Rapid visualization of nonmelanoma skin cancer

Background: Mohs micrographic surgery examines all margins of the resected sample and has a 99% cure rate. However, many nonmelanoma skin cancers (NMSCs) are not readily amenable to Mohs micrographic surgery. This defines an unmet clinical need to assess the completeness of non‐Mohs micrographic surgery resections during surgery to prevent re‐excision/recurrence. Objective: We sought to examine the utility of quenched activity‐based probe imaging to discriminate cancerous versus normal‐appearing skin tissue. Methods: The quenched activity‐based probe GB119 was applied to NMSC excised from 68 patients. We validated activation of the probe for hematoxylin‐eosin–confirmed cancerous tissue versus normal‐appearing skin tissue. Results: Topical application of the probe differentiated basal cell carcinoma and squamous cell carcinoma from normal‐appearing skin with overall estimated sensitivity and specificity of 0.989 (95% confidence interval 0.940‐1.00) and 0.894 (95% confidence interval 0.769‐0.965), respectively. Probe activation accurately defined peripheral margins of NMSC as compared with conventional hematoxylin‐eosin–based pathology. Limitations: This study only examined NMSC debulking excision specimens. The sensitivity and specificity for this approach using final NMSC excision margins will be clinically important. Conclusions: These findings merit further studies to determine whether quenched activity‐based probe technology may enable cost‐effective increased cure rates for patients with NMSC by reducing re‐excision and recurrence rates with a rapid and easily interpretable technological advance. Graphical abstract Figure. No caption available.

[1]  H. Okabe,et al.  Cathepsin K expression in basal cell carcinoma , 2013, Journal of the European Academy of Dermatology and Venereology : JEADV.

[2]  Matthew Bogyo,et al.  Activity-based probes that target diverse cysteine protease families , 2005, Nature chemical biology.

[3]  Georges von Degenfeld,et al.  Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes. , 2007, Nature chemical biology.

[4]  C. Lawrence,et al.  Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. , 2003, The British journal of dermatology.

[5]  Bonnie F. Sloane,et al.  Cysteine cathepsins in human cancer , 2004, Biological chemistry.

[6]  Cecelia E Schmalbach,et al.  On the horizon: Optical imaging for cutaneous squamous cell carcinoma , 2016, Head & neck.

[7]  Hisataka Kobayashi,et al.  Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe , 2012, Gut.

[8]  Kinneret Keren,et al.  Dynamic imaging of protease activity with fluorescently quenched activity-based probes , 2005, Nature chemical biology.

[9]  S. Feldman,et al.  Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. , 2015, JAMA dermatology.

[10]  E. Rosenthal,et al.  Use of Panitumumab-IRDye800 to Image Cutaneous Head and Neck Cancer in Mice , 2013, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[11]  M. Bogyo,et al.  A nonpeptidic cathepsin S activity-based probe for noninvasive optical imaging of tumor-associated macrophages. , 2012, Chemistry & biology.

[12]  R. Carroll,et al.  Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. , 1992, Journal of the American Academy of Dermatology.

[13]  Peter L. Choyke,et al.  Rapid Cancer Detection by Topically Spraying a γ-Glutamyltranspeptidase–Activated Fluorescent Probe , 2011, Science Translational Medicine.

[14]  Andrew E. Sloan,et al.  Topical Application of Activity-based Probes for Visualization of Brain Tumor Tissue , 2012, PloS one.

[15]  P. Robins Mohs micrographic surgery. , 1993, The Journal of dermatologic surgery and oncology.

[16]  F. Mohs Chemosurgical treatment of cancer of the skin; a microscopically controlled method of excision. , 1944, Journal of the American Medical Association.

[17]  Y. Ghavami,et al.  Evaluation of diagnostic values of photodynamic diagnosis in identifying the dermal and mucosal squamous cell carcinoma. , 2012, Photodiagnosis and photodynamic therapy.

[18]  K. Hara,et al.  Cathepsin B and D expression in squamous cell carcinoma , 1996, The British journal of dermatology.

[19]  E. Fröhlich,et al.  Cathepsins in basal cell carcinomas: activity, immunoreactivity and mRNA staining of cathepsins B, D, H and L , 2004, Archives of Dermatological Research.

[20]  B. Coldiron,et al.  AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. , 2012, Journal of the American Academy of Dermatology.

[21]  M. Bogyo,et al.  A selective activity-based probe for the papain family cysteine protease dipeptidyl peptidase I/cathepsin C. , 2006, Journal of the American Chemical Society.

[22]  D. Kuijpers,et al.  Basal Cell Carcinoma , 2002, American journal of clinical dermatology.

[23]  Ki-Hoon Song,et al.  Efficacy of Photodynamic Diagnosis‐Guided Mohs Micrographic Surgery in Primary Squamous Cell Carcinoma , 2013, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[24]  Anthony J. Durkin,et al.  In vivo Fluorescence Spectroscopy of Nonmelanoma Skin Cancer¶ , 2001, Photochemistry and Photobiology.

[25]  Brett M. Coldiron,et al.  Incidence estimate of nonmelanoma skin cancer in the United States, 2006. , 2010, Archives of dermatology.

[26]  M. Bogyo,et al.  Design of cell-permeable, fluorescent activity-based probes for the lysosomal cysteine protease asparaginyl endopeptidase (AEP)/legumain. , 2007, Bioorganic & medicinal chemistry letters.

[27]  M. Bogyo,et al.  Microscopic Detection of Quenched Activity-Based Optical Imaging Probes Using an Antibody Detection System: Localizing Protease Activity , 2014, Molecular Imaging and Biology.

[28]  J. L. Smith,et al.  Incidence Estimate of Nonmelanoma Skin Cancer in the United States, 2006 , 2011 .

[29]  T Yamamoto,et al.  Expression of cathepsin D and B in invasion and metastasis of squamous cell carcinoma , 1997, The British journal of dermatology.

[30]  M. Bogyo,et al.  Detection of intestinal cancer by local, topical application of a quenched fluorescence probe for cysteine cathepsins. , 2015, Chemistry & biology.

[31]  B. Peat,et al.  Excision Margins for Nonmelanotic Skin Cancer , 2003, Plastic and reconstructive surgery.

[32]  R. Griffiths,et al.  Audit of histologically incompletely excised basal cell carcinomas: recommendations for management by re-excision. , 1999, British journal of plastic surgery.

[33]  Désirée Ratner,et al.  Current concepts : Basal-cell carcinoma , 2005 .

[34]  M. Bogyo,et al.  Enzyme activity--it's all about image. , 2004, Trends in cell biology.