Well-Differentiated Systemic Mastocytosis with KIT K509I Mutation and Uterus Infiltration in an Asian Woman with Good Response to Imatinib
Systemic mastocytosis (SM) is a group of disorders characterized by the abnormal proliferation and accumulation of neoplastic mast cells (MCs) in one or more organ systems. This condition predominantly affects adults and can manifest in various forms, ranging from indolent to aggressive disease. The World Health Organization (WHO) 2016 classification further categorizes SM into indolent SM, smoldering SM (SSM), SM with an associated clonal hematologic non-MC-lineage disease, aggressive SM (ASM), and mast cell leukemia. A rare variant of SM, known as well-differentiated systemic mastocytosis (WDSM), has been identified, characterized by mature MC morphology and specific genetic mutations, often showing a favorable response to tyrosine kinase inhibitors like imatinib.
This case report presents a 27-year-old Asian woman with a 2-month history of irregular uterine bleeding between periods. The patient’s medical history revealed blistering on the head at the age of 2 months, followed by the gradual development of red maculopapular lesions over her neck and back during puberty. These lesions were notably itchy after exposure to physical friction. On admission, physical examination revealed diffuse faint maculopapular rash predominantly on the neck and back. Pelvic examination identified a smooth red lump measuring 5 cm on the cervix. Initial laboratory tests, including a complete blood count, showed no abnormalities.
The cervical lump was surgically resected and subjected to pathological investigation, which confirmed the infiltration of mature mast cells. A skin nodule biopsy also demonstrated a mass aggregation of MCs. Further evaluation through a bone marrow (BM) biopsy revealed a significant population of round MCs with abundant cytoplasmic granules, accounting for approximately 22.5% of all cells in the aspirate smears. Flow cytometry immunophenotypic analysis of the BM indicated that an aberrant MC population represented 10% of the total analyzed cells. These MCs were positive for CD117, CD33, and CD9, partially positive for CD2 and CD68, and negative for CD25. Genetic testing through exome-wide sequencing identified a K509I mutation in the KIT gene, a receptor tyrosine kinase.
Based on these findings, the patient was diagnosed with smoldering SM-WDSM (SSM-WDSM). This diagnosis was supported by the presence of mature MCs in the BM and uterus, the characteristic skin lesions, and the KIT K509I mutation. The patient was initiated on imatinib mesylate therapy, starting with a daily dose of 100 mg for nearly 3 months, followed by an increased dose of 400 mg daily for an additional 3 months. Remarkably, the patient achieved complete remission in the BM, and her symptoms significantly improved.
The clinical course and prognosis of SM are largely determined by the WHO-designated variant rather than the well-differentiated morphology of MCs. In this case, the patient’s response to imatinib aligns with previous reports of WDSM, where patients with wild-type KIT or specific molecular alterations in KIT often exhibit sensitivity to tyrosine kinase inhibitor therapy. The K509I mutation, in particular, has been associated with favorable responses to imatinib, as seen in this patient.
This case is notable for several reasons. Firstly, it represents the first known case of WDSM in Asia, highlighting the global distribution of this rare variant. Secondly, it is the first report of well-differentiated MCs infiltrating the uterus, expanding the understanding of the organ involvement in WDSM. The successful treatment with imatinib underscores the importance of genetic testing in guiding therapeutic decisions for patients with SM.
The management of SM requires a comprehensive approach, including accurate diagnosis, genetic profiling, and tailored therapy. The WHO 2016 classification provides a valuable framework for categorizing SM variants, which aids in predicting disease behavior and guiding treatment strategies. In this case, the identification of the K509I mutation in the KIT gene was pivotal in selecting imatinib as the optimal treatment.
The patient’s clinical presentation, including the history of skin lesions and uterine infiltration, underscores the diverse manifestations of SM. The maculopapular rash observed in this patient is consistent with urticaria pigmentosa, a common cutaneous manifestation of SM. The involvement of the uterus, however, is a rare finding that adds to the growing body of knowledge on the extramedullary manifestations of SM.
The therapeutic success achieved in this case highlights the potential of targeted therapies in managing SM. Imatinib, a tyrosine kinase inhibitor, has shown efficacy in patients with specific KIT mutations, including K509I. The patient’s rapid and complete response to imatinib therapy further validates the role of genetic profiling in identifying treatment-responsive mutations.
In conclusion, this case report illustrates the clinical and pathological features of WDSM with a KIT K509I mutation and uterus infiltration in an Asian woman. The patient’s favorable response to imatinib therapy underscores the importance of genetic testing and targeted therapy in managing SM. This case also expands the understanding of the organ involvement and treatment outcomes in WDSM, contributing to the evolving landscape of SM diagnosis and management.
doi.org/10.1097/CM9.0000000000000355
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