female (mean [SD] age, 40 [12] years). Five of the 9 patients (55.6%) had previously diagnosed RP; in 3 the RP was primary, and 2 it was secondary to scleroderma. The other 4 patients (44.4%) were newly diagnosed with RP. Eight of the 9 patients (88.9%) had chronic migraine; 4 had migraine with aura, and 5 had migraine without aura. The CGRP antagonist agents temporally associated with the microvascular complications included galcanezumab (in 3 patients), erenumab (in 5 patients), and fremanezumab (in 1 patient). Conclusions and Relevance The results of this study indicate that microvascular complications of CGRP antagonist use in patients with underlying RP are uncommon. The incidence of serious adverse events, although rare, warrant caution when considering the use of these agents in patients with RP., This cohort study investigates microvascular complications associated with calcitonin gene-related peptide (CGRP) antagonists in patients with underlying Raynaud phenomenon.

Objective To report on the survival and the associations of treatments upon survival of patients with calciphylaxis seen at a single center. Patients and Methods Using the International Classification of Diseases, Ninth Revision diagnosis code of 275.49 and the keyword "calciphylaxis" in the dismissal narrative, we retrospectively identified 101 patients with calciphylaxis seen at our institution between January 1, 1999, through September 20, 2014, using a predefined, consensus-developed classification scheme. Results The average age of patients was 60 years: 81 (80.2%) were women; 68 (68.0%) were obese; 19 (18.8%) had stage 0 to 2 chronic kidney disease (CKD), 19 (18.9%) had stage 3 or 4 CKD; 63 (62.4%) had stage 5 or 5D (dialysis) CKD. Seventy-five patients died during follow-up. Six-month survival was 57%. Lack of surgical debridement was associated with insignificantly lower 6-month survival (hazard ratio [HR]=1.99; 95% CI, 0.96-4.15; P =.07) and significantly poorer survival for the entire duration of follow-up (HR=1.98; 95% CI, 1.15-3.41; P =.01), which was most pronounced in stage 5 or 5D CKD (HR=1.91; 95% CI, 1.03-3.56; P =.04). Among patients with stage 5/5D CKD, subtotal parathyroidectomy (performed only in patients with hyperparathyroidism) was associated with better 6-month (HR=0.12; 95% CI, 0.02-0.90; P =.04) and overall survival (HR= 0.37; 95% CI, 0.15-0.87; P =.02). Conclusion Calciphylaxis is associated with a high mortality rate. Significantly effective treatments included surgical debridement and subtotal parathyroidectomy in patients with stage 5/5D CKD with hyperparathyroidism. Treatments with tissue-plasminogen activator, sodium thiosulfate, and hyperbaric oxygen therapy were not associated with higher mortality.

Objective To identify coagulation risk factors in patients with calciphylaxis and the relationship between anticoagulation use and overall survival. Patients and Methods Study subjects were 101 patients with calciphylaxis seen at Mayo Clinic from 1999 to September 2014. Data including thrombophilia profiles were extracted from the medical records of each patient. Survival status was determined using patient registration data and the Social Security Death Index. Survival was estimated using the Kaplan-Meier method, and associations were evaluated using Cox proportional hazards models. Results Sixty-four of the 101 patients underwent thrombophilia testing. Of these, a complete test panel was performed in 55 and a partial panel in 9. Severe thrombophilias observed in 60% (33 of 55) of the patients included antiphospholipid antibody syndrome protein C, protein S, or antithrombin deficiencies or combined thrombophilias. Of the 55 patients, severe thrombophilia (85%, 23 of 27) was noted in patients who were not on warfarin at the time of testing (27). Nonsevere thrombophilias included heterozygous factor V Leiden (n=2) and plasminogen deficiency (n=1). For the comparison of survival, patients were divided into 3 treatment categories: Warfarin (n=63), other anticoagulants (n=20), and no anticoagulants (n=18). There was no statistically significant survival difference between treatment groups. Conclusion Laboratory testing reveals a strikingly high prevalence of severe thrombophilias in patients with calciphylaxis, underscoring the importance of congenital and acquired thrombotic propensity potentially contributing to the pathogenesis of this disease. These findings may have therapeutic implications; however, to date, survival differences did not vary by therapeutic choice.

Background: Although 50% to 90% of patients who receive epidermal growth factor receptor (EGFR) inhibitors develop a rash, options for rash prevention or palliation remain limited. This issue is particularly important from a palliative care standpoint because these agents are prescribed only to patients with incurable cancer. Here, we report (1) gene expression profiling of skin biopsies from patients with an EGFR inhibitor–induced rash and (2) a randomized, placebo-controlled feasibility trial with the antiandrogen, spironolactone. Both investigations were undertaken to begin to explore the hypothesis that androgens mediate EGFR inhibitor–induced rash and that antiandrogens palliate it. Methods/Results: First, 4 skin biopsies from patients with EGFR inhibitor–induced rash (3 men and 1 woman) were subject to gene expression microarray profiling. A public data set of normal skin gene expression (Gene Expression Omnibus, GSE22998) served as a reference. Sixty percent of commonly interrogated androgen receptor genes (207 of 308 between the 2 data sets) were differentially expressed ( P < .05) in the rash samples. Second, in a 17-patient double-blinded, placebo-controlled trial with topical spironolactone applied to the face, although the primary feasibility end point was not achieved, patients in the spironolactone arm received more doses of EGFR inhibitor, and anecdotal photographic evidence suggested salutatory effects of spironolactone on rash. Conclusions: Epidermal growth factor receptor inhibitor–induced rash appears to be androgen-mediated; antiandrogen therapy merits further study for rash prevention/palliation.

Nonclonal expansions of immature T cells outside of the thymus, termed indolent T-lymphoblastic proliferation (iT-LBP), have been identified in rare lymphoproliferative disorders. We report that iT-LBP is a frequent finding in cases of follicular dendritic cell sarcoma (FDCS), and shows an association with paraneoplastic autoimmune multiorgan syndrome (PAMS). We studied 31 cases of FDCS by paraffin immunohistochemistry using antibodies to CD21, CD23, CD35, clusterin, CXCL13, podoplanin, CD3, CD4, CD8, CD20, CD1a, and TdT. Chart review was performed to characterize the clinical behavior including evidence of autoimmune disease. FDCS occurred in a wide variety of nodal and extranodal sites. Fourteen of 31 (45%) cases contained immature TdT-positive T cells; in 5 cases these cells were numerous and present throughout the tumor. Four of these 5 patients with numerous immature T cells developed autoimmune disease, clinically categorized as PAMS and/or myasthenia gravis. PAMS persisted after tumor resection, causing severe morbidity and mortality. These findings suggest that the neoplastic follicular dendritic cells can recruit or foster the proliferation of immature T cells and that these cells may play a role in mediating PAMS. Recognition of iT-LBP in FDCS is important to avoid misdiagnosis as thymoma or T-lymphoblastic lymphoma, and may predict serious autoimmune complications in some patients.

Inositol polyphosphate 5-phosphatase (INPP5A) has been shown to play a role in development and progression of cutaneous squamous cell carcinoma (cSCC). The goal of the current study was to explore the prognostic value of INPP5A expression in cSCC.A total of 189 cases of actinic keratosis and SCC in 174 patients were identified; clinical and outcome data were abstracted, histopathology was rereviewed, and immunohistochemical staining and interpretation was performed for INPP5A.The majority of tumors (89.4%) had an INPP5A score of 2 or 3. No patients had complete loss of INPP5A. Tumors with an INPP5A score of 1 were more likely to be intermediate- to high-risk tumors (Brigham and Women's Hospital stage ≥T2a 85.0% vs 23.7% [P .0001]) characterized by a larger diameter (2.4 cm vs 1.3 cm [P = .0004]), moderate-to-poor differentiation (86.7% vs 17.6% [P .0001]), and perineural invasion (37.5% vs 5.3%, [P .0001]). An INPP5A score of 1 was associated with a worse 3-year survival (a rate of 42.3% [hazard ratio, 2.81, P = .0006]) and a local metastasis rate of 48.0% (hazard ratio, 4.71; P .0001).Low INPP5A scores are predictive of aggressive tumors and may be a useful adjunct to guide clinical management of cSCC.

Background Published case series describe lenalidomide as an effective treatment of refractory cutaneous lupus erythematosus (CLE). Objectives The present study aimed to further characterize lenalidomide use in the treatment of CLE. Methods A retrospective review of patients treated with lenalidomide for CLE from January 1, 2000, to December 17, 2014, was conducted. Results Eight of the nine patients (89%) were women. Their median age at initiation of lenalidomide was 62 years (range: 41–86 years). Subtypes of CLE included discoid lupus erythematosus (DLE) (n = 6), lupus panniculitis (n = 2), and subacute CLE (n = 1). Before the initiation of lenalidomide, all patients had been previously treated unsuccessfully or were intolerant to at least one antimalarial and one immunosuppressive agent. With lenalidomide, five patients achieved a complete response (CR), two a partial response, and two had no response (lupus panniculitis). Time to initial response (dose range: 2.5–10.0 mg/d) varied from 2 weeks to 3 months; the median time to CR in five patients was 3 months (range: 3–6 months). The median duration of lenalidomide therapy was 12 months (range: 2–67 months). The median duration of follow-up was 48 months (range: 20–103 months). Adverse effects included mild leukopenia; one patient had deep vein thrombosis of unclear etiology during a hospitalization. No patients developed or showed progression of systemic LE while receiving lenalidomide. Conclusions Lenalidomide was effective for the treatment of CLE (particularly DLE) but not for the treatment of lupus panniculitis in this series.

Prognosis is markedly improved when melanoma is diagnosed early. Improved methods are needed for earlier detection and screening. We hypothesized that epigenetic analysis of blood samples could discriminate patients with melanoma from patients with other cutaneous lesions and from healthy volunteers. After institutional review board approval and consent, whole blood was obtained from 59 patients with melanoma, 20 patients with other skin cancers, 20 patients with benign skin conditions, and 20 healthy volunteers. Fifteen conformation biomarkers from five gene loci were analyzed on chromatin with the EpiSwitch technology using a modified chromatin conformation capture assay. Differentiation between patients with melanoma and those with nonmelanoma skin cancers was correct 85% of the time, resulting in a sensitivity of 88% and a specificity of 82%. Differentiation of patients with melanoma from healthy controls was correct 80% of the time, resulting in a sensitivity of 85% and a specificity of 75%. The noninvasive test was more accurate in early-stage melanoma (1/10 and 1/16 stage I and stage II patients were misclassified, respectively) and became less accurate with more advanced disease (3/14 and 4/19 stage III and IV patients were misclassified, respectively). We report the results of a noninvasive test using chromosomal aberrations and epigenetic changes identified in peripheral blood that, in this pilot study, distinguished patients with early-stage melanoma from other cohorts.

Purpose Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma. Patients and Methods Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. Results ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk). Conclusion The addition of cell adhesion–linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.

Background Granuloma annulare (GA) is a granulomatous skin eruption rarely associated with cancer. We report seven cases of paraneoplastic GA in association with solid organ malignancy. Objective To compare the clinical and histopathological features of paraneoplastic GA to case-matched controls of classic GA. Methods Retrospective chart and histopathological review of 7 individuals and 13 age- and sex-matched controls. Paraneoplastic GA was defined as GA occurring within 6 months of the diagnosis of solid organ malignancy and/or persistent GA that resolved with cancer treatment. Results Most cases of paraneoplastic GA were associated with lung cancer (4/7). The clinical and histopathological features of paraneoplastic and classic GA were similar. Compared to classic GA, paraneoplastic GA cases were more often generalized disease (6/7 vs 6/13), refractory to treatment, and had a perivascular inflammatory cell infiltrate (5/7 vs 2/13). All cases of paraneoplastic GA that underwent definitive treatment of their cancer improved. Limitations Single-institution, retrospective review with a small sample size. Conclusion Paraneoplastic GA is rare, similar to classic GA, and refractory to treatment. We advocate for age-appropriate screening in individuals with GA that is nonresponsive to multiple lines of systemic treatment and evaluating patients with concerning signs or symptoms for an underlying neoplasm.

Summary Background Itching, burning, numbness and tingling of the skin are frequent reasons for dermatology consultation. We hypothesized that these sensations may be attributable to a small-fibre neuropathy. Sweating, which is mediated by small nerve fibres, may be a surrogate marker of small-fibre neuropathy. Objectives To investigate the results of thermoregulatory sweat testing (TST), which depicts and estimates whole-body sweating, in patients with itching, burning, numbness and tingling sensations. Methods We retrospectively reviewed the medical records of 227 patients with itching, burning, numbness and tingling sensations involving the skin who were seen at our institution during 2008 and also underwent TST. Results The mean age of the cohort was 54 years (range 3–89), and 58% were female. In all, 149 patients (66%) had abnormal TST results; in 119 (80%) of these patients the areas of anhidrosis on TST corresponded to their symptomatic areas. For each symptom analysed separately, the area of anhidrosis correlated with the area of symptoms in most patients. Conclusions Patients with burning, itching, numbness and tingling have abnormal sweating patterns and often do not sweat in the symptomatic areas. These novel findings suggest that a small-fibre neuropathy may underlie many cutaneous symptoms and that the neuropathy can be estimated using TST.

Autoimmune pancreatitis is the prototypical manifestation of immunoglobulin G4-related disease, a fibroinflammatory syndrome that can affect virtually any organ. Rarely, skin involvement has been reported in immunoglobulin G4-related disease. Isolated case reports have described other distinct associated dermatoses.Our objective was to determine the frequency and nature of dermatologic manifestations of immunoglobulin G4-related disease in patients with autoimmune pancreatitis.Retrospective analysis of dermatologic conditions of patients with autoimmune pancreatitis.Among the 118 identified patients, 31 (26.3%) had a dermatologic diagnosis [mean (standard deviation; SD) follow-up 5.9 (4.6) years]. Two patients (1.7%) had necrobiotic xanthogranuloma; three (2.5%) had another xanthomatous or xanthogranulomatous process. One patient (0.8%) had pemphigus erythematosus. No patient had immunoglobulin G4-related skin disease.Skin involvement in immunoglobulin G4-related disease appears to be rare. A disproportionately high number of patients had xanthomatous or xanthogranulomatous processes, including necrobiotic xanthogranuloma. It remains unclear whether the association between immunoglobulin G4-related disease and necrobiotic xanthogranuloma or other xantho(granulo)matous processes represents shared pathophysiology, a mutual underlying driver, or coincidence, though the results of this study cast doubt on the latter. Although pemphigus was not reported in immunoglobulin G4-related disease previously, the prominent role of the immunoglobulin G4 subclass in each condition makes this association intriguing.

A Mayo Clinic analysis of melanoma distribution showed a high frequency of lesions on the heel and fewer lesions on the front of the foot than shown in a Japanese study that indicated that melanomas may be most common in weight-bearing areas of the plantar surface.

Summary Background Delusional infestation (DI) is a well-recognized clinical entity but there is a paucity of reliable data concerning its epidemiology. Knowledge of the epidemiology is fundamental to an understanding of any disease and its implications. Epidemiology is most accurately assessed using population-based studies, which are most generalizable to the wider population in the U.S. and worldwide. To our knowledge, no population-based study of the epidemiology (particularly incidence) of DI has been reported to date. Objectives To determine the incidence of delusional infestation (DI) using a population-based study. Methods Medical records of Olmsted County residents were reviewed using the resources of the Rochester Epidemiology Project to confirm the patient's status as a true incident case of DI and to gather demographic information. Patients with a first-time diagnosis of DI or synonymous conditions between 1 January 1976 and 31 December 2010 were considered incident cases. Results Of 470 identified possible diagnoses, 64 were true incident cases of DI in this population-based study. The age- and sex-adjusted incidence was 1·9 [95% confidence interval (CI) 1·5–2·4] per 100 000 person-years. Mean age at diagnosis was 61·4 years (range 9–92 years). The incidence of DI increased over the four decades from 1·6 (95% CI 0·6–2·6) per 100 000 person-years in 1976–1985 to 2·6 (95% CI 1·4–3·8) per 100 000 person-years in 2006–2010. Conclusions Our data indicate that DI is a rare disease, with incidence increasing across the life span, especially after the age of 40 years.

Background Tumor necrosis factor (TNF)-α antagonists have been associated with the induction of de novo or worsening psoriasis. Objective We sought to retrospectively examine the clinical characteristics and outcomes of patients with psoriasis associated with anti–TNF-α therapy. Methods We performed a retrospective review of patients with new-onset or worsening psoriasis during TNF-α inhibitor therapy between 1998 and 2010. Results Of the 56 patients (mean age at psoriasis onset, 48.1 years), 41 (73%) were female. In all, 22 patients (39%) had Crohn's disease and 14 (25%) had rheumatoid arthritis. Thirty patients (54%) were treated with infliximab, 19 (34%) with adalimumab, and 7 (12%) with etanercept. New-onset or worsening psoriasis occurred after a mean treatment duration of 17.1 months. Plaque psoriasis (n = 27), palmoplantar pustulosis (n = 25), scalp psoriasis (n = 12), generalized pustular psoriasis (n = 7), erythrodermic psoriasis (n = 2), and inverse psoriasis (n = 2) were the cutaneous presentations. Among the 39 patients for whom full treatment response data were available, 33 (85%) had a complete or partial response; combined response rates (complete and partial) were slightly higher among those who discontinued anti–TNF-α therapy (16 of 17 patients [94%]) than among those who continued anti–TNF-α therapy (17 of 22 patients [77%]). Limitations Retrospective nature, possible referral bias, and lack of complete follow-up for some patients are limitations. Conclusion Although some patients sufficiently controlled their psoriasis while continuing anti–TNF-α therapy, those who discontinued therapy achieved higher rates of complete response. Further studies should explore the efficacy and safety of switching to an alternative anti–TNF-α agent.

Axillary web syndrome (AWS) is defined as a cord-like structure extending from the axilla to the medial arm following axillary surgery in women with breast cancer. There is only limited literature on the pathogenesis of this syndrome and the etiology of the cord. A 57-year-old man presented with a band-like skin depression and tightness over the medial aspect of his arm extending from the axilla to the antecubital fossa following development of a furuncle in the ipsilateral axilla. Histopathologic examination of the ‘band’ revealed fibroblastic proliferation surrounding the lymphatic vessel which was identified by presence of an obvious valve as well as positive staining for D2-40, a specific marker for lymphatic endothelium. This is the first report of AWS following axillary furunculosis. This case adds to the limited data on the histopathology of AWS, further confirming the etiology of the ‘cord’ to be of lymphatic origin.

This population-based study reports the prevalence of delusional infestation in Olmsted County, Minnesota.

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE(0)DQ2). These AE(0)DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE(0)DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE(0)DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE(0)DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE(0)DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a 'fingerprint' substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE(0)DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE(0)DQ2 mice compared with AE(0)DQ6 mice (p < 0.001). In conclusion, AE(0)DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815-829.

Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic antitumor immunity. To improve the clinical and immunologic efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma.We conducted a dose-escalation clinical trial of HLA-A2 patients with metastatic melanoma to the lung treated with aerosolized granulocyte macrophage colony stimulating factor (GM-CSF) (500-2000 microg/dose, with increments of 250 microg/dose/cohort) twice/d on days 1 to 7 and 15 to 21 every 28 days until progression or severe toxicity to find a dose where a majority of patients develop antitumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined.The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which a majority of patients (or =3 of 5) demonstrated significant up-regulation of antitumor immunity. Three of 16 patients who were tetramer positive for at least one melanoma antigen (eg, MART-1) pretreatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pretreatment developed an IR against gp100. The greatest changes in antitumor immunity occurred at the highest dose levels.A dose of aerosolized GM-CSF capable of inducing antitumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in antitumor T cell IRs was achieved at the highest doses of GM-CSF.

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with intestinal gluten sensitivity. Epidermal transglutaminase (TGe) and closely related tissue transglutaminase (tTG) are considered to be autoantigens in DH, because a majority of DH patients have IgA specific for TGe and for tTG. It is unknown where and how these autoantigen-specific IgAs are generated in DH. Results reported in this paper on nine DH patients on a gluten containing diet demonstrate that the levels of circulating anti-tTG IgA and anti-TGe IgA in DH are correlated with each other and that both appear to be correlated with the degree (extent) of enteropathy. An analysis of 15 untreated celiac sprue (CS) patients demonstrated that approximately 33% of CS patients had elevated levels of anti-TGe IgA. These results would indicate that intestinal damage is associated with the production of anti-tTG IgA and anti-TGe IgA in DH patients.

In patients with chronic lymphocytic leukemia, squamous cell carcinoma behaves aggressively. Our purpose was to compare squamous cell carcinoma metastasis and mortality between patients with chronic lymphocytic leukemia and control subjects. Medical records were assessed retrospectively for 28 patients with chronic lymphocytic leukemia who underwent surgical excision of cutaneous squamous cell carcinoma and for 56 matched control subjects. The rate of metastasis and mortality from cutaneous squamous cell carcinoma were determined on a per-patient basis. Three of 28 patients with chronic lymphocytic leukemia had metastasis and died of metastatic disease. No metastases or deaths occurred among the 56 control subjects. Compared with control subjects, chronic lymphocytic leukemia patients with cutaneous squamous cell carcinoma were more likely to have metastasis (P = .0031) and die of metastasis (P = .0033). No significant association was detected between metastasis and history of chemotherapy administration for chronic lymphocytic leukemia. Among patients with chronic lymphocytic leukemia, surveillance for skin cancer and a decreased threshold for biopsy of suspect lesions are warranted.

BACKGROUND. Cutaneous cancers exhibit a much higher incidence in patients with chronic lymphocytic leukemia than in nonleukemic patients. Squamous and basal cell carcinomas also exhibit greater subclinical tumor extension in patients with chronic lymphocytic leukemia. OBJECTIVE. The purpose of this study was to estimate and compare the recurrence rates of squamous cell carcinoma after Mohs’ surgery in patients with chronic lymphocytic leukemia compared with those in controls and to evaluate differences among squamous cell carcinoma size and histologic grade. METHODS. We retrospectively assessed the clinical histories, postoperative notes, and surgical photographs of patients with chronic lymphocytic leukemia and controls matched (2:1) for age, sex, and surgical year. Both patients and controls underwent Mohs’ surgery for squamous cell carcinoma of the head and neck at the Mayo Clinic between March 1988 and April 1999. RESULTS. Twenty-eight patients who underwent Mohs’ surgery for 57 squamous cell carcinomas had 7 recurrences. The cumulative incidence of recurrence on a per-tumor basis was 4.3% at 1 year, 14.8% at 3 years, and 19.0% at 5 years. Squamous cell carcinoma was seven times more likely to recur in patients with chronic lymphocytic leukemia than in controls (p 5 .003). The distribution of tumor histologic grade was not significantly different between patients and controls (p 5 .39). Maximum preoperative tumor diameters were clinically similar between patients and controls (median 15 mm vs 14 mm;p 5 .04). CONCLUSION. The recurrence rates of squamous cell carcinoma were significantly higher in patients with chronic lymphocytic leukemia. Squamous cell carcinomas in patients with chronic lymphocytic leukemia did not exhibit a significant difference in histologic grade or clinical difference in preoperative tumor size. Close surveillance for squamous cell carcinoma recurrence is warranted in patients with chronic lymphocytic leukemia.

Background Pili annulati is an inherited hair shaft abnormality with a wide range of clinical expression. Objective We have examined closely three kindreds to reveal levels and character of expression of the phenotype and supplement current literature on the threshold for detection and aspects of hair shaft fragility. Patients and methods Eleven cases of pili annulati from three families were included in a clinical and morphological study. All cases were assessed clinically and by light and scanning electron microscopy (SEM) of hair shafts. In addition, transmission electron microscopy (TEM) (four patients) and amino acid analysis (three patients) were undertaken on clinically overt cases. Results Examination by light microscopy with a fluid mountant was more sensitive than clinical examination, increasing the detection rate by 120%. Microscopic examination revealed that the characteristic periodic bands become less frequent distally in the hair shaft. Microscopic features of weathering were found in two cases, adding pili annulati to the list of structural hair shaft dystrophies that may weaken hair and dispose to weathering. Amino acid analysis of the hair of three patients with pili annulati showed elevated lysine and decreased cystine content compared to 12 normal controls, consistent with the reduced threshold for weathering. Conclusion Careful light microscopy with fluid-mounted hair is needed to detect subjects mildly affected by pili annulati. Expression of the phenotype varies widely between individuals, between hairs and within hairs of the same individual, where ageing of the hair diminishes detectable features.

Since the original descriptions of follicular mucinosis, accumulating experience shows that patient age, distribution of lesions, and duration or extent of disease do not reliably distinguish benign primary follicular mucinosis from secondary follicular mucinosis, associated with cutaneous lymphoma. More recently, it has been suggested that individuals with follicular mucinosis demonstrating a clonal T-cell receptor gene rearrangement may be at higher risk for the development of lymphoma. Long-term follow-up of 7 patients younger than 40 years with primary follicular mucinosis are reported. In all cases, there was no clinical or histologic evidence of associated dermatoses or lymphoma at the time of diagnosis. Five of the patients have clonal T-cell gene rearrangement as determined by Southern blot analysis. Clinically, at the time of diagnosis, lesions of primary follicular mucinosis ranged from papules confined to the face to widespread cutaneous plaques. After a mean follow-up of 10 years (range, 5-23 years) from the onset of disease, the majority of patients continue to have cutaneous manifestations of follicular mucinosis despite various treatments. There is no evidence of progression to cutaneous T-cell lymphoma in any patient despite the presence of a clonal T-cell receptor gene rearrangement. Continued prolonged follow-up of patients with clonal primary follicular mucinosis is necessary to determine the significance of infiltrates harboring a T-cell receptor gene rearrangement. However, in our experience with this group of selected patients, primary follicular mucinosis has been a clonal disorder with limited or "benign" cutaneous manifestations. (J Am Acad Dermatol 2002;47:856-62.)

IMPORTANCE Isotretinoin is the standard treatment for refractory severe nodulocystic acne.A true association between prior isotretinoin use and development of inflammatory bowel disease (IBD) is uncertain. Addressing the reality of this association is important in decision making for both the clinician and the patient when isotretinoin treatment is indicated.OBJECTIVE To assess the risk of IBD mainly in patients with acne with and without isotretinoin exposure.DESIGN, SETTING, AND PARTICIPANTS In this retrospective, single-center study, the electronic medical records of patients who were primarily seeking acne treatment were reviewed for isotretinoin exposure. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to search for IBD diagnosis. participants included 1078 patients from 1995 to 2011,with isotretinoin referenced in their medical records, and who had ongoing local medical care defined as having had a serum sample collected between 2006 to 2011 for any reason while an Olmsted County, Minnesota, resident at the time of serum sample collection.EXPOSURES The exposed group included the patients with confirmed prior isotretinoin exposure (n = 576), and the nonexposed group were defined as patients who never received isotretinoin or received it after the diagnosis of IBD (n = 502).MAIN OUTCOMES AND MEASURES Risk of IBD among isotretinoin-exposed vs non exposed patients.RESULTS Both groups were comparable by race, prior systemic antibiotic use, and systemic tetracycline use. Inflammatory bowel disease developed less frequently in the isotretinoin-exposed group vs the nonexposed group (0.9%vs 2.6%; P = .03; unadjusted odds ratio [OR], 0.33; 95%CI, 0.12-0.93; P = .04). The negative association between isotretinoin exposure and IBD remained after adjusting for sex (OR, 0.28; 95%CI, 0.10-0.80;P = .02) and for sex and non acne indication (OR, 0.28; 95%CI, 0.10-0.79; P = .02).CONCLUSIONS AND RELEVANCE Our study did not show an increased risk of IBD with prior isotretinoin use. If anything, the risk seemed to be decreased. Although these results may be due to chance given the small number of IBD cases, the anti-inflammatory and immune-modulating effects of isotretinoin may be worth exploring.

Background Bullous pemphigoid (BP) has been associated with neurologic disorders. Objective We sought to analyze the association between BP and neurologic disorders. Methods We retrospectively identified residents of Olmsted County, Minnesota, with a first lifetime diagnosis of BP between January 1, 1960, and December 31, 2009. Three age- and sex-matched Olmsted County, Minnesota, residents without BP were selected as control subjects for each patient. We compared history of or development of neurologic disorders (dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, cerebrovascular disease, and seizures) between groups using case-control and cohort designs. Results In all, 87 patients with BP were identified and matched to 261 control subjects. The odds of a previous diagnosis of any neurologic disorder or a history of dementia were significantly increased among cases compared with controls (odds ratio 6.85; 95% confidence interval [CI] 3.00-15.64; P P = .002, respectively). Both Parkinson disease (hazard ratio 8.56; 95% CI 1.55-47.25; P = .01) and any type of neurologic disorder (hazard ratio 2.02; 95% CI 1.17-3.49; P = .01) were significantly more likely to develop during follow-up in patients with than without BP. Limitations Small geographic area and retrospective study design are limitations. Conclusion Findings confirmed an association of BP with neurologic disorders, especially dementia and Parkinson disease.

Most reports describe an increased risk of malignancy in Peutz-Jeghers syndrome (PJS). We identified individuals with PJS-like pigmentation but no polyposis, designated as isolated mucocutaneous melanotic pigmentation (IMMP), and 1) characterized their clinical features, 2) assessed them for cancer events, and 3) screened a sample of these subjects for mutations in LKB1, a gene responsible for a portion of PJS cases. Review of Mayo Clinic records from 1945 to 1996 identified 26 patients with IMMP. All were then interviewed or their medical records reviewed to determine if cancer had developed. Conformation-sensitive gel electrophoresis (CSGE) screening for LKB1 mutations was followed by direct sequencing. Ten of these 26 individuals (38%) developed 12 malignancies that arose in the cervix (n = 3), endometrium (n = 3), breast (n = 1), kidney (n = 1), lung (n = 2), colon (n = 1), and lymphatic tissue (n = 1). In females with IMMP, the relative risk for cancer was 3.2 (95% CI, 1.2-6.9), while that for males was not increased. The relative risk for breast and gynecologic cancers was 7.8 (95% CI, 2.5-18.1) in affected females. Of 9 individuals tested, no LKB1 mutations were detected. Classical PJS is associated with an increased cancer risk. Our results indicate that IMMP is another lentiginosis with cancer predisposition. In particular, the relative risk for cancer in females with IMMP was significantly increased, as is true in females with PJS. However, LKB1 mutations did not contribute to the development of IMMP in the patients tested.

Objective To determine the frequency of ophthalmic abnormalities in patients with cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome) and T-cell lymphoma involving the skin and to describe the clinical course of the disease with selected examples. Design Retrospective, clinic-based, cross-sectional study. Participants A computerized diagnostic retrieval system was used to identify all patients with T-cell lymphoma involving the skin who were examined at the Mayo Clinic (Rochester, Minnesota) between January 1, 1976 and December 31, 1990. The medical records of affected patients were reviewed. Main outcome measures Identification of ophthalmic abnormalities. Results During the 15-year interval from 1976 through 1990, cutaneous T-cell lymphoma was diagnosed in 2155 patients. Of these, 42 (1.95%; 26 male and 16 female) had at least one ophthalmic abnormality attributable to the disease. The diagnoses in these 42 patients were mycosis fungoides in 19, clinical variants of T-cell lymphoma of the skin (most commonly peripheral T-cell lymphoma) in 11, and Sezary syndrome in 12. Cicatricial eyelid ectropion was the most common finding, affecting 17 (40.4%) of the 42 patients. Thirty-seven patients had findings that, although probably not a direct consequence of cutaneous T-cell lymphoma, have been cataloged in previous studies. Conclusion Although ophthalmic abnormalities in patients with cutaneous T-cell lymphoma are relatively uncommon, the manifestations of the disease are diverse and frequently difficult to treat.

In Hermansky–Pudlak Syndrome (HPS) a mutation in a 79.3 kDa transmembrane protein has been shown. The function of this protein has escaped definition so far. This study unveils a defective (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH 4 ) de novo synthesis/recycling for this cofactor in HPS, where activities of the key enzyme GTP-cyclohydrolase I are in the normal range, but total biopterin levels are significantly decreased in homozygotes (n = 5) compared with unaffected controls (n = 4) (p = 0.00001). Phenylalanine hydroxylase and 4a-hydroxy-6BH 4 -dehydratase activities are significantly lower. mRNA of all enzymes involved in 6BH 4 biosynthesis/recycling and GTP-cyclohydrolase I feedback regulatory protein were expressed in keratinocytes from homozygotes, heterozygotes, and healthy controls. Thioredoxin/thioredoxin reductase can directly control the redox status of 6BH 4 . These activities are allosterically controlled by calcium. Therefore calcium would directly affect this redox status. In HPS these enzyme activities are low concomitant with a defective calcium uptake, suggesting an extracellular accumulation of this second messenger. In this context phenylalanine hydroxylase is subject to phosphorylation/activation by calcium/calmodulin activated kinases. Therefore it was anticipated that calcium could directly affect the cellular L-phenylalanine turnover to L-tyrosine. A significantly more rapid L-phenylalanine uptake and its turnover to L-tyrosine was identified in normal human melanocytes (n = 5) and keratinocytes (n = 2), and was more enhanced in melanocytes in the presence of 2 × 10 –3 M calcium. The turnover to L-tyrosine was significantly slower. Based on all evidence to date, we speculate that the mutated protein in HPS could be primarily involved in maintaining calcium homeostasis in this patient group.

Patients with atopic eczema have significantly higher norepinephrine levels in plasma than healthy controls. In addition, significantly higher levels of the essential cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4) were found in this patient group. Cell extracts from epidermal suction blister roofs revealed only half the normal activity of phenylethanolamine-N-methyl transferase (PNMT) together with a threefold induction of the norepinephrine-degrading enzyme monoamine oxidase A (MAO-A). Taken together, these results support earlier observations of a defective catecholamine/adrenoceptor signal in patients with atopic eczema.

Background: Neutrophilic and lymphocytic vascular inflammation is common in vasculitis associated with connective tissue disease (CTD). We recently identified eight patients with CTD and eosinophilic vasculitis. Objective: The purpose of this study was to characterize a variant form of vasculitis in CTD with eosinophilic infiltration. Methods: Of 98 CTD patients with cutaneous necrotizing vasculitis, eight were found with predominantly eosinophilic vascular infiltration. Nine CTD patients with cutaneous neutrophilic vasculitis were identified for comparison. Clinical and laboratory findings were reviewed and compared. Indirect immunofluorescence for eosinophil granule major basic protein (MBP), neutrophil elastase, and mast cell tryptase was performed on lesional tissue. MBP levels and eosinophil survival enhancing activity were assayed in sera from three patients. Results: The patients with eosinophilic vasculitis had depressed serum complement levels and peripheral blood eosinophilia; MBP levels were elevated in serum and eosinophil survival was prolonged. Immunofluorescence of tissue showed marked angiocentric eosinophil MBP staining with peripheral neutrophil elastase staining; mast cell tryptase staining was notably absent. The patients with neutrophilic vasculitis were variably hypocomplementemic and did not have peripheral blood eosinophilia. Immunofluorescence showed marked angiocentric neutrophil elastase staining with scattered eosinophil MBP staining; mast cell tryptase staining showed normal mast cell numbers. Conclusion: Patients with eosinophilic vasculitis, CTD, and hypocomplementemia show vessel wall destruction in association with vessel wall deposition of cytotoxic eosinophil granule MBP, which suggests that eosinophils mediate vascular damage in this disease process. In addition, perivascular mast cells appear diminished, therby suggesting that mast cell degranulation occurs.

Irreversible growth arrest and commitment to differentiation are among the earliest events in the pros gram of cellular terminal differentiation, The transition from highly proliferative human keratinocytes in subconfluent culture to stationary cells in confluent culture was studied in a serum-free culture system to identify conditions that regulate the initiation of terminal differentiation in keratinocytes. We observed that culture confluence strongly induced commitment to terminal differentiation, as demonstrated by a dramatic loss of keratinocyte clonogenicity. Commitment was accompanied by the rapid induction of early differentiation markers, represented by expression of suprabasal keratin 1 (K1) and 10 (K10) genes. Induction of differentiation was independent of low (0.1 mM) or high (1.5 mM) calcium concentration In the medium. Epidermal growth factor suppressed expression of K1 and K10 mRNA in cultures induced to differentiate. Suspension of keratinocytes in methylcellulose medium failed to induce in subconfluent cultures, or enhance in confluent cultures, the expression of K1 and K10 genes. Subconfluent cells cultured in medium containing high calcium and no exogenous growth factor induced expression of K1 and K10 transcripts, but commitment and loss of proliferative potential were not observed. Confluent cell density primarily controlled keratinocyte commitment to terminal differentiation and differentiated keratin gene expression. However, suprabasal K1 and K10 gene expression also was regulated by medium calcium and exogenous growth-factor concentrations in subconfluent cultures that promoted cell-cell association. Epidermal growth factor inhibited the expression of suprabasal keratins but not the commitment to terminal differentiation mediated by cell confluence. Control of keratinocyte commitment and expression of selected differentiation genes are mediated by cell confluence and, at subconfluence, by specific culture factors.

Angiosarcoma is an uncommon but aggressive tumor of endothelial origin that may occur in the upper extremities of patients with postmastectomy lymphedema (Stewart-Treves syndrome) as well as in other regions. We present an unusual case of angiosarcoma associated with congenital nonhereditary lymphedema in an 18-year-old man. Our case underscores the need for a careful clinical examination and shows the importance of appropriate sampling and thorough pathologic examination of suspicious areas to exclude the presence of a malignant process.

Adult Henoch-Schönlein purpura (HSP) is rarely associated with solid-organ malignancies. We describe here three adult patients with HSP diagnosed within 3 months of the diagnosis of associated solid-organ malignancies, including pulmonary, prostate, and renal carcinomas. Two patients had complete remission with a combination of immunosuppressive therapies and treatment of the associated malignancy. The third patient had partial remission with immunosuppressive therapies, but never received treatment for the associated malignancy and did not achieve complete remission before his death 10 months after diagnosis of HSP. These cases suggest that HSP associated with solid-organ malignancies may be resistant to immunosuppressive therapies without treatment of the associated malignancy. Therefore, evaluation for solid-organ malignancies should be considered in adult patients without an identifiable cause of HSP, especially if the disease is not self-limited or does not respond appropriately to treatment.

Background Sezary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma, is characterized by erythroderma and by atypical lymphocytes (Sezary cells) in peripheral blood. Although numerous studies have examined the range of disease in cutaneous T-cell lymphoma, a relative paucity of data exists to describe the long-term outcome of patients with SS. Objective We sought to study long-term survival and prognostic factors of patients with SS. Methods A retrospective chart review was conducted to identify patients with SS seen at Mayo Clinic from 1976 to 2010. Cox proportional hazards regression models, adjusted for age, were fit to evaluate factors associated with overall survival. Results In total, 176 patients were identified with a clinicopathologic diagnosis of SS. Overall survival was 86.1% and 42.3% at 1 and 5 years, respectively, after diagnosis (median survival, 4.0 years). After adjustment for age, potential predictors of worse survival included lactate dehydrogenase level at presentation (hazard ratio [HR] 1.71; 95% confidence interval [CI] 1.18-2.47 per doubling), prior diagnosis of mycosis fungoides (HR 2.68; 95% CI 1.44-4.98), and the presence of T-cell receptor gene rearrangements in skin (HR 2.59; 95% CI 1.38-4.87) and in blood (HR 2.05; 95% CI 1.00-4.21). Limitations This study is retrospective and represents a single academic center population. Conclusions To our knowledge, this research evaluated the largest population of patients with SS studied to date. It shows that overall survival continues to be poor, with a median survival of 4.0 years after diagnosis.

Porphyria cutanea tarda (PCT) is a vesiculobulIous disorder often associated with estrogens, hepatitis C virus (HCV), alcoholism, hereditary hemochromatosis (HH), and human immunodeficiency virus. Hepcidin, a peptide hormone produced by the liver, has been associated with iron metabolism in 3 common precipitating factors for PCT: HCV, HH, and alcohol consumption. We present the case of a patient with erosions and noninflammatory bullae on his hands and forearms who received a diagnosis of PCT. On further examination, the patient was found to be positive for 3 precipitating factors: HCV, an HH gene mutation, and alcohol use. For patients with PCT, it is important to perform phenotypic screening for HCV and HH. Targeting hepcidin with replacement therapy to decrease iron may be a treatment of not only HCV, HH, and alcoholic cirrhosis, but also PCT.

Objective To review the results of skin biopsies and patient-provided specimens from patients whose assessment was consistent with delusional infestation, including delusions of parasitosis. Design Retrospective medical record review. Setting Mayo Clinic, Rochester, Minnesota. Patients The study population comprised all patients who were seen at Mayo Clinic and had a diagnosis of delusional skin infestation, including delusions of parasitosis, between 2001 and 2007, and who underwent biopsies as part of their dermatologic evaluations or brought samples to their clinical consultations. Main Outcome Measures The results of examination of these biopsy and patient-provided specimens. Results A total of 108 patients met inclusion criteria for this study: 80 received biopsies, 80 had self-procured skin specimens, and 52 patients received biopsies and provided specimens. No biopsy specimen (0 of 80) provided evidence to support skin infestation. The most common interpretations in the 80 biopsy specimens were dermatitis in 49 of 80 (61%); excoriation, ulceration, or erosion in 38 (48%); and nonspecific dermal inflammation in 25 (31%). Patient-provided specimens were most frequently assessed by the physician (generally a dermatologist) evaluating the patient, although 20 of the 80 samples (25%) were submitted for pathologic evaluation. Of these 80 specimens, 10 (13%) contained insects. All but 1 of the insects were noninfesting varieties; 1 (1%) was a pubic louse. The remaining findings consisted of cutaneous debris, environmental detritus, or plant material. Conclusion In patients with suspected delusional infestation, neither skin biopsies nor examination of patient-provided specimens provided objective evidence of skin infestation.

BACKGROUND: Chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary nonmelanoma skin cancers (NMSCs) in immunocompromised post-transplantation recipients. There is limited evidence for the use of systemic retinoids in the nontransplantation patient. To the authors' knowledge, this is the first randomized controlled trial to assess the efficacy of acitretin as a chemopreventive agent in nontransplantation patients at high-risk for NMSC. METHODS: The study was designed as a prospective, randomized, double-blind, placebo-controlled clinical trial. To test the possible skin cancer-preventing effect of a 2-year treatment with acitretin, 70 nontransplantation patients aged ≥18 years who had a history of ≥2 NMSCs within 5 years of trial onset were randomized to receive either placebo or acitretin 25 mg orally 5 days per week. The primary outcome measure was the rate of new NMSC development. RESULTS: Seventy patients were randomized to receive either acitretin alone (N = 35) or placebo (N = 35). During the 2-year treatment period, the patients who received acitretin did not have a statistically significant reduction in the rate of new primary NMSCs (odds ratio, 0.41; 95% confidence interval, 0.15-1.13; 54% vs 74%; P = .13). However, using the incidence of new NMSC, the time to new NMSC, and total NMSC counts, an umbrella test indicated a significant trend that favored the use of acitretin (chi-square statistic, 3.94; P = .047). The patients who received acitretin reported significantly more mucositis and skin toxicities compared with the patients who received placebo. CONCLUSIONS: Although there was not a statistically significant benefit observed with the use of acitretin, this may have been the result of low statistical power. Cancer 2012;. © 2011 American Cancer Society.