This study aims to outline the histological progression of the Spirocerca lupi nodule from infection to neoplastic transformation. Sixty-two spirocercosis-induced nodules, 42 non-neoplastic and 20 neoplastic, were stained with HE. Ten non-overlapping high power fields per nodule were examined and non-neoplastic and neoplastic nodules were compared. Inflammation was scored 0–3 and revealed a score of 1.91 ± 0.52 in the non-neoplastic and 0.97 ± 0.5 in the neoplastic cases (p < 0.01). In most non-neoplastic cases the inflammatory infiltrate was lymphoplasmacytic and in the neoplastic cases neutrophils predominated. Necrosis was scored 0–3 and revealed a score of 0.88 ± 0.41 in the non-neoplastic and 1.47 ± 0.5 in the neoplastic cases (p < 0.01). The average number of mitoses over 10 high power fields per nodule was 1.31 ± 1.55 in the non-neoplastic compared to 42.85 ± 30.79 in the neoplastic cases (p < 0.01). The average number of multinucleated giant cells over 10 high power fields per nodule was 0.9 ± 1.45 in the non-neoplastic compared to 13.9 ± 14.66 in the neoplastic cases (p < 0.01). In the non-neoplastic cases, collagen, immature fibroblasts and fibroblast activation (excessively plump euchromatic nuclei with single or multiple prominent nucleoli) were scored 0–3 and a combined score, fibroblasts + activation score − collagen was calculated. The non-neoplastic cases were divided into a combined score of ≤1 (n = 15) or >1 (n = 27). The 2 groups had similar scores for inflammation and necrosis, but were significantly different (p < 0.01) in mitotic index (0.26 ± 0.46 vs. 1.89 ± 1.65) and number of multinucleated cells (0 vs. 1.4 ± 1.6). These results indicate 2 stages in the non-neoplastic nodules: early inflammation, characterized by fibrocytes and abundant collagen, and a pre-neoplastic stage, characterized by activated fibroblasts and reduced collagen.