Tumor budding - a potential biomarker in low grade salivary gland carcinomas?

Abstract

Background: Low-grade salivary gland carcinoma is regularly treated with surgical therapy of the salivary gland without elective neck dissection in T1/2 carcinomas, either alone or with adjuvant radiation therapy. However, occult metastasis and locoregional recurrence influence therapy and outcome. Tumor budding is an emerging prognostic pathological factor in many carcinomas, but has not yet been adequately considered in salivary gland carcinomas.

Methods: We conducted a retrospective single-center study of 64 patients diagnosed with low-grade carcinoma of the major salivary glands treated between 2003 and 2017. Pathological risk factors and TNM classification were thoroughly assessed for each case. All hematoxylin and eosin (HE)-stained histological specimens underwent careful examination, and tumor budding was identified following the guidelines set forth by the International Tumor Budding Consensus Conference in 2016.

Results: Tumor budding was not statistically significant concerning 5-year survival rate (5-YSR) (p=0.969) and mean overall survival (log-rank p=0.315). Whereas 5-year disease-free survival rate (5-YDFSR) was 87% in the low tumor budding group and 61.1% in the intermediate and high tumor budding group (p=0.021). Mean disease-free survival accounted for 100.2 months (CI: 88.6;111.9) in the low budding score group and 58.7 months (CI: 42.8;74.6) in the other group (log-rank p=0.032). Notably, pT1/2 showed significantly lower tumor buds than pT3/4 stages (2.43 tumor buds/0.785 mm² vs. 4.19 tumor buds/0.785 mm², p=0.034). Similar findings were noted comparing nodal-positive and nodal-negative patients, as well as patients with and without lymphovascular invasion and perineural invasion (each p<0.05).

Conclusions: Tumor budding might be used as an additional prognostic factor for recurrence in low-grade salivary gland carcinoma, seemingly associated with a higher nodal metastasis rate and advanced tumor stages and a worse 5-YDFSR. Consequently, the evaluation of tumor budding in resection specimens of low-grade salivary gland tumor may prove valuable in decision-making for neck dissection and follow-up strategy.

Keywords: biomarker; cancer; low grade salivary gland carcinoma; prognostic factor; salivary gland carcinoma; tumor budding.

Figure 1

Tumor budding in low-grade MSGC. (A) Digitalized specimen of MSGC. (B) Tumor budding in HE stained SGC slides was analyzed using QuPath at 20-fold magnification at the tumor host interface to reveal the morphology of the budding cells as a cell cluster (≤ four tumor cells, red circle) separated from the main tumor mass (yellow circles).

Figure 2

Estimated mean OS and DFS of low-grade SGC patients analyzing the impact of (A) UICC stages, showing a statistically significant decreased mean OS in patients with higher UICC stages, (B) as does the Kapan-Meier analysis for mean DFS separated between the UICC stages. (C) Kaplan-Meier showing a significantly longer mean OS for patients without nodal positive neck and (D) demonstrating a significantly longer mean DFS for patients with nodal negative neck.

Figure 3

Here estimated mean OS and DFS for patients with low and high tumor budding are depicted as Kaplan-Meier analysis and Hazard ratio, respectively. (A) Kapan-Meier analysis shows no statistically significant difference between the groups. (B) Depiction of a significantly higher mean DFS in patients with low tumor budding score.

Figure 4

(A) shows a boxplot comparing tumor buds in pT1/2 and pT3/4 patients, showing a significant difference. In boxplot (B) Tumor buds in patients with and without recurrence are compared, also showing a statistically significant difference. (C) The boxplot depicts that patients with recurrence do have more tumor buds than patients without recurrence. (D) There was no significant difference in mean tumor buds/0.785mm² between the group of patients with and without vascular invasion. The Boxplots (E) for lymphovascular invasion and (F) for perineural invasion both show a significantly higher tumor budding in patients with lymphovascular/perineural invasion. * = p<0.05. ** = p<0.01. NS = not significant.