Reappraisal of Grading in Intestinal-Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter

Abstract

Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC.

Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding

“…The second study by Meerwein et al (31 patients) was also monocentric and applied the same TB stratification. The authors concluded that TB is an independent negative prognostic marker regardless of the tumor subtype and stage [16]. Our data strengthen the evidence of an independent prognostic value of TB in ITAC and are therefore in line with previous conclusions.…”

“…So far, only two studies (for a total of 63 patients) have investigated the presence of TB in ITAC. The authors found that TB is a negative prognostic marker, similar to CRC and many HNSCCs [13,16], but their results required further validation.…”

“…There is a great desire for new therapeutic approaches to improve the clinical management of patients affected by ITAC [13,15]. So far, only a few studies have suggested a possible prognostic role of TB in ITAC [13,16], and in all cases, no correlation has been established with other recognized biomolecular tumor markers, such as p53 [17,18].…”

Precision Medicine in the Treatment of Malignancies Involving the Ventral Skull Base: Present and Future

“…Another morphological feature associated with worse prognosis is tumor budding, a finding described in colorectal oncologic pathology as the presence of isolated single tumor cells or small clusters of up to 5 cells in the tumor stroma. Maffeis et al and Meerwein et al found a substantial association between tumor budding and prognosis [14,15]. Thus, tumor budding might act as TDTC, but data on pre-treatment detectability are currently lacking.…”

“…Tumor budding [14,15] High copy number alterations [16,17] Aneuploidy, 4q32-ter, ANXA2, DCC, H-RAS, MET, MYC, PFOU5F1B, PTP4A3, PTPN1, TIMP2, TIMP3, TP53 [6] miR-205 and miR-449 overexpression [18] Functional p53 [19][20][21] Neoadjuvant chemotherapy with cisplatin, 5-fluorouracile, and leucovorin MET mutation [26,27] MET inhibitors HRAS mutation [27] RAS or MAPK/ERK pathway inhibitors EIF2S1 and/or EIF6 upregulation [28] Anti-eukaryotic translation initiation factor agents Mutation of PIK3CA, BRCA1, IDH1, ERBB2, BRAF, KRAS, CDKN2A, NF1 [29] Use of respective targeted therapies as orbital encroachment [33,[35][36][37][38][39][40]. Recently, short-term prognosis was found to be improved in patients with sinonasal SCC undergoing neoadjuvant chemotherapy compared with the standard of care [41].…”