Main Findings
In this retrospective clinico-pathological study on ITAC patients at a tertiary referral center, we found the presence of intermediate/high TB to be a strong prognostic factor of poor outcome in terms of both, DSS and OS. In contrast to intermediate/high TB, all patients with low TB reached CR after primary treatment protocols and no patient died of disease. However, DFS was not different between low TB and intermediate/high TB patients, indicating that also low TB does not prevent from recurrence. Similar to previous findings and in accordance with CRC, no association between TB and tumor stage or tumor subtype (indicative of grading) was observed.
In our study we confirmed ITAC to mainly originate from the nasoethmoidal complex with a strong predominance for the male gender and incidence peaking in the seventh decade [
3,
5,
31]. Overall survival (78.3%), DSS (78.5%) and DFS (69.9%) at 5 years were similar to previous studies, which reported survival rates between 53 and 83%, 82 and 83 and 62 and 74%, respectively [
7,
11,
12,
31‐
34]. With regard to the pattern of recurrence, local recurrence was confirmed to be by far the most common site of treatment failure [
12,
32,
35,
36]. From a therapeutic point of view, transnasal endoscopic techniques have evolved as standard-of-reference for most sinonasal malignancies, providing excellent outcomes and decreased morbidity, when compared to external approaches [
11,
12,
37]. The role of external approaches remains as an option for selected patients with gross invasion of brain, orbital content or bone [
25]. For ITAC in particular, a transnasal endoscopic tumor resection is the preferred approach in most patients, since it can be expanded to a transnasal-craniectomy (transnasal–transcribriform technique), as it was performed in the majority of all surgically treated patients in our cohort (60%) [
25]. In case of close proximity or infiltration of the bony or dural anterior skull base, resection of the “ethmoidal box” is pivotal in order to achieve adequate surgical margins [
7]. In these patients, dural reconstruction with pedicled flaps or other grafts is mandatory. In terms of adjuvant radiation therapy, there is broad consensus on its necessity in high-grade and/or advanced tumors, while in locally-defined, low-grade tumors with clear surgical margins surgery-only may be justified [
7,
12,
14,
38]. Especially for advanced high-grade ITACs as well as patients with exposure to known carcinogens, lifetime clinical and radiological follow up (beyond the often reported 5 years) should be scheduled [
7,
39].
As it was shown previously, ITAC and adenocarcinomas of the intestinal tract show to a great extent morphological similarities, as well as overlapping immunohistochemical expression profile, including typically positive staining for CK20, CDX2, villin, MUC2 and SATB2 [
22,
23,
40,
41]. As a consequence of this resemblance, TB, a widely accepted concept in CRC, has recently been adapted for ITAC [
42]. Tumor budding is to understand as a morphological feature defined as single cells or small cell clusters, so called tumor buds, constituting up to four cells at the invasive front of the tumor or within the tumor mass [
21,
43]. For CRC, TB is known to be associated with high and advanced tumor stage, lymphatic and vascular invasion, nodal and distant metastasis and worsening of OS, DFS and recurrence free survival. Furthermore, TB is thought to be part of the epithelial–mesenchymal transition (EMT) spectrum, which allows epithelial cells to lose polarity and cell–cell-adhesions, resulting in migratory and invasive properties, resistance to anoikis/apoptosis and increase extracellular matrix production [
21]. Thus, EMT is hypothesized to be one of the drivers of cancer progression [
44]. To the best of our knowledge, only Maffeis et al. investigated TB in ITAC and demonstrated that TB is frequent (40%) and associated with worse OS and DFS [
21]. Similar to their findings, we found patients with low TB to reveal a favorable prognosis in terms of both, DSS and OS. In comparison, we used the supplementary aid of immunohistochemical pancytokeratin staining, which has been shown to reliably help in identifying tumor buds in CRC [
45]. Further it is a highly standardized, cost-effective and widely available special staining. Additionally, we confirmed the presence of TB to be independent from initial tumor stage and Barnes subtype/grading. Interestingly, all patients with low TB reached CR after primary treatment protocols and no patients died of the disease. With regard to DFS, we did not find a significant difference between low and intermediate/high TB. Congruently, recurrences were observed in both groups, however, progressive disease was only seen in the intermediate/high TB group. Based on these findings we hypothesize that low TB does not ultimately protect from development of recurrences. However, patients with intermediate/high TB seem to be at risk for non-treatable disease progression and dead of disease. Interestingly, in our cohort the presence of signet ring cells was not associated with distinct outcomes (OS, DSS), leading us to a more cautious interpretation of this typically negative parameter. With regard to the immunophenotypical description of our cohort and in line with previous findings, no evidence of microsatellite instability was found [
40,
46].
Strengths and Limitations
To the best of our knowledge this is only the second study on the role of TB in ITAC patients [
21]. Similar to the study by Maffeis et al., we decided for a validated three-tier-system for TB (low-intermediate-high), depending on the number of buds, however they opted for an overall dichotomous categorization (yes vs. no) [
28]. Besides its retrospective design, we acknowledge that our study has some noteworthy limitations. Firstly, although we included all available ITAC patients at our institution, our sample size was rather small, owing to the low incidence of these neoplasms. Consecutively, due to the low absolute numbers of samples and events, no statement on the role of intermediate/high TB for the development of metastases could be made. Secondly, due to natural fragmented histological specimen, identification of the invasive front can be challenging. Thus, the mucinous subtype and patients with no determinable tumor front had to be excluded from this analysis.