Clinicopathologic and molecular analyses of cutaneous leiomyosarcoma: A retrospective, multicenter study of 79 cases

Abstract

To the Editor: Cutaneous leiomyosarcoma (cLMS) is a rare skin sarcoma reported to have a good prognosis.1Winchester D.S. Hocker T.L. Brewer J.D. et al.Leiomyosarcoma of the skin: clinical, histopathologic, and prognostic factors that influence outcomes.J Am Acad Dermatol. 2014; 71: 919-925https://doi.org/10.1016/j.jaad.2014.07.020Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In this large, retrospective, and multicenter study of cLMS (confined to the dermis or involving the subcutis layers), conducted from January 2000 to June 2019, we aimed to better define its clinicopathologic features and prognostic factors. Statistical analyses combined the Kaplan-Meier method (to estimate overall survival and progression-free survival) and the log-rank test (to identify prognostic factors). We also performed molecular analyses using whole-genome copy number analyses as well as targeted DNA and RNA sequencing. Seventy-nine patients were included (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/sjk9p9rgtz/1). Most cases occurred in the lower portion of the limbs (n = 29 [36.7%]) and showed subcutis invasion (n = 35 [44.3%]) and a low histologic grade (grade I, n = 49, [62.0%]) according to the Fédération Nationale des Centres de Lutte Contre le Cancer2Coindre J.M. Trojani M. Contesso G. et al.Reproducibility of a histopathologic grading system for adult soft tissue sarcoma.Cancer. 1986; 58: 306-309https://doi.org/10.1002/1097-0142(19860715)58:2<306::aid-cncr2820580216>3.0.co;2-7Crossref PubMed Google Scholar grading system. The margin status was R0 in 59 cases (74.7%, ie, complete surgical resection, without residual tumor). Recurrence occurred in 12 patients (15.2%), whereas regional or distant metastasis occurred in 7 patients (8.9%). Eight patients died, 6 of them because of metastatic cLMS. The median overall survival and progression-free survival was 38.8 (range, 4.9-73.9) and 25.2 months (range, 2.8-66.1), respectively. The estimated 24-month overall survival and progression-free survival rates were 92% and 77%, respectively. There was no significant association between outcomes and clinical parameters (age, sex, tumor location, and tumor size). However, the margin sizes were wider in the population without relapse (n = 33, margin size = 1.80 cm) than in the population with relapse (n = 9, margins size = 1.06 cm, P = .03). Conversely, an intermediate or high Fédération Nationale des Centres de Lutte Contre le Cancer grade (II-III) was significantly associated with a higher risk of recurrence or metastasis (hazard ratio, 4.8; 95% CI, 1.6-14.6; P = .01). There was no prognostic association with other histologic factors; the hazard ratio of the recurrence/metastasis of subcutis invasion was 7.4 (95% CI, 0.9-58.2; P = .06). Subcutis invasion (n = 35) was observed in 51% of cases with grade I versus 40% of cases with grade II/III cLMS. Eleven cases were molecularly explored, showing heterogeneous profiles (Supplementary Table II, available via Mendeley at https://data.mendeley.com/datasets/8t7hcb8jw7/1): 4 cases presented with >10 segmental copy number alterations (CNAs) (case numbers, 1-4), 3 cases presented with only 1 CNA (case numbers, 5-7). The recurrent abnormalities were the deletion of the RB1 (n = 5) or TP53 gene (n = 4) and the amplification of MYOCD (n = 2). Four cases presented with no CNA (case numbers, 8-11). TP53 mutations were identified, but no fusion gene was identified. The limitation of this study is its retrospective design; nevertheless, the following data deserve to be highlighted. cLMS has a good prognosis, with the 5-year survival rate ranging from 86% (in our series) to 92% (Surveillance, Epidemiology, and End Results Database). However, recurrence/metastasis may have occured.1Winchester D.S. Hocker T.L. Brewer J.D. et al.Leiomyosarcoma of the skin: clinical, histopathologic, and prognostic factors that influence outcomes.J Am Acad Dermatol. 2014; 71: 919-925https://doi.org/10.1016/j.jaad.2014.07.020Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar,3Wong G.N. Webb A. Gyorki D. et al.Cutaneous leiomyosarcoma: dermal and subcutaneous.Australas J Dermatol. 2020; 61: 243-249https://doi.org/10.1111/ajd.13307Crossref PubMed Scopus (5) Google Scholar Few previous studies correlated prognosis with clinicohistologic parameters.3Wong G.N. Webb A. Gyorki D. et al.Cutaneous leiomyosarcoma: dermal and subcutaneous.Australas J Dermatol. 2020; 61: 243-249https://doi.org/10.1111/ajd.13307Crossref PubMed Scopus (5) Google Scholar We reported for the first time that Fédération Nationale des Centres de Lutte Contre le Cancer grading is the most important prognostic factor. Therefore, cLMS of grade II/III should be managed with wider local excision, as already suggested, and we recommend margins of 2 cm.4Kazlouskaya V. Lai Y.C. Khachemoune A. Leiomyosarcoma of the skin: review of the literature with an emphasis on prognosis and management.Int J Dermatol. 2020; 59: 165-172https://doi.org/10.1111/ijd.14705Crossref PubMed Scopus (9) Google Scholar Our study was the first to explore pan-genomic CNAs as well as targeted mutations and fusion genes. Patients with cLMS with a complex genomic quantitative profile (case numbers, 1-4, which showed subcutaneous extension) share some molecular features described in patients with deep soft tissue leiomyosarcoma: TP53 and RB1 alterations and MYOCD amplification.5Dry S.M. Fröhling S. Leiomyosarcoma. WHO Classification of Soft Tissue and Bone Tumours.5th ed. IARC, 2019: 195-197Google Scholar Patients with cLMS with such molecular features might have a pejorative prognosis, which should be confirmed in a larger cohort. None disclosed.