Feline Invasive Mammary Carcinomas: Prognostic Value of Histological Grading

Abstract

Feline mammary carcinomas are highly malignant tumors usually associated with poor outcome. Nevertheless, survival times can differ significantly according to various prognostic factors. The Elston and Ellis (EE) histologic grading system, originally developed for human breast cancer, is commonly used to grade feline mammary carcinomas, although it is not really adapted for this species, hence the need of a more relevant grading system. Although few veterinary studies attempted to validate previously published results in an independent cohort, the aim of our study was to evaluate the prognostic value of different histologic grading systems in feline invasive mammary carcinomas, including the EE grading system applicable to human breast cancers and the modified and newly designed histologic grading systems recently proposed by Mills et al. Survey data and histologic features of 342 feline invasive mammary carcinomas were analyzed with respect to overall and cancer-specific survival. The histological grading system with best prognostic value was the mitotic-modified Elston and Ellis (MMEE) grading system: grade III carcinomas ( P = .04, hazard ratio [HR] = 1.46, 95% CI, 1.01–2.11), grade II ( P = .03, HR = 1.39, 95% CI, 1.03–1.88), and grade I carcinomas (HR = 1.00, reference), with decreasing hazard ratios significantly were associated with a worse overall survival, independently from the pathologic tumor size (pT ≥ 20 mm: P = .002, HR = 1.45, 95% CI, 1.15–1.83) and positive nodal stage ( P = .001, HR = 1.51, 95% CI, 1.18–1.94). This retrospective study validates Mills et al’s proposal to adapt the thresholds for mitotic counts to better assess the histological grade of the highly proliferative mammary carcinomas encountered in the cat.

Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

“…Consistent with other studies 1,34,107 , a high-Ki-67 index remained associated with reduced cancer-specific OS in the multivariate analysis. As previously reported 1,36,38,72,108 the EE, and the MMEE grading systems were correlated with poor outcome in the univariate analysis. Nonetheless, among the grading systems employed, the Mills-2015 system showed the highest level of agreement (66.7%) between well-differentiated tumours and low Ki-67 indexes.…”

“…The mitotic cut-offs for the EE and MMEE grading systems in our cohort were adapted according to the field diameter (0.51 in Castagnaro et al 36 , 0.53 in Mills et al 37 , and 0.575 in our study). For the Mills-2015 system, as suggested by Dagher et al 38 , we determined the mitotic count cut-off by using receiver-operating characteristic (ROC) analysis for the study period OS-cancer specific survival rate of the cats included in this study. Therefore the mitotic count cut-off used in this study (≥35 mitoses in 10 high-power fields) was different from that proposed by Mills et al 37 and used by Dagher et al 38 (>62, and ≥33 mitoses in 10 high-power fields; respectively).…”

“…For the Mills-2015 system, as suggested by Dagher et al 38 , we determined the mitotic count cut-off by using receiver-operating characteristic (ROC) analysis for the study period OS-cancer specific survival rate of the cats included in this study. Therefore the mitotic count cut-off used in this study (≥35 mitoses in 10 high-power fields) was different from that proposed by Mills et al 37 and used by Dagher et al 38 (>62, and ≥33 mitoses in 10 high-power fields; respectively). Complete surgical excision and lymph node metastasis were histopathologically confirmed in all cases.…”

“…Important differences were observed when applying the three histological grading systems reported on FMCs (i.e. Elston and Ellis [EE] 35,36 , mitotic-modified EE [MMEE] 37,38 , and the novel histological malignancy grading system for evaluation of FMCs [Mills-2015] 37,38 ), Supplementary Table 3. There was a minimal level of agreement when the histological grade assigned to each tumour using the three different systems was compared using Cohen's Kappa test: EE and MMEE (K = 0.25), EE and Mills-2015 (K = 0.27), MMEE and Mills-2015 (K = 0.24).…”

Identification of an immune-suppressed subtype of feline triple-negative basal-like invasive mammary carcinomas, spontaneous models of breast cancer

“…In the case of multifocal (within a given mammary gland) or multicentric (within different mammary glands) invasive mammary carcinomas, the largest one was selected for analysis. Recorded histological data were the histological types, lymphovascular invasion (LVI), histological grade according to the Elston and Ellis grading system for human breast cancer, 39 which has been validated in FMCs, 40 presence/absence of central necrosis or squamous differentiation, and tumorassociated lymphohistiocytic inflammation, as previously described. 36 The pathologic tumor (pT) size was measured on histological sections as the greatest tumor diameter, in millimeters.…”