Keratoacanthoma Pathobiology in Mouse Models

Abstract

Recently we described skin tumors driven by skin-specific expression of Zmiz1 and here we define keratoacanthoma pathobiology in this mouse model. Similar to human keratoacanthoma development, we were able to segregate murine keratoacanthomas into three developmental phases: growth, maturation, and regression. These tumors had areas with cellular atypia, high mitotic rate, and minor local invasion in the growth phase, but with development they transitioned to maturation and regression phases with evidence of resolution. The early aggressive appearance could easily be misdiagnosed as a malignant change if the natural pathobiology was not well-defined in the model. To corroborate these findings in the Zmiz1 model, we examined squamous skin tumors from another tumor study in aging mice, and these tumors followed a similar biological progression. Lastly, we were able to evaluate the utility of the model to assess immune cell infiltration (F4/80, B220 Granzyme B, CD3 cells, arginase-1) in the regression phase; however, because inflammation was present at all phases of development, a more comprehensive approach will be needed in future investigations. Our study of keratoacanthomas in selected murine models suggests that these squamous tumors can appear histologically aggressive during early development, but with time will enter a regression phase indicating a benign biology. Importantly, studies of squamous skin tumor models should be cautious in tumor diagnosis as the early growth distinction between malignant versus benign based solely on histopathology may not be easily discerned without longitudinal studies to confirm the tumor pathobiology.

A clinical and biological review of keratoacanthoma*

“…Both murine models and human KAs have been utilized to characterize each of the phases by histopathology (Figure 1). 40,76,78 Rare cases of metastasis purported to originate from KAs can be found in the literature; however, these exceptional scenarios can be challenged in a number of ways. [82][83][84] Firstly, cSCC can probably arise within a KA, and it is that component that would be likely to metastasize.…”

“…3 The histopathological features of KAs are phase dependent (Figure 1). 75,76 Early lesions consist of an exo-endophytic proliferation of pale squamous cells in lobules, some resembling distorted infundibular structures. 39 These start in contiguity with the adjacent epidermis and then progressively extend into the mid-to-deeper portions of the reticular dermis, with further extension beyond the sweat glands being unusual.…”

“…79 The peripheral keratinocytes notably have enlarged, pink, glassy-appearing cytoplasm, a low nuclear-tocytoplasmic ratio, and minimal nuclear atypia. 39,76,80 A mixed infiltrate of inflammatory cells is common. In some cases, neutrophils and eosinophils may be prominent, often extending into the epithelial islands and forming small microabscesses.…”

Keratoacanthoma, committed stem cells and neoplastic aberrant infundibulogenesis integral to formulating a conceptual model for an infundibulocystic pathway to squamous cell carcinoma

“…More recently, genetically engineered mouse models for human KAs have been developed 5 . These KAs often had a component that was indistinguishable from SCC, which also involuted.…”

“…3 Early carcinogen-induced KA mouse models 4 to show their relationship to follicles have been augmented by genetically engineered models. 5 Significant advances have been made in defining skin stem cells that underpin both the homeostasis and dynamic physiology of follicles and the interfollicular epidermis. [6][7][8] Advances in stem cell biology in humans have been reviewed in detail in respect to epidermal regeneration and carcinogenesis 9 The increased mutational burden in the infundibulocystic pathway has been shown in the study by Ko et al 13 This study included 9 Misago et al 16 extended the infundibular histogenic basis for KA to include the follicular isthmus.…”