REVIEW ARTICLE
Advances in Diagnosis and Treatment of Nonmelanoma Skin Cancer Omer Ibrahim, MD, Brian Gastman, MD, PhD, and Alexandra Zhang, MD Abstract: The incidence of nonmelanoma skin cancer (NMSC) is rising. Research in the field of these tumors is aimed toward developing earlier and less invasive diagnostic methods and more effective, more accessible therapeutic options. Although there is much advancement in the diagnosis and treatment of NMSC, there are few literatures cataloging these developments. The aim of this review was to present the sensitivity and specificity of new imaging modalities, the dosing regimen and clearance rates of topical treatments, newer systemic treatment modalities, and discuss developments in the use of radiation as a mode of therapy. Recent developments in the diagnosis of NMSC include imaging modalities such as reflectance confocal microscopy, elastic scattering spectroscopy, and spectrophotometric intracutaneous analysis. Recent advances in the treatment of these tumors include systemic therapies such as epidermal growth factor receptor inhibitors, and topical immunomodulating drugs such as imiquimod. The progress in the diagnosis and treatment of these tumors is a gradual but fruitful growth. Scientists and clinicians alike must continue their exploration and study to address these tumors and, hopefully in the future, prevent their occurrence. Key Words: nonmelanoma skin cancer, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, actinic keratosis, advances, diagnosis, treatment (Ann Plast Surg 2014;73: 615Y619)
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onmelanoma skin cancer (NMSC) is the most common form of malignancy in humans and represents almost 95% of all cutaneous cancers.1 The worldwide incidence of NMSC has increased by 3% to 8% every year.2 Nearly 3.5 million people in the United States were diagnosed with NMSC in 2006, and the incidence of NMSC in the United States may increase by 50% by the year 2030.3,4 Given the steady rise in the incidence of NMSC, researchers and clinicians alike are striving toward earlier, more accurate, less invasive diagnostic methods, and more effective, more accessible therapeutic options, especially in recurrent, advanced, or metastatic disease. Although there is much advancement in the diagnosis and treatment of NMSC, there are few literatures cataloging them. The aim of this review was to present the sensitivity and specificity of new imaging modalities, the dosing regimen and clearance rates of topical treatments, newer systemic treatment modalities, and discuss developments in the use of radiation as a mode of therapy. The resulting compilation not only will allow the readers to understand the current state of options but also will serve as a basis for design of the next set of developments.
Received March 31, 2014, and accepted for publication, after revision, July 15, 2014. From the Dermatology and Plastic Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH. Conflicts of interest and sources of funding: none declared. Reprints: Omer Ibrahim, MD, Dermatology and Plastic Surgery Institute, Cleveland Clinic Foundation, A61, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Omer Ibrahim, MD, executed the first working draft of the manuscript; Brian Gastman, MD, PhD, executed major revisions, deletions, and additions to the first draft; and Alexandra Zhang, MD, executed major revisions and additions, and designed the tables. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7305-0615 DOI: 10.1097/SAP.0000000000000330
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METHODS PubMed searches separately containing the following phrases: ‘‘actinic keratosis,’’ ‘‘squamous cell carcinoma,’’ ‘‘basal cell carcinoma,’’ and ‘‘Merkel cell carcinoma’’ in conjunction with the phrase ‘‘diagnosis’’ or ‘‘treatment,’’ were conducted to include publications from January 1, 2004, to December 31, 2013. Case reports, review articles, and experimental trials including retrospective and prospective trials were all reviewed for relevant data on the newer and novel clinical diagnostic and treatment modalities being investigated and implemented in the realm of these tumors. The primary tumor sites especially in squamous cell carcinoma (SCC) were reserved to the skin. The resultant articles were further categorized based on level of evidence and number of reported cases. Diagnostic or treatment modalities that were reported with 2 or less cases were eliminated due to insufficient data. In contrast, diagnostic or treatment modalities with 3 or more cases in the literature were selected for further investigation, and were additionally narrowed down based on level of evidence, resulting in more detailed review of articles with higher levels of evidence.
RESULTS Our initial search yielded 1198 publications. Table 1 summarizes the general results of our literature search, including numbers of articles or trials found, our assigned level of evidence associated with each modality, dates of reports, and their countries of origin.
Newer and Emerging Modalities in the Diagnosis of NMSCs Imaging for Primary Diagnosis of Tumors A widely studied diagnostic modality in the evaluation of NMSCs is ref lectance confocal microscopy (RCM). Ref lectance confocal microscopy has been investigated mainly in the diagnosis of basal cell carcinoma (BCC). This technique uses laser at nearinfrared wavelength to image human skin, delivering sections of the skin with good contrast and resolution without the need for invasive biopsies.5 Most of the literature regarding RCM and NMSC has described the diagnostic features and patterns of BCCs, as well as actinic keratoses (AKs) when evaluated with RCM imaging.6 In addition, 1 study describes certain RCM imaging features specific to SCC that included an atypical honeycomb or disarranged pattern of the spinous-granular layer, round nucleated cells at the spinous-granular layer, and round blood vessels traversing through the dermal papillae.7 However, the hyperkeratosis and ulceration typically seen with SCCs represent significant limitations for evaluation with RCM. Additional studies have demonstrated success of RCM in differentiating pigmented BCCs from melanoma.8,9 Finally, RCM might be used not only in the diagnosis of NMSCs but also possibly in the monitoring of the efficacy of noninvasive or minimally invasive treatment for these tumors, such as cryotherapy or photodynamic therapy.6,10 Several other imaging techniques have been investigated to aid in the primary diagnosis of NMSCs, including elastic scattering spectroscopy, spectrophotometric intracutaneous analysis, optical coherence tomography (OCT), high-definition OCT, and Raman spectroscopy. Elastic scattering spectroscopy uses a lamp that emits a wavelength from 330 to 750 nm to interrogate lesions suspicious of BCC; the system senses the
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TABLE 1. Summary of Literature Search on Diagnosis and Treatment of NMSC Therapeutic Modality
Relevant Publications (n) Level of Evidence Dates of Publication*
Novel diagnostic modalities Reflex confocal microscopy Elastic scattering spectroscopy Spectrophotometric intracutaneous analysis Optical coherence tomography High-definition optical coherence tomography Raman spectroscopy Novel therapeutic modalities Imiquimod Ingenol mebutate Vismodegib and BCC Cetuximab and SCC Capecitabine and SCC
Countries of Origin
100+ 4 3 70 6 35
Level II-1 Level II-2 Level II-3 Level II-1 Level II-3 Level II-2
2004Y2013 2012 2007 2004Y2013 2012, 2013 2004Y2013
United States, among many others United Kingdom, Turkey United Kingdom, Sweden United States, among many others Germany, France, Belgium United Kingdom, Canada, among others
100+ 35 100+ 100+ 25
Level I Level I Level II-1 Level II-1 Level II-1
2004Y2013 2005Y2013 2009Y2013 2004Y2013 2004Y2013
United States, among many others United States, among many others United States, among many others United States, among many others United States, among many others
*Dates within January 1, 2004, to December 31, 2013 search criteria.
scattering and absorptive properties of the tissue in question, generating a wavelength-dependent plot that imitates the structure of the tissue.11 SIAscopy is a commercially available system that emits radiation ranging from 400 to 1000 nm to produce images in real time, giving information regarding total melanin content of the skin, and has been mainly investigated in the diagnosis of melanoma. One study by Tehrani and colleagues12 demonstrated marked success in differentiating NMSC from benign tumors using SIAscopy. Optical coherence tomography, also commercially available, uses infrared radiation and real-time measurement of the backscatter and reflective properties of the tissue in question, creating cross-sectional 2-dimensional and 3-dimensional images. This technique is successful in distinguishing NMSC from normal skin; however, AK/SCC cannot be distinguished easily from BCC, nor can subtypes of BCC be differentiated.13 High-definition OCT uses the same principles as conventional OCT; however, these newer commercially available systems provide greater resolution and enhanced ability to differentiate between types of NMSC (AK/SCC vs BCC), as well as between different subtypes of BCC.14Y16 Raman spectroscopy uses a monochromatic light source in the visible, near-infrared, or near-UV range, and measures the inelastic scattering properties of the tissue in question. In addition to its use in melanoma, Raman spectroscopy has also shown success in accurate diagnosis of BCC and its differentiation from melanoma.17,18 Table 2 summarizes the key properties of these diagnostic imaging modalities.
Imaging for Staging of High-Risk or Metastatic Tumors The accurate evaluation of high-risk NMSCs is a field of intense interest and extensive research. Despite the scant reports, one interesting and possible key imaging modality in the future deserves attention. Fluorodeoxyglucose positron emission tomographyYcomputed tomography (FDG-PET/CT) imaging is an imaging modality that allows
for system-wide scanning to detect and monitor malignancies. Although mainly used in malignant melanoma, this technique has recently been applied to the evaluation and staging of aggressive NMSCs. In 1 study, 20 patients with Merkel cell carcinoma (MCC) were evaluated with imaging technique, and 4 (20%) had major changes in their medical plans due to new information gathered through FDG-PET/CT imaging, whether it was newly detected metastases, newly detected lymph node involvement, or lack of detected visceral metastases when initially presumed to be existent.20 Another report showed that this technique tended to upstage patients with more advanced MCC, detecting metastases, particularly in bone/bone marrow, that were not picked up on conventional ultrasound-CT scan workup algorithm.21 Thus, although this imaging technique may be more expensive and with higher false-positive rates than the traditional route of ultrasoundguided lymph node imaging followed by CT scan, it may be prudent to use this imaging modality before lymph node biopsy for high-risk patients such as the chronically immunosuppressed or in cases of highrisk malignancies.21
Molecular Evaluation In the realm of molecular-based diagnosis of NMSCs, one field of research stands far beyond any other in terms of extent of investigation and evolution: the Merkel cell polyomavirus (MCPyV). The MCPyV is a newly described polyomavirus that monoclonally integrates into approximately 80% of human MCCs. Iwasaki and colleagues standardized several morphological characteristics of MCPyV-positive MCCs on hematoxylin and eosin. The study on CM2B4 immunostaining in the MCCs showed 100% specificity and 94% sensitivity for MCPyV detection.22 Also, MCPyV status of the MCC can be confirmed with real-time polymerase chain reaction. The significance of MCPyV remains a topic of extensive debate.
TABLE 2. Novel Optical Diagnostic Modalities in the Diagnosis of NMSC Method
Tumor Studied
Sensitivity, %
Specificity, %
References
Reflex confocal microscopy Elastic scattering spectroscopy Spectrophotometric intracutaneous analysis Optical coherence tomography High-definition optical coherence tomography Raman spectroscopy
BCC, AK, SCC BCC, SCC SCC, BCC, AK BCC, AK BCC, AK BCC
82.9Y100 (BCC) 84Y88 94.6Y99.1 79Y94 76 81Y99
88.5Y95.7 (BCC) 74Y89 81.2Y91.9 85Y96 64 76Y94
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Currently, MCCs are staged based on 2 factors: size of the tumor and extent of disease spread at diagnosis.22 Some researchers believe that MCPyV status of a MCC predicts its behavior and some research has shown that MCPyV-positive MCCs have less metastatic potential and better prognoses than MCPyV-negative MCC.22 However, another study reported conf licting results.23 The significance of MCPyV status of an MCC is a controversial area of investigation and will continue to generate future research in that realm.
Tissue Sampling The standard tissue sampling techniques in dermatologic practice include biopsies (shave, punch, wedge, etc) and excisions. In recent years, although fine-needle aspiration (FNA) has been widely used in the surgical realm, it has made its way into dermatologic practice, at least through anecdotal reports. Kalogeraki and colleagues reported a successful sampling using FNA of an eccrine porocarcinoma, a rare and malignant sweat gland neoplasm. They showed that FNA can be a safe, convenient, and effective method of diagnosis.24 In another report, FNA was successfully used to sample a granular cell tumor of the tongue; the authors presented a safe, effective, and repeatable technique for the sampling of oral lesions.25
Newer and Emerging Therapeutic Options for the Treatment of NMSCs
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radiation.27 In one randomized study, patients with locally advanced SCC of the head and neck treated with cetuximab and radiation demonstrated an overall response rate of 74% in contrast to 64% in patients treated with radiotherapy alone.28 Recent evidence has also shown that cetuximab in combination with platinum-based chemotherapy and 5-f luorouracil (5-FU) is a promising therapeutic regimen in metastatic SCC of the head and neck.29 In addition to EGFRIs, studies are underway to investigate the efficacy of antibodies against vascular endothelial growth factor receptor including bevacizumab and other tyrosine kinase inhibitors including sorafenib and sunitinib in the treatment of SCC.27 Additionally, capecitabine has been shown in several studies and reports to be of benefit in the treatment of advanced or recurrent SCC of the head and neck. Capecitabine is a prodrug that is converted to 5-FU in tumor tissue, mimicking continuous 5-FU infusion, and ultimately inhibits DNA synthesis.30 In one study by Gupta and colleagues,30 patients treated with cisplatin/capecitabine combination showed better overall response rate, fewer nodes, and better rate of complete response, than patients treated with cisplatin/5-FU; overall, 3-year survival rates were not significantly different but the capecitabine treatment group demonstrated greater improvements in quality of life.
Noninvasive Treatment
Systemic Treatment Chemotherapy has emerged on the forefront in the management of advanced, aggressive, or metastasized NMSCs. In the case of BCC, vismodegib, an inhibitor of the hedgehog (Hh) pathway, was recently approved for the treatment of refractory advanced or metastatic disease. The Hh pathway is inactive in most normal adult tissue; it is composed of patched-1 (PTCH), a transmembrane receptor, which normally exhibits an inhibitory effect on smoothened (SMO), a transmembrane protein.26 In most BCCs, PTCH is dysfunctional, and thus cannot exert its normal inhibitory effect on SMO, and in its now aberrant active form, SMO induces a complex intracellular pathway that ultimately triggers cellular replication and formation of BCC.26 Vismodegib acts as an SMO inhibitor, preventing the intracellular cascade that ultimately results in BCC proliferation. Among several similar reports, a phase I trial of 33 patients with refractory advanced or metastasized BCC, there was an overall 58% response, either partial or complete, and the duration of response was 12.8 months and ongoing, demonstrating the important therapeutic strategy of Hh inhibition in the treatment of BCC.26 In SCC, especially of the head and neck, there is an overexpression of epidermal growth factor receptors (EGFR).27 Cetuximab, an EGFR inhibitor (EGFRI), has shown promise in the treatment of locally advanced, metastatic, or recurrent SCC of the head and neck, and is the only targeted EGFRI to receive US Food and Drug Administration (FDA) clearance for use in localized disease in combination with
Topical Therapy Imiquimod, a topical immunomodulator, is a novel noninvasive option in the treatment of NMSC. Imiquimod activates toll-like receptor 7 (TLR 7), which in turn triggers a cellular immune response.31 TLR 7 is responsible for the up-regulation of hundreds of different cytokines, including interferon >, tumor necrosis factor >, and interleukin 12.32 This inf lammatory cascade induces apoptosis of neoplastic cells. Imiquimod 5.0% is approved by the FDA to treat nonfacial superficial BCC.31 Imiquimod 5% is also used to treat SCC in situ and AKs.33Y35 Limitations of therapy with imiquimod for NMSC include high rates of adverse effects (erythema, pruritus, and pain), lower clearance rates compared to other treatment modalities especially with larger tumors like nodular BCC, lack of border control, and variability of patient adherence to application of the medication.33 Another topical modality that has been investigated for its use in the treatment of NMSC is ingenol mebutate, a natural substance found in the sap of the plant Euphorbia peplus. Ingenol mebutate has shown cytotoxic activity against SCC and BCC, and was FDA approved in 2012 for the treatment of AKs.36Y39 Table 3 summarizes the newer topical modalities and their respective efficacies and applications. Radiotherapy Helical tomotherapy (HT) is a form of CT-guided intensity modulated radiation therapy. The basic principles of HT involve the use of helical or spiral imaging of the tumor from several angles all the way around a patient in a setup position; then, a 3-dimensional
TABLE 3. Novel Topical Modalities in the Treatment of NMSC Topical Treatment
Tumor Studied
Dosing Regimen
Clearance Rate, %
References
Imiquimod 5%
Superficial BCC Nodular BCC SCC in situ AK AK AK AK SCC in situ Superficial BCC
3Y7 times per week for 6Y12 wk 3Y7 times per week for 6Y12 wk 3Y7 times per week for 6Y16 wk 2Y3 times per week for 16 wk Once daily for 2Y3 wk on, 2Y3 wk off, 2Y3 wk on Once daily for 2Y3 wk on, 2-3 wk off, 2Y3 wk on Once daily for 2Y3 d Once daily for 3 d Once daily for 2 d
73Y100 0Y100 50Y88 45Y57 34Y35.6 25Y30 v34Y54.4 94 57Y71
34
Imiquimod 3.75% Imiquimod 2.5% Ingenol 0.05%
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image of the tumor is generated, and a precise dosage of radiation can be calculated. Finally, radiation is administered slice-by-slice at the highest calculated intensity from each angle, while minimizing the radiation to surrounding uninvolved tissue.40 One retrospective analysis described the use of HT in the treatment of SCC, adnexal carcinoma, and MCC in 25 patients.40 In these cases, HT was used because of incomplete excision, lymph node involvement, nonoperable lesions, and high risk of relapse. Twenty-two (88%) patients exhibited complete remission, demonstrating that HT may be an effective option for advanced NMSC as a radical treatment or adjunct to surgery.40
DISCUSSION The diagnosis and treatment of NMSC are areas of fervent research and progress. Investigators are aiming to develop noninvasive tools to improve accuracy in diagnosis and prognosis of these tumors, and research is geared toward developing nonsurgical treatment options for NMSC. In this review, we described and compared the sensitivity and specificity of these newer diagnostic modalities, and presented the latest topical and systemic treatment options for these tumors. Excellent reviews in the literature exist that compile the treatment options of NMSC31; however, few of them describe the novel up-and-coming diagnostic modalitiesVespecially those that may in the future become useful tools to the cutaneous surgeon. Skin biopsy remains the gold standard for diagnosing NMSC. The newer diagnostic modalities described in this work remain largely confined to the research realm for now. Some of the disadvantages of these imaging modalities are their need for an experienced operatory and their difficulty in distinguishing among different NMSC; however, these tools can fairly easily distinguish tumors from benign lesions or normal skin. As such, these imaging tools may have more use intraoperatively with the surgeon, where mapping out surgical margins is of utmost importance, or posttreatment to assess response to nonsurgical management. Research is underway in attempts to assimilate these modalities into these roles.6,10 Moreover, the nonsurgical treatment of NMSC has become a mainstay in the field of cutaneous medicine. Although surgical removal remains the gold standard, it is important for the surgeon to be familiar with other available options in cases where the patient is not a surgical candidate, in cases where disease is too extensive for surgical management, or in cases where the patient declines surgical intervention. Despite the increase in public awareness campaigns on the harmfulness of excessive ultraviolet exposure, the incidence of NMSCs continues to rise.31 Scientists and clinicians must continue their exploration and study to address these tumors and, hopefully in the future, prevent their occurrence.
REFERENCES 1. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005;353:2262Y2269. 2. Glass AG, Hoover RN. The emerging epidemic of melanoma and squamous cell skin cancer. JAMA. 1989;262:2097Y2100. 3. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010; 146:283Y287. 4. Diffey BL, Langtry JA. Skin cancer incidence and the ageing population. Br J Dermatol. 2005;153:679Y680. 5. Nori S, Rius-Diaz F, Cuevas J, et al. Sensitivity and specificity of reflectancemode confocal microscopy for in vivo diagnosis of basal cell carcinoma: a multicenter study. J Am Acad Dermatol. 2004;51:923Y930. 6. Gonzalez S, Sanchez V, Gonzalez-Rodriguez A, et al. Confocal microscopy patterns in nonmelanoma skin cancer and clinical applications. Actas Dermosifiliogr. 2013;105(5):446Y458. 7. Rishpon A, Kim N, Scope A, et al. Reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. Arch Dermatol. 2009;145:766Y772.
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8. Agero AL, Busam KJ, Benvenuto-Andrade C, et al. Reflectance confocal microscopy of pigmented basal cell carcinoma. J Am Acad Dermatol. 2006; 54:638Y643. 9. Casari A, Pellacani G, Seidenari S, et al. Pigmented nodular basal cell carcinomas in differential diagnosis with nodular melanomas: confocal microscopy as a reliable tool for in vivo histologic diagnosis. J Skin Cancer. 2011;2011:406859. 10. Ahlgrimm-Siess V, Horn M, Koller S, et al. Monitoring efficacy of cryotherapy for superficial basal cell carcinomas with in vivo reflectance confocal microscopy: a preliminary study. J Dermatol Sci. 2009;53:60Y64. 11. Upile T, Jerjes W, Radhi H, et al. Elastic scattering spectroscopy in assessing skin lesions: an ‘‘in vivo’’ study. Photodiagnosis Photodyn Ther. 2012;9: 132Y141. 12. Tehrani H, Walls J, Price G, et al. A prospective comparison of spectrophotometric intracutaneous analysis to clinical judgment in the diagnosis of nonmelanoma skin cancer. Ann Plast Surg. 2007;58:209Y211. 13. Mogensen M, Joergensen TM, Nurnberg BM, et al. Assessment of optical coherence tomography imaging in the diagnosis of nonmelanoma skin cancer and benign lesions versus normal skin: observer-blinded evaluation by dermatologists and pathologists. Dermatol Surg. 2009;35:965Y972. 14. Maier T, Braun-Falco M, Laubender RP, et al. Actinic keratosis in the en-face and slice imaging mode of high-definition optical coherence tomography and comparison with histology. Br J Dermatol. 2013;168:120Y128. 15. Boone MA, Norrenberg S, Jemec GB, et al. Imaging actinic keratosis by highdefinition optical coherence tomography. Histomorphologic correlation: a pilot study. Exp Dermatol. 2013;22:93Y97. 16. Boone MA, Norrenberg S, Jemec GB, et al. Imaging of basal cell carcinoma by high-definition optical coherence tomography: histomorphological correlation. A pilot study. Br J Dermatol. 2012;167:856Y864. 17. Larraona-Puy M, Ghita A, Zoladek A, et al. Development of Raman microspectroscopy for automated detection and imaging of basal cell carcinoma. J Biomed Opt. 2009;14:054031. 18. Silveira L Jr, Silveira FL, Bodanese B, et al. Discriminating model for diagnosis of basal cell carcinoma and melanoma in vitro based on the Raman spectra of selected biochemicals. J Biomed Opt. 2012;17:077003. 19. Guitera P, Menzies SW, Longo C, et al. In vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases. J Invest Dermatol. 2012;132:2386Y2394. 20. Ibrahim SF, Ahronowitz I, McCalmont TH, et al. 18F-fluorodeoxyglucose positron emission tomography-computed tomography imaging in the management of Merkel cell carcinoma: a single-institution retrospective study. Dermatol Surg. 2013;39:1323Y1333. 21. Hawryluk EB, O’Regan KN, Sheehy N, et al. 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. J Am Acad Dermatol. 2013;68:592Y599. 22. Iwasaki T, Matsushita M, Kuwamoto S, et al. Usefulness of significant morphologic characteristics in distinguishing between Merkel cell polyomaviruspositive and Merkel cell polyomavirus-negative Merkel cell carcinomas. Hum Pathol. 2013;44:1912Y1917. 23. Schrama D, Peitsch WK, Zapatka M, et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol. 2011;131:1631Y1638. 24. Kalogeraki A, Tamiolakis D, Tsagatakis T, et al. Eccrine porocarcinoma: cytologic diagnosis by fine needle aspiration biopsy (FNAB). Acta Med Port. 2013;26:467Y470. 25. Fitzhugh VA, Maniar KP, Gurudutt VV, et al. Fine-needle aspiration biopsy of granular cell tumor of the tongue: a technique for the aspiration of oral lesions. Diagn Cytopathol. 2009;37:839Y842. 26. LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17:2502Y2511. 27. O’Bryan KW, Ratner D. The role of targeted molecular inhibitors in the management of advanced nonmelanoma skin cancer. Semin Cutan Med Surg. 2011;30:57Y61. 28. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21Y28. 29. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116Y1127.
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30. Gupta S, Khan H, Barik S, et al. Clinical benefits of concurrent capecitabine and cisplatin versus concurrent cisplatin and 5-flurouracil in locally advanced squamous cell head and neck cancer. Drug Discov Ther. 2013;7:36Y42. 31. Dubas LE, Ingraffea A. Nonmelanoma skin cancer. Facial Plast Surg Clin North Am. 2013;21:43Y53. 32. A Gaspari A, Tyring A, Rosen SK. Beyond a decade of 5% imiquimod topical therapy. J Drugs Dermatol. 2009;8:467Y474. 33. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen’s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54: 1025Y1032. 34. Chitwood K, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons. Dermatol Surg. 2013;39:1306Y1316. 35. Hanke CW, Swanson N, Bruce S, et al. Complete clearance is sustained for at least 12 months after treatment of actinic keratoses of the face or balding scalp
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36.
37.
38. 39.
40.
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via daily dosing with imiquimod 3.75% or 2.5% cream. J Drugs Dermatol. 2011;10:165Y170. Siller G, Rosen R, Freeman M, et al. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Australas J Dermatol. 2010;51:99Y105. Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009;60:934Y943. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366:1010Y1019. Ramsay JR, Suhrbier A, Aylward JH, et al. The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers. Br J Dermatol. 2011; 164:633Y636. Kramkimel N, Dendale R, Bolle S, et al. Management of advanced nonmelanoma skin cancers using helical tomotherapy. J Eur Acad Dermatol Venereol. 2013;28(5):641Y650.
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Advances in Diagnosis and Treatment of Nonmelanoma Skin Cancer Omer Ibrahim, MD, Brian Gastman, MD, PhD, and Alexandra Zhang, MD Abstract: The incidence of nonmelanoma skin cancer (NMSC) is rising. Research in the field of these tumors is aimed toward developing earlier and less invasive diagnostic methods and more effective, more accessible therapeutic options. Although there is much advancement in the diagnosis and treatment of NMSC, there are few literatures cataloging these developments. The aim of this review was to present the sensitivity and specificity of new imaging modalities, the dosing regimen and clearance rates of topical treatments, newer systemic treatment modalities, and discuss developments in the use of radiation as a mode of therapy. Recent developments in the diagnosis of NMSC include imaging modalities such as reflectance confocal microscopy, elastic scattering spectroscopy, and spectrophotometric intracutaneous analysis. Recent advances in the treatment of these tumors include systemic therapies such as epidermal growth factor receptor inhibitors, and topical immunomodulating drugs such as imiquimod. The progress in the diagnosis and treatment of these tumors is a gradual but fruitful growth. Scientists and clinicians alike must continue their exploration and study to address these tumors and, hopefully in the future, prevent their occurrence. Key Words: nonmelanoma skin cancer, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, actinic keratosis, advances, diagnosis, treatment (Ann Plast Surg 2014;73: 615Y619)
N
onmelanoma skin cancer (NMSC) is the most common form of malignancy in humans and represents almost 95% of all cutaneous cancers.1 The worldwide incidence of NMSC has increased by 3% to 8% every year.2 Nearly 3.5 million people in the United States were diagnosed with NMSC in 2006, and the incidence of NMSC in the United States may increase by 50% by the year 2030.3,4 Given the steady rise in the incidence of NMSC, researchers and clinicians alike are striving toward earlier, more accurate, less invasive diagnostic methods, and more effective, more accessible therapeutic options, especially in recurrent, advanced, or metastatic disease. Although there is much advancement in the diagnosis and treatment of NMSC, there are few literatures cataloging them. The aim of this review was to present the sensitivity and specificity of new imaging modalities, the dosing regimen and clearance rates of topical treatments, newer systemic treatment modalities, and discuss developments in the use of radiation as a mode of therapy. The resulting compilation not only will allow the readers to understand the current state of options but also will serve as a basis for design of the next set of developments.
Received March 31, 2014, and accepted for publication, after revision, July 15, 2014. From the Dermatology and Plastic Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH. Conflicts of interest and sources of funding: none declared. Reprints: Omer Ibrahim, MD, Dermatology and Plastic Surgery Institute, Cleveland Clinic Foundation, A61, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Omer Ibrahim, MD, executed the first working draft of the manuscript; Brian Gastman, MD, PhD, executed major revisions, deletions, and additions to the first draft; and Alexandra Zhang, MD, executed major revisions and additions, and designed the tables. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7305-0615 DOI: 10.1097/SAP.0000000000000330
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METHODS PubMed searches separately containing the following phrases: ‘‘actinic keratosis,’’ ‘‘squamous cell carcinoma,’’ ‘‘basal cell carcinoma,’’ and ‘‘Merkel cell carcinoma’’ in conjunction with the phrase ‘‘diagnosis’’ or ‘‘treatment,’’ were conducted to include publications from January 1, 2004, to December 31, 2013. Case reports, review articles, and experimental trials including retrospective and prospective trials were all reviewed for relevant data on the newer and novel clinical diagnostic and treatment modalities being investigated and implemented in the realm of these tumors. The primary tumor sites especially in squamous cell carcinoma (SCC) were reserved to the skin. The resultant articles were further categorized based on level of evidence and number of reported cases. Diagnostic or treatment modalities that were reported with 2 or less cases were eliminated due to insufficient data. In contrast, diagnostic or treatment modalities with 3 or more cases in the literature were selected for further investigation, and were additionally narrowed down based on level of evidence, resulting in more detailed review of articles with higher levels of evidence.
RESULTS Our initial search yielded 1198 publications. Table 1 summarizes the general results of our literature search, including numbers of articles or trials found, our assigned level of evidence associated with each modality, dates of reports, and their countries of origin.
Newer and Emerging Modalities in the Diagnosis of NMSCs Imaging for Primary Diagnosis of Tumors A widely studied diagnostic modality in the evaluation of NMSCs is ref lectance confocal microscopy (RCM). Ref lectance confocal microscopy has been investigated mainly in the diagnosis of basal cell carcinoma (BCC). This technique uses laser at nearinfrared wavelength to image human skin, delivering sections of the skin with good contrast and resolution without the need for invasive biopsies.5 Most of the literature regarding RCM and NMSC has described the diagnostic features and patterns of BCCs, as well as actinic keratoses (AKs) when evaluated with RCM imaging.6 In addition, 1 study describes certain RCM imaging features specific to SCC that included an atypical honeycomb or disarranged pattern of the spinous-granular layer, round nucleated cells at the spinous-granular layer, and round blood vessels traversing through the dermal papillae.7 However, the hyperkeratosis and ulceration typically seen with SCCs represent significant limitations for evaluation with RCM. Additional studies have demonstrated success of RCM in differentiating pigmented BCCs from melanoma.8,9 Finally, RCM might be used not only in the diagnosis of NMSCs but also possibly in the monitoring of the efficacy of noninvasive or minimally invasive treatment for these tumors, such as cryotherapy or photodynamic therapy.6,10 Several other imaging techniques have been investigated to aid in the primary diagnosis of NMSCs, including elastic scattering spectroscopy, spectrophotometric intracutaneous analysis, optical coherence tomography (OCT), high-definition OCT, and Raman spectroscopy. Elastic scattering spectroscopy uses a lamp that emits a wavelength from 330 to 750 nm to interrogate lesions suspicious of BCC; the system senses the
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TABLE 1. Summary of Literature Search on Diagnosis and Treatment of NMSC Therapeutic Modality
Relevant Publications (n) Level of Evidence Dates of Publication*
Novel diagnostic modalities Reflex confocal microscopy Elastic scattering spectroscopy Spectrophotometric intracutaneous analysis Optical coherence tomography High-definition optical coherence tomography Raman spectroscopy Novel therapeutic modalities Imiquimod Ingenol mebutate Vismodegib and BCC Cetuximab and SCC Capecitabine and SCC
Countries of Origin
100+ 4 3 70 6 35
Level II-1 Level II-2 Level II-3 Level II-1 Level II-3 Level II-2
2004Y2013 2012 2007 2004Y2013 2012, 2013 2004Y2013
United States, among many others United Kingdom, Turkey United Kingdom, Sweden United States, among many others Germany, France, Belgium United Kingdom, Canada, among others
100+ 35 100+ 100+ 25
Level I Level I Level II-1 Level II-1 Level II-1
2004Y2013 2005Y2013 2009Y2013 2004Y2013 2004Y2013
United States, among many others United States, among many others United States, among many others United States, among many others United States, among many others
*Dates within January 1, 2004, to December 31, 2013 search criteria.
scattering and absorptive properties of the tissue in question, generating a wavelength-dependent plot that imitates the structure of the tissue.11 SIAscopy is a commercially available system that emits radiation ranging from 400 to 1000 nm to produce images in real time, giving information regarding total melanin content of the skin, and has been mainly investigated in the diagnosis of melanoma. One study by Tehrani and colleagues12 demonstrated marked success in differentiating NMSC from benign tumors using SIAscopy. Optical coherence tomography, also commercially available, uses infrared radiation and real-time measurement of the backscatter and reflective properties of the tissue in question, creating cross-sectional 2-dimensional and 3-dimensional images. This technique is successful in distinguishing NMSC from normal skin; however, AK/SCC cannot be distinguished easily from BCC, nor can subtypes of BCC be differentiated.13 High-definition OCT uses the same principles as conventional OCT; however, these newer commercially available systems provide greater resolution and enhanced ability to differentiate between types of NMSC (AK/SCC vs BCC), as well as between different subtypes of BCC.14Y16 Raman spectroscopy uses a monochromatic light source in the visible, near-infrared, or near-UV range, and measures the inelastic scattering properties of the tissue in question. In addition to its use in melanoma, Raman spectroscopy has also shown success in accurate diagnosis of BCC and its differentiation from melanoma.17,18 Table 2 summarizes the key properties of these diagnostic imaging modalities.
Imaging for Staging of High-Risk or Metastatic Tumors The accurate evaluation of high-risk NMSCs is a field of intense interest and extensive research. Despite the scant reports, one interesting and possible key imaging modality in the future deserves attention. Fluorodeoxyglucose positron emission tomographyYcomputed tomography (FDG-PET/CT) imaging is an imaging modality that allows
for system-wide scanning to detect and monitor malignancies. Although mainly used in malignant melanoma, this technique has recently been applied to the evaluation and staging of aggressive NMSCs. In 1 study, 20 patients with Merkel cell carcinoma (MCC) were evaluated with imaging technique, and 4 (20%) had major changes in their medical plans due to new information gathered through FDG-PET/CT imaging, whether it was newly detected metastases, newly detected lymph node involvement, or lack of detected visceral metastases when initially presumed to be existent.20 Another report showed that this technique tended to upstage patients with more advanced MCC, detecting metastases, particularly in bone/bone marrow, that were not picked up on conventional ultrasound-CT scan workup algorithm.21 Thus, although this imaging technique may be more expensive and with higher false-positive rates than the traditional route of ultrasoundguided lymph node imaging followed by CT scan, it may be prudent to use this imaging modality before lymph node biopsy for high-risk patients such as the chronically immunosuppressed or in cases of highrisk malignancies.21
Molecular Evaluation In the realm of molecular-based diagnosis of NMSCs, one field of research stands far beyond any other in terms of extent of investigation and evolution: the Merkel cell polyomavirus (MCPyV). The MCPyV is a newly described polyomavirus that monoclonally integrates into approximately 80% of human MCCs. Iwasaki and colleagues standardized several morphological characteristics of MCPyV-positive MCCs on hematoxylin and eosin. The study on CM2B4 immunostaining in the MCCs showed 100% specificity and 94% sensitivity for MCPyV detection.22 Also, MCPyV status of the MCC can be confirmed with real-time polymerase chain reaction. The significance of MCPyV remains a topic of extensive debate.
TABLE 2. Novel Optical Diagnostic Modalities in the Diagnosis of NMSC Method
Tumor Studied
Sensitivity, %
Specificity, %
References
Reflex confocal microscopy Elastic scattering spectroscopy Spectrophotometric intracutaneous analysis Optical coherence tomography High-definition optical coherence tomography Raman spectroscopy
BCC, AK, SCC BCC, SCC SCC, BCC, AK BCC, AK BCC, AK BCC
82.9Y100 (BCC) 84Y88 94.6Y99.1 79Y94 76 81Y99
88.5Y95.7 (BCC) 74Y89 81.2Y91.9 85Y96 64 76Y94
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Currently, MCCs are staged based on 2 factors: size of the tumor and extent of disease spread at diagnosis.22 Some researchers believe that MCPyV status of a MCC predicts its behavior and some research has shown that MCPyV-positive MCCs have less metastatic potential and better prognoses than MCPyV-negative MCC.22 However, another study reported conf licting results.23 The significance of MCPyV status of an MCC is a controversial area of investigation and will continue to generate future research in that realm.
Tissue Sampling The standard tissue sampling techniques in dermatologic practice include biopsies (shave, punch, wedge, etc) and excisions. In recent years, although fine-needle aspiration (FNA) has been widely used in the surgical realm, it has made its way into dermatologic practice, at least through anecdotal reports. Kalogeraki and colleagues reported a successful sampling using FNA of an eccrine porocarcinoma, a rare and malignant sweat gland neoplasm. They showed that FNA can be a safe, convenient, and effective method of diagnosis.24 In another report, FNA was successfully used to sample a granular cell tumor of the tongue; the authors presented a safe, effective, and repeatable technique for the sampling of oral lesions.25
Newer and Emerging Therapeutic Options for the Treatment of NMSCs
Advances in Diagnosis and Treatment of NMSC
radiation.27 In one randomized study, patients with locally advanced SCC of the head and neck treated with cetuximab and radiation demonstrated an overall response rate of 74% in contrast to 64% in patients treated with radiotherapy alone.28 Recent evidence has also shown that cetuximab in combination with platinum-based chemotherapy and 5-f luorouracil (5-FU) is a promising therapeutic regimen in metastatic SCC of the head and neck.29 In addition to EGFRIs, studies are underway to investigate the efficacy of antibodies against vascular endothelial growth factor receptor including bevacizumab and other tyrosine kinase inhibitors including sorafenib and sunitinib in the treatment of SCC.27 Additionally, capecitabine has been shown in several studies and reports to be of benefit in the treatment of advanced or recurrent SCC of the head and neck. Capecitabine is a prodrug that is converted to 5-FU in tumor tissue, mimicking continuous 5-FU infusion, and ultimately inhibits DNA synthesis.30 In one study by Gupta and colleagues,30 patients treated with cisplatin/capecitabine combination showed better overall response rate, fewer nodes, and better rate of complete response, than patients treated with cisplatin/5-FU; overall, 3-year survival rates were not significantly different but the capecitabine treatment group demonstrated greater improvements in quality of life.
Noninvasive Treatment
Systemic Treatment Chemotherapy has emerged on the forefront in the management of advanced, aggressive, or metastasized NMSCs. In the case of BCC, vismodegib, an inhibitor of the hedgehog (Hh) pathway, was recently approved for the treatment of refractory advanced or metastatic disease. The Hh pathway is inactive in most normal adult tissue; it is composed of patched-1 (PTCH), a transmembrane receptor, which normally exhibits an inhibitory effect on smoothened (SMO), a transmembrane protein.26 In most BCCs, PTCH is dysfunctional, and thus cannot exert its normal inhibitory effect on SMO, and in its now aberrant active form, SMO induces a complex intracellular pathway that ultimately triggers cellular replication and formation of BCC.26 Vismodegib acts as an SMO inhibitor, preventing the intracellular cascade that ultimately results in BCC proliferation. Among several similar reports, a phase I trial of 33 patients with refractory advanced or metastasized BCC, there was an overall 58% response, either partial or complete, and the duration of response was 12.8 months and ongoing, demonstrating the important therapeutic strategy of Hh inhibition in the treatment of BCC.26 In SCC, especially of the head and neck, there is an overexpression of epidermal growth factor receptors (EGFR).27 Cetuximab, an EGFR inhibitor (EGFRI), has shown promise in the treatment of locally advanced, metastatic, or recurrent SCC of the head and neck, and is the only targeted EGFRI to receive US Food and Drug Administration (FDA) clearance for use in localized disease in combination with
Topical Therapy Imiquimod, a topical immunomodulator, is a novel noninvasive option in the treatment of NMSC. Imiquimod activates toll-like receptor 7 (TLR 7), which in turn triggers a cellular immune response.31 TLR 7 is responsible for the up-regulation of hundreds of different cytokines, including interferon >, tumor necrosis factor >, and interleukin 12.32 This inf lammatory cascade induces apoptosis of neoplastic cells. Imiquimod 5.0% is approved by the FDA to treat nonfacial superficial BCC.31 Imiquimod 5% is also used to treat SCC in situ and AKs.33Y35 Limitations of therapy with imiquimod for NMSC include high rates of adverse effects (erythema, pruritus, and pain), lower clearance rates compared to other treatment modalities especially with larger tumors like nodular BCC, lack of border control, and variability of patient adherence to application of the medication.33 Another topical modality that has been investigated for its use in the treatment of NMSC is ingenol mebutate, a natural substance found in the sap of the plant Euphorbia peplus. Ingenol mebutate has shown cytotoxic activity against SCC and BCC, and was FDA approved in 2012 for the treatment of AKs.36Y39 Table 3 summarizes the newer topical modalities and their respective efficacies and applications. Radiotherapy Helical tomotherapy (HT) is a form of CT-guided intensity modulated radiation therapy. The basic principles of HT involve the use of helical or spiral imaging of the tumor from several angles all the way around a patient in a setup position; then, a 3-dimensional
TABLE 3. Novel Topical Modalities in the Treatment of NMSC Topical Treatment
Tumor Studied
Dosing Regimen
Clearance Rate, %
References
Imiquimod 5%
Superficial BCC Nodular BCC SCC in situ AK AK AK AK SCC in situ Superficial BCC
3Y7 times per week for 6Y12 wk 3Y7 times per week for 6Y12 wk 3Y7 times per week for 6Y16 wk 2Y3 times per week for 16 wk Once daily for 2Y3 wk on, 2Y3 wk off, 2Y3 wk on Once daily for 2Y3 wk on, 2-3 wk off, 2Y3 wk on Once daily for 2Y3 d Once daily for 3 d Once daily for 2 d
73Y100 0Y100 50Y88 45Y57 34Y35.6 25Y30 v34Y54.4 94 57Y71
34
Imiquimod 3.75% Imiquimod 2.5% Ingenol 0.05%
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image of the tumor is generated, and a precise dosage of radiation can be calculated. Finally, radiation is administered slice-by-slice at the highest calculated intensity from each angle, while minimizing the radiation to surrounding uninvolved tissue.40 One retrospective analysis described the use of HT in the treatment of SCC, adnexal carcinoma, and MCC in 25 patients.40 In these cases, HT was used because of incomplete excision, lymph node involvement, nonoperable lesions, and high risk of relapse. Twenty-two (88%) patients exhibited complete remission, demonstrating that HT may be an effective option for advanced NMSC as a radical treatment or adjunct to surgery.40
DISCUSSION The diagnosis and treatment of NMSC are areas of fervent research and progress. Investigators are aiming to develop noninvasive tools to improve accuracy in diagnosis and prognosis of these tumors, and research is geared toward developing nonsurgical treatment options for NMSC. In this review, we described and compared the sensitivity and specificity of these newer diagnostic modalities, and presented the latest topical and systemic treatment options for these tumors. Excellent reviews in the literature exist that compile the treatment options of NMSC31; however, few of them describe the novel up-and-coming diagnostic modalitiesVespecially those that may in the future become useful tools to the cutaneous surgeon. Skin biopsy remains the gold standard for diagnosing NMSC. The newer diagnostic modalities described in this work remain largely confined to the research realm for now. Some of the disadvantages of these imaging modalities are their need for an experienced operatory and their difficulty in distinguishing among different NMSC; however, these tools can fairly easily distinguish tumors from benign lesions or normal skin. As such, these imaging tools may have more use intraoperatively with the surgeon, where mapping out surgical margins is of utmost importance, or posttreatment to assess response to nonsurgical management. Research is underway in attempts to assimilate these modalities into these roles.6,10 Moreover, the nonsurgical treatment of NMSC has become a mainstay in the field of cutaneous medicine. Although surgical removal remains the gold standard, it is important for the surgeon to be familiar with other available options in cases where the patient is not a surgical candidate, in cases where disease is too extensive for surgical management, or in cases where the patient declines surgical intervention. Despite the increase in public awareness campaigns on the harmfulness of excessive ultraviolet exposure, the incidence of NMSCs continues to rise.31 Scientists and clinicians must continue their exploration and study to address these tumors and, hopefully in the future, prevent their occurrence.
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8. Agero AL, Busam KJ, Benvenuto-Andrade C, et al. Reflectance confocal microscopy of pigmented basal cell carcinoma. J Am Acad Dermatol. 2006; 54:638Y643. 9. Casari A, Pellacani G, Seidenari S, et al. Pigmented nodular basal cell carcinomas in differential diagnosis with nodular melanomas: confocal microscopy as a reliable tool for in vivo histologic diagnosis. J Skin Cancer. 2011;2011:406859. 10. Ahlgrimm-Siess V, Horn M, Koller S, et al. Monitoring efficacy of cryotherapy for superficial basal cell carcinomas with in vivo reflectance confocal microscopy: a preliminary study. J Dermatol Sci. 2009;53:60Y64. 11. Upile T, Jerjes W, Radhi H, et al. Elastic scattering spectroscopy in assessing skin lesions: an ‘‘in vivo’’ study. Photodiagnosis Photodyn Ther. 2012;9: 132Y141. 12. Tehrani H, Walls J, Price G, et al. A prospective comparison of spectrophotometric intracutaneous analysis to clinical judgment in the diagnosis of nonmelanoma skin cancer. Ann Plast Surg. 2007;58:209Y211. 13. Mogensen M, Joergensen TM, Nurnberg BM, et al. Assessment of optical coherence tomography imaging in the diagnosis of nonmelanoma skin cancer and benign lesions versus normal skin: observer-blinded evaluation by dermatologists and pathologists. Dermatol Surg. 2009;35:965Y972. 14. Maier T, Braun-Falco M, Laubender RP, et al. Actinic keratosis in the en-face and slice imaging mode of high-definition optical coherence tomography and comparison with histology. Br J Dermatol. 2013;168:120Y128. 15. Boone MA, Norrenberg S, Jemec GB, et al. Imaging actinic keratosis by highdefinition optical coherence tomography. Histomorphologic correlation: a pilot study. Exp Dermatol. 2013;22:93Y97. 16. Boone MA, Norrenberg S, Jemec GB, et al. Imaging of basal cell carcinoma by high-definition optical coherence tomography: histomorphological correlation. A pilot study. Br J Dermatol. 2012;167:856Y864. 17. Larraona-Puy M, Ghita A, Zoladek A, et al. Development of Raman microspectroscopy for automated detection and imaging of basal cell carcinoma. J Biomed Opt. 2009;14:054031. 18. Silveira L Jr, Silveira FL, Bodanese B, et al. Discriminating model for diagnosis of basal cell carcinoma and melanoma in vitro based on the Raman spectra of selected biochemicals. J Biomed Opt. 2012;17:077003. 19. Guitera P, Menzies SW, Longo C, et al. In vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases. J Invest Dermatol. 2012;132:2386Y2394. 20. Ibrahim SF, Ahronowitz I, McCalmont TH, et al. 18F-fluorodeoxyglucose positron emission tomography-computed tomography imaging in the management of Merkel cell carcinoma: a single-institution retrospective study. Dermatol Surg. 2013;39:1323Y1333. 21. Hawryluk EB, O’Regan KN, Sheehy N, et al. 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. J Am Acad Dermatol. 2013;68:592Y599. 22. Iwasaki T, Matsushita M, Kuwamoto S, et al. Usefulness of significant morphologic characteristics in distinguishing between Merkel cell polyomaviruspositive and Merkel cell polyomavirus-negative Merkel cell carcinomas. Hum Pathol. 2013;44:1912Y1917. 23. Schrama D, Peitsch WK, Zapatka M, et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol. 2011;131:1631Y1638. 24. Kalogeraki A, Tamiolakis D, Tsagatakis T, et al. Eccrine porocarcinoma: cytologic diagnosis by fine needle aspiration biopsy (FNAB). Acta Med Port. 2013;26:467Y470. 25. Fitzhugh VA, Maniar KP, Gurudutt VV, et al. Fine-needle aspiration biopsy of granular cell tumor of the tongue: a technique for the aspiration of oral lesions. Diagn Cytopathol. 2009;37:839Y842. 26. LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17:2502Y2511. 27. O’Bryan KW, Ratner D. The role of targeted molecular inhibitors in the management of advanced nonmelanoma skin cancer. Semin Cutan Med Surg. 2011;30:57Y61. 28. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21Y28. 29. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116Y1127.
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30. Gupta S, Khan H, Barik S, et al. Clinical benefits of concurrent capecitabine and cisplatin versus concurrent cisplatin and 5-flurouracil in locally advanced squamous cell head and neck cancer. Drug Discov Ther. 2013;7:36Y42. 31. Dubas LE, Ingraffea A. Nonmelanoma skin cancer. Facial Plast Surg Clin North Am. 2013;21:43Y53. 32. A Gaspari A, Tyring A, Rosen SK. Beyond a decade of 5% imiquimod topical therapy. J Drugs Dermatol. 2009;8:467Y474. 33. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen’s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54: 1025Y1032. 34. Chitwood K, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons. Dermatol Surg. 2013;39:1306Y1316. 35. Hanke CW, Swanson N, Bruce S, et al. Complete clearance is sustained for at least 12 months after treatment of actinic keratoses of the face or balding scalp
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via daily dosing with imiquimod 3.75% or 2.5% cream. J Drugs Dermatol. 2011;10:165Y170. Siller G, Rosen R, Freeman M, et al. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Australas J Dermatol. 2010;51:99Y105. Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009;60:934Y943. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366:1010Y1019. Ramsay JR, Suhrbier A, Aylward JH, et al. The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers. Br J Dermatol. 2011; 164:633Y636. Kramkimel N, Dendale R, Bolle S, et al. Management of advanced nonmelanoma skin cancers using helical tomotherapy. J Eur Acad Dermatol Venereol. 2013;28(5):641Y650.
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