In breast cancer of women, the estrogen receptor-α (ERα) and progesterone receptor (PR) status has prognostic and therapeutic significance. The aim of this study was (1) to characterize by immunohistochemistry the expression of ERα and PR in nonneoplastic and neoplastic mammary gland tissue of pet rabbits and (2) to correlate the ERα/PR status and histological features. All 124 rabbits included in this study had a mammary tumor; in addition, 2 rabbits had lobular hyperplasia and 25 had multiple cysts. Of the 124 neoplasms, 119 (96%) were carcinoma, 2 (2%) were carcinoma in situ, and 3 (2%) were adenoma. ERα or PR or both were detected in 2 of 2 carcinomas in situ, 3 of 3 adenomas, 19 of 25 cysts, and 2 of 2 lesions of lobular hyperplasia. Most carcinomas (75/119, 63%) were negative for both ERα and PR; 22 of 119 carcinomas (18%) were double-immunopositive. The ERα and PR expression was not influenced by histotype or histological tumor grade. In carcinomas, there was a statistically significant correlation between increased mitotic count and reduced expression of ERα and PR, and the mitotic count was higher in double-immunonegative carcinomas (75/119). The findings suggest that in rabbit mammary carcinomas, proliferative activity is mainly influenced by factors other than estrogen and progesterone and provides the basis for future investigations into the prognostic significance of the ERα and PR status of mammary tumors.

Simple SummaryIn recent years mammary cancer has been increasingly recognized in pet rabbits. In addition to uterine carcinomas—the most common tumor of female rabbits—mammary cancer can also markedly reduce the life expectancy of pet rabbits. The aim of this review is to raise awareness for these tumors and to report recent progress in related research. Their detailed characterization will likely improve medical care for affected rabbits. Moreover, study results will contribute to comparative pathology and may reveal if the rabbit is a suitable model for certain types of breast cancer in humans. Available information suggests that most invasive cancer cases develop through stepwise progression from non-invasive forms. Thus, early recognition will likely improve a complete cancer cure. So far, the only treatment option is surgical excision and prognostic factors are unknown. Recent investigations have identified tumor features with likely prognostic value. They have also revealed differences and similarities to mammary tumors in other species and breast cancer in women. Despite these initial data, continued research is necessary to gain more insights into the development of these tumors and their molecular features.AbstractThe aim of this review is to raise awareness for mammary tumors in rabbits and to report progress in related research. Currently, a standardized tumor classification for rabbits is not available, prognostic factors are unknown and the only treatment option is surgical excision. Studies showed that affected rabbits have a wide age range and are nearly exclusively female or female spayed. Most mammary tumors are carcinomas. These may occur together with non-neoplastic or benign mammary lesions. Frequent microscopic findings are lipid droplets in tumor cells, secretory activity and microscopic heterogeneity. Since carcinomas are often negative for estrogen and progesterone receptors (ER-α/PR), modulation of receptor function will unlikely be beneficial for most rabbits. ER-α and PR status may have prognostic significance, since ER-α- or PR-negative tumors have significantly higher mitotic rates than ER-α- or PR-positive tumors. The frequent secretory activity of rabbit mammary tumors may suggest an influence of prolactin on tumorigenesis. Available data contribute to comparative pathology and are the basis for future molecular studies into the identification of additional prognostic factors and novel therapeutic options. They will also reveal the suitability of the rabbit as a model for certain types of breast cancer in women.

Simple SummaryMammary cancer is a serious health issue in pet rabbits; prognostic factors are unknown. In a normal mammary gland, glandular secretory cells are surrounded by a single continuous layer of myoepithelial cells. In non-invasive mammary carcinomas, tumor cells are delineated by an intact myoepithelial layer, which is gradually lost to invasive carcinomas. The main aim of this study was to determine in rabbit mammary carcinomas (n = 119) the expression of myoepithelial markers that have prognostic significance in human cancer. Results show that all cases contained some retained myoepithelial cells. In 93% of the tumors, neoplastic cells expressed the myoepithelial marker calponin. There was a statistically significant association between higher percentages of calponin-containing cancer cells and histological features indicative of a better tumor differentiation, i.e., a lower proliferation of tumor cells, an increased percentage of tubular growth within the tumor, and a lower tumor grade, respectively. These results suggest that rabbit mammary carcinomas develop from progression of non-invasive cancer forms, and that calponin expression in cancer cells likely represents a favorable prognostic factor. The latter hypothesis has to be confirmed in long-term follow-up studies.AbstractMost mammary tumors in pet rabbits are carcinomas; prognostic factors are unknown. The aim of this study on rabbit mammary carcinomas was to determine the expression of myoepithelial markers that have a prognostic relevance in human cancers. Mammary carcinomas (n = 119) of female or female-spayed pet rabbits were immunostained for cytokeratin AE1/AE3, vimentin, smooth muscle actin (SMA), and calponin; and percentages of non-neoplastic myoepithelial cells (ME cells) and calponin-positive neoplastic cells were determined. Using statistical analysis, data were correlated with the age of the rabbits and histological tumor characteristics. All carcinomas contained retained spindle-shaped ME, while 115 also contained hypertrophic ME (HME). A statistically significant relationship existed between a higher age and an increase in HME. In 111 carcinomas (93%), tumor cells expressed calponin. There was a significant correlation between higher percentages of calponin-positive tumor cells and a lower mitotic count, an increased percentage of tubular growth, and a lower grading score, respectively. Data suggest that pet rabbit mammary carcinomas develop from progression of in situ cancer and that the extent of calponin expression in tumor cells influences their biological behavior. These results provide the basis for a long-term follow-up on the prognostic significance of calponin expression in mammary cancer cells.

Tumor infiltrating lymphocytes (TILs) serve as prognostic biomarker in human breast cancer. Rabbits have the potential to act as animal model for human breast cancer, and close similarities exist between the rabbit and human immune system. The aim of this study is to characterize TILs in pet rabbit mammary carcinomas and to statistically correlate results with histological and immunohistochemical tumor characteristics. Microscopic evaluation of TILs was performed in hematoxylin and eosin stained sections of 107 rabbit mammary carcinomas according to international guidelines for human breast cancer. Data on histological features of malignancy, estrogen and progesterone receptor status and calponin expression were obtained from the data base. This study revealed a statistical association between stromal TILs in the central tumor (CT) and infiltrative margin. Higher maximal percentages of stromal TILs at the CT were statistically correlated with decreased mitotic count and lower tumor grade. An increased number of calponin positive tumor cells was statistically associated with a lower mitotic count and a higher percentage of stromal TILs. Results suggest that higher percentages of stromal TILs are useful biomarkers that may point toward a favorable prognosis in rabbit mammary carcinomas and support the concept of the use of rabbits for translational research.

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