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A 60-year-old man with a history of cerebrovascular accident, recurrent deep vein thrombosis and pulmonary embolism, and renal cell carcinoma (RCC) was evaluated for long-standing and unexplained erythrocytosis (panel Ai). He had a markedly elevated serum erythropoietin (EPO, panel Aii), initially attributed to RCC although it persisted postnephrectomy (panel A, black triangles). Tests for polycythemia vera and hereditary erythrocytosis mutations were negative (JAK2, CALR, MPL, VHL, HIF-2α, EGLN1, EPO receptor mutation), as were tests for high-affinity hemoglobin. Physical examination was notable for facial/flank telangiectasias (panel B), and imaging demonstrated a small perinephric fluid collection. Serum protein electrophoresis revealed M-protein and an immunoglobulin G λ monoclonal gammopathy (panel Aiii-v). This constellation of findings raised concern for telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting (TEMPI) syndrome. Bone marrow biopsy showed a plasma cell neoplasm (PCN; panel A, black arrow) and ¹⁸F-fluorodeoxyglucose–avid skeletal lesions on PET confirmed stage II multiple myeloma. The patient was initiated with daratumumab-cyclophosphamide-bortezomib-dexamethasone treatment (panel A, red triangle), resulting in a rapid decline in EPO and minimal residual PCN (panel Avi). A follow-up biopsy (panel A, red arrow) showed frequent large and multinucleated plasma cells (arrows in panel C, Wright-Giemsa stain, 100× objective; and panel D, CD138 immunohistochemistry, 40× objective).

Diagnosis of TEMPI syndrome was made more challenging by a recent RCC therapy. We observed frequent, enlarged multinucleated plasma cells in a normocellular marrow, likely reflecting the lingering effect of mildly elevated EPO in the setting of positive measurable residual disease.

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