Lymphomatoid papulosis associated with myeloid neoplasm with eosinophilia and FIP1L1::PDGFRA rearrangement: Successful imatinib treatment in two cases

Lymphomatoid papulosis (LyP) is a benign condition, listed among primary cutaneous CD30+ lymphoproliferative disorders. Its typical picture consists of relapsing–remitting papular lesions and it can be encountered in the course of a hematologic disease, at times representing its first manifestation. Hypereosinophilic syndromes are a heterogeneous group of disorders characterized by persistent peripheral blood hypereosinophilia that may lead to life‐threatening organ damage. Among eosinophilic disorders, the subtype identified as myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions has aroused particular interest due to its excellent response to tyrosine kinase inhibitors, including imatinib. Here, we described the case of two 33‐year‐old men presenting with LyP and myeloid neoplasm with eosinophilia and FIP1L1::PDGFRA rearrangement who achieved complete clinical and molecular remission of both conditions a few months after starting imatinib.

to be approximately 23% (range 3%-56%).Currently, imatinib is the drug of choice for myeloid neoplasms with eosinophilia and PDGFRA/B rearrangement, as its hematologic has been confirmed in several studies, even at lower dosages than those used for chronicmyeloidleukemia. 3 Here we describe the case of two 33-year-old Caucasian men who presented with both these conditions, achieving complete response on imatinib.

| Case 1
A 33-year-old Caucasian man was referred to our department in November2021duetoincreasedeosinophilcount(6.5 × 10 9 /L) during dermatological follow-up.He had an unremarkable past medi-calhistoryexceptforLyPdiagnosedinJune2020onaskinbiopsy.
In a complete blood count (CBC) performed at that time, eosinophilswereonlyslightlyincreased(0.9 × 10 9 /L).Due to persistence and recurrence of erythematous papules followed by a necrotic evolution,treatmentwithmethotrexate10 mgweeklywasstarted, withinitialresolutionofskinlesions.InJuly2021methotrexatewas stopped, leading to LyP relapse 1 week later, so that therapy was resumed.

| Case 2
In August 2018 a 33-year-old Caucasian man was referred to our department for HE.In 2018 he developed self-healing erythematous, ulcerated papules in the upper limbs with a tendency to relapse (Figure 2a).A punch biopsy was then performed showing a dermal, wedge-shaped, polymorphic infiltration comprising scattered granulocytes and plasma cells, and a predominance of small to medium predominantly CD4+ lymphocytes, with a minor component of large immunoblastic CD4+/CD30+ cells.The clinic-pathologic picture was consistent with type A LyP (Figure 2b,c As the immunophenotype on PB was inconclusive for LPD, a BM biopsy was obtained in September 2018 revealing eosinophilic hyperplasia (Figure 2d).Molecular analyses were negative for both JAK2V617F mutation and BCR::ABL1 p210 fusion transcript, while Tothebestofourknowledge,only12casesofLyP-associated HES have been reported in the literature so far.7][8][9][10][11] Why LyP can be associated with (or causal of) HES is still uncertain.HE can be secondary to clonal T-cell expansion, as in its lymphocytic variant, in which the atypical lymphocytes have been shown to release eosinophilopoietic cytokines, such as IL-5 and IL-3. 12However, in FIP1L1::PDGFRA-positive myeloid neoplasms, TA B L E 1 Lymphomatoidpapulosisandhypereosinophiliacoexistenceandrelatedtherapies.

Characteristics Therapy Main findings
LyP and its relationship to idiopathic HES 5 ( representing an antiangiogenic target with the ability to destroy neovascular integrity. 14nsequently, testing for FIP1L1::PDGFRA rearrangement should always be performed in LyP patients who present with HE at diagnosis or develop it during dermatological follow-up in light of its potential clinical and therapeutic consequences.

ACK N OWLED G M ENTS
This study was partially funded by the Italian Ministry of Health, Current research IRCCS.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare they have no potential conflicts of interest.

I N FO R M E D CO N S E NT
The patients have given written informed consent to publish these cases (including the publication of images).

R E FE R E N C E S
Serumlactatedehydrogenaselevelwasincreased(236 IU/L,normal range 135-225 IU/L), as well as vitamin B12 serum concentration (>2000 ng/mL),whileIgEandtriptaselevelswereunremarkable.An echocardiography ruled out any cardiac damage.Second-level analyses were then performed: PB immunophenotype was not indicative of LPD.Autoimmunity tests revealed onlyantinuclearantibodypositivitywithaspeckledpattern(1:160).Stools for parasites were all negative, whereas radiological investigations only detected a spleen diameter of 12.5 cm.Screening for BCR::ABL1 p210 fusion transcript and JAK2V617F mutation was negative.In contrast, molecular analysis with NESTED/RT-PCR on PB was positive for FIP1L1::PDGFRA rearrangement, thus leading to a diagnosis of myeloid neoplasm with eosinophilia and PDGFRA rearrangement.Bone marrow (BM) biopsy featured only minor signs of morphologic dysmyelopoiesis, with eosinophilic hyperplasia, foci of interstitial accumulation of spindle-shaped, phenotypically nonaberrant (tryptase+/CD25-/CD2-/CD30-) mast cells, and an F I G U R E 1 Clinicalpicturefrompatient1detailsapapularlesionwithcentralescharadjacenttoanalmostregressedlesion;morphologic detail (a) displays an ulcerated epidermis underpinned by a wedge shaped, polymorphic infiltrate (b, H/E, 20×) featuring polymorphic lymphocytes, a small amount of eosinophils and scattered CD30+ large, atypical cells (c, H/E, 400×; inset, CD30, 200×).Bone marrow biopsy (d, H/E, 200×) displays a hyperplastic eosinophilic lineage and foci of proliferation of interstitial, spindle-shaped cells consistent with mast cells.unremarkablelymphoidinfiltrate,thusbeingsupportiveofthemoleculardiagnosis (Figure1d).
). Laboratory tests performed during dermatological follow-up revealed a normal CBC with the exception of eosinophilia (3.64 × 10 9 /L).Autoimmunity screening and stools for intestinal parasites were negative, while serum tryptase levels were only slightly increased (19 μg/L).Radiological examinations were unremarkable, and electrocardiogram and echocardiogram showed good cardiac function.

4 F
FIP1L1::PDGFRA rearrangement was detected on both PB and BM, thus leading to a diagnosis of myeloid neoplasm with eosinophilia and PDGFRA rearrangement.Treatment with imatinib 100 mg QD was started in February 2019.After 3 months of therapy a reevaluation was performed showing the absence of FIP1L1::PDGFRA rearrangement on PB, while it persisted on BM.Finally, in September 2020, 18 months from imatinib start, molecular analysis for FIP1L1::PDGFRA was negative on both PB and BM.Importantly, during follow-up imatinib continued to be well tolerated and no cutaneous lesions related to LyP occurred.3 | DISCUSS ION Prognosis of myeloid neoplasms with eosinophilia and PDGFRA/B rearrangements has significantly improved after imatinib introduction.Conversely, despite its minor impact on the prognosis of affected patients, LyP relapsing behavior may constitute a matter of discomfort and concern, particularly when diagnosed in the context of concurrent hematologic diseases: notably, its distinction from transformation of mycosis fungoides may be challenging.I G U R E 2 Cutaneouspictureofpatient2(a)featuresmultiplepapular,erythematouslesionsatvariousstagesofdevelopment,including ulceratedandscarringtissue.Skinbiopsy(b,H/E,20×) features a wedge-shaped infiltrate with perivascular accumulation of immunoblastic to anaplastic cells, CD30+Tcells,withanunremarkablecomponentofeosinophils(c,H/E400×; inset, CD30, 200×).Bone marrow biopsy (d, H/E, 200×) features minor signs of dysmyelopoieis with eosinophilic hyperplasia.