Aberrant Cytoplasmic INSM1 Expression in Erythroid Cells: A Potential Diagnostic Pitfall Versus Neuroendocrine Neoplasms

Insulinoma-associated protein 1 (INSM1) is a relatively new immunostain used in the diagnostic assessment of tumors with neuroendocrine differentiation. While INSM1 positivity has been described in some non-neuroendocrine neoplasms, reactivity in red blood cells (RBCs) has only been anecdotally noted in one prior study without description of the degree/extent of staining. INSM1 staining in nucleated erythroid precursors has not been previously reported. Herein, 100 small biopsy specimens containing RBCs where INSM1 was used for diagnostic workup were reviewed. Additionally, 5 benign bone specimens and 5 adrenal myelolipoma specimens containing nucleated erythroid precursors were stained with INSM1. INSM1 staining intensity (0-3) and staining extent (0-100%) in RBC/erythroid cells was evaluated and an H-score was calculated (0-300). Positive cytoplasmic INSM1 staining in RBCs was observed in 99/100 (99%) specimens, with mean staining intensity of 2.1 (median = 2) and mean staining percent of 59% (median = 70%), with mean H-score of 125 (median = 140). Positive cytoplasmic INSM1 staining was identified in 10/10 (100%) specimens containing nucleated erythroid precursors, with mean staining intensity of 2.7 (median = 3) and mean staining percent of 53% (median = 50%), with mean H-score of 132 (median = 120). INSM1 is frequently positive in RBCs and nucleated erythroid precursors, albeit with variable staining intensity and extent. Although the INSM1 staining is cytoplasmic in RBCs (lacking nuclei) and nucleated erythroid precursors, the morphological features can mimic positive nuclear staining of neuroendocrine neoplasms. Particularly in small biopsy samples, which often contain background RBCs, positive INSM1 staining should be reviewed with caution to avoid misdiagnosis of neuroendocrine differentiation.