Lymphomatoid Papulosis Associated with Myeloid Neoplasm with Eosinophilia and FIP1L1-Pdgfra Rearrangement: Successful Imatinib Treatment in Two Cases

INTRODUCTION

Lymphomatoid papulosis (LyP) is a chronic primary cutaneous lymphoproliferative disorder (LPD) characterized by a benign course with a tendency to relapse.

Hypereosinophilic syndromes (HES), on the other hand, are a heterogeneous group of disorders characterized by hypereosinophilia (HE) [i.e., peripheral blood (PB) eosinophil count (AEC) >1.5 ×10⁹/L] and may be associated with life-threatening organ damage.

In 2016 WHO classification, a subtypes classification based on molecular profile was approved, including myeloid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. Currently, imatinib is the drug of choice for so-called myeloid neoplasms with eosinophilia and PDGFRA/B rearrangement.

Here we described the case of two 33-year-old Caucasian men who presented with both these conditions, achieving complete remission under imatinib.

CASE 1

His medical history was notable for LyP diagnosed in June 2020. Early lesions were characterized by self-healing papules with central ulceration and subsequent necrosis, mainly in the lower limbs. Punch biopsy showed dermal and hypodermic infiltration with atypical small and medium-sized CD30+/CD4+/CD2+/-/CD3-/+/CD5-/+/CD7- T lymphocytes, concluding for primary cutaneous CD30+ T-cell LPD consistent with type A LyP. Due to recurrence of erythematous papules followed by necrotic evolution, methotrexate 10 mg once weekly was started with symptoms resolution. Importantly, AEC was only mildly increased at LyP diagnosis. However, in October 2021 a new CBC revealed severe HE (AEC 6.5 x10⁹/L). Routine blood testing showed only mild leukocytosis with significantly increased AEC (6.13 x10⁹/L), while PB immunophenotype was not indicative for LPD.

Screening for BCR-ABL1 p210 fusion transcript and JAK2V617F mutation was negative; conversely, FIP1L1-PDGFRA rearrangement was detected, thus leading to a diagnosis of myeloid neoplasms with eosinophilia and PDGFRA rearrangement. Bone marrow (BM) biopsy confirmed the diagnosis, excluding any lymphoid infiltration.

Methotrexate treatment was then discontinued and imatinib 100 mg QD started. After 3 months molecular analysis on both PB and BM was negative for FIP1L1-PDGFRA rearrangement. Interestingly, after methotrexate discontinuation LyP-related cutaneous lesions never recurred during imatinib therapy.

CASE 2

In 2018 he developed erythematous papules on upper limbs: the histological exam revealed a wedge-shaped dermal infiltration consisting of neutrophils, eosinophils, histocytes and atypical CD2+/CD3+/CD4+/CD5+/CD7+/CD8+/CD30+/MUM1+/Ki67+(30-40%) lymphocytes. These findings were consistent with a type A LyP diagnosis.

Laboratory analysis showed normal CBC except for moderate HE (AEC 3.64 x10⁹/L), with an immunophenotype on PB inconclusive for LPD. A BM biopsy revealed only eosinophilic hyperplasia. Search for JAK2V617 mutation and BCR-ABL1 p210 fusion transcript was negative, while 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 then initiated, and after 3 months FIP1L1-PDGFRA rearrangement was not detected, with a significant improvement in BM morphology. Furthermore, LyP-related skin lesions never occurred during follow-up.

CONCLUSION

Myeloid neoplasms with eosinophilia and PDGFRA/B rearrangements prognosis is significantly improved after imatinib introduction. In contrast, LyP relapses are very common and approximately 20% of patients may subsequently develop NHL.

To our knowledge, only 12 cases of LyP-associated HES have been reported in the literature so far: 7 patients were treated with imatinib, 5 of whom expressed FIP1L1-PDGFRA rearrangement.

Why LyP can be associated with HES is still uncertain. In some cases, it may be linked to the release of eosinophilopoietic cytokines, such as IL-5 and IL-3, by abnormal LyP T lymphocytes. In addition, FIP1L1-PDGFRA rearrangement has been identified in both eosinophils and clonal T cells in some patients, thus suggesting a common pathogenetic mechanism and the reason why imatinib is capable of inducing a clinical-molecular remission of both conditions.

Consequently, search for FIP1L1-PDGFRA rearrangement should always be performed in LyP patients who present with HE at diagnosis or develop it during follow-up.

No relevant conflicts of interest to declare.