Accepted Manuscript

Basal Cell Carcinoma: Part 1

Michael C. Cameron, MD, Erica Lee, MD, Brian Hibler, MD, Christopher A. Barker,
MD, Shoko Mori, BS, Miguel Cordova, MD, Kishwer S. Nehal, MD, Anthony M. Rossi,
MD

PII: S0190-9622(18)30775-8
DOI: 10.1016/j.jaad.2018.03.060
Reference: YMJD 12520

To appear in: Journal of the American Academy of Dermatology

Received Date: 27 September 2017

Revised Date: 19 March 2018
Accepted Date: 21 March 2018

Please cite this article as: Cameron MC, Lee E, Hibler B, Barker CA, Mori S, Cordova M, Nehal KS,
Rossi AM, Basal Cell Carcinoma: Part 1, Journal of the American Academy of Dermatology (2018), doi:
10.1016/j.jaad.2018.03.060.

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1 Basal Cell Carcinoma

2 PART I: Current Understanding

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3 Michael C Cameron, MDa, Erica Lee, MDa, Brian Hibler, MDa, Christopher A.

4 Barker, MDb, Shoko Mori, BSa , Miguel Cordova MDa, Kishwer S Nehal, MDa,

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5 and Anthony M Rossi, MDa

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6 Dermatology Service, Department of Medicine and bDepartment of Radiation

7 Oncology, Memorial Sloan Kettering Cancer Center, 16 E. 60th Street, 4th Floor,

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8 New York, New York

9 Word Count (Abstract): 84

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10 Word Count (Body Text): 3,499

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11 The authors involved with this journal-based CME activity have reported no

12 conflicts of interest or relevant financial relationships with commercial interest(s).

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13 Funding Sources: This research was funded in part through the NIH/NCI Cancer
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14 Center Support Grant P30 CA008748.

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15 Acknowledgements: Cristian Navarrete-Decent, MD for his contribution of

16 clinical images.

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18 Correspondence to:

19 Anthony Rossi, MD

20 Division of Dermatology

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21 Memorial Sloan Kettering Cancer Center

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22 16 E. 60th Street, 4th Floor

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23 New York, NY 10022

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34 Learning Objectives

35 After completing this learning activity, participants should be able to recount

36 epidemiology, cost, and risk factors associated with basal cell carcinoma, as well

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37 as describe the clinicopathologic presentations, pathophysiology, and natural

38 history of this disease.

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50 Disclosures

51 The authors involved with this journal-based CME activity have reported no

52 relevant financial relationships with commercial interest(s).

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66 Abstract

67 As the most common human cancer worldwide and continuing to increase in

68 incidence, basal cell carcinoma is associated with significant morbidity and cost.

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69 Continued advances in research have refined both our insight and approach to this

70 seemingly ubiquitous disease. This 2-part continuing medical education article

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71 will provide a comprehensive and contemporary review of basal cell carcinoma.

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72 Part I of this series will describe our current understanding of this disease in

73 regards to epidemiology, cost, clinical and histopathologic presentations,

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carcinogenesis, natural history, and disease associations.
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84 Key words

85 Basal cell carcinoma, BCC, Skin cancer, Keratinocyte carcinoma, Non-melanoma

86 skin cancer, Epidemiology, Cost, Natural history, Genetics, Associations

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100 Abbreviations Used

101 KC: Keratinocyte carcinoma

102 BCC: Basal cell carcinoma

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103 SCC: Squamous cell carcinoma

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104 BCNS: Basal cell nevus syndrome

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105 UV: Ultraviolet

106 PNI: Perineural invasion

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107 NBCC: Nevoid basal cell carcinoma syndrome
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108 Hh: Hedgehog signaling

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109 Shh: Sonic hedgehog protein

110 laBCC: Locally advanced BCC

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111 mBCC: Metastatic BCC

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116 EPIDEMIOLOGY AND COST

117 Key Points

118 • Basal cell carcinoma (BCC) and squamous cell carcinoma comprise the

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119 keratinocyte carcinomas, which are the most common malignancies

120 worldwide and are increasing in incidence.

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121 • Lifetime risk of developing BCC in the United States is estimated to be at

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122 least 20% and greater than 30% for Caucasians.

123 • Male gender and age are independent BCC risk factors.

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• BCC cost burden continues to increase with rising incidence
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125 • Physician office-based BCC management is less costly compared to
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126 ambulatory surgery or inpatient settings.

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128 Keratinocyte carcinomas (KCs) are by far the most common malignancies
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129 worldwide and exceed prevalence of all other cancers combined. Traditionally,

130 approximately 80% of KC cases were attributed to basal cell carcinoma (BCC)
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131 and 20% to squamous cell carcinoma (SCC). However, recent studies point to an
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132 increasing SCC incidence relative to BCC, moving historical 4:1 ratio to 2.5:1 or
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133 even closer.1-4 Some evidence attributes this to a relative SCC increase in the

134 elderly secondary to chronic ultraviolet (UV) exposure, while BCC remains much

135 more common in younger populations.1,5,6 Regardless, the majority of

136 epidemiologic studies still show a higher BCC incidence of at least 2:1.5,7-16

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137 Although most cancer registries exclude KCs due to their ubiquity and

138 relatively low mortality rates, numerous studies provide evidence for increasing

139 incidence worldwide. Incidence in the US has increased by an average rate of 4 to

8% annually.17 A large US gender-stratified cohort study (1986-2006) showed

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141 age-adjusted BCC incidence rate increases from 519 cases to 1,019 cases per

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142 100,000 person-years in women and from 606 cases to 1,488 cases per 100,000

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143 person-years in men.18 Similar rising incidence rates have been found in Europe,

144 Canada, Asia, and Australia.11,12,15,19-23 BCCs occur in an estimated 2 million

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145 Americans annually.24 Lifetime risk in the US is estimated to be at least 20% and
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146 greater than 30% for Caucasians, and could be greater since these estimates are

147 based on data from almost twenty years ago.25,26 Incidence rates are predicted to
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148 continue to increase until at least 2040 due to an aging population with historical
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149 UV exposure.27-29
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150 While BCCs can develop early in life both sporadically and with certain

151 genodermatoses, age is an independent risk factor.30 Incidence rate doubles from
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152 age 40 to 70 years.31 Incidence for those <40 years age is also increasing.32 Men
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153 have higher BCC rates (1.5-2:1).11,24,33-39 However, this gender disparity may not
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154 exist in populations younger than 40 years.5

155 BCC cost burden is unsurprisingly increasing, as well. The National

156 Ambulatory Medical Care Survey showed a 70% increase from 1995 to 2007 of

157 KC-related office visits; 59% of visits were associated with a procedure.40 A study

158 comparing US Medical Expenditure Panel Survey data from periods 2002-2006

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159 and 2007-2011 found an increased average annual cost for skin cancer of 126.2%

160 (from USD$3.6 billion to 8.1 billion annually), while average annual cost for all

161 other cancers increased by 25.1%.41 A large cohort study in Australia found that

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162 patients diagnosed with KCs consumed significantly more healthcare dollars than

163 patients without this diagnosis.42

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164 Cost varies greatly based on chosen treatment modality. A study which

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165 calculated average cost of treatment for a standard lesion (BCC on cheek,

166 averaged across the four lesion size reimbursement ranges) using the 2008

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167 Resource-Based Relative Value Scale, which included costs of biopsy, pathology,
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168 repair, and follow-up, found that radiation (USD$2591–3460) was the most

169 expensive treatment, followed by Mohs micrographic surgery (USD$1263),

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170 standard excision (USD$1006–1170), topical imiquimod (USD$959), and

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171 electrodessication/curettage (USD$471).43,44 Vismodegib was not included in this

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172 analysis. While this analysis gives us a basic understanding of cost for various

173 treatment modalities, studies such as this are problematic due to the numerous
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174 assumptions incorporated into their design and the possibility of inherent biases
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175 and conflicts of interest.

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176 Physician office setting is the most common KC treatment setting in the US

177 (about 91% of cases), compared to 8% in ambulatory surgical centers and 1% in

178 hospital inpatient settings.45 While physician office-based procedures account for

179 the greatest percentage of US dollars spent treating KCs, average cost per care

180 episode is substantially less in the physician office compared to the inpatient or

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181 ambulatory surgery center settings.45,46 Average cost per KC episode treated in the

182 physician office setting ($492, in one study) is substantially less than other cancer

183 diagnoses.45 As such, rising incidence more than cost-per-episode is driving the

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184 increasing BCC cost burden.

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187 CLINICAL PRESENTATION AND ASSOCIATED HISTOLOGIC

188 FINDINGS

189 Key Points

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190 • Patients with BCC often report an enlarging, non-healing lesion that may
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191 sometimes bleed. They may also describe pruritus or deny any symptoms.

192 • Many lesions exhibit more than one histopathologic pattern, most
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193 commonly nodular-micronodular.

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194 • Morpheaform (sclerosing, desmoplastic) and infiltrative, as well as lesions

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195 with micronodular or basosquamous histopathologic changes, are more

196 aggressive variants.

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197 • Although rare, perineural invasion indicates an aggressive variant with

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198 increased rates of metastasis and locoregional recurrence.

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200 Arising in sun-damaged skin, BCCs present clinically and

201 histopathologically in various ways. Patients often complain of an enlarging, non-

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202 healing lesion that may sometimes bleed. They may also complain of pruritus, or

203 report no symptoms at all. Nodular, superficial, infundibulocystic, fibroepithelial,

204 morpheaform (sclerosing, desmoplastic), and infiltrative are well-defined subtypes

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205 with distinct clinical and histopathologic findings (Table I). Micronodular and

206 basosquamous are two additional descriptors with primarily histopathologic (as

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207 well as therapeutic and prognostic) significance. Perineural invasion (PNI) is a

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208 primarily microscopic finding that portends aggressive clinical behavior. Age does

209 not vary greatly between subtypes. All variants are most common in the sixth,

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210 seventh, and eighth decades of life.30 While differentiating between these subtypes
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211 is helpful in management, many lesions (up to 40%) exhibit more than one

212 histopathologic pattern, most commonly nodular-micronodular.47 When this is the

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213 case, it is prudent to guide management based on the most aggressive subtype. In
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214 addition, BCCs may histopathologically show a variety of other cell lineage
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215 differentiation features that do not impact treatment or prognosis (i.e. keratotic,

216 follicular, pleomorphic, eccrine, and myoepithelial differentiation patterns).

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217 As the most common subtype, nodular BCC accounts for approximately
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218 50% to 80% of lesions. With a predilection for the head and neck, lesions typically
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219 present as a shiny, pearly papule or nodule with smooth surface, rolled borders,

220 and arborizing telangiectasias (Fig 1A). While slow growing, advanced tumors can

221 become large and ulcerate, classically referred to as a “rodent ulcer” (Fig 1B).

222 Advanced, infiltrative tumors can cause distortion of the structures they invade

223 (Fig 1C). Histopathologically, they show large dermal nodules of malignant

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224 basaloid keratinocytes, peripheral palisading (secondary to clefting artifact

225 between tumor epithelium and stroma), and mucoid stroma containing plump

226 spindle cells (Fig 1D).

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227 Accounting for approximately 10-30% of tumors, superficial BCCs are the

228 second most common subtype. Some epidemiologic studies have shown a

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229 somewhat younger average age of onset for this subtype (i.e. 5th decade of life);

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230 others have shown a relative increase of incidence in females compared to other

231 subtypes.30,48,49 Superficial BCCs classically present as a well circumscribed and

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232 erythematous thin plaque or patch with scale, central clearing, and thin rolled
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233 borders (Fig 2A). They can sometimes be mistaken for inflammatory lesions, as

234 well as SCC in-situ. These slow-growing lesions are most commonly found on the
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235 trunk, but can also often be seen on the legs and, less commonly, head and neck.49
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237 pigmented BCCs (Fig 2B). On histopathology, superficial BCCs demonstrate

238 multiple lobular foci of basaloid palisading keratinocyte tumors attached

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239 superficially to epidermis with a myxoid stroma and band-like lichenoid infiltrate
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240 (Fig 2C).50,51

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241 Fibroepithelial BCCs (Fibroepitheliomas of Pinkus) are an uncommon,

242 indolent subtype with a predilection for the trunk. Commonly mistaken for a

243 fibroepithelial polyp or non-pigmented seborrheic keratosis, these indolent lesions

244 present as a skin-colored or erythematous sessile plaque or pedunculated

245 papulonodule (Fig 3A). On histopathology, they exhibit multiple collections of

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246 delicate strands of epidermal basaloid keratinocytes arranged in a reticular pattern

247 within a spindle cell stroma (Fig 3B).52

248 Usually arising on the head and neck of the elderly, infundibulocystic

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249 BCCs present as well-circumscribed pearly papules (Fig 4A). Known for their

250 follicular differentiation on histopathology, these lesions present microscopically

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251 as a well-circumscribed tumor of anastomosing strands of basaloid cells and

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252 scattered small infundibulum-like cystic structures (Fig 4B).53 Due to their clinical

253 appearance and indolent nature, they can be mistaken for benign follicular adnexal

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255 Less than 10% of BCCs exhibit morpheaform (sclerosing, desmoplastic) or

256 infiltrative changes.47 However, these lesions are significantly more difficult to
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257 treat due to aggressive biologic behavior with local destruction and subclinical
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258 extension, as well as higher local recurrence rates.54,55 Morpheaform BCCs present
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259 clinically as an infiltrated plaque with poorly defined borders and shiny surface.

260 Often resembling a scar or plaque of morphea, they’re commonly found on the
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261 head and neck (Fig 5A). Infiltrative BCCs present clinically as a poorly defined,
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262 indurated, flat or depressed plaque with white, yellow, or pale pink color (Fig 5B).
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263 Overlying crusts, erosions, ulcerations, and papules may be seen. For both

264 morpheaform and infiltrative subtypes, thin cords with angulated ends of very few

265 basaloid keratinocytes are seen on histopathology. In the case of infiltrative BCC,

266 basaloid cells are embedded in a classic mucinous/myxoid stroma (Fig 5C).51 In

267 morpheaform lesions, a sclerotic collagenous stroma surrounds the basaloid cords.

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268 Peripheral palisading and stromal cleft formation are mostly absent (Fig 5D), and

269 tumor stroma stains positive for smooth muscle alpha-actin with

270 immunohistochemistry.56

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271 Micronodular BCC is a predominantly histopathologic term referring to

272 lesions with multiple small aggregates of basaloid cells within the dermis, often

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273 with no appreciable connection to overlying epidermis. Peripheral palisading and

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274 retraction artifact are subtle compared to nodular BCC lesions (Fig 6A).51 Due to

275 their multifocal nature, these lesions often have subclinical extension and resulting

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276 higher recurrence rates. Clinically, micronodular BCCs are often difficult to
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277 differentiate from superficial and nodular BCCs and can present as erythematous

278 macules or thin papules/plaques (Fig 6B). Occurring in an estimated 15% of

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279 BCCs, micronodular changes are often seen together with other histopathologic
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281 significantly higher percentages of Ki-67 and EZH2-positive cells than nodular,

282 and have been suggested as potential markers for risk stratification in advanced
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283 tumors.57
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284 Representing less than 2% of KCs, basosquamous type (metatypical BCC)

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285 is another primarily histopathologic term referring to neoplasms that have

286 histologic features of both BCC and SCC.58,59 Microscopically, there is a well-

287 defined nodular or superficial BCC component overlying an invasive front

288 showing BCC and SCC histologic features (Fig 6C).51 Since they can be confused

289 with BCC/SCC collision tumors, basosquamous type and its status as a distinct

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290 clinicopathologic entity has been debated.59 However, immunohistochemical and

291 staining techniques show areas of BCC and SCC with a transition zone, suggesting

292 differentiation from one tumor cell to the other.60 Given their more pluripotent

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293 nature, BCC cells are now believed to differentiate into more aggressive SCC-like

294 cells.48 Basosquamous is an aggressive subtype with elevated recurrence rates and

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295 a significant rate of metastasis (estimated to be greater than 5%).61 The vast

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296 majority of these lesions are found on the head and neck.59 In addition to

297 BCC/SCC collision tumors, they can be confused with BCCs with squamous

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298 metaplasia.51
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299 In addition to basosquamous and micronodular histopathologic changes,

300 PNI indicates an aggressive BCC variant. PNI occurs in an estimated 2-6% of KC
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301 lesions (majority of which are SCCs) and refers to malignant cells surrounding a
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302 nerve sheath and spreading down the length of a superficial or intracranial
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303 nerve.62-69 If PNI is detected only on histopathology, it is considered microscopic

304 PNI (still high-risk). If a patient exhibits evidence of neuropathy (i.e. paresthesia,
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305 hyperesthesia) in tumor vicinity or there is gross evidence of perineural tumor

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306 invasion on imaging, then the term clinical PNI or perineural spread is
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307 warranted.66,69 Both microscopic and clinical PNI have significantly greater rates

308 of metastasis and locoregional recurrence, and are associated with other risk

309 factors including recurrent tumors, high-grade lesions, large lesion size, and

310 aggressive histopathologic subtypes.62,70-73

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312 CARCINOGENESIS AND NATURAL HISTORY

313 Key Points

314 • Predominantly through UVB-driven mutagenesis, keratinocyte progenitor

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316 • Constitutive activation of Hedgehog signaling pathway is responsible and

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317 alone sufficient for BCC carcinogenesis.

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318 • BCCs have the greatest mutational burden in coding DNA of any human

319 cancer, perhaps allowing for greater antigenicity and contributing to

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321 • While BCCs grow indolently with local invasion, a small portion progress

322 to locally advanced and metastatic tumors, usually as a result of neglect.

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324 Sporadic BCCs arise from long-term resident keratinocyte progenitor cells
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325 of the interfollicular epidermis and upper infundibulum that undergo

326 mutagenesis.74,75 The majority of these mutations are UVB-induced, with one
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327 study showing 75.7% of mutations in coding DNA with a “UV signature
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328 mutation” – cyclobutane dimer formation attributed to UVB radiation.76,7778

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329 Nearly all BCCs show constitutive activation of Hedgehog signaling

330 pathway (Hh), and several animal models have shown that amplified Hh is alone

331 sufficient for tumorigenesis (Fig 7).79,80 Via its effector protein sonic hedghehog

332 (SHH), the Hh pathway is critical for neural, musculoskeletal, hematopoietic, and

333 skin development by governing embryonic development and adult tissue

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334 homeostasis, as well as regulating cell type differentiation, patterning, and

335 proliferation.79 Hh signaling maintains cutaneous stem cell populations and

336 controls development of hair follicles and sebaceous glands.78

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337 SHH binding to extracellular receptor PTCH1 relives PTCH1 inhibition of

338 Smoothened (SMO), which can then activate GLI transcription factors that

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339 regulate transcription of Hh pathway target genes; these target genes encode

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340 proteins that can execute aforementioned Hh pathway responsibilities.76 The Hh

341 pathway is also involved in cell cycle regulation, particularly at the G2/M

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342 checkpoint. PTCH1 interaction with cyclin B1 prevents the latter protein’s
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343 translocation into the nucleus and subsequent promotion of transition to

344 mitosis.78,81 SHH binding to PTCH1 relieves cyclin B1 of this suppression,

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345 allowing its nuclear translocation and cell cycle progression. SHH activity also
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346 functions at the G1/S checkpoint, upregulating cyclin D1 (S-phase entry promoter)
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347 and inhibiting cyclin-dependent kinase inhibitor 1A (S-phase entry

348 inhibitor).78,81,82 BCCs exhibit aberrant Hh pathway activation usually either via
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349 inactivating mutations of PTCH1 (chromosome 9q) or activating mutations of

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350 SMO (chromosome 7q).75,83-85 A small portion of BCCs exhibit loss-of-function

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351 mutations in SUFU, which is a negative regulator of the Hh pathway.75,83,84,86

352 Recent advances in whole-exome sequencing technology have allowed

353 characterization of the mutational landscape of various cancers. Interestingly,

354 sporadic BCCs show the greatest number of mutations of any human cancer,

355 perhaps due to the ubiquitous nature of the primary source of mutagenesis, UV

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356 light.76 Whether this high mutational burden is, in part, responsible for BCCs

357 indolent nature (via increased antigenicity and heightened immunosurveillance) is

358 a matter of debate.76 Correspondingly, BCC is one of the cancers increased most

by immunosuppression.76

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360 While BCCs progress indolently through local invasion, a small subset

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361 develop into locally advanced (laBCC) or metastatic (mBCC) tumors. These

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362 lesions have usually been neglected for years and developed multiple histologic

363 patterns. Estimated to comprise 1% of tumors, laBCCs are tumors not amenable to

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364 curative treatment with surgical excision due to size or anatomic location.87 mBCC
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365 is extremely uncommon (estimated risk ranging from 0.0028 to 0.005% of

366 tumors).88,89 While metastasis can occur hematologically or through subcutaneous

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367 spread, lymphatic spread accounts for an estimated 70% of cases.89,90 All subtypes
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368 have been shown to metastasize.89,91 Common metastatic sites include lymph
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369 nodes, bone, lungs, and skin.89,92 Although median mBCC survival has

370 traditionally been deemed 8 months, recent studies have shown survival lengths of
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371 up to 54 months or more, particularly for disease metastatic to lymph nodes

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372 alone.93-98
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378 ENVIRONMENTAL, DISEASE, AND TREATMENT ASSOCIATIONS

379 Key Points

380 • Intermittent intense sun exposure is significantly associated with BCC

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381 development via UV-driven mutagenesis and is exacerbated by fair skin,

382 red or blond hair, light eye color, and inability to tan.

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383 • Nevoid basal cell carcinoma, Multiple hereditary infundibulocystic, Dupre-

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384 Christol, Rombo, and Xeroderma pigmentosum syndromes are

385 characterized by increased BCC risk.

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387 independently associated with increased risk, while evidence exists that

388 others (i.e. vitiligo, alopecia areata) may be BCC protective.

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389 • BCC risk increases secondary to a variety of therapies, including psoralen

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390 ultraviolet A (PUVA) therapy, immunosuppression in organ transplant

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391 patients, and ionizing radiation.

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393 Given the predominance of UV-signature mutations underlying BCC

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394 carcinogenesis, UV exposure via sunlight unsurprisingly is a well-established

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395 environmental carcinogen. The nature of this association is complex. A majority

396 of evidence suggests that intermittent sun exposure (i.e. recreational tanning,

397 occupational exposure, childhood sunburns) is a predominant risk factor, while

398 chronic cumulative sun exposure may not play the critical role it does in SCC

399 carcinogenesis.38,99-110 Other studies show BCC risk still increases in patients with

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400 clinical signs of chronic UV exposure (i.e. cutis rhomboidalis nuchae, and

401 leukoderma punctate).103,111 A 20-year observational study involving 73,494

402 female nurses showed a strong dose-related association between tanning bed use

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403 and skin cancer risk; this association was stronger for patients with younger age of

404 exposure and most significant for BCC.112

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405 Skin phenotype plays an important role in mitigating the association

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406 between UV exposure and BCC. Fair skin, red or blond hair, light eye color,

407 inability to tan, and propensity to freckle are independent BCC risk factors.38,99-107

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408 Skin pigmentation’s protective role from carcinogenesis is exemplified by low
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409 incidence rates in individuals of African descent.33 BCC is estimated to occur 19

410 times less often in such patients compared to Caucasians, although Africans
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411 suffering from albinism may develop tumors at early ages.33 In addition, KC
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412 development rates for non-Hispanic whites have been estimated to be 11 times
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413 greater than those for Hispanics.113 As should be expected, variants at

414 melanocortin 1 receptor gene – crucial to tanning response after UV irradiation via
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415 melanocyte eumelanin production – are associated increased BCC incidence.114,115

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416 Cigarette smoking does not appear to be associated with increased

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417 incidence rates.116-120 Studies on BCC and alcohol consumption have been limited

418 and contradictory, with some reporting an independent association and others

419 not.116,117,120-125 The epidemiologic evidence for long-term residential radon

420 exposure and BCC is similarly sparse and contradictory.126,127 128,129 However,

421 substantial evidence exists for a dose-related relationship between arsenic-

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422 contaminated water and food and BCC.130-135

423 Several genetic syndromes with increased BCC rates have been

424 characterized (Table 2). Nevoid basal cell carcinoma syndrome (NBCC, Gorlin

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425 Syndrome) is an autosomal dominant disorder with an incidence of 1 per 40,000 to

426 57,000 individuals characterized by aberrant upregulation of the Shh pathway and

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427 resultant developmental defects and multiple neoplasms, including BCCs

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428 (commonly infundibulocystic subtype). While some patients may develop >1000

429 BCCs (and some may develop none), median number in NBCC patients is 8.136

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430 Similar to NBCC, multiple hereditary infundibulocystic syndrome is characterized
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431 by autosomal inheritance, upregulation of the Shh pathway, and numerous

432 infundibulocystic BCCs, located commonly on the face; however, there is an

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433 absence of palmar pits, jaw cysts, and other developmental stigmata of
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434 NBCC.137,138 Bazex-Dupre-Christol syndrome is a rare (<20 reported sporadic and

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435 familial cases) x-linked dominant disorder characterized by the triad of diffuse

436 hypotrichosis, follicular atrophoderma, and BCCs.136,139 Milia cysts, hypohidrosis,

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437 trichoepitheliomas, and facial hyperpigmentation can also be seen. BCCs typically
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438 develop in the face by second decade of life and present atypically, often
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439 pigmented and found in comedones, milium cysts, or areas of follicular

440 atrophoderma.136 Rombo syndrome is a rare autosomal dominant disorder

441 presenting with acral erythema, facial vermiculate atrophoderma, multiple milia,

442 telangiectasias, hypotrichosis, and a tendency to develop milia and BCCs.136,140

443 While distinguishing between Bazex-Dupre-Christol and Rombo syndromes is

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444 difficult, the latter presents later in childhood with a diffuse erythema not seen in

445 the former. Follicular arophoderma is more prominent in Bazex-Dupre-Christol.136

446 Xeroderma pigmentosum, a group of inherited disorders characterized by impaired

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447 DNA repair and hypersensitivity to UV-induced mutagenesis, have an 1000-fold

448 increased risk of cutaneous malignancies, including BCC. KCs begin to develop at

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449 median age of 8.5 years.136 Other genetic disorders characterized by increased

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450 BCC risk (but not necessarily as a prominent and specific finding) include diseases

451 of DNA replication/repair functions (Werner, Rothmund-Thomson, Bloom,

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452 Werner, Muir-Torre syndromes), immune response (cartilage-hair hypoplasia,
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453 epidermodysplasia verruciformis), folliculosebaceus unit (Brooke-Spiegler,

454 Schöpf-Schulz-Passarge ,Cowden syndromes), melanin biosynthesis

M

455 (oculocutaneous albinism, Hermansky-Pudlak syndrome), and epidermal nevus

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456 syndromes.141
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457 Rheumatoid arthritis patients have a mildly increased BCC risk.142-145 While

458 some evidence exists for an exacerbation of this association with biologic
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459 therapies, a recent large population-based cohort study showed this may only
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460 apply to SCC.142,146,147 Antineutrophil cytoplasmic antibody-associated

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461 vasculitides may also increase risk.148 Recent studies have shown a decreased

462 incidence in vitiligo patients.149,150 While this association is poorly understood and

463 seems counterintuitive, it’s thought to be secondary to keratinocyte upregulation

464 of wild-type p53 and p76 controlling DNA damage/repair.151,152 Alopecia areata,

465 which shares a similar pathogenesis to vitiligo, may also be associated with

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466 decreased incidence.153

467 Increased BCC rates have been associated with a variety of therapies.

468 While the dose-dependent relationship between increased SCC and psoralen

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469 ultraviolet A (PUVA) therapy is more pronounced, a similar relationship exists for

470 BCC. Increased risk is most apparent for >100 sessions.62,154-157 Large

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471 epidemiologic studies have shown ionizing radiation increases BCC risk in area of

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472 treatment; younger age at time of radiation may increase this association.158-162

473 BCC incidence increases 5-to-10 fold secondary to immunosuppression in organ

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474 transplant patients (compared to close to 100-fold increase with SCC). Compared
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475 to the general population, lesions more often present at a younger age (on average,

476 15 years earlier), outside the cephalic region, and as the superficial subtype.62,163-
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169
477 Oral contraceptive use may also be associated with increased risk and more
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478 aggressive subtypes, potentially helping explain recent data showing a higher rate
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479 of incidence increase in women.10,170-172

480
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481
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482
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483

484

485

486

487

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488 REFERENCES

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816 107. Kricker A, Armstrong BK, English DR, et al. Pigmentary and cutaneous risk
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936 143. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and
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949 147. Amari W, Zeringue AL, McDonald JR, et al. Risk of non-melanoma skin cancer
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952 148. Rahmattulla C, Berden AE, Wakker SC, et al. Incidence of Malignancies in

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953 Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis
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955 Dec 2015;67(12):3270-3278.
956 149. Teulings HE, Overkamp M, Ceylan E, et al. Decreased risk of melanoma and
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959 150. Schallreuter KU, Tobin DJ, Panske A. Decreased photodamage and low incidence
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962 151. Schallreuter KU, Behrens-Williams S, Khaliq TP, et al. Increased epidermal
963 functioning wild-type p53 expression in vitiligo. Experimental dermatology. Jun
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971 patients with alopecia areata: A retrospective cohort study. Cancer epidemiology.
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973 154. Stern RS. The risk of squamous cell and basal cell cancer associated with psoralen
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977 treated with PUVA. The New England journal of medicine. May 3
978 1984;310(18):1156-1161.
979 156. Stern RS, Liebman EJ, Vakeva L. Oral psoralen and ultraviolet-A light (PUVA)
980 treatment of psoriasis and persistent risk of nonmelanoma skin cancer. PUVA

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981 Follow-up Study. Journal of the National Cancer Institute. Sep 2

982 1998;90(17):1278-1284.
983 157. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoralen UV-A
984 therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic
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987 158. Perkins JL, Liu Y, Mitby PA, et al. Nonmelanoma skin cancer in survivors of

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989 study. Journal of clinical oncology : official journal of the American Society of
990 Clinical Oncology. Jun 1 2005;23(16):3733-3741.

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991 159. Karagas MR, Nelson HH, Zens MS, et al. Squamous cell and basal cell carcinoma
992 of the skin in relation to radiation therapy and potential modification of risk by
993 sun exposure. Epidemiology (Cambridge, Mass.). Nov 2007;18(6):776-784.

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994 160. Watt TC, Inskip PD, Stratton K, et al. Radiation-related risk of basal cell
995 carcinoma: a report from the Childhood Cancer Survivor Study. Journal of the
996 National Cancer Institute. Aug 22 2012;104(16):1240-1250.
997 161. Schwartz JL, Kopecky KJ, Mathes RW, et al. Basal cell skin cancer after total-

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998 body irradiation and hematopoietic cell transplantation. Radiation research. Feb
999 2009;171(2):155-163.
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1000 162. Lichter MD, Karagas MR, Mott LA, et al. Therapeutic ionizing radiation and the
1001 incidence of basal cell carcinoma and squamous cell carcinoma. The New
1002 Hampshire Skin Cancer Study Group. Archives of dermatology. Aug
1003 2000;136(8):1007-1011.
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1004 163. Park GH, Chang SE, Won CH, et al. Incidence of primary skin cancer after organ
1005 transplantation: An 18-year single-center experience in Korea. Journal of the
1006 American Academy of Dermatology. Mar 2014;70(3):465-472.
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1007 164. Jensen AO, Svaerke C, Farkas D, et al. Skin cancer risk among solid organ
1008 recipients: a nationwide cohort study in Denmark. Acta dermato-venereologica.
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1009 Sep 2010;90(5):474-479.

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1011 transplantation in The Netherlands. Transplantation. Mar 1990;49(3):506-509.
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1012 166. Harwood CA, Mesher D, McGregor JM, et al. A surveillance model for skin
1013 cancer in organ transplant recipients: a 22-year prospective study in an ethnically
1014 diverse population. American journal of transplantation : official journal of the
1015 American Society of Transplantation and the American Society of Transplant
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1016 Surgeons. Jan 2013;13(1):119-129.

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1018 cancer after heart transplant. Archives of dermatology. Dec 2009;145(12):1391-

1019 1396.
1020 168. Rashtak S, Dierkhising RA, Kremers WK, et al. Incidence and risk factors for
1021 skin cancer following lung transplantation. Journal of the American Academy of
1022 Dermatology. Jan 2015;72(1):92-98.
1023 169. Fortina AB, Piaserico S, Caforio AL, et al. Immunosuppressive level and other
1024 risk factors for basal cell carcinoma and squamous cell carcinoma in heart
1025 transplant recipients. Archives of dermatology. Sep 2004;140(9):1079-1085.

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1026 170. Kuklinski LF, Zens MS, Perry AE, et al. Sex hormones and the risk of
1027 keratinocyte cancers among women in the United States: A population-based
1028 case-control study. International journal of cancer. Jul 15 2016;139(2):300-309.
1029 171. Flohil SC, Seubring I, van Rossum MM, et al. Trends in Basal cell carcinoma
1030 incidence rates: a 37-year Dutch observational study. The Journal of investigative
1031 dermatology. Apr 2013;133(4):913-918.
1032 172. Birch-Johansen F, Jensen A, Mortensen L, et al. Trends in the incidence of

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1033 nonmelanoma skin cancer in Denmark 1978-2007: Rapid incidence increase
1034 among young Danish women. International journal of cancer. Nov 1
1035 2010;127(9):2190-2198.

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1036

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1037 Table 1

1038 Clinical and histopathologic findings of BCC subtypes.

U
Clinical Features Histopathological Features
AN
Nodular • Shiny, pearly papule or • Discrete nests of
nodule with a smooth malignant basaloid cells
surface, rolled borders, in the dermis
and arborizing • Peripheral palisading
M

telangiectasias • Mucoid stroma

• Predilection for head and containing plump spindle
neck52-54 cells
D

Superficial • Well-circumscribed and • Multiple lobular foci of

erythematous thin plaque basaloid palisading
TE

or patch with scale, keratinocyte tumors

central clearing, and thin attached superficially to
rolled borders the epidermis with a
• Most common on the myxoid stroma and band-
EP

trunk54 like lichenoid infiltrate51,

55

Infundibulocystic • Well-circumscribed • Well-circumscribed,

pearly papule anastomosing strands of
C

• Commonly on head and basaloid cells and

neck of the elderly scattered infundibulum-
AC

like cystic structures59

Fibroepithelial • Skin-colored or
erythematous sessile
plaque or pedunculated
papulonodule55
• Predilection for the trunk
Morpheaform • Infiltrated plaque with
poorly defined borders
and shiny surface
• Multiple collections of
delicate strands of
epidermal basaloid
keratinocytes arranged in
a reticular pattern within
a spindle cell stroma56
• Thin cords of basaloid
cells surrounded by a
sclerotic collagenous

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• Commonly on head and stroma, with mostly

neck absent peripheral
palisading and stromal
cleft formation
• Positive staining of tumor
stroma with smooth
muscle alpha-actin62

Infiltrative • Poorly defined, indurated,
flat or depressed plaque
with white, yellow or pale
pink color, may have
PT
• Thin cords with angulated
ends of very few basaloid
keratinocytes, embedded
in a classic

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overlying crusts, erosions, mucinous/myxoid
ulcerations, or papules stroma55
Micronodular • Erythematous macule or • Multiple small aggregates

SC
thin papule/plaque of basaloid cells within
the dermis, with subtle
peripheral palisading and
retraction artifact55

U
Basosquamous • Majority found on the • Well-defined nodular or
head and neck65 superficial BCC
AN
component overlying an
invasive front showing
BCC and SCC histologic
features55
M

1039

1040
D

1041
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1042
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1043

1044
C

1045
AC

1046

1047

1048

1049

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1050 Figure 1

1051 Nodular BCC

1052 Fig. 1A. Nodular BCC, presenting as a shiny, pearly papule with smooth surface,

PT
1053 rolled borders, and overlying arborizing telangiectasias.

1054 Fig. 1B. Large, advanced nodular BCC on the temple.

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1055 Fig. 1C. Nodular BCC of the right eye causing free margin distortion.

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1056 Fig. 1D. H&E stain of nodular BCC demonstrating large dermal nodules of

1057 malignant basaloid keratinocytes, peripheral palisading, and mucoid stroma

U
1058 containing plump spindle cells.
AN
1059

1060 Figure 2
M

1061 Superficial BCC

D

1062 Fig. 2A. Superficial BCC, presenting as a well-circumscribed and erythematous

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1063 thin plaque.

1064 Fig. 2B. Pigmented Superficial BCC.

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1065 Fig. 2C. H&E stain of superficial BCC demonstrating lobular foci of basaloid
C

1066 palisading keratinocytes attached superficially to the epidermis.

AC

1067

1068 Figure 3. Fibroepithelial BCC

1069 Fig. 3A. Fibroepithelial BCC, presenting as a pink sessile plaque.

1070 Fig. 3B. H&E stain demonstrating multiple collections of delicate strands of

1071 epidermal basaloid keratinocytes arranged in a reticular pattern within a spindle

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1072 cell stroma

1073

1074 Figure 4

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1075 Infundibulocystic BCC

1076 Fig. 4A. Infundibulocystic BCC, presenting as a well-circumscribed pearly papule.

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1077 Fig. 4B. H&E stain of infundibulocystic BCC, demonstrating anastomosing

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1078 strands of basaloid cells and scattered small infundibulum-like cystic structures.

1079

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1080 Figure 5
AN
1081 Morpheaform and infiltrative BCC

1082 Fig. 5A. Morpheaform BCC, presenting as a large infiltrated scar-like plaque with
M

1083 poorly defined borders and shiny surface.

D

1084 Fig. 5B. Multiple infiltrative BCCs, presenting as large poorly defined plaques
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1085 with overlying crust, erosions, and ulcerations.

1086 Fig. 5C. H&E stain of infiltrative BCC, demonstrating basaloid cells embedded in
EP

1087 a mucinous/myxoid stroma.

C

1088 Fig. 5D. H&E stain of morpheaform BCC, demonstrating a sclerotic collagenous
AC

1089 stroma surrounding basaloid cords.

1090

1091 Figure 6

1092 Micronodular and basosquamous BCC

1093 Fig. 6A. H&E stain of micronodular BCC, demonstrating multiple small

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1094 aggregates of basaloid cells within the dermis.

1095 Fig. 6B. Micronodular BCC, presenting as an erythematous macule.

1096 Fig. 6C. H&E stain of basosquamous BCC, showing features of both BCC and

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1097 squamous cell carcinoma.

1098

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1099 Figure 7

SC
1100 Schematic of the sonic hedgehog (SHH) pathway in a representative keratinocyte.

1101 Used with permission from Jaju et al136

U
1102
AN
1103 Normally, hedgehog ligand activates the pathway by binding to and inhibiting

1104 PTCH1, allowing derepression of smoothened (SMO), activation of suppressor of

M

1105 fused gene (SUFU), and the downstream upregulation of GLI1 transcription
D

1106 factors that are involved in cell growth and proliferation.

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1107

1108
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1109
C

1110
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1111

1112

1113

1114

1115

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1116 Table 2

1117 Summary of select genetic conditions associated with an increased risk of non-

1118 melanoma skin cancer

Adapted with permission from Jaju et al136

PT
1119

1120

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Pattern of Commercial

Condition Gene Locus Function Transmission Tests

SC
Basal cell PTCH1, 9q22.32, Hedgehog AD Ambry
nevus PTCH2, SUFU 1p34.1, signaling Genetics,

U
syndrome 10q24.32 pathway Prevention
members Genetics,
Fulgent
AN
Diagnostics,
Invitae,
Emory
Genetics
M

Bazex-Dupre- Unknown Xq25- DNA repair XLD

D

Chrisol 27.1 and regulation

syndrome of cell cycle
TE

Rombo Unknown Unknown Unknown AD

EP

syndrome
C

Xeroderma XPA-XPG, 9q22.33, Nucleotide AR Fulgent

α
pigmentosum XPV 2q14.3, excision repair Diagnostics
AC

3p25.1, and
19q13.32, Prevention
11p11.2, Genetics
16p13.12,
13q33.1,
and
6p21.1

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Rothmund- RECQL4 and 8q24.3, Chromosomal AR Fulgent

Thomson C16Orf57 16q13 Diagnostics,
syndrome
α stability, Prevention
Genetics,
telomere
Emory
maintenance, Genetics

PT
trafficking

Werner WRN/RECQL2 8p12 Chromosomal AR Fulgent

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α
syndrome stability Diagnostics,
Prevention
Genetics

SC
Bloom BLM/RECQL3 15q26.1 Chromosomal AR Centogene

U
α
syndrome stability AG-The Rare
Disease
AN
Company
M

Muire-Torre MLH1, MSH2, 3p22.2, Mismatch AD Ambry

β
syndrome MSH6, PMS2 2p21, repair Genetics,
2p16.3, Fulgent
D

7p22.1 Diagnostics
TE

1121
EP

1122 α : Also increased risk of squamous cell carcinoma.

1123 β : Also increased risk of soft tissue tumors and squamous cell carcinoma
C
AC

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 ACCEPTED MANUSCRIPT

PT
RI
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AN
M
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 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
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 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
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 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
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 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
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 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC