Leukemia cutis as the first manifestation of acute myeloid leukemia

Dear Editors, We report the case of a 60-year-old man, who presented to the outpatient clinic of the Department of Dermatology of the Medical University of Vienna. He reported a generalized exanthema and severe itch that had been present for 2 months. He had previously been treated with topical corticosteroids, systemic antihistamines and antibiotics, without improvement. Primary dermatological examination revealed a generalized exanthema with flat, polygonal, erythematous papules that occasionally coalesced into plaques, and linear excoriations and crusts (Figure 1a). Initial blood work showed leukopenia of 1.97 G/l (× 109/l, reference range, 4,000–10,000 cells/µl), a hemoglobin level of 12.3 g/dl (13.5–18.0 g/dl), and a normal thrombocyte count of 194 G/l (150–350 G/l). The differential leukocyte count showed 36 % segmented neutrophils (50 %–75 %), 4 % banded neutrophils (3.0 %–5.0 %), 46 % lymphocytes (25.0 %–40.0 %) and 1 % blasts, without any myelocytes or metamyelocytes. After a punch skin biopsy was performed, the patient was treated with clobetasol propionate twice a day locally. One week after the initial presentation the skin changes appeared progressive despite local therapy (Figure 1c), and the patient was hospitalized for intensified therapy and further examination. The follow-up laboratory tests showed a gradual increase in leukocytes and circulating blast cells with 33 % blasts 13 days after initial presentation (Figure 1b). Immunophenotypically, the blasts were positive for CD117, negative for CD34, and showed strong expression of CD123 and CD33. The skin biopsy showed dense infiltration with CD33-positive cells and cells bearing cytoplasmic nucleophosmin (NPMcy+), indicating leukemia cutis. Further immunohistochemical analysis revealed no reaction with CD34 and partial reaction with CD117 and myeloperoxidase (MPO) (Figure 2a). A bone marrow biopsy confirmed the diagnosis of acute myeloid leukemia (AML), showing infiltration with NPMcy+ blasts, which remained spared in the chloroacetate esterase staining (CAE) (Figure 2b). The diagnostic implications of the immunophenotypic markers displayed in Figure 2 are listed in Table 1. CD34 CD117 Genetic testing revealed an FLT3-ITD mutation, with no other mutations or chromosomal abnormalities detectable, in particular no NPM1 mutation. While NMPcy acts as surrogate parameter for NMP1 mutation, NMPcy positivity can occur in the absence of NMP1 mutation in rare cases. Based on the genetic analysis, the patient was assigned to the intermediate risk category, according to the European LeukemiaNet (ELN) risk stratification from 2022.1 Subsequently, the patient received induction chemotherapy with 7 days of cytarabine and 3 days of daunorubicin. He achieved a complete hematological remission, which was accompanied by a complete regression of skin changes. The patient then received four cycles of consolidation therapy with a cytarabine-containing regimen and maintenance therapy with addition of the FLT3-inhibitor midostaurin, due to the detected FLT3-ITD mutation, which leads to constitutive activation of the receptor tyrosine kinase FLT3 resulting in increased proliferation of hematopoietic and leukemic cells. Unfortunately, treatment was followed by a relapse of the underlying disease, from which the patient died approximately 1 year after the initial diagnosis. Here, we report on a patient whose generalized papular skin eruptions ultimately led to a diagnosis of AML, a hematopoietic neoplasm characterized by uncontrolled proliferation of immature myeloid cells.6, 7 In addition to symptoms based on qualitative and quantitative cellular aberrations, leukemia occasionally presents with signs of extramedullary infiltration.8 One such manifestation is leukemia cutis, a condition in which leukemia cells infiltrate the skin, leading to the development of cutaneous lesions.9, 10 Recent studies have indicated that leukemia cutis in AML patients is associated with an unfavorable outcome.11, 12 A matched cohort-study demonstrated a lower 5-year survival of 8.6 % in AML patients with biopsy-proven leukemia cutis, compared to 28.3 % among AML patients without leukemia cutis, suggesting that these patients may require more intensive therapy.11 Therapeutic opportunities have steadily expanded in recent years. Our patient displayed an FLT3-ITD mutation, which itself is associated with a decreased overall survival and is the subject of the development of targeted therapies.13, 14 Indeed, several studies could demonstrate that the addition of FLT3 inhibitors (e.g., midostaurin, gilteritinib) to intensive chemotherapy resulted in improved survival in AML patients with an FLT3-ITD mutation.13, 15, 16 A retrospective study by Bazinet et al. demonstrated that AML patients treated with an FLT3 inhibitor achieved a significantly longer relapse-free survival of 32.3 months and overall survival of 35.5 months, compared to 14.3 and 18.9 months, respectively, in patients who did not receive an FLT3 inhibitor.13 In patients who are not eligible for intensive chemotherapy, the combination of low-intensity therapy with an FLT3 inhibitor and BCL-2-inhibitor venetoclax significantly improved overall survival to 19.1 months, compared to other treatment combinations, rendering triplet regimens a promising approach in patients unfit for intensive chemotherapy.13, 17 Leukemia cutis was reported in 3.7 % of patients with AML, with 2.9 % confirmed by biopsy.18 In the reviewed literature, most cases of skin lesions occurred after or during the development of the blood disease. Only a few cases have been described in which the skin changes preceded the onset of the blood disease.19, 21 Recent literature cases of leukemia cutis are listed in Table 2. According to the patient's history, the skin lesions had been present for 2 months prior to the initial presentation at our outpatient clinic and previous attempts at treatment had not led to any improvement. Due to the low proportion of blasts at the time of initial presentation and the fact that the skin disease had been present for some time, it can be deduced that the skin changes preceded the florid hematological disease. The skin is rarely the site of the primary manifestation of AML and raises the question of the pathogenetic mechanisms by which leukemic cells primarily infiltrate the skin and how these cells differ from leukemic cells that do not lead to extramedullary infiltration. A possible explanation is offered by the function of chemokine receptors and adhesion molecules.12 Leukemic skin infiltration may result from aberrant expression of skin-homing chemokine receptors such as CCR4 and CXCR4 and adhesion molecules like CD56 and ICAM-1.30 Immunohistochemical studies showed a discordantly higher expression of CD56 and lower expression of CD117 and CD34 in myeloid leukemia cutis, compared to the immunophenotype of blasts in the bone marrow.31 In addition to a potential role of adhesion molecules and chemokine receptors, various mutations in the blasts are associated with a tendency to extramedullary infiltration of the latter. Indeed, FLT3 mutation is linked to extramedullary infiltration in AML patients,32 and has been shown to be positively correlated with CXCR4 expression.33 Other mutations associated with extramedullary manifestation include NPM1 and KMT2A, which are linked to a monocytic phenotype of the leukemia cells.11, 24 This is consistent with the finding that AML with monocytic and myelomonocytic differentiation in particular is associated with extramedullary manifestations.18 Due to heterogeneous clinical presentation and clinical resemblance to other skin diseases, diagnosis of aleukemic leukemia cutis can be challenging. In the present case, generalized lichen planus, drug eruption, primary cutaneous lymphoma, or pityriasis lichenoides et varioliformis acuta (PLEVA) were among the differential diagnoses at initial presentation. Leukemia cutis is usually characterized by single or multiple, rapidly developing papules, nodules or plaques on extremities, trunk, scalp or face.34, 35 Clinical morphology may allow distinction of lichen planus (polygonal, flat-topped papules with Wickham stripes and localization on flexural sites and mucosa),36 and PLEVA (papules that develop into erosions, ulcers and hemorrhagic crusts).37 Anamnesis including drug exposure and lesion duration may distinguish drug eruptions and cutaneous T-cell lymphoma.38, 39 A structured algorithm for the diagnosis of leukemia cutis and the distinction of important differential diagnoses with a focus on histological and immunohistochemical analyses was proposed by Jenei et al.35 The present case underlines the importance of considering a malignant hematological disease in the differential diagnosis of therapy-resistant exanthema. In view of the poor prognosis associated with leukemia cutis, early biopsy with extended immunophenotyping is essential for timely diagnosis and adequate therapy. Open Access funding provided by Medizinische Universitat Wien/KEMÖ. None.