Work

Features of cutaneous acute graft‐versus‐host disease by reflectance confocal microscopy

Year: 2019

Type: article

Abstract: Dear Editor, Confident diagnosis of acute cutaneous graft‐versus‐host disease (aGVHD) is often challenging owing to nonspecific clinical appearance and histopathology.1 2 Biopsies from different locations on the same patient frequently differ in grade, while normal‐appearing skin may show aGVHD features.3 Serial biopsies of a single lesion are not possible. Some clinicians advocate empirical treatment in lieu of skin biopsies, particularly when they lack the ability to make an informed site selection, for reasons of timing or when serial noninvasive microscopic monitoring is not possible.4 In vivo reflectance confocal microscopy (RCM), shown to be of proven value in many skin diseases,5 might offer some of these missing insights and has been considered for aGVHD.6 A description of RCM features in patients is the next essential step towards evaluating possible clinical utility. To create a consensus understanding and initial description of the features of aGVHD visible by RCM, we convened a panel of experts (S.G., M.A., M.G., E.R.T. and C.A‐F.), including an RCM‐trained dermatopathologist (M.G.). We retrospectively reviewed all upper chest RCM cases from the Vanderbilt transplant programme with a clinical diagnosis of aGVHD rendered by a transplant physician. We included only patients whose biopsy, taken immediately from the RCM site, was consistent with aGVHD. Patients already treated for aGVHD were excluded. This yielded five patients (three male, two female) aged 54–70 years, 22–34 days after haematopoietic cell transplantation for acute myeloid leukaemia (n = 2) and myelodysplastic syndrome (n = 3). Skin biopsies showed Lerner7 grade two (4/5 cases) or grade three (1/5). The panel had 20 videoconferences (seven with most experts present). Additionally, E.R.T. had five in‐person data review meetings with one or more coauthors at the World Congress of Confocal Microscopy in Rome. Full datasets (histopathology, clinical history, images, and four to six 64‐mm2 RCM blocks per case) were available to the panel and were frequently consulted throughout this process. Through a modified Delphi method (without total anonymity), we resolved points of disagreement and agreed on a glossary of the essential features, and also agreed on specific terminology to describe them. E.R.T. and I.S. then jointly reconfirmed the presence or absence of each feature in all five RCM datasets. We assessed the following features based on the previously published RCM descriptions: (i) spongiosis (present in 4/5 cases by RCM, 3/5 by histopathology); (ii) exocytosis (5/5, 3/5); (iii) dermal inflammation (5/5, 5/5); (iv) vesicles (1/5, 2/5) and (v) obscured dermoepidermal junction (DEJ) (1/5 by RCM).8 By contrast, our consensus created or refined the following definitions: (vi) irregular honeycomb – the epidermal honeycomb architecture is visible but irregular in terms of the size and/or shape of cells (5/5 by RCM); (vii) disarranged epidermis – the epidermal architecture is so severely abnormal that it is difficult to see any honeycomb pattern (2/5 by RCM); (viii) vacuolization – cell‐sized dark holes in the epidermis and/or at the DEJ (5/5, 5/5); (ix) necrotic keratinocytes – variably bright, homogenized usually round but may be bizarrely shaped structures that fit within the epidermal pattern but appear disconnected from the surrounding epithelium (5/5, 5/5); (x) satellite necrosis – necrotic keratinocytes that are physically touching one or more adjacent lymphocytes (5/5, 5/5); (xi) periadnexal inflammation and necrosis – inflammatory cells (4/5, 4/5) or necrotic keratinocytes (4/5, 2/5) within two to three cells of adnexae; (xii) colloid bodies – light grey, homogenous and uniform round aggregated structures (typically consisting of individual 15–25‐μm elements) just beneath the epidermis (2/5, 2/5) and (xiii) prominent vessels – vessels that appear more pronounced than in normal skin, either owing to larger than usual dark lumina, or increased density or movement of variably bright, variably sized bright structures (3/5, 2/5). The most prominent RCM features of aGVHD (present in at least 4/5 cases) are spongiosis, irregular honeycomb, vacuolization, necrotic keratinocytes (including periadnexal and satellite necrosis), and epidermal, dermal and periadnexal inflammation. Several features, such as irregular honeycomb pattern, epidermal disarrangement and exocytosis (especially in effaced epidermis), are more readily visible in en face RCM views than on traditional vertical section histopathology. Because numerous adnexal structures are typically visible on the 8 × 8 mm2 horizontal sections, RCM enables a thorough examination of their involvement, which is a valuable, but nonspecific histopathological finding. Although we observed the main aGVHD histopathological features by RCM, as in histopathology, they may not be specific to aGVHD. Additionally, RCM cannot distinguish eosinophils from other granulocytes. In summary, we have created and validated in five patients a glossary defining the RCM features of aGVHD (numbered in the list above and Fig. 1). The following RCM features were present in all cases: irregular honeycomb, vacuolization, necrotic keratinocytes, satellite necrosis, exocytosis and dermal inflammation. This work will aid future studies that aim to improve patient care by monitoring aGVHD evolution and response to treatment over time. Reflectance confocal microscopy (RCM) features of acute graft‐versus‐host disease in a 66‐year‐old male, 28 days post‐transplant for myelodysplastic syndrome from a match‐related female donor. (a, b) Clinical and dermatoscopic photograph including the biopsy site (blue) and the RCM imaging site (white square). (c) Corresponding histopathology showing basilar and suprabasilar vacuolization (focally bordering on vesiculation), necrotic keratinocytes, keratinocytic nuclear pleomorphism (likely induced by chemotherapy), a sparse exocytosis, interface and dermal inflammation, and solar elastosis. (d) Satellite necrosis, a necrotic keratinocyte (arrowhead) adjacent to a lymphocyte (arrow). (e) Colloid bodies (arrowheads). (f) Irregular honeycomb (focally disarranged), lymphocytes (arrows) in the epidermis (exocytosis), and necrotic keratinocytes (arrowheads). Keratinocyte pleomorphism is also noted as in histopathology. Presence of vacuolization (v), cell‐sized dark holes; these are sometimes referred to as ‘signet rings’. Obscured dermoepidermal junction, periadnexal inflammation and necrosis, dermal inflammation, and prominent vessels in the dermis were also present. A more comprehensive figure with additional images can be provided on direct request to the corresponding author. Funding sources: the work was supported by the Vanderbilt University Medical Center Department of Medicine, Career Development Award Number IK2 CX001785 from the United States Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service, and the National Institutes of Health Grant K12 CA090625 to E.R.T. Conflicts of interest: M.G. is a consulting investigator on an investigator‐initiated study sponsored by DBV Technologies. C.A‐F. is an employee and a shareholder of Caliber Imaging and Diagnostics Inc, the company that manufactures and sells the VivaScope confocal microscope. S.G. is a scientific advisory board member of Caliber ID. E.R.T. has served as a paid scientific advisory board member for graft‐versus‐host disease biomarker development to Incyte Corporation.

Source: British Journal of Dermatology

DOI: 10.1111/bjd.17921