Myelodysplasia cutis is an emerging concept in cutaneous neoplasia. Many of these cases were previously included under the umbrella of histiocytoid Sweet syndrome. However, with the advent of next-generation sequencing, cutaneous involvement by myelodysplastic syndrome is being increasingly recognized.
To review histiocytoid Sweet syndrome and myelodysplasia cutis and discuss our current understanding of these entities. Additionally, to discuss how next-generation sequencing can be applied in the evaluation of cutaneous infiltrates of immature histiocytoid cells.
The English-language literature from 2005 to 2023 on the topic of histiocytoid Sweet syndrome and myelodysplasia cutis was reviewed.
Biopsy specimens showing infiltrates of histiocytoid, immature myeloid cells may represent cutaneous involvement by myelodysplastic syndrome. Close clinical correlation is recommended in these cases. Recent studies suggest that next-generation sequencing is useful in separating myelodysplasia cutis from true histiocytoid Sweet syndrome. This distinction has important implications for patients.
Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, was first described in 1964 as a rare, reactive neutrophilic dermatosis characterized by the abrupt onset of tender plaques on the face and extremities associated with fever and a neutrophilic leukocytosis.1 Patients responded rapidly to oral steroids and had no evidence of an infection, although a subset described a recent, prior infection. We now know that SS may be associated with neoplasms, especially myeloid neoplasms, infections, autoimmune diseases, vaccination, pregnancy, and drugs.2 Histopathologically, it is characterized by a dense, dermal neutrophilic infiltrate that may extend into the subcutis with karyorrhexis and often with papillary dermal edema (Figure 1).
In 2005, Requena et al3 described histiocytoid SS (H-SS) as a variant of SS with a reactive cutaneous infiltrate of “histiocytoid” immature myeloid cells that involved the dermis and/or superficial subcutis with associated neutrophils and papillary dermal edema (Figure 2). Patients presented similarly to those with SS, with erythematous plaques and nodules, neutrophilic leukocytosis, and response to oral steroids. The characteristic “histiocytoid” cells had slightly eosinophilic cytoplasm and eccentric, elongated, twisted, or kidney-shaped nuclei. They expressed CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme, supporting a monocytic/histiocytic origin; however, these cells also expressed strong myeloperoxidase. Moreover, the authors noted that the KP1 clone of CD68, which also marks granulocytes and immature myeloid cells, highlighted more cells than the PGM1 clone of CD68, which more specifically marks histiocytes.3 The authors concluded that the histiocytoid cells represented immature myeloid cells.3 Acknowledging the possibility of cutaneous involvement by a myeloid neoplasm, the authors used cytologic examination of the peripheral blood, fluorescence in situ hybridization for BCR::ABL1, and follow-up (ranging from 1 to 16 years) to assess for cutaneous involvement by leukemia.3 One patient in the series had a prior diagnosis of “chronic monocytic leukemia,” but the immature myeloid cells in the skin were thought to be unrelated to that disease.
Subsequent studies have confirmed the existence of H-SS and highlighted that similar to conventional SS, it may be associated with infections, drugs, or autoimmune diseases, or it may also be idiopathic.4–8 In addition, several studies have shown a strong association between H-SS and myeloid neoplasms, including a significantly higher frequency of hematologic malignancies, especially myelodysplastic syndrome (MDS), compared with conventional SS.7–14 Patients with H-SS and associated malignancies tended to be older8,9 and more likely to have systemic symptoms.9 Those with hematologic malignancies are more likely to have relapses and a prolonged course.8,11,14,15 In addition, the immature myeloid cells in cutaneous lesions called H-SS are morphologically similar to the neoplastic cells in the bone marrow or peripheral blood of patients with hematologic cancers.12–14,16 Moreover, a subset of patients with an underlying hematologic malignancy who also have H-SS have matching genetic abnormalities in the bone marrow and skin.13,14,17,18
MYELODYSPLASIA CUTIS
In 2015, Osio et al18 examined skin biopsies in 800 patients with a diagnosis of MDS and found 24 patients with immature myeloid cells in the skin. They coined the term “myelodysplasia cutis” to describe patients with known MDS and cutaneous involvement by atypical, immature, but nonblastic, myeloid cells.18 The authors noted that these lesions were similar to those previously described as H-SS and suggested that such lesions arising in patients with MDS were best called myelodysplasia cutis (MDS-cutis).18 Fluorescence in situ hybridization in 4 of 6 tested cases showed the same genetic abnormality in tumor cells of the skin and bone marrow. Importantly, these lesions preceded the diagnosis of bone marrow MDS in most cases by months to years, a finding that has been reported in other studies.11,12,15 The authors recommended a long follow-up for elderly patients with a histopathologic appearance of H-SS and normal initial bone marrow biopsy.18
With the application of myeloid next-generation sequencing (NGS), also known as high-throughput sequencing or massively parallel sequencing, investigators have been able to more fully evaluate cases of suspected MDS-cutis. Myeloid NGS panels target genes known to be important in myeloid neoplasia and can provide diagnostic, prognostic, and therapeutically relevant information.19 Myeloid NGS has been used to demonstrate that cases of MDS-cutis share genetic abnormalities with MDS in the bone marrow.20–22 Using NGS, Martin de Fremont et al22 demonstrated that MDS involving the skin often has a histopathologic appearance compatible with H-SS and shares genetic abnormalities with MDS in the bone marrow. Delaleu et al20 suggested 3 criteria for the diagnosis of MDS-cutis: (1) diagnosis of MDS, (2) skin biopsy showing “histiocytoid” immature myeloid cells, and (3) matching mutation(s) of 1 or more genes in the bone marrow and skin (Figures 3 and 4). Although the numbers of studied patients so far are small, MDS-cutis patients may have a more aggressive course than typically seen in MDS and may respond better to hypomethylating agents than to steroids, the latter a typical treatment for Sweet syndrome.20 More specifically, MDS-cutis patients treated with steroids often become steroid dependent.20 Interestingly, a subset of patients with MDS-cutis have VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome,20,22 a severe, adult-onset autoinflammatory syndrome seen in older men that is associated with MDS.23 The clinical use of myeloid NGS panels for MDS-cutis may be limited at some institutions because formalin-fixed, paraffin-embedded tissue may not be an accepted specimen type. Moreover, there are no current guidelines on when NGS should be used to evaluate H-SS.
DIFFERENTIAL DIAGNOSIS
The 2 most important considerations in the differential diagnosis of MDS-cutis include H-SS and myeloid sarcoma/leukemia cutis (Table). H-SS characteristically presents as erythematous plaques that may resemble those seen in MDS-cutis. Both entities can show a relapsing and remitting course and respond to oral steroids. Moreover, both entities may be associated with fever and arthralgia. Histopathologically, H-SS and MDS-cutis both show a dermal infiltrate of immature myeloid cells, often with papillary dermal edema. However, MDS-cutis may also demonstrate a clinical appearance resembling myeloid sarcoma/leukemia cutis with diffuse papulonodules.20 Patients may have a known history of MDS, although MDS-cutis may precede a diagnosis of MDS by years.11,12,15 Moreover, patients with MDS-cutis are likely to become steroid dependent and may have a better response to hypomethylating agents.20 Finally, skin biopsy in MDS-cutis may show evidence of myeloid dysplasia, with some maturing myeloid cells showing “pince-nez” or pseudo–Pelger-Huet anomaly.18,20,21 The differential diagnosis for H-SS is broad and includes a variety of neoplastic and reactive conditions.24,25
Myeloid sarcoma/leukemia cutis is another important consideration in the differential diagnosis of MDS-cutis and has a much worse prognosis. Myeloid sarcoma/leukemia cutis can be distinguished from MDS-cutis by the presence of sheets of blasts or blast forms that are more likely to express CD34, CD117, and/or CD56 and form persistent clinical papulonodule(s) (Figure 5).18 In contrast, cases of MDS-cutis do not include numerous blasts or blast forms, but rather maturing myeloid forms, including those with a “pince-nez” or pseudo–Pelger-Huet anomaly.18,20,21 Moreover, MDS-cutis is more likely to show papillary dermal edema, intermixed CD3+ lymphocytes, and a low Ki-67 proliferation index. Clinically, MDS-cutis is more likely to appear as relapsing erythematous, annular plaques and is more likely to be associated with fever and/or arthralgia.
Cases of MDS-cutis related to chronic myelomonocytic leukemia, a myelodysplastic/myeloproliferative neoplasm, and essential thrombocythemia, a myeloproliferative neoplasm, have also been reported.26,27 These studies did not include genetic evaluation. Considering a strict definition of MDS-cutis as MDS involving the skin,20,28 these cases may rather represent cutaneous involvement by the patient's non-MDS hematologic malignancy.22
CONCLUSIONS
Older patients with morphologic features compatible with H-SS may in fact have MDS-cutis or cutaneous involvement by another hematologic malignancy. Complete blood counts are important in these patients to assess for a cytopenia or other hematologic abnormality that could prompt a more thorough evaluation.17 Because some patients may present with MDS-cutis many years before the development of overt MDS, close clinical follow-up is recommended.11,12,18 In particular, older patients with histopathologic features of H-SS would benefit from close hematologic follow-up to assess for the development of MDS. Patients with a known diagnosis of MDS who develop MDS-cutis may have a worse prognosis compared with MDS patients who do not develop cutaneous disease.20 NGS is an important tool that can facilitate the diagnosis of MDS-cutis or hematologic malignancy involving the skin in patients with infiltrates resembling H-SS. Although the diagnosis of MDS-cutis has important clinical implications, additional studies are needed to better understand this entity more fully. Furthermore, future studies may provide insight into how myeloid NGS can best be used in the evaluation of cutaneous infiltrates of myeloid neoplasms.
References
Competing Interests
The authors have no relevant financial interest in the products or companies described in this article.
Author notes
Presented at the New Frontiers in Pathology Conference; October 26–28, 2022; Ann Arbor, Michigan.
![Conventional Sweet syndrome showing a dense dermal neutrophilic infiltrate (A). Neutrophils are mature without cytologic atypia (B) (hematoxylin-eosin, original magnifications ×100 [A] and ×400 [B]).](https://allen.silverchair-cdn.com/allen/content_public/journal/aplm/148/4/10.5858_arpa.2023-0132-ra/8/m_i1543-2165-148-4-385-f01.png?Expires=1736856565&Signature=EP3EHLzioYaXPkN~r0VHgaCBpns6KfNPfgZZEimHoq0zKGxfme7B8uoXgDRko~MG9eP3oBreXcmzyW21FOK5iescjY3aCCIeHzLoIga23P8yQEGY9MXReej3F4v0zrh2PvdOD1qKpD4kGrzXxEP-~DKtesCLMDNQ0kMTKVDzp4EEAvg4ERG9MEmVevuDOcIJ-0S9ZBfM47cENxVvKbicZntOTG5nZTh58BfXj6Y-iu~xaCoRkoL3D1p2YE2ejh9zgk0bljDpyJLOdaFjAE4XVBwX2DngphprQoNCpcWeHUaJ1Cz6Y0WmDV0WGF7JG6dwTwFjrf2544mQaS~nK9Ci7Q__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
![Histiocytoid Sweet syndrome following otitis media treated with amoxicillin. There is a superficial dermal infiltrate of histiocytoid cells with papillary dermal edema (A). These cells display reniform nuclei with moderate eosinophilic cytoplasm (B) and express myeloperoxidase (C) (hematoxylin-eosin, original magnifications ×100 [A] and ×400 [B]; original magnification ×100 [C]).](https://allen.silverchair-cdn.com/allen/content_public/journal/aplm/148/4/10.5858_arpa.2023-0132-ra/8/m_i1543-2165-148-4-385-f02.png?Expires=1736856565&Signature=G84MHoJQU3gb3J5ZadeXVKiSpMkqtA50KySeQEU2WOppgJPSUtboZr0cUxwJjfq3Ecc~oUjMwI9vQmoA~22IrSbCi7N97OZihYe56L-NOfiODbhJpTNifPYbFVwCZvcduYtDh1Ltkvd2Rzm9q-WBac7BAjeHDBsw0VsAW3391rfnfYoqMoU4eX~ayPTWFSJtHSeclzq45uDXfsmHduk-Jhr~-fiTizSsyomk9bDYmqxRCSy2fpgiGXfvjRUQZgnBth4fPSKsTSTpgw8jbr9UWphqJ1W5xC6MV~fo5O-yvGEgR38EKy2klVh1kfB4b4NPTGUCIQi9FZJiast7kAHB2g__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
![Myelodysplasia cutis in a patient with known history of myelodysplastic syndrome. The patient presented with a tender, erythematous papule, as indicated by the black arrow (A). Biopsy showed an ulcer (B) with an atypical, dermal hematolymphoid infiltrate (C). On higher magnification, the atypical cells demonstrate reniform nuclei and eosinophilic cytoplasm and include some pseudo–Pelger-Huet anomalies (D). These atypical cells express lysozyme (E) and myeloperoxidase (F) (hematoxylin-eosin, original magnifications ×20 [B], ×200 [C], and ×600 [D]; original magnification ×200 [E and F]).](https://allen.silverchair-cdn.com/allen/content_public/journal/aplm/148/4/10.5858_arpa.2023-0132-ra/8/m_i1543-2165-148-4-385-f03.png?Expires=1736856565&Signature=EsoSobsbAx2Y1sv3BmQjMYxQehYAd69-7Tk1aKN3IexMUCLeUfKiXmsvz~COWEavBy-R0dYHsL-NQlQEFNTrfK4S5j3H0QLSRzqNAqUYb4fDENyi9XXnR6k5tZcRGWuO9GgXc1bxqVJjymWN3yphIBTym701A2q2tY68lBLT3Dhn7KaVav-7bsw4HexKAMJDSuZKpmoRPVWXShaM~kTNNagHaVUTJD4HcRL2fYZmKn7n4M1Tz1YUo5~Ux6QRTMzwAl~nn6xjuu2-ZT-VWTQxpHkSQ7fYviJTFuyvP-1q11cepQSV3UPypU5r54a2fuTe1tGI3vhWk-sTADste2WHSw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
![Myelodysplasia cutis in a patient with known history of myelodysplastic syndrome. Next-generation sequencing performed on the biopsy displayed in Figure 3 demonstrated SF3B1, NRAS, and TET2 mutations. SF3B1 mutation is associated with myelodysplastic syndrome with ring sideroblasts, a favorable prognosis, and response to luspatercept. Subsequent review of a bone marrow biopsy performed 13 years earlier revealed a hypercellular marrow with mild erythroid and megakaryocytic dysplasia (A) and ring sideroblasts (B) compatible with myelodysplastic syndrome with mutated SF3B1 (myelodysplastic neoplasm with low blasts and SF3B1 mutation). Next-generation sequencing was performed on the bone marrow and was technically suboptimal but appeared to also show the SF3B1 mutation (hematoxylin-eosin, original magnification ×200 [A]; iron stain, original magnification ×600 [B]).](https://allen.silverchair-cdn.com/allen/content_public/journal/aplm/148/4/10.5858_arpa.2023-0132-ra/8/m_i1543-2165-148-4-385-f04.png?Expires=1736856565&Signature=pfDDwK2L3bxoaxZfxPzDVel44TIWuGe88d0QPDFVs7u6~IbIJYz81QXHktRuc-5YdRKFXvz00Imh3WJq~9LCKbKvVnGJoFCc3DJeiFdJ2nq~qF8ul-FA5cuEWich3~-pevU~BITzc5ftBFyzG31SjynZdBJ6GY3Jio9dvldtJhm001DIZovqG8pC7XkhOVbqegQP-8V04eoSS6ZHsSbP0ZenKpcRRYe253~WmaYhK4r~Q8KUhP2NmOMTipeB1M-Co9yiOYiMiVwXB4IBC0qAhBFLbh6a-qFXtsJzGzJFSFOJosOoxyVj8m6EA6wLY36~TxIODgR102iPKuwiw6RSNg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
![Myeloid sarcoma/leukemia cutis. Blast cells replace the dermis and show a grenz zone and a “box car” distribution, with linear arrays of cells infiltrating between collagen bundles (A). Cytologically, they display enlarged nuclei with high nuclear-cytoplasmic ratios, open chromatin, and visible nucleoli (B). The blasts show monocytic differentiation, expressing lysozyme (C) and weak CD56 (D), but not myeloperoxidase (E) (hematoxylin-eosin, original magnifications ×100 [A] and ×600 [B]; original magnification ×100 [C through E]).](https://allen.silverchair-cdn.com/allen/content_public/journal/aplm/148/4/10.5858_arpa.2023-0132-ra/8/m_i1543-2165-148-4-385-f05.png?Expires=1736856565&Signature=digBECRoeejQqQy66CjI4mGmVxLS9gnNxShq0NN1oTvfGesQOYKWQeo2~24X3GS5L5hjv44kklAGimYzwATBXZaaUWBdPnl~odyg0z~npLMLd8mwPMLD97Rcnk7XiwAiXr8KFHhCqmvXLO4hZEe2kRD-ptf~ADJewI1zKH1588couUXPSnguUuqcjZbdjD0GGNEZDMnc-ypjuZrIyTgsycndxx3~a~Ew7hPLnXY7PfvyMFIi65dw4KGVi68FBQBk2f0A~e5QagTwq~WmHZUuJvBaMI6U31tIkWUG9s6YOzLyiNsCRZ2YgSNQsG4IEIlg7ApkHXqt93oJ43RkjzDV5Q__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
