Michi M. Shinohara

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

BACKGROUND Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. RESULTS A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. CONCLUSIONS In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).

Cutaneous Inoculation of Nontuberculous Mycobacteria During Professional Tattooing: A Case Series and Epidemiologic Study

BACKGROUND  The increase in popularity of tattoos has coincided with an increase in reports of cutaneous inoculation of nontuberculous (atypical) mycobacteria (NTM) during the tattooing process. We report 3 NTM infections in otherwise healthy persons who received tattoos, which prompted a multiagency epidemiologic investigation. METHODS  Tattoo artists involved were contacted and interviewed regarding practices, ink procurement and use, and other symptomatic clients. Additional patients were identified from their client lists with an Internet survey. RESULTS  Thirty-one cases of suspected or confirmed NTM inoculation from professional tattooing were uncovered, including 5 confirmed and 26 suspected cases. Clinical biopsy specimens from 3 confirmed infections grew Mycobacterium abscessus strains that were indistinguishable by pulsed-field gel electrophoresis testing. Another 2 skin specimens grew Mycobacterium chelonae, which also grew from a bottle of graywash ink obtained from the tattoo artist. CONCLUSIONS  The pathogenicity and antibiotic resistance patterns of certain NTM isolates highlight the importance of correct diagnosis and potential difficulty in treating infections. Enforcement of new standards for the regulation and use of tattoo inks should be considered.

The histopathologic spectrum of decorative tattoo complications

Tattooing for ornamental purposes is an ancient practice that remains popular in modern times. Tattoos are encountered by the dermatopathologist either as incidental findings on skin biopsies or because of complications specific to the tattoo. A range of neoplasms and inflammatory conditions are seen in association with tattoos, many of which may be attributed to hypersensitivity to tattoo inks. The composition of tattoo inks is highly variable, and inks can contain numerous potentially allergenic or carcinogenic compounds. Infections with bacterial, viral and fungal species can occur after tattooing, sometimes after substantial delay. Atypical mycobacterial infections in particular are increasingly reported; special stains for mycobacteria should be performed and cultures recommended particularly when dense, mixed or granulomatous infiltrates are present.

Complications of Decorative Tattoos: Recognition and Management

Tattooing is an ancient practice that enjoys continued popularity. Although a modern, professionally performed tattoo is generally safe, complications can occur. A skin biopsy of all tattoo reactions is recommended as some tattoo reactions have systemic implications. Tattoo-related infections are seen days to decades after tattooing, and range from acute pyogenic infections to cutaneous tuberculosis. In particular, non-tuberculous mycobacterial infections happen in tattoos with increasing frequency and are introduced at the time of tattooing through contaminated ink or water used to dilute inks. Despite a transition in tattoo pigments from metal salts to industrial azo dyes, hypersensitivity reactions also persist, and include eczematous, granulomatous, lichenoid, and pseudoepitheliomatous patterns (among others). Granulomatous tattoo reactions can be a clue to cutaneous or systemic sarcoidosis, particularly in the setting of interferon use. Pseudoepitheliomatous tattoo reactions have substantial overlap with squamous cell carcinoma and keratoacanthoma, making diagnosis and management difficult. Other malignancies and their benign mimics can occur in tattoos, raising questions about the safety of tattoo ink and its role in carcinogenesis.

WLS inhibits melanoma cell proliferation through the β-catenin signalling pathway and induces spontaneous metastasis.

Elevated levels of nuclear β‐catenin are associated with higher rates of survival in patients with melanoma, raising questions as to how ß‐catenin is regulated in this context. In the present study, we investigated the formal possibility that the secretion of WNT ligands that stabilize ß‐catenin may be regulated in melanoma and thus contributes to differences in ß‐catenin levels. We find that WLS, a conserved transmembrane protein necessary for WNT secretion, is decreased in both melanoma cell lines and in patient tumours relative to skin and to benign nevi. Unexpectedly, reducing endogenous WLS with shRNAs in human melanoma cell lines promotes spontaneous lung metastasis in xenografts in mice and promotes cell proliferation in vitro. Conversely, overexpression of WLS inhibits cell proliferation in vitro. Activating β‐catenin downstream of WNT secretion blocks the increased cell migration and proliferation observed in the presence of WLS shRNAs, while inhibiting WNT signalling rescues the growth defects induced by excess WLS. These data suggest that WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/β‐catenin signalling.

Tumor-infiltrating merkel cell polyomavirus-specific T cells are diverse and associated with improved patient survival

Merkel cell carcinoma patients had improved survival if their tumors contained a greater frequency or diversity of T cells that were specific for a prevalent Merkel cell polyomavirus epitope. Thus, transgenic T-cell receptor therapy could potentially benefit patients. Tumor-infiltrating CD8+ T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8+ T-cell infiltration is robust in only 4% to 18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, “KLL”) and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome. HLA-A*02:01/KLL tetramer+ CD8+ T cells from MCC patient peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) were isolated via flow cytometry. TCRβ (TRB) sequencing was performed on tetramer+ cells from PBMCs or TILs (n = 14) and matched tumors (n = 12). Functional avidity of T-cell clones was determined by IFNγ production. We identified KLL tetramer+ T cells in 14% of PBMC and 21% of TIL from MCC patients. TRB repertoires were strikingly diverse (397 unique TRBs were identified from 12 patients) and mostly private (only one TCRb clonotype shared between two patients). An increased fraction of KLL-specific TIL (>1.9%) was associated with significantly increased MCC-specific survival P = 0.0009). T-cell cloning from four patients identified 42 distinct KLL-specific TCRa/b pairs. T-cell clones from patients with improved MCC-specific outcomes were more avid (P < 0.05) and recognized an HLA-appropriate MCC cell line. T cells specific for a single MCPyV epitope display marked TCR diversity within and between patients. Intratumoral infiltration by MCPyV-specific T cells was associated with significantly improved MCC-specific survival, suggesting that augmenting the number or avidity of virus-specific T cells may have therapeutic benefit. Cancer Immunol Res; 5(2); 137–47. ©2017 AACR.

Scedosporium apiospermum: an emerging opportunistic pathogen that must be distinguished from Aspergillus and other hyalohyphomycetes.

We report a case of cutaneous Scedosporium apiospermum infection in an immunocompromised host. S.apiospermum is an emerging opportunistic pathogen, especially in organ transplant recipients. Prompt identification is critical because of its resistance to most antifungal drugs. Its histopathologic features are indistinct and overlap with those of more commonly recognized hyalohyphomycetes such as Aspergillus species. Cultures from infected tissue are generally required for correct identification. Clinicians and pathologists must be familiar with this organism and recognize the need for culture studies in addition to histopathology in the evaluation of specimens from immunocompromised patients with suspected fungal infection.

Equestrian perniosis: a report of 2 cases and a review of the literature.

Equestrian perniosis (EP) is a rare condition in which patients develop tender burning nodular plaques on their bilateral thighs after riding in the cold. These lesions tend to resolve rapidly with minimal exposure to cold, and wearing loose, layered warm clothing. Unlike acral perniosis, EP has no known systemic disease associations, although 2 reported cases did have elevated cold agglutinins. The histology of this disease is similar to perniosis; however, EP is distinct in that the perivascular lymphocytic infiltrate prominently involves the fat. In this case report, we discuss the clinical and histological findings in 2 cases of EP, including the first documented in a man.

Direct-acting antiviral-associated dermatitis during chronic hepatitis C virus treatment.

Telaprevir and boceprevir are novel protease inhibitors recently approved for treatment of chronic hepatitis C virus infection, and have gained widespread use. Skin rash has been reported frequently in patients treated with telaprevir, but less commonly with boceprevir. Despite a high incidence in clinical trials, the telaprevir-related eruption has not been fully described in the literature. We describe six patients treated with telaprevir and three treated with boceprevir who developed skin rash related to the antiviral medication. Four patients treated with telaprevir developed laboratory abnormalities and/or systemic symptoms and five required discontinuation of their antiviral medication because of these adverse effects, including two patients who fit criteria for drug reaction with eosinophilia and systemic symptoms (DRESS). Patients with boceprevir-related rash had a milder course and none required discontinuation of the medication. This report confirms that cutaneous adverse effects from telaprevir and boceprevir are common. Patients treated with telaprevir may have a more severe course and more frequently require discontinuation of their antiviral therapy due to extensive rash or laboratory abnormalities. Dermatologists must be aware of these cutaneous adverse effects, as early intervention with topical corticosteroids and antihistamines may minimize the severity of the eruption and allow patients to complete antiviral therapy.

Cutaneous metastatic breast carcinoma with clear cell features.

Breast carcinoma remains one of the most common sources of skin metastases in women. Cutaneous breast carcinoma metastases have variable clinical and histopathologic presentations that can make diagnosis challenging. We report a unique case of metastatic breast carcinoma with prominent clear cell features, thus mimicking a xanthomatous process. Dermatopathologists should be aware of this entity given its resemblance to other clear cell infiltrates and neoplasms.