Aaron R. Mangold

Advanced basal cell carcinoma of the skin: Targeting the hedgehog pathway

Purpose of review This article provides an update on basal cell carcinoma (BCC), with a focus on the advanced BCC (aBCC), and the recent progress with targeted hedgehog signaling pathway inhibition for treatment of aBCC. Recent findings The hedgehog signaling pathway is aberrantly activated in most BCC tumors providing an attractive therapeutic target in this cancer. Recently developed targeted hedgehog pathway inhibitors have demonstrated remarkable efficacy in the treatment of aBCC and the first oral hedgehog pathway inhibitor vismodegib was granted the US Food and Drug Administration (FDA) approval. Toxicities of the current hedgehog pathway inhibitors are mostly mild to moderate, but with prolonged treatment can pose a therapeutic challenge. Summary Hedgehog pathway inhibition is a novel and powerful approach for treatment of aBCC. Current research efforts aim to enhance the activity and minimize toxicity of this promising new therapy.

Skin cancer screening: recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Forces 2016 Draft Recommendation Statement on skin cancer screening.

Risk Factors Predicting Positive Margins at Primary Wide Local Excision of Cutaneous Melanoma.

BACKGROUND A small percentage of patients will have positive histological margins after primary wide local excision (WLE) of cutaneous melanoma (CM). Risk factors that predict marginal involvement at WLE remain unclear. OBJECTIVE To identify risk factors associated with positive margins after WLE of CM. MATERIALS AND METHODS A retrospective review of patients treated at a single institution for CM with sentinel lymph node biopsy from 1997 to 2011 was conducted. RESULTS Positive margins occurred in 6% of patients. Patients with positive margins were older (72.4 vs 60.7, p < .001), had thicker tumors (3.6 vs 1.9 mm, p < .001), and often involved the head and neck region (p < .001). Patients with positive margins at WLE had positive margins on initial biopsy (p = .012) and a higher rate of a melanoma in situ component on initial biopsy (24% vs 11%, p = .02). The 5-year local recurrence rate was significantly different between those with positive and negative margins at WLE (16.0% vs 6.9%; p = .047). CONCLUSION Positive margins after WLE are uncommon. When a patient has multiple risk factors for positive margins at WLE, histologically clear margins should be obtained through mapped serial excision or Mohs micrographic surgery.

Diseases of the tongue.

The tongue is a complex organ involved in speech and expression as well as in gustation, mastication, and deglutition. The oral cavity, along with the tongue, are sites of neoplasms, reactive processes, and infections, and may be a harbinger of systemic diseases. This review includes both common and rare diseases that occur on the tongue, including: vascular and lymphatic lesions (infantile hemangiomas and oral varices), reactive and inflammatory processes (hairy tongue, pigmented fungiform papillae of the tongue, benign migratory glossitis, and fissured tongue), infections (oral hairy leukoplakia, herpes simplex and varicella-zoster virus infections, human papillomavirus, and candidiasis), premalignant lesions (leukoplakia and erythroplakia), malignant lesions (squamous cell carcinoma, Kaposi sarcoma, and lymphoproliferative diseases), and signs of systemic disease (nutritional deficiency and systemic amyloidosis).

Early clinical manifestations of Sézary syndrome: A multicenter retrospective cohort study

Background: Classic Sézary 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.

Chronic interstitial granulomatous dermatitis in coccidioidomycosis.

Coccidioides species are soil‐dwelling fungi endemic to the Southwest U.S.A., especially Arizona and California and Northern Mexico. The cutaneous findings of coccidioidomycosis have a wide range of pathology, which includes organism‐specific and reactive processes. Interstitial granulomatous dermatitis (IGD), a granuloma annulare‐like reaction, has been described, in a limited form, in association with acute pulmonary coccidioidomycosis. We present a case of chronic, widespread IGD spanning over 9 years in association with an active coccidioidomycosis infection. Similar clinical and histopathological features have been described in association with drug reactions, connective tissue diseases, systemic vasculitis, lymphomas, other infectious diseases and inflammatory bowel disease. Our patients dramatic presentation and chronic course expands upon the clinical spectrum of IGD occurring in association with pulmonary coccidioidomycosis. While IGD in association with coccidioidomycosis is rare, both dermatologists and general practitioners see IGD reactions, and our case highlights the importance of identifying the underlying driver.

Chemoprevention agents for melanoma: a path forward into phase 3 clinical trials

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

Treatment of epidermolysis bullosa pruriginosa using systemic and topical agents

be aware that radiosensitization may be associated with vemurafenib administration and carefully monitor patients receiving concomitant radiotherapy, as well as patients who start vemurafenib after radiotherapy. Neither radiotherapy nor vemurafenib need be stopped if radiation dermatitis develops, in that reported cases resolved without further adverse events after topical corticosteroid administration, cessation of radiotherapy, or both.

The Use of Central Pathology Review with Digital Slide Scanning in Advanced-stage Mycosis Fungoides and Sézary Syndrome

This pathology PILOT study aims to define the role and feasibility of centralized pathology review in a cohort of 75 patients from different centers in the United States and Europe using digital slide scanning. The pathologic material from 75 patients who had been diagnosed with mycosis fungoides/Sézary syndrome and were clinically staged as IIb or above was retrieved from 11 participating centers. Each pathology reviewer was provided with the pathologic diagnosis (by the referring pathologist), and the following list of histopathologic criteria (presence or absence) from the initial report: epidermotropism, folliculotropism (FT), large cell transformation, syringotropism, and granulomas. Patients with advance stage were selected for this study as this is a population where there is significant variability in the diagnosis of pathologic prognostic and predictive biomarkers. The slides were digitally scanned with an Aperio scanner and consensus review of cases occurred when major or minor discrepancies between the referral diagnosis and central pathology review occurred. Among the 75 cases, 70 (93.3%) had a final consensus diagnosis between the 3 central review pathologists. The overall agreement between the consensus review and the referring pathologist was 60%. The overall agreement was also higher between the reviewers and consensus review, compared with the referring pathologist and consensus. 65.3% of cases had some type of discrepancy (major or minor) between the outside and consensus review. Major discrepancies were seen in 34 of 73 cases (46.6%; 73 cases indicated a yes or no response). Minor discrepancies were seen in 32 of 75 (42.7%) of cases. Most of the major discrepancies were accounted by a difference in interpretation in the presence or absence of large cell transformation or FT. Most minor discrepancies were explained by a different interpretation in the expression of CD30. We found digital slide scanning to be a beneficial, reliable, and practical for a methodical approach to perform central pathology review in the context of a large clinical prospective study.

Unicentric castleman disease complicated by paraneoplastic bronchiolitis obliterans and pemphigus

Bronchiolitis obliterans (BO) and paraneoplastic pemphigus are rare and ominous complications of Castleman disease. Collectively, these processes have been reported as part of paraneoplastic autoimmune multiorgan syndrome (PAMS), and they can occur in the setting of various hematologic malignant tumors, carcinoid tumors, and melanoma. Irrespective of the underlying malignancy driving PAMS, the clinical outcomes are uniformly poor, and there are no standard treatment regimens, given the clinical rarity of the syndrome. We describe 2 patients with unicentric Castleman disease complicated by paraneoplastic pemphigus and bronchiolitis obliterans. In addition to primary surgical resection for Castleman disease, we also used therapy from a treatment protocol used for bronchiolitis obliterans resulting from hematopoietic stem cell transplant (HSCT). We were able to treat the patients using intravenous immunoglobulin; rituximab; fluticasone, azithromycin, and montelukast (FAM); and rosuvastatin therapy. One patient demonstrated a favorable response, while the other demonstrated minimal response to this therapy.