Aasi SZ

Hirotsu KE

Kibbi N

Maloney NJ

Rajan N

Zacher NC

\ua9 2023. Background: Visceral malignancies in patients with Lynch syndrome behave less aggressively than in those without Lynch syndrome. The behavior of sebaceous carcinoma (SC) in Muir-Torre syndrome (MTS), a variant of Lynch syndrome, is incompletely investigated. Objective: To investigate features and survival of SC patients with and without MTS. Methods: Retrospective cohort study in the Surveillance, Epidemiology, and End Results 17 database from 2000 to 2019 of patients with SC. Patients were classified as MTS or non-MTS cases based on a threshold score of 2 on the Mayo MTS risk score. Results: We identified 105 (2.8%) MTS cases and 3677 (97.2%) non-MTS cases. On univariate analysis, MTS patients were younger, had a higher proportion of tumors outside the head/neck, and had fewer high-grade tumors. On Kaplan-Meier analysis, MTS patients trended toward having better SC-specific survival. On multivariate Cox proportional hazards analysis adjusting for other covariates, MTS status was an independent predictor of worse overall survival. However, there was no association between MTS status and SC-specific survival. Limitations: Given relatively high disease-specific survival in SC, our study may have been underpowered to detect a difference on Kaplan-Meier analysis. Conclusions: Our study suggests SC does not behave more aggressively in patients with MTS

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Article type: Original Article 1 Title: Comparison of clinicopathologic features, survival, and demographics in sebaceous 2 carcinoma patients with and without Muir-Torre syndrome  3 Nolan J. Maloney1 MD, Natasha C. Zacher1 MD, Kelsey E. Hirotsu1 MD, Neil Rajan MD PhD2,3, 4 Sumaira Z. Aasi1 MD, Nour Kibbi1 MD 5 1 Department of Dermatology, Stanford University School of Medicine, Palo Alto, California 6 2 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. 7 3 Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.  8  9  10 Corresponding Author: Nour Kibbi MD 11 Department of Dermatology, Stanford University 12 450 Broadway, Fl 4 13 Redwood City, CA 94063 14 Telephone: 650-725-5272 15 Email: kibbi@stanford.edu  16  17 Funding sources: None. 18  19 Conflicts of Interest: None declared. 20 Prior Presentation: None. 21 IRB Approval Status: Exempt.   22  23 Patient Consent: Not applicable for this study 24  25 Word Counts:  26 Abstract: 197, Capsule Summary: 39 27 Manuscript: 1307 28 Reference Count:  13 29 Figures: 2 30 Tables: 3 31 Key words: sebaceous carcinoma; Muir-Torre; MTS; SEER; Lynch syndrome; HNPCC; hereditary non-32 polyposis colorectal cancer; epidemiology; survival; cutaneous oncology.  33 Abstract 34  35 Background: Visceral malignancies in patients with Lynch syndrome behave less aggressively 36 than in those without Lynch syndrome. The behavior of sebaceous carcinoma (SC) in Muir-Torre 37 syndrome (MTS), a variant of Lynch syndrome, is incompletely investigated.   38  39 Objective: Investigate features and survival of SC patients with and without MTS.  40  41 Methods: Retrospective cohort study in the Surveillance, Epidemiology, and End Results 17 42 database from 2000-2019 of patients with SC. Patients were classified as MTS or non-MTS 43 cases based on a threshold score of 2 on the Mayo MTS Risk Score.  44  45 Results: We identified 105 (2.8%) MTS cases and 3677 (97.2%) non-MTS cases. On univariate 46 analysis, MTS patients were younger, had a higher proportion of tumors outside the head/neck, 47 and had fewer high-grade tumors. On Kaplan-Meier analysis, MTS patients trended toward 48 having better SC-specific survival. On multivariate Cox proportional hazards analysis adjusting 49 for other covariates, MTS status was an independent predictor of worse overall survival. 50 However, there was no association between MTS status and SC-specific survival.  51  52 Limitations: Given relatively high disease-specific survival in SC, our study may have been 53 underpowered to detect a difference on Kaplan-Meier analysis.  54  55 Conclusions: Our study suggests SC does not behave more aggressively in patients with MTS.   56  57 Capsule Summary 58  59 • Visceral malignancies in patients with Lynch syndrome are less aggressive than the same 60 malignancies in those without Lynch syndrome. 61 • Our study suggests sebaceous carcinoma does not behave more aggressively in patients 62 with Muir-Torre syndrome, a variant of Lynch syndrome.  63   64 Introduction 65 Muir-Torre syndrome (MTS), a variant of Lynch syndrome (LS), presents with an LS-66 associated neoplasm (colorectal/small bowel, endometrial, urologic, ovarian, biliary tract) and 67 sebaceous neoplasms including sebaceous carcinoma (SC), sebaceoma, or sebaceous adenoma. 68 LS-associated, mismatch-repair-deficient colorectal cancers show lower propensity for distant 69 metastasis, are diagnosed at earlier stage, and have better prognosis regardless of stage upon 70 initial diagnosis when compared to non-LS colorectal cancers.1,2 While the behavior of 71 mismatch-repair-deficient colorectal cancer in LS is understood to be less aggressive than non-72 LS colorectal cancer, little data exists on the behavior of sebaceous carcinoma in MTS patients 73 versus those without MTS. One report suggests more aggressive behavior of SC in MTS patients, 74 finding 5-year SC-specific survival of 52.5% in MTS patients compared to 78.2% in non-MTS 75 patients; however, this was based on a small sample of patients.3  76 To further clarify the behavior of SC in MTS versus non-MTS patients, we compared 77 survival and examined clinicopathologic features in MTS and non-MTS patients.  78  79 Methods 80 Patient Population 81 We performed a retrospective cohort study using the Surveillance, Epidemiology, and 82 End Results (SEER) Research Plus Database, 17 Registries for sebaceous carcinoma cases 83 diagnosed from 2000-2019.4 SEER is a population-based dataset that collects information on 84 patient demographics, tumor features, treatment, and survival, covering an approximate 47.9% of 85 the US population. Inclusion criteria encompassed known primary site on the skin, known 86 surgical treatment, and complete data on cause of death and months of survival. We defined 87 MTS using criteria from the Mayo MTS risk score. Points are based on four factors: age at 88 diagnosis of sebaceous neoplasm less than 60 years (1 point), two or more sebaceous neoplasms 89 (2 points), and presence of a personal or family history of a LS-associated neoplasm (1 point 90 each).5 Using the SEER multiple-primary session, we were able to identify patients with an SC 91 diagnosed before 60 who also had a diagnosis of a LS-associated neoplasm (colorectal/small 92 bowel, gastric, endometrial, urologic, ovarian, biliary tract). This combination of factors earns a 93 patient 2 points on the Mayo MTS risk score, which has a reported 100% sensitivity and 81% 94 specificity for MTS.5 Since we could not reliably distinguish between multiple primary 95 sebaceous carcinomas versus recurrences in the SEER data, and because SEER does not include 96 data on sebaceoma or sebaceous adenoma, we could not assess the multiple sebaceous neoplasm 97 component of the Mayo MTS risk score. In addition, there is no data on family history of LS-98 associated cancers in SEER. This study was exempt from institutional review board approval.  99  100 Statistical Analysis 101 Kaplan-Meier curves were generated to compare survival between non-MTS and MTS 102 patients with log-rank testing to evaluate for significance. For analysis of overall survival, 103 Kaplan-Meier analysis was restricted to patients less than age of 60, since our definition of MTS 104 required a diagnosis of sebaceous carcinoma before 60. Chi-squared testing was performed to 105 assess for differences in clinicopathologic and demographic features and treatments performed 106 between MTS and non-MTS patients. Multivariate cox proportional hazards modeling was used 107 to assess for the impact of MTS status on both overall survival and sebaceous-carcinoma specific 108 survival, while adjusting for other covariates. These covariates included patient demographics 109 (age, race, sex), tumor features (primary site, histologic grade, stage), and treatment (surgery, 110 radiation), since these are factors thought to impact survival in sebaceous carcinoma.6–8 Proper 111 selection of covariates for the Cox models was assessed with the Akaike’s information criteria 112 statistic.  113  114 Results 115 Our study population comprised 105 MTS cases (2.8% of total study population), and 116 3677 non-MTS cases (97.2%). On chi-squared analysis, MTS patients were younger and 117 predominantly male. They had a higher proportion of black patients, fewer periocular and 118 head/neck tumors, a lower proportion of high-grade tumors, and were less frequently treated with 119 Mohs surgery (Table 1). On Kaplan-Meier assessment of overall survival, restricted to patients 120 <60 years of age (since all MTS patients were <60), MTS patients had significantly worse 10-121 year overall survival (Figure 1A, 67.0% versus 83.9%, log-rank test p=0.0007). However, on 122 analysis of disease-specific survival (DSS), MTS patients trended toward having better survival 123 compared to non-MTS patients (10-year DSS of 97.9% versus 93.1%, Figure 1B, p=0.0780, log-124 rank testing). DSS did not change when only patients <60 with or without MTS were compared.  125 On multivariate Cox proportional hazard analysis accounting for covariates including 126 age, sex, race, primary site location, histologic grade, stage, type of surgery received, and receipt 127 of adjuvant radiation, MTS status was associated with significantly worse overall survival (Table 128 2, hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.21-2.62, p=0.0036). Other significant 129 factors included high histologic grade (HR 1.29, 95% CI 1.06-1.56), location outside the 130 periocular region (HR 1.31 for other head/neck, 95% CI 1.13-1.52; HR 1.38 for 131 trunk/extremities, 95% CI 1.15-1.63), and primary treatment with wide local excision (HR 1.37, 132 95% CI 1.06-1.79). On multivariate analysis of SC-specific survival accounting for the same 133 factors, MTS status was not associated with a difference in sebaceous-carcinoma specific 134 survival (Table 3, HR 0.41, 95% CI 0.097-1.78, p=0.236).  135  136 Discussion  137 The impact of MTS diagnosis on the behavior of SC has not been fully elucidated, and 138 recent clinical practice guidelines in SC excluded MTS-associated cases.8 In this population-139 based cohort study, we show that MTS-associated SC cases were lower-grade and trended 140 towards improved SC-specific survival (though this was not significant). This contrasts with a 141 prior smaller study that suggested substantially worse outcomes of SC in patients with MTS.3 142 However, our findings are more consistent with what is reported about mismatch-repair-deficient 143 visceral tumors in Lynch syndrome patients—that these tumors tend to be less aggressive and 144 lower-grade, with less propensity for metastasis than their non-LS counterparts.3,9,10 It is not 145 surprising that the overall survival of MTS patients was worse than an age-matched non-146 syndromic cohort, as MTS confers significantly increased risk of other malignancies. However, 147 the trend towards improved SC-specific survival in the MTS cohort suggests that this worse 148 survival is not due to their SC tumors. In clinical context, our study suggests that MTS should 149 not modify how any particular individual SC is treated and that the workup and treatment should 150 depend on each individual SC’s characteristics including location, size, histologic grade, depth of 151 invasion, and patient comorbidities.8  152 Our study also demonstrates location on the trunk and extremities is associated with 153 worse overall and disease-specific survival after controlling for sex, age, histologic grade, MTS 154 status, and treatment type. In contrast, other research has demonstrated higher local recurrence 155 rates for periocular SC and higher rates of nodal metastasis in periocular SC versus other 156 head/neck SC.7,11 With respect to our study and other registry based studies, it is possible that 157 anatomic location was confounded by tumor size, which could not be included in this study due 158 to missing data for this variable in SEER, and trunk/extremity tumors could on average be larger 159 than periocular tumors. Other registry studies both in SEER and the National Cancer Database 160 have also suggested worse survival outcomes for extraocular SC compared with periocular 161 SC.6,12 The possibility of MTS as an independent risk factor for mortality has been proposed as a 162 possible explanation, but our study suggests that worse outcomes of tumors of the 163 trunk/extremities is independent of MTS.12 Another possible explanation is that sebaceous 164 carcinoma of the trunk and extremities is more common in solid organ transplant recipients, and 165 immunosuppression may predispose these patient to worse cancer-specific outcomes.13 Given 166 lack of data on immunosuppression or transplant status in our dataset, we could not control for 167 these potential covariates.  168 Limitations of our study include lack of confirmatory data on germline testing for 169 mismatch repair deficiency in MTS cases. Despite the excellent sensitivity and specificity 170 afforded by the Mayo MTS risk score of 2 as used in our study, we could not capture all MTS 171 cases, given that we could not include patients with multiple sebaceous neoplasms or family 172 history of other LS-associated cancers. In addition, our study may have been underpowered to 173 detect a difference between disease-specific survival in MTS versus non-MTS patients given that 174 overall disease-specific survival is high in SC, and hence a larger number of patients is required 175 to observe a significant difference. Lastly, data on recurrences were not available.    176 In conclusion, this study suggests MTS-associated SC cases do not have worse outcomes 177 than other SC cases. We hope our investigation prompts further investigation into the behavior of 178 SC in MTS patients and guides development of future clinical guidelines, which do not 179 specifically comment on management of MTS-associated SC.  180  181   182 REFERENCES 183 1.  Sinicrope FA. Lynch Syndrome–Associated Colorectal Cancer. N Engl J Med. 184 2018;379(8):764-773. doi:10.1056/NEJMcp1714533 185 2.  Koopman M, Kortman GAM, Mekenkamp L, et al. Deficient mismatch repair system in 186 patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266-273. 187 doi:10.1038/sj.bjc.6604867 188 3.  Tripathi R, Bordeaux JS. Impact of Muir-Torre Syndrome on Survival in Patients With 189 Sebaceous Carcinoma: A  SEER Population-Based Study. Dermatologic Surg  Off Publ 190 Am Soc Dermatologic  Surg [et al]. 2019;45(1):148-149. 191 doi:10.1097/DSS.0000000000001503 192 4.  Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) 193 SEER*Stat Database: Incidence - SEER Research Plus Data, 17 Registries, Nov 2021 Sub 194 (2000-2019). National Cancer Institute, Surveillance Research Program. 195 5.  Roberts ME, Riegert-Johnson DL, Thomas BC, et al. A clinical scoring system to identify 196 patients with sebaceous neoplasms at risk  for the Muir-Torre variant of Lynch syndrome. 197 Genet Med  Off J Am Coll Med  Genet. 2014;16(9):711-716. doi:10.1038/gim.2014.19 198 6.  Tripathi R, Chen Z, Li L, Bordeaux JS. Incidence and survival of sebaceous carcinoma in 199 the United States. J Am Acad Dermatol. 2016;75(6):1210-1215. 200 doi:https://doi.org/10.1016/j.jaad.2016.07.046 201 7.  Tryggvason G, Bayon R, Pagedar NA. Epidemiology of sebaceous carcinoma of the head 202 and neck: Implications for lymph node management. Head Neck. 2012;34(12):1765-1768. 203 doi:https://doi.org/10.1002/hed.22009 204 8.  Owen JL, Kibbi N, Worley B, et al. Sebaceous carcinoma: evidence-based clinical 205 practice guidelines. Lancet Oncol. 2019;20(12):e699-e714. doi:10.1016/S1470-206 2045(19)30673-4 207 9.  Sinicrope FA. Lynch Syndrome–Associated Colorectal Cancer. N Engl J Med. 208 2018;379(8):764-773. doi:10.1056/NEJMcp1714533 209 10.  Koopman M, Kortman GAM, Mekenkamp L, et al. Deficient mismatch repair system in 210 patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266-273. 211 doi:10.1038/sj.bjc.6604867 212 11.  In ’t Veld EH, Keizer R, Post N, et al. Outcome after treatment for sebaceous carcinoma: 213 A multicenter study. J Surg Oncol. 2022;125(4):730-735. 214 doi:https://doi.org/10.1002/jso.26774 215 12.  Liszewski W, Amon G, Blanchette D, Maher IA. Survival and demographic differences of 216 periocular and nonperiocular sebaceous carcinomas. J Am Acad Dermatol. 217 2020;83(1):224-227. doi:10.1016/j.jaad.2019.10.070 218 13.  Sargen MR, Cahoon EK, Lynch CF, Tucker MA, Goldstein AM, Engels EA. Sebaceous 219 Carcinoma Incidence and Survival Among Solid Organ Transplant Recipients in the 220 United States, 1987-2017. JAMA Dermatology. 2020;156(12):1307-1314. 221 doi:10.1001/jamadermatol.2020.3111 222  223   224 Figure 1. Kaplan-Meier survival of sebaceous carcinoma patients stratified by Muir-Torre 225 syndrome status. Panel A demonstrating overall survival (restricted to patients <60 years of age), 226 and panel B demonstrating disease-specific survival (all ages included).  227 A) 228  229  230 B) 231   232 Table 1: Demographic, clinical, and pathologic features of sebaceous carcinoma patients stratified by 233 presumed Muir-Torre syndrome status.   234  MTS cohort n = 105 (2.8%)   Non-MTS cohort n = 3677 (97.2%)  χ2 Characteristics N % N %  Sex     0.359   Female 35 33.3 1403 38.2    Male 70 66.7 2274 61.8  Age     <0.0001   ≤60 105 100 629 17.1    61-74 0 0 1295 35.2    ≥75 0 0 1753 47.7  Race     0.0436   White 88 83.8 3141 85.4    Black 7 6.7 99 2.7    Other/Unknown 10 9.5 437 11.9  Primary site     <0.0001   Periocular 10 9.5 752 20.4    Other Head/Neck 29 27.6 1969 53.6    Trunk/Extremities 66 62.9 956 26.0  Histologic Grade     0.0377   High 5 4.8 315 8.6    Low 26 24.8 597 16.2    Unknown 74 70.4 2765 75.2  Summary Stage     0.465   Localized 63 60.0 2438 66.3    Regional 2 1.9 101 2.7    Distant 4 3.8 110 3.0    Unknown 36 34.3 1028 38.0  Surgery     <0.0001   MMS 1 1.0 515 14.0    Narrow-margin excision 65 61.9 2006 54.6    Wide-local excision 28 26.7 714 19.4    None 11 10.4 442 12.0  Adjuvant Radiation     0.437   No 103 98.1 3526 95.9    Yes 2 1.9 151 4.1  Abbreviations: MMS = mohs micrographic surgery. 235   236 Table 2: Multivariate Cox proportional hazards model for independent prognosticators of overall survival 237 in sebaceous carcinoma patients with Muir-Torre syndrome as a covariate. 238  Hazard Ratio (95% CI) P value Sex     Female Reference    Male 1.11 (0.99-1.23) 0.0615 Age     ≤60 Reference    61-74 2.37 (1.88-3.00) <0.0001   ≥75 7.78 (6.23-9.72) <0.0001 Race     White Reference    Black 1.41 (1.04-1.90) 0.0255   Other/Unknown 0.51 (0.41-0.64) <0.0001 Primary Site     Periocular Reference    Other Head/Neck 1.31 (1.13-1.52) 0.0004   Trunk/Extremities 1.38 (1.15-1.63)  0.0002 Histologic Grade     Low Reference    High 1.29 (1.06-1.56) 0.0101   Unknown 0.94 (0.82-1.08)  0.374 Summary Stage     Localized Reference    Regional 1.35 (0.97-1.88) 0.0767   Distant 1.43 (1.09-1.87) 0.0097   Unknown 0.95 (0.84-1.07) 0.379 Surgery Performed      MMS Reference    Wide-local excision  1.37 (1.06-1.79) 0.0179   Narrow-margin excision 1.21 (1.01-1.44) 0.0357   None 1.47 (1.19-1.80) 0.0003 Adjuvant Radiation     None/Unknown Reference    Yes 1.30 (1.02-1.67) 0.0340 MTS Patient     No Reference    Yes 1.78 (1.21-2.62) 0.0036 Abbreviations: CI = confidence interval; MMS = mohs micrographic surgery; MTS = Muir-Torre Syndrome. 239  240   241 Table 3: Multivariate Cox proportional hazards model for independent prognosticators of disease-specific 242 survival in sebaceous carcinoma patients with Muir-Torre syndrome as a covariate. 243  Hazard Ratio (95% CI) P value Sex     Female Reference    Male 1.49 (1.05-2.11) 0.0247 Age     ≤60 Reference    61-74 1.13 (0.67-1.90) 0.653   ≥75 2.35 (1.45-3.80) 0.0005 Race     White Reference    Black 2.19 (1.01-4.75) 0.0481   Other/Unknown 0.85 (0.49-1.46) 0.548 Primary Site     Periocular Reference    Other Head/Neck 1.34 (0.84-2.15) 0.221   Trunk/Extremities 1.96 (1.18-3.24) 0.0090 Histologic Grade     Low Reference    High 3.69 (2.07-6.57) <0.0001   Unknown 1.27 (0.76-2.11) 0.3580 Summary Stage     Localized Reference    Regional 4.96 (2.71-9.08) <0.0001   Distant 6.36 (3.46-11.68) <0.0001   Unknown 1.48 (0.99-2.20) 0.0536 Surgery Performed      MMS Reference    Wide-local excision  1.44 (0.74-2.82) 0.286   Narrow-margin excision 1.28 (0.71-2.32) 0.416   None 1.84 (0.94-3.61) 0.0765 Adjuvant Radiation     None/Unknown Reference    Yes 2.33 (1.37-3.94) 0.0017 MTS Patient     No Reference    Yes 0.41 (0.09-1.78) 0.236 Abbreviations: CI = confidence interval; MTS = Muir-Torre Syndrome. 244  245  246 

Comparison of clinicopathologic features, survival, and demographics in sebaceous carcinoma patients with and without Muir-Torre syndrome

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