Granuloma annulare-like pseudohistiocytosis: a specific manifestation of ETV6::SYK-rearranged myeloid neoplasm with eosinophilia

Skin manifestations of hypereosinophilic syndromes (HES) are mostly non-specific, including eczema- or urticaria-like instances. Alongside the improvement in their molecular understanding, possible clinical associations of specific entities are also emerging.¹ In 2023, a novel instance of myeloid neoplasm with eosinophilia (MLN-E) with other tyrosine kinase (TK) gene fusions, carrying t(9;12)(q22;p13) ETV6::SYK, was identified in a patient with a hypereosinophilic clinical picture, associated with a cutaneous manifestation interpreted as eruptive xanthogranuloma.² Starting from the diagnosis of a new case, we aim at discussing the clinicopathologic picture and the published literature on MLN-E, characterized by ETV6::SYK rearrangement.

A novel case, as evaluated during the diagnostic routine, is discussed. The study was conducted in accordance with the Declaration of Helsinki; patient consent was obtained. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded 3 μm-slides via automated system (Ventana-Roche platform). Chromosome analysis was conducted on bone marrow (BM) cultures by QFQ-banding technique; at least 20 metaphases from both cultures were analyzed at a 300-band resolution level. Following karyotype, fluorescense in situ hybridization (FISH) analysis for ETV6 locus and real-time polymerase chain reaction (RT-PCR) were performed³ on peripheral blood (PB) and BM, to determine the presence of ETV6::SYK gene fusion. Targeted next-generation sequencing (NGS) was conducted in PB via NGS Oncomine myeloid panel, while variant-specific Sanger sequencing was performed to assess ASXL1 mutation in the skin. FISH analysis on cutaneous biopsy was conducted using the locus-specific probes XL ETV6 Break Apart (MetaSystems Group, Inc., Belmont, MA) and SYK Break Apart (Empire genomics), following the manufacturer’s instructions.

The case involves a 67-year-old woman who developed monocular diplopia and paresis, with slit-lamp examination suggestive of choroidal granulomas. The patient subsequently developed multiple, firm, partly confluent, erythematous to yellowish cutaneous plaques, some with a slightly raised border, involving the scalp and progressing to the face, back and limbs (Figure 1A, B). The clinical picture was deemed suspicious for disseminated sarcoidosis/ granuloma annulare (GA). Due to worsening of ocular signs and progression of the skin lesions, the patient visited our institution, where a hematological workup revealed mild leukocytosis (white blood cell [WBC] count 16.62x10⁹/L) with severe eosinophilia (absolute eosinophil count [AEC] 6.01x10⁹/L) and 1% PB blasts; hemoglobin level and platelets counts were normal. PB flow immunophenotyping showed no evidence of aberrant T cells, specifically excluding the lymphocytic variant of HES. A concomitant positron emission tomography (PET) scan showed hypercaptation in cutaneous-subcutaneous lesions, mammary glands, inguinal lymph nodes, paravertebral spaces, sinus cavities, hepatic venous branches, superior mesenteric artery, and endometrial cavity (standardized uptake value [SUV] range 5.21-19.93, with the highest values in the scalp). Skin biopsy (Figure 1C-E) revealed an interstitial accumulation of histiocytoid histiocytes with a non-descript phenotype (CD163⁺, MPO^-, S100^-, CD1a^-, langerin^-, ALK1^-), reminiscent of the interstitial variant of GA, while BM aspirate and biopsy supported clonal eosinophilia (Figure 2A, B), as carrying dysplastic-type megakaryocytes, both with an unremarkable lymphoid infiltrate. Endometrial biopsy documented an accumulation of eosinophilic granulocytes (Figure 2E). BM karyotype revealed t(9;12)(q22;p13), further confirmed as ETV6::SYK by RT-PCR in both BM and PB samples (Figure 2C, D), where ASXL1 c.2404G>T, p.(Glu802Ter) mutation was also found by targeted NGS (variant allele frequency [VAF] 15.71%). The latter was absent in the skin. RT-PCR and FISH analysis demonstrated the lack of ETV6 and/or SYK rearrangement on histiocytes in the skin, the latter highlighting scattered, small-sized clonal cells, likely corresponding to granulocytes (Figure 1F).

A final diagnosis of GA-like pseudohistiocytosis/histiocytic proliferation was made, as manifestation of MLN-E and other TK gene fusions (2024 World Health Organization classification). Adjuvants such as ultrapotent topical corticosteroids and hydroxychloroquine were tried but proved ineffective on the cutaneous picture. The patient was then treated off-label with imatinib 400 mg four times daily (QD) with an initial taper of prednisone, leading to partial metabolic remission, as documented by PET scan, along with gradual improvement of ocular and flattening of cutaneous lesions. Because the combination of imatinib and high-dose prednisone failed to effectively reduce AEC, along with the development of steroid-related adverse events, SYK inhibition with entospletinib was considered, but it was not approved by the manufacturer, as still an investigational drug. Due to severe, persistent eosinophilia, after 1 year on imatinib, the patient began off-label treatment with dasatinib 100 mg QD, achieving marked improvement in AEC within a few days, until stable normalization. Unfortunately, she died 3 months later from a fungal infection, likely related to the immunosuppressive state induced by prolonged treatment with high-dose steroids.

PubMed database was queried for “SYK ETV6 myeloid” and “SYK ETV6 rearrangement” and related papers, and a total of five cases was retrieved (Table 1)^2,5-8. All patients (N=6, including ours) presented with absolute eosinophilia (range, 1.2-9.5x10⁹/L), with variable leukocytosis and anemia, and skin lesions involving the head and, to a lesser extent, the trunk and limbs. Ocular signs were present in two instances. The disease was defined by ETV6 locus rearrangement in all cases, five of which were proved to carry the specific ETV6::SYK fusion. Additionally, our case harbored ASXL1

mutation in PB, and one case³ had a minor clone with a complex karyotype. Follow-up data are detailed in Table 1. MLN-E are driven by a variety of TK gene rearrangements, and ETV6 itself is a well-known actor of hematological neoplasms, including MLN-E with ETV6::ABL1-rearrangement, myelodysplastic syndromes/neoplasms and acute myeloid and lymphoblastic leukemia. However, the collected evidence shows that ETV6::SYK-rearranged neoplasms are stereotyped, comprising progressive eosinophilia and an unclassifiable histiocytic proliferation, recapitulating the clinical features of disseminated sarcoidosis or, alternatively, GA.

Patients experience a protracted clinical course and a multisystem disease mimicking an immune-mediated disorder, with ocular and cutaneous involvement. Notably, our patient had been followed extensively in various immunology departments with clinical diagnoses of “granulomatosis”, sarcoidosis, Wells syndrome, or IgG4-related disease. First, it should be noted that the SUV range of fluorodeoxyglucose-avid lesions in our case exceeded the values commonly detected in inflammatory disorders. Also, histology of skin lesions, showing a dense, patternless accumulation of histiocytoid histiocytes with a non-descript phenotype and intermixed scattered granulocytes, fairly exceeds the common picture of GA and sarcoidosis. To some extent, the morphological pattern resembles generalized palisaded neutrophilic and granulomatous dermatitis, as clonal manifestation of chronic myelomonocytic leukemia with SRSF2 P95 hotspot mutation.⁹ A clonal skin manifestation of a myeloid neoplasm could be considered, with the atypical morphology of myelomonocytic cells suggesting leukemia cutis or the newly developed concept of myelodysplasia cutis.¹⁰ Finally, given the clinical picture, a cutaneous manifestation of multisystem histiocytosis could be considered. This interpretation was also provided by Risch et al.,⁸ who purportedly found ETV6::SYK rearrangement in the skin lesion. However, we were unable to confirm the same observation in our patient: skin biopsy proved negative for clonal markers, both by Sanger sequencing for ASXL1 and by RT-PCR and FISH analysis for ETV6 and/ or SYK rearrangements. On this basis, our data support an “inflammatory”, albeit aberrant, manifestation of a myeloid neoplasm, similar to the histiocytoid variant of Sweet syndrome.¹¹ Notably, a similar pattern of cutaneous disease is currently regarded as the GA-like variant of Wells’ syndrome,¹² in patients lacking a clinical picture of clonal eosinophilia, thus supporting the hypothesis of an inflammatory lesion, not limited to ETV6::SYK⁺ MLN-E, but stereotypical of this peculiar molecular subset.

Figure 1.Clinic-pathologic picture of cutaneous, histiocytic manifestation. Representative panels depicting the clinical appearance of the skin lesions, as multiple, firm, partly confluent, erythematous to yellowish plaques, some with a slightly elevated border and an intensely yellowish, depressed central area involving (A) the face, scalp, and (B) the back. Dermoscopy (A, inset) showed yellowish structureless areas with short, branched vessels surrounded by peripheral erythema, a finding indicative of a granulomatous process. Cutaneous biopsy displaying a «busy dermis», secondary to the presence of an interstitial, patternless accumulation of “histiocytoid”, CD163⁺ histiocytes ((C) CD163, 100x magnification; ((D) hematoxylin and eosin staining, 400x magnification), with foci of accumulation of granulocytes with abnormal nuclear segmentation; ((E) myeloperoxidase stain, 200x magnification and inset, Giemsa stain, 400x magnification). (F) Fluorescense in situ hybridization analysis (SYK break apart probe) of skin biopsy displays scattered, small-sized nuclei featuring SYK locus break (red arrow) consistent with granulocytes, as compared to larger cells with a wild-type SYK pattern (yellow arrows).

The field of histiocytic neoplasms is slowly shifting towards a molecularly based classification paradigm, as TK imbalances (mutations and rearrangements) are almost invariably present in driving the disease. Intriguingly, cutaneous manifestations of MLN-E are uncommon, and rather non-specific, including erythematous eruptions, pruritus, urticaria, and eosinophilic cellulitis.¹ A peculiar association has been found between FIP1L1::PDGFRA⁺ MLN-E and lymphomatoid papulosis,¹³ and a single case of FIP1L1::PDGFRA⁺ MLN-E associated with generalized eruptive histiocytosis has been reported,¹⁴ with both conditions showing clinical response to TK inhibition, despite the lack of evidence of clonal relationship. Likewise, in our patient, a near-complete remission of the “histiocytosis-like” disease was achieved and maintained on imatinib, but was followed by a steady progression of the eosinophilia, with increase of t(9;12)(q22;p13)-positive metaphases, thus suggesting both a non-target specific effect of the TK inhibition on MLN-E-associated manifestations and the need for a more tailored approach. In this regard, we may only speculate on the predictive impact of the ASXL1 mutation, a gene associated with therapeutic resistance and increased risk of progression in several myeloid neoplasms.¹⁵ Based on the collected experience, ETV6::SYK⁺ MLN-E has been shown to be sensitive in vitro and, to some extent, in vivo to SYK inhibition (entospletinib and fostamatinib),^2,8 while a partial response to MEK inhibition with cobimetinib was recorded in another patient.⁷ Finally, in the patient reported by Beauverd et al.,⁶ sustained remission was achieved following allogeneic stem cell transplantation (HSCT), after failing several systemic therapies for the control of blood condition, including imatinib.

Figure 2.Morphologic and molecular picture of eosinophilic neoplasm. Bone marrow (BM) aspirate and biopsy feature mild trilinear dysplasia, left shifting and hypogranularity of eosinophils, with small-sized, hypolobated megakaryocytes ((A) May-Grünwald stain, 600x magnification; (B) hematoxylin and eosin stain, 400x magnification). (C) Karyotype analysis detected t(9;12)(q22;p13), (D) further confirmed by real-time polymerase chain reaction for ETV6::SYK, rearrangement. WT: wild-type probes; PB: peripheral blood; C-: negative control. (E) Histologic detail of endometrial biopsy (Giemsa staining, 400x magnification) documented accumulation of eosinophils, with defective nuclear segmentation.

Table 1.Summary of major clinical and pathologic features of the collected cases of myeloid neoplasm, featuring eosinophilia and skin lesions and rearrangement of ETV6 locus at 12p13.

ETV6::SYK-related neoplasms are exceedingly rare but easily overlooked or dismissed as inflammatory/autoimmune processes. Their recognition should prompt appropriate management, potentially benefiting from novel targeted therapies, including the oral SYK inhibitor entospletinib and, ultimately, HSCT,^6,8 with the aim of ameliorating their potentially aggressive clinical course (which led to the death of our patient less than 24 months after diagnosis). This unique, GA-like presentation provides a novel, and intriguing, model of disease, and may serve as a relatively specific clue for the timely diagnosis of MLN-E harboring ETV6::SYK rearrangement, hopefully leading to a better prognosis for this rare and challenging subset of patients.

Footnotes

• Received June 24, 2025
• Accepted November 11, 2025

Correspondence

*GAC and DC contributed equally as first authors

G. A. CROCI - giorgio.croci@unimi.it

Disclosures

No conflicts of interest to disclose.

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