ORF12-01 - Medullary Thyroid Carcinoma Mimicking Acute Leukemia: Bone Marrow Metastasis with Rapid Hematologic Recovery Following Selpercatinib in a RET-Mutant Tumor

Background: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy, where metastases commonly involve liver and bone; bone marrow infiltration, cytopenias and a disseminated intravascular coagulation (DIC) picture is rare and may mimic acute leukemia. Selective RET inhibitors are effective in advanced RET-mutant MTC, outcomes in patients with marrow involvement and coagulopathy are poorly characterized. Here we describe a case with rapid hematological recovery.
Clinical Presentation: A 19-year-old woman with no prior medical history presented with dizziness, near-syncope, dyspnea, and a 40-pound weight loss over two months. Laboratory workup revealed normocytic anemia and severe thrombocytopenia. Peripheral smear raised concern for acute promyelocytic leukemia with features of consumptive coagulopathy, prompting empiric initiation of all-trans retinoic acid.
Bone marrow biopsy showed metastatic neuroendocrine neoplasm with markedly decreased trilineage hematopoiesis. PET-CT showed diffuse hypermetabolic involvement of bone and liver with a hypermetabolic right thyroid nodule. Liver biopsy confirmed metastatic neuroendocrine tumor with patchy calcitonin staining. Tumor markers were markedly elevated (CEA 199,826 ng/mL; calcitonin 709 pg/mL). Thyroid ultrasound showed a 1.1-cm thyroid nodule, and FNA confirmed MTC.
Given atypical histology and uncertain primary, tumor next-generation sequencing performed on liver biopsy identified a pathogenic RET C634Y mutation. Germline testing had not yet been completed; however, the mutation and young age raised strong concern for hereditary MTC (MEN2A). After confirmation of RET mutation, therapy was changed to Selpercatinib, which was complicated by tumor lysis syndrome followed by rapid improvement. Within one month, hemoglobin and platelets normalized, with marked biochemical response; calcitonin decreasing to 53 pg/mL and CEA to 782 ng/mL. Associated features like hyperparathyroidism and pheochromocytoma were negative.

Discussion: MTC can have early hematogenous spread, but bone marrow involvement is rare. Diagnostic uncertainty can be compounded by acute leukemia-like presentation and tumor heterogeneity at metastatic sites, raising importance of molecular evaluation.
Activating alterations in the RET proto-oncogene are central to the MTC pathogenesis. Codon 634 mutations represent a high-risk variant with early onset, aggressive disease. Identification of RET mutation has important therapeutic implications as a selective second-generation RET inhibitor can induce rapid clinical and biochemical response in patients with high disease burden.

Conclusion: This case highlights the critical role of how tumor-based molecular profiling can resolve diagnostic uncertainty, enabling prompt initiation of targeted RET inhibited therapy and genetic counseling when MEN2A is suspected