Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix

Abstract

A novel histopathological grading system based on tumour budding and cell nest size has recently been shown to outperform conventional (WHO‐based) grading algorithms in several tumour entities such as lung, oral, and oesophageal squamous cell carcinoma (SCC) in terms of prognostic patient stratification. Here, we tested the prognostic value of this innovative grading approach in two completely independent cohorts of SCC of the uterine cervix. To improve morphology‐based grading, we investigated tumour budding activity and cell nest size as well as several other histomorphological factors (e.g., keratinization, nuclear size, mitotic activity) in a test cohort (n = 125) and an independent validation cohort (n = 122) of cervical SCC. All parameters were correlated with clinicopathological factors and patient outcome. Small cell nest size and high tumour budding activity were strongly associated with a dismal patient prognosis (p < 0.001 for overall survival [OS], disease‐specific survival, and disease‐free survival; test cohort) in both cohorts of cervical SCC. A novel grading algorithm combining these two parameters proved to be a highly effective, stage‐independent prognosticator in both cohorts (OS: p < 0.001, test cohort; p = 0.001, validation cohort). In the test cohort, multivariate statistical analysis of the novel grade revealed that the hazard ratio (HR) for OS was 2.3 for G2 and 5.1 for G3 tumours compared to G1 neoplasms (p = 0.010). In the validation cohort, HR for OS was 3.0 for G2 and 7.2 for G3 tumours (p = 0.012).In conclusion, our novel grading algorithm incorporating cell nest size and tumour budding allows strongly prognostic histopathological grading of cervical SCC superior to WHO‐based grading. Therefore, our data can be regarded as a cross‐organ validation of previous results demonstrated for oesophageal, lung, and oral SCC. We suggest this grading algorithm as an additional morphology‐based parameter for the routine diagnostic assessment of this tumour entity.

Importance of tumor budding grade as independent prognostic factor for early tongue squamous cell carcinoma

“…The acquisition of metastatic potential is thought to be based on an epithelial mesenchymal transition that manifests as morphological change . In addition to colon cancer, this has recently been associated with lung, esophageal, cervical, and skin cancer, as well as with head and neck cancers . Budding can be simply counting buds at the most prevalent site, namely the invasive front of the tumor within a field of view at 20 × 10 magnification .…”

Post-neoadjuvant cellular dissociation grading based on tumour budding and cell nest size is associated with therapy response and survival in oesophageal squamous cell carcinoma

“…Tumour budding, a histologic parameter that measures the quantitative extent of cellular dissociation of a neoplasia, has been identified as a highly prognostic factor in ESCC 31 – 36 and other squamous cell carcinoma entities. 37 , 38 Our proposed grading algorithm that has been shown to nicely discriminate prognostic subgroups in primary resected ESCCs 26 as well as in pre-therapeutic ESCC biopsies 25 and several other squamous cell carcinoma entities, 23 , 24 , 39 pairs up tumour budding with cell nest size, a second parameter measuring cellular dissociation from a more qualitative angle. Therefore, our novel grading approach has been termed “Cellular Dissociation Grade”.…”

Human myoma tissue-based extracellular matrix models for testing the effects of irradiation on the HPV positive cells

“…The differences in invasion depth (f) and invasion area (g) were measured and compared before (0 Gy) and after (4 Gy) irradiation. Statistically significant differences have been marked to figures as *p ≤ 0.001 cervical adenocarcinomas and CSCCs, tumor budding has been associated with higher histological tumor grade, invasive pattern, lymph node metastasis, bigger tumor size and poorer prognosis [41,42]. Jesinghaus and collagues [42] have suggested in their study, that tumor budding could be used as an individual prognostic factor in CSCCs.…”

“…Statistically significant differences have been marked to figures as *p ≤ 0.001 cervical adenocarcinomas and CSCCs, tumor budding has been associated with higher histological tumor grade, invasive pattern, lymph node metastasis, bigger tumor size and poorer prognosis [41,42]. Jesinghaus and collagues [42] have suggested in their study, that tumor budding could be used as an individual prognostic factor in CSCCs. There have not been similar studies concerning HPV positive carcinomas in either HNSCCs or CSCCs, but we would speculate that similar effect might be seen regardless of the HPV status, as was observed with HPV positive SiHa cell in our study.…”