Abstract
This cohort study examines the odds of developing basal cell carcinoma, squamous cell carcinoma, or melanoma among insured adults with neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is a multisystem autosomal dominant genetic syndrome affecting 1 in 4000 individuals and characterized by heterozygous loss of the tumor suppressor gene, neurofibromin.1 Patients with NF1 develop benign skin, eye, and nervous system tumors and susceptibility to nervous system and other solid organ cancers.1,2 Biallelic loss of NF1 (OMIM 613113) leads to hyperactivation of RAS signaling pathways.3 Although patients with NF1 often present to dermatologists for skin concerns, the risk of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma in these patients remains unclear.
Methods
We conducted a retrospective cohort study between January 1, 2009, and March 31, 2021, using the Clinformatics Data Mart, a de-identified national insurance claims database. Stanford University Institutional Review Board approved this study and waived the informed consent requirement because we used deidentified data. We followed the STROBE reporting guideline.
Inclusion criteria included patients 18 years or older with an NF1 International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis code (237.71 or Q85.01) and at least 1 year of continuous insurance enrollment. Each patient with NF1 was matched using greedy nearest neighbor matching with up to 10 patients without NF1 on age, sex, race and ethnicity, region, and enrollment length. The database derived race and ethnicity from patients’ name and location. Primary outcomes of melanoma, BCC, and SCC were identified by ICD-9 or ICD-10 codes (eTable 1 in the Supplement). Sensitivity analysis excluding patients with either malignant peripheral nerve sheath tumors or optic gliomas was performed (eTable 2 in the Supplement).
We used χ2 testing to assess for differences between groups. Conditional logistic regressions calculated associations between NF1 and skin cancers in patients with vs without NF1; P < .05 indicated statistical significance. Stata 16 (StataCorp LLC) was used in statistical analysis.
Results
We included 4122 patients with NF1 (mean [SD] age, 47 [18] years; 2288 women [55.5%], 1834 men [44.5%]) (Table 1). Compared with patients without NF1, patients with NF1 had increased odds of melanoma (odds ratio [OR], 2.27; 95% CI, 1.75-2.93; P < .001) and keratinocyte carcinomas (OR, 1.31; 95% CI, 1.15-1.51; P < .001) (Table 2). Patients with NF1 had increased odds for BCC (OR, 1.30; 95% CI, 1.10-1.53; P = .002) and SCC (OR, 1.32; 95% CI, 1.07-1.63; P = .008). In stratified analyses, similar increased odds of melanoma and keratinocyte carcinoma were observed across racial and ethnic groups (Table 2).
Table 1. Demographic Characteristics of Patients With NF1 vs Matched Patients Without NF1.
| Characteristic | Patients, No. (%)a | P value | |
|---|---|---|---|
| With NF1 (n = 4122) | Without NF1 (n = 41 064) | ||
| Sex | |||
| Female | 2288 (55.5) | 22 803 (55.5) | .99 |
| Male | 1834 (44.5) | 18 261 (44.5) | |
| Age group, y | |||
| 18-34 | 1271 (30.9) | 12 763 (31.1) | .62 |
| 35-44 | 613 (14.9) | 6942 (16.9) | |
| 45-54 | 655 (15.9) | 6449 (15.7) | |
| 55-64 | 695 (16.9) | 6186 (15.1) | |
| 65-74 | 555 (13.5) | 5231 (12.7) | |
| ≥75 | 333 (8.1) | 3493 (8.5) | |
| Race and ethnicityb | |||
| Asian | 155 (3.8) | 1528 (3.7) | >.99 |
| Black | 474 (11.5) | 4697 (11.4) | |
| Hispanic | 400 (9.7) | 3953 (9.6) | |
| White | 3093 (75.0) | 30 886 (75.2) | |
| Region | |||
| Midwest | 1038 (25.2) | 10 353 (25.2) | >.99 |
| Northeast | 524 (12.8) | 5186 (12.6) | |
| South | 1762 (42.8) | 17 574 (42.9) | |
| West | 795 (19.2) | 7921 (19.3) | |
Abbreviation: NF1, neurofibromatosis type 1.
Percentages may not total 100 because of rounding.
Clinformatics Data Mart derived race and ethnicity data from patients' name and location.
Table 2. Odds of Skin Cancers in Patients With NF1, With and Without Stratification by Race and Ethnicity.
| Skin cancer | Patients, No. (%) | OR (95% CI) | P value | |
|---|---|---|---|---|
| With NF1 | Without NF1 | |||
| All race and ethnicity groups | ||||
| BCC | 176 (4.3) | 1383 (3.4) | 1.30 (1.10-1.53) | .002 |
| SCC | 109 (2.6) | 837 (2.0) | 1.32 (1.07-1.63) | .008 |
| Keratinocyte carcinomaa | 267 (6.5) | 2096 (5.1) | 1.31 (1.15-1.51) | <.001 |
| Melanomab | 74 (1.8) | 333 (0.8) | 2.27 (1.75-2.93) | <.001 |
| Asian | ||||
| Keratinocyte carcinomaa | <11 | 16 (1.1) | 1.25 (0.29-5.51) | .77 |
| Melanomab | <11 | <11 | 2.50 (0.28-22.37) | .41 |
| Black | ||||
| Keratinocyte carcinomaa | 18 (3.8) | 92 (2.0) | 2.02 (1.19-3.42) | .009 |
| Melanomab | <11 | <11 | 4.44 (1.37-14.43) | .01 |
| Hispanic | ||||
| Keratinocyte carcinomaa | 12 (3.0) | 60 (1.5) | 2.03 (1.07-3.85) | .03 |
| Melanomab | <11 | 17 (0.4) | 2.93 (1.08-7.93) | .04 |
| White | ||||
| Keratinocyte carcinomaa | 235 (7.6) | 1928 (6.2) | 1.25 (1.08-1.45) | .002 |
| Melanomab | 64 (2.1) | 303 (1.0) | 2.16 (1.64-2.84) | <.001 |
Abbreviations: BCC, basal cell carcinoma; NF1, neurofibromatosis type 1; OR, odds ratio; SCC, squamous cell carcinoma.
Keratinocyte carcinoma includes BCC and SCC.
Melanoma includes melanoma and melanoma in-situ.
Discussion
This study found increased odds of melanoma, BCC, and SCC in patients with NF1. Whole-exome sequencing has established NF1 as the third most frequently mutated gene in melanomas.3 About 12% to 18% of melanomas and 45% to 93% of desmoplastic melanomas harbor NF1 alterations.4 Functional genomic studies demonstrated that suppressing NF1 activates RAS in melanomas, supporting the role of RASopathies in melanogenesis.3 Similarly, activation of RAS signaling pathways has been implicated in SCC pathogenesis, with SCCs carrying RAS alterations exhibiting more aggressive, infiltrative patterns.5 In BCCs, RAS/MAPK pathway activation confers drug resistance to certain BCC subtypes.6 These findings implicate RAS/MAPK activation in skin cancer susceptibility in patients with NF1.
A study strength is use of a large national database to identify associations between a rare genetic disorder and skin cancers. Study limitations are that only patients with commercial insurance were available, and diagnosis code reliability was not guaranteed. Data on race and ethnicity were imputed; thus, results should be interpreted cautiously. Patients with NF1 may see dermatologists more frequently, increasing chances of diagnosing skin cancer and creating potential bias. Although relative risk differences exist, absolute risk differences are small and may not be clinically meaningful to change screening recommendations.
These results highlight the role of germline RAS pathway hyperactivation in skin carcinogenesis. Whether photoprotection mitigates skin cancer development in patients with NF1 is unknown. Nevertheless, quantifying skin cancer risk may empower physicians to educate patients with NF1 and guide dermatologic management.
eTable 1. International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) Codes for Skin Cancers
eTable 2. International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) Codes for Malignant Peripheral Nerve Sheath Tumor and Optic Glioma
References
- 1.Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med. 2018;20(9):1082-1086. doi: 10.1038/gim.2017.215 [DOI] [PubMed] [Google Scholar]
- 2.Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br J Cancer. 2013;108(1):193-198. doi: 10.1038/bjc.2012.535 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47(9):996-1002. doi: 10.1038/ng.3361 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kiuru M, Busam KJ. The NF1 gene in tumor syndromes and melanoma. Lab Invest. 2017;97(2):146-157. doi: 10.1038/labinvest.2016.142 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Campos MA, Macedo S, Fernandes MS, et al. Prognostic significance of RAS mutations and P53 expression in cutaneous squamous cell carcinomas. Genes (Basel). 2020;11(7):E751. doi: 10.3390/genes11070751 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kuonen F, Huskey NE, Shankar G, et al. Loss of primary cilia drives switching from hedgehog to Ras/MAPK pathway in resistant basal cell carcinoma. J Invest Dermatol. 2019;139(7):1439-1448. doi: 10.1016/j.jid.2018.11.035 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) Codes for Skin Cancers
eTable 2. International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) Codes for Malignant Peripheral Nerve Sheath Tumor and Optic Glioma