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Charcot neuropathic arthropathy is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for Charcot neuropathic arthropathy previously relied on Eichenholtz stage. There is limited histopathologic data on this entity. We wanted to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy.Retrieval of surgical pathology midfoot specimens from Charcot patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large (≥half 40× hpf) to small (half 40× hpf) periarticular bone fragments to resolution, we devised and applied a Charcot neuropathic arthropathy novel FEMASK-score (named after coauthors: Fanburg-Smith, Frauenhoffer, Flemming, Fritsche, Elfar, Murie, Aynardi, Stauch, Smith, King, and Klein): 0 (initial) = the observed intraneural arteriolosclerosis in all diabetic neuropathic patient specimens (not observed in other diabetic nerves); and finally scored with the most destruction observed: 1 = large bone fragments without host histiocytic response; 2 = mixed bone fragments with host histiocytic response; 3 = small minute bone spicules resorption to fibrosis. Eichenholtz stage and outcome were then compared.Forty-eight cases of Charcot neuropathic arthropathy included 34 males and 14 females, mean age 60.3 and age range 28-83 years, with clinical diabetes mellitus (predominantly Type II) and longstanding neuropathy. Elevated HbA1C, Eichenholtz stage, American Society of Anesthesia score, and Charlson comorbidity index indicated initial clinical amputation. Pathologic specimens varied from fixation tissue to amputation. In addition to neurotraumatic, neurovascular and inflammatory findings, a distinctive intraneural hyalinized arteriolosclerosis was observed. FEMASK-scores: 1 = 10%, 2 = 58%, and 3 = 32%. Score comparisons were 98% accurate compared with Eichenholtz and 98% reproducible among pathologists. FEMASK 2 and 3 correlate with clinical need for amputation.Our novel Charcot neuropathic arthropathy FEMASK-score classification, derived from the largest cohort of diabetic neuropathic specimens, is reproducible, explains pathophysiologic progression of destructive phase of Charcot, correlates with Eichenholtz, and predicts progression to or clinical need for amputation. The unique intraneural vasculopathy observed contributes to Charcot neuropathic arthropathy etiology.