Elena B. Hawryluk

Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease

Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.

BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition

Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, “driver” oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.

Non-Infectious Granulomatous Diseases of the Skin and their Associated Systemic Diseases

Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities. As a group, they are relatively difficult to diagnose and distinguish both clinically as well as histologically. Many of these disorders have significant associations with systemic diseases that impact the patient’s overall prognosis. In this update, we offer a discussion of emerging concepts and controversies in this field, as presented through evidence-based answers to seven important clinical questions regarding palisading and epithelioid granulomata. These questions offer an opportunity to review ten non-infectious granulomatous conditions that have implications for systemic disease: granuloma annulare, annular elastolytic giant cell granuloma, necrobiosis lipoidica, methotrexate-induced accelerated rheumatoid nodulosis, necrobiotic xanthogranuloma, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, palisaded neutrophilic granulomatous dermatitis, sarcoidosis, and metastatic Crohn disease. Recent clinical, epidemiologic, and laboratory studies have shed some light on these diseases, the association of these conditions with systemic disorders, and their overall prognoses.

Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: A study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women's Cancer Center

BACKGROUND Merkel cell carcinoma (MCC) is a rare and lethal cutaneous neuroendocrine carcinoma. Imaging is crucial for accurate staging, which remains a strong predictor of survival, as well as earlier detection of recurrence and progression, which are common despite aggressive management. There is no consensus on the role of initial and subsequent imaging for MCC. OBJECTIVE We sought to evaluate the use of 2-fluoro-[(18)F]-deoxy-2-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in the management of MCC. METHODS In all, 270 FDG-PET/CT studies were performed in 97 patients with pathology-proven MCC at the Dana-Farber/Brigham and Womens Cancer Center, Boston, Mass, from August 2003 to December 2010. RESULTS FDG-PET/CT scans were obtained as part of the initial (61 scans in 61 patients) and subsequent (209 scans in 79 patients) treatment strategies. MCCs were FDG-avid with a mean maximum standardized uptake value of primary lesions of 6.5 (range 1.3-12.9) and a mean maximum standardized uptake value of regional and distant metastases of 7.2 (range 1.5-9.9). FDG-PET/CT upstaged 16% of patients who underwent baseline scans. FDG-PET/CT studies showed that bone and bone-marrow metastases were more common than previously reported, and were often undetected by CT. LIMITATIONS Our study is limited by its retrospective design, and potential referral bias associated with a tertiary care center. CONCLUSIONS FDG-PET/CT performed as part of the initial management strategy tended to upstage patients with more advanced disease. FDG-PET/CT performed as part of the subsequent treatment strategy identified metastatic disease, particularly in bone/bone marrow, which was not seen on CT. FDG-PET/CT imaging is a valuable staging and restaging tool in MCC management.

Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists

Biologic therapies targeting tumor necrosis factor (TNF)‐alpha have become a mainstay in the management of a number of autoimmune diseases. We report a series of adverse skin eruptions in six patients (four females, two males, age: 21–58 years, mean: 39) receiving 4 months to 10 years (mean 3.1 years) of anti‐TNF‐alpha therapies (infliximab, n = 4; adalimumab, n = 1 or etanercept, n = 1). The following drug‐associated diagnoses were made in eight skin biopsies performed at Massachusetts General Hospital between 3/2007 and 10/2010: pustular folliculitis, psoriasis, interface dermatitis, neutrophilic eccrine hidradenitis, Sweets syndrome, lupus, vasculitis and palmoplantar pustulosis. The descriptions of neutrophilic eccrine hidradenitis‐like and Sweets‐like hypersensitivity eruptions induced by anti‐TNF‐alpha therapies are the first such cases described in the literature. Each cutaneous eruption improved or resolved with switching to a different TNF‐alpha inhibitor, discontinuation of the anti‐TNF‐alpha agent, and/or topical or systemic steroids. There was a clear chronologic relationship with, and clinical remission upon withdrawal or steroid suppression of the anti‐TNF‐alpha agents. The mechanism for such diverse cutaneous eruptions among this class of medications remains poorly understood. The cutaneous adverse reaction profile of TNF‐alpha inhibitors is broad and should be considered in the histopathologic differential in this clinical setting.

Cutaneous Granulomatous Eruption and Successful Response to Potent Topical Steroids in Patients Undergoing Targeted BRAF Inhibitor Treatment for Metastatic Melanoma

IMPORTANCE Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective, novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported. OBSERVATIONS Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy. CONCLUSIONS AND RELEVANCE We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management.

Voriconazole phototoxicity in children: A retrospective review

BACKGROUND Voriconazole, an antifungal agent, is associated with various cutaneous reactions, including phototoxicity, accelerated photoaging, and skin cancer. Incidence and risk factors for these reactions in children have not been well described. OBJECTIVE We sought to determine the incidence of and factors associated with phototoxic reactions and nonmelanoma skin cancer in pediatric patients treated with voriconazole. METHODS This was a retrospective analysis of 430 pediatric patients treated with voriconazole between 2003 and 2013 at Boston Childrens Hospital. RESULTS Incidence of phototoxicity was 20% in all children treated with voriconazole and 47% in children treated for 6 months or longer. Factors associated with phototoxicity included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. Four patients (1%) had nonmelanoma skin cancer; all experienced a phototoxic reaction during voriconazole treatment. Of those with phototoxicity, 5% were discontinued on voriconazole, 6% were referred to dermatology, and 26% received counseling about sun protection from their primary physician. LIMITATIONS Our study is limited by its retrospective design and potential referral bias associated with a tertiary-care center. CONCLUSIONS Voriconazole-associated phototoxicity is relatively common in children and may lead to nonmelanoma skin cancer. However, those with phototoxic reactions are often continued on therapy, rarely referred to dermatology, and infrequently counseled on sun protection.

Histologically challenging melanocytic tumors referred to a tertiary care pigmented lesion clinic

BACKGROUND The histopathologic diagnosis of some melanocytic tumors is extraordinarily difficult. With this in mind, melanocytic tumors from patients referred to the Massachusetts General Hospital (MGH) Pigmented Lesion Clinic (PLC) are routinely reviewed in the MGH Dermatopathology Unit. OBJECTIVE We sought to determine the frequency of diagnostically challenging cases from patients treated at the MGH PLC, as measured by a change in the diagnosis upon review of the referral materials. METHODS We retrospectively reviewed the MGH and referral pathology reports for 478 consecutive cutaneous melanocytic tumors: 126 from 1996-1997 and 352 from 2010-2011. Differences in diagnosis and in therapeutic impact were evaluated. RESULTS Changes in diagnosis occurred in 168 of 478 cases (35%), more frequently when the original diagnostician was a general pathologist (P = .003). A similar fraction of diagnoses were changed from malignant to benign or vice versa, in both historic and contemporary cohorts. In 64 patients (13%), changes in diagnosis led to a change in therapy. Changes in stage or grading led to the most changes in therapy (78%; 50/64) versus changes from benign to malignant or vice versa (22%; 14/64). LIMITATIONS This is a retrospective study with the bias of a tertiary-care referral center. CONCLUSIONS These findings demonstrate the diagnostic difficulty of a subset of melanocytic tumors and highlight the utility of review by more than one pathologist; patient treatment is affected in more than 10% of cases. Identification of melanoma prognostic factors and melanocytic nevus grading led to clinically significant changes in diagnosis leading to a change in patient management.

Melanoma: Clinical Features and Genomic Insights

Recent efforts in genomic research have enabled the characterization of molecular mechanisms underlying many types of cancers, ushering novel approaches for diagnosis and therapeutics. Melanoma is a molecularly heterogeneous disease, as many genetic alterations have been identified and the clinical features can vary. Although discoveries of frequent mutations including BRAF have already made clinically significant impact on patient care, there is a growing body of literature suggesting a role for additional mutations, driver and passenger types, in disease pathophysiology. Although some mutations have been strongly associated with clinical phenotypes of melanomas (such as physical distribution or morphologic subtype), the function or implications of many of the recently identified mutations remains less clear. The phenotypic and clinical impact of genomic mutations in melanoma remains a promising opportunity for progress in the care of melanoma patients.

Multidisciplinary interventions in the management of atopic dermatitis

Atopic dermatitis (AD) is the most common pediatric skin disease. AD has a significant effect on patient and family quality of life caused by intense pruritus, sleep disruption, dietary and nutritional concerns, and psychological stress associated with the disease and its management. Multidisciplinary approaches to AD care have been developed in appreciation of the complex interplay among biological, psychological, behavioral, and dietary factors that affect disease control and the wide range of knowledge, skills, and support that patients and families require to effectively manage and cope with this condition. Common components of multidisciplinary treatment approaches include medical evaluation and management by an AD specialist, education and nursing care, psychological and behavioral support, and nutritional assessment and guidance. Models of care include both clinical programs and structured educational groups provided as adjuncts to standard clinical care. Available evidence suggests beneficial effects of multidisciplinary interventions in improving disease severity and quality of life, particularly for patients with moderate-to-severe disease. Additional research is needed to identify the best candidates for the various multidisciplinary approaches and evaluate the cost-effectiveness of these programs.