The patients are described in  Tables 1 ,  2 . The median age of the 14 patients was 70 years old at MDS/CMML diagnosis (ranging 62-81) and was 69 years old at the time of cutaneous manifestations (ranging 30-82). The MDS subtypes were MDS with multilineage dysplasia (n=3, including one with myelofibrosis), MDS with excess blasts (n=1), MDS with unilineage dysplasia (n=1), MDS/myeloproliferative neoplasm (MPN) (n=2), and CMML (n=7). Karyotype was normal in eight patients, abnormalities were found in five patients [del(20)(q11q13) in patient 5; iso(X)(p10) and t(3,12)(p2?2;q24) in patient 6; trisomy 18 in patient 11; trisomy 8, del(1)(p?3?4), and del(5) (q?3?1q35) in patient 13; and del(4)(q?23q?26) in patient 14], and the karyotype could not be performed for one patient (patient 7). The MDS were low or intermediate-1 risk in 93% cases with median IPSS at 0.5 (0-2) and very-low, low, or intermediate risk in 93% cases with median IPSS-R at 2.3 (0.6-5.1).
Skin lesions preceded the MDS/CMML diagnosis in 5 (36%) patients. In 7 (50%) cases, extracutaneous symptoms were associated; fever (n=5; 36%) and arthralgia and/or arthritis (n=6; 43%) were the most prevalent.
Based on clinical, histological, and immunohistochemical findings and before NGS results, skin lesions have been classified as H-SS in four cases (patients 2, 7, 9, and 12), CMML cutis in three cases (patients 4, 6, and 11), and ECD associated with CMML cutis in two cases (patients 1 and 3), Kikuchi-Fujimoto disease in one case (patient 5), neutrophilic folliculitis in one case (patient 10), erythema nodosum in one case (patient 13), pyoderma gangrenosum in one case (patient 14), and extensive livedo reticularis with non-specific findings on skin biopsy in one case (patient 8) ( Tables 1 ,  2 ). Clinical and histological lesions are shown for patients 6, 7, and 14 ( Figure 1 ).
Patients all had concomitant blood/marrow and skin sampling apart from patient 2 (skin biopsy performed 1 year before blood analysis with NGS) and patient 13 (skin biopsy performed 2 years before bone marrow analysis with NGS). At least one mutation was identified using NGS in blood/bone marrow in all patients with a median number of two mutations (ranging 1-8) and in skin biopsies in 12 patients with a median number of 3.5 mutations (ranging 1-7). Patient 5 was considered negative on skin owing to a very low skin VAF (<1%). Patient 8 was considered as a blood contamination as the weakly positive skin NGS (3% VAF) was not associated with a cutaneous myeloid infiltrate. Median VAF in skin was 12% (ranging from 1 to 76%) ( Table 1 ). The same main mutation between blood/bone marrow and skin was found in eight patients (67% of patients with mutations in the skin). Six patients had paired mutations in blood/marrow and skin lesions (patients 1, 2, 3, 4, 11, 12 with respectively ECD/CMML cutis, H-SS, ECCD/CMML cutis, CMML cutis, CMML cutis, and H-SS). For the six other patients, three had more mutations on blood/marrow than skin (patients 6, 10, and 14, with respectively CMML cutis, neutrophilic folliculitis, and pyoderma gangrenosum), and three had more mutations on skin than blood/marrow (patients 7, 9, and 13, with respectively H-SS, H-SS, and erythema nodosum). Patient 7 had one extra-mutation in skin (in TP53, VAF 2%), patient 9 had two extra-mutations in skin (in SETBP1, VAF 4%, and in KMT2D/MLL2, VAF 3%), and patient 13 had two extra-mutations in skin (in KRAS, VAF 11%, and in RUNX1, VAF 6%) and one extra-mutation in blood (in ZRSR2, VAF 7%) with a bone marrow analysis performed 2 years after skin sampling ( Tables 2 ,  3 ). Regarding VAF, 10 patients had at least one mutation in skin with VAF >10% (patients 1, 3, 4, 6, 7, 9, 10, 11, 13, 14, with respectively ECD/CMML cutis, ECD/CMML cutis, CMML cutis, CMML cutis, H-SS, H-SS, neutrophilic folliculitis, CMML cutis, erythema nodosum, and pyoderma gangrenosum), of whom six had at least one mutation with VAF >20% (patients 4, 7, 10, 11, 13, 14, with respectively CMML cutis, H-SS, neutrophilic folliculitis, CMML cutis, erythema nodosum, and pyoderma gangrenosum), and two patients had detectable mutation with VAF <10% (patients 2 and 12 with 40 and 20% myeloid cells in the infiltrate, respectively, both diagnosed with H-SS). The myeloid infiltrate was of only 5% in three patients, but all of them had VAF >10% (patients 4, 7, and 9) ( Tables 2 ,  3 ). The most frequent mutations were in DNMT3A and TET2 both found in four patients. Two patients harbored the recently identified mutations in UBA1 (2 and 12), both having H-SS associated with a febrile polyarthritis.
Eleven patients have been treated and received oral steroids (n=8), hydroxychloroquine (n=2), immunosuppressive therapies (dapsone n=1), biological-targeted therapy (anakinra n=2, low-dose interleukin-2 n=1), or azacytidine as the hematological therapy (n=7). Azacytidine was associated with complete skin disease remission in three patients (two H-SS and one CMML cutis), partial in two (H-SS and pyoderma gangrenosum), and did not improve skin lesions in two (xanthelasma and folliculitis) ( Table 4 ).
Two out of the 14 patients were dead by the end of data collection. One of them died of central nervous system infection (patient 11), and the other one of acute myeloid leukemia (patient 13).
It is known that leukemia cutis is characterized by a skin infiltrate of blastic cells directly related to the myeloid leukemia. Therefore, NGS mutational profile of blood and skin lesions should be similar, and these patients could be used as "positive controls." We aimed to compare the results of our MDS/CMML patients with patients having leukemia cutis focusing on the "VAF/percentage of myeloid cells in the skin infiltrate" ratio. Four patients referred for cutaneous lesions compatible with leukemia cutis had NGS on skin samples. Two had AML and two had CMML evolving to AML. Skin symptoms were prominent with nodular lesions diagnosed in three patients and erythroderma in one. Leukemia cutis NGS found a median number of mutations of 4 (versus 4,5 in blood or marrow for the same patients). The median VAF was of 22% (ranging from 2 to 71%) in leukemia cutis (with a median percentage of myeloid cells in the infiltrate of >50%) compared with 12% (ranging from 1 to 76%) in the skin samples analyzed in our study (with a median percentage of myeloid cells in the infiltrate of 20%). The "VAF/percentage of myeloid cells in the skin infiltrate" ratio was similar between leukemia cutis and our skin samples (p=0.265 using Mann-Whitney test), supporting that mutations detected in skin biopsies of our MDS/CMML patients were related to a significant clonal myeloid infiltrate.