Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2023;13(4):e2023241 1 M2 Polarization May Contribute to Formation of Granulomatous Dermatitis in Progression of Myelodysplastic Syndrome to Acute Myeloid Leukemia Wei-Cheng Fang1,5, Jeng-Shiun Du2,4, Yue-Chiu Su3,4, Li-Wen Chiu1,4, Ting-Ting Yang1,4 1 Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 3 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Dermatology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan Key words: granulomatous dermatitis, myelodysplastic syndrome, acute myeloid leukemia, M2 macrophage Citation: Fang WC, Du JS, Su YC, Chiu LW, Yang TT. M2 Polarization May Contribute To Formation Of Granulomatous Dermatitis In Progression Of Myelodysplastic Syndrome To Acute Myeloid Leukemia. Dermatol Pract Concept. 2023;13(4):e2023241. DOI: https://doi.org/10.5826/dpc.1304a241 Accepted: April 30, 2023; Published: October 2023 Copyright: ©2023 Fang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Ting-Ting Yang, MD, 100 Shih-Chuan 1st Rd, Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Tel: 886-7-3208223 E-mail: tingalingyang@gmail.com Introduction Myelodysplastic syndromes (MDS) are a group of clonal he- matopoietic disorders which may convert into acute myeloid leukemia (AML). Cutaneous manifestations are uncom- mon but can be the first clinical sign of disease progression. Herein, we report a MDS patient who abruptly developed florid foreign body granulomas when progressing to AML. Case Presentation A 73-year-old Asian male with MDS-excess blasts-2 (MDS-EB-2) presented with multiple scattered, painful er- ythematous to violaceous nodules over the face, chest, abdomen, and anterior aspect of limbs for 1 week (Figure 1, A and C). Associated symptoms included fever and malaise. Laboratory tests revealed progressing pancytopenia with increased blast cells. Gross examination of the skin biopsy specimen revealed black stone-like materials (Figure  1B). According to the patient, he had survived a mining acci- dent 43 years ago, leaving multiple asymptomatic subcuta- neous blue-gray papules over the face, trunk, and anterior aspect of extremities. Histopathological examination re- vealed foreign body granulomas with black substances in the deep dermis and subcutis infiltrated with multinucleated giant cells, histiocytes and lymphocytes (Figure 2A). No blasts or neoplastic cells were noted. Immunohistochem- ical staining was negative for CD34, lysozyme, CD117, 2 Research Letter | Dermatol Pract Concept. 2023;13(4):e2023241 Figure 1. Clinical images of foreign bodies and treatment response of the patient. (A) Multiple scattered, erythematous, violaceous, and painful nodules over face, chest, abdomen, and anterior aspect of 4 limbs. (B) Black stone-like foreign bod- ies. (C) Cutaneous presentation before systemic corticosteroid treatment. (D) Lesions resolved after systemic corticosteroid treatment. and myeloperoxidase (Figure 2B). The infiltrated cells were composed of CD68-positive cells (Figure 2C) and numerous CD163-positive cells (Figure 2D). Tissue cultures were all negative. Intravenous methylprednisolone 80 mg/day was administered and the erythematous granulomatous nodules resolved within 1 week, reverting to its original blue grey ap- pearance (Figure 1D). Unfortunately, the patient progressed into AML within 1 month and died shortly after. Conclusions Granulomatous dermatitis, including cutaneous sarcoid- osis, granuloma annulare and necrobiosis lipoidica have all been reported to herald the onset of MDS or precede MDS progression to AML [1-3]. We present a case of florid foreign body granulomatous reaction associated with MDS progres- sion to AML. M2 macrophages play an important role in granuloma formation [4], which may be the link between the two phenomena. Immunohistochemical staining of the foreign body granulomas showed infiltration of CD163+ M2 macrophages with elevated CD163/CD68 ratio. As for MDS transformation to AML, recent reports have shown the im- portance of M2-like tumor-associated macrophages (TAMs) with elevated CD163/CD68 ratio [5]. The macrophages in the bone marrow of high risk MDS patients were shown to polarize to M2 and not to M1 macrophages leading to in- sufficient antitumor effect [6]. Therefore, we hypothesized that the increased M2 macrophage population in the present Research Letter | Dermatol Pract Concept. 2023;13(4):e2023241 3 case was due to M2 polarization in the bone marrow. These M2 macrophages were then attracted by the foreign body in the skin, thus leading to acute foreign body granulomatous reaction. In summary, we present a case of a MDS patient with subsequent progression to AML associated with an abrupt appearance of diffuse foreign body granulomas. Predomi- nant M2 macrophages in the foreign body granulomas may correlate to M2 polarization in the bone marrow of high risk MDS or AML patients. Therefore, it is important to recog- nize that the granulomatous dermatitis in MDS patients may associate with disease progression and poor prognosis. References 1. Vestey JP, Turner M, Biddlestone L, McLaren K, Goulden N, Hunter JA. Disseminated cutaneous granulomatous eruptions associated with myelodysplastic syndrome and acute myeloid leukaemia. Clin Exp Dermatol. 1993;18(6):559-563. DOI: 10.1111/j.1365-2230.1993.tb01031.x. PMID: 8252798. 2. Balin SJ, Wetter DA, Kurtin PJ, Letendre L, Pittelkow MR. My- elodysplastic syndrome presenting as generalized granulomatous dermatitis. Arch Dermatol. 2011;147(3):331-5. DOI: 10.1001 /archdermatol.2011.39. PMID: 21422341. 3. Cornejo KM, Lum CA, Izumi AK. A cutaneous interstitial granu- lomatous dermatitis-like eruption arising in myelodysplasia with leukemic progression. Am J Dermatopathol. 2013;35(2):e26-e29. DOI: 10.1097/DAD.0b013e31826ff6a6. PMID: 23221468. 4. Terai S, Ueda-Hayakawa I, Nguyen CTH, et al. Palisaded neu- trophilic and granulomatous dermatitis associated with systemic lupus erythematosus: possible involvement of CD163(+) M2 mac- rophages in two cases, and a review of published works. Lupus. 2018;27(14):2220-2227. DOI: 10.1177/0961203318809892. PMID: 30376790. 5. Cencini E, Fabbri A, Sicuranza A, Gozzetti A, Bocchia M. The Role of Tumor-Associated Macrophages in Hematologic Ma- lignancies. Cancers (Basel). 2021;13(14):3597. DOI: 10.3390 /cancers13143597. PMID: 34298810. PMCID: PMC8304632. 6. Zhang G, Yang L, Han Y, et al. Abnormal Macrophage Polar- ization in Patients with Myelodysplastic Syndrome. Mediators Inflamm. 2021;2021:9913382. DOI: 10.1155/2021/9913382. PMID: 34335093. PMCID: PMC8286189. Figure 2. Histopathology and immunohistochemical staining of skin biopsy. (A) Histopathological examination revealed retained foreign bodies in the deep der- mis and subcutis infiltrated with multinucleated giant cells, histiocytes and lym- phocytes (hematoxylin and eosin, original magnification ×20). (B) Cells in foreign body granulomas showed negative for myeloperoxidase (immunohistochemistry for myeloperoxidase, original magnification ×200). (C) Multiple scattered CD68+ macrophages in foreign body granuloma (immunohistochemistry for CD68, orig- inal magnification ×200). (D) A large number of CD163+ macrophages in foreign body granuloma (immunohistochemistry for CD163, original magnification ×200).