Discussion
Despite recent advancements in diagnostic and therapeutic approaches for
LSCC, the overall survival rate for this common neoplasm remains modest
(17). Currently, the UICC/TNM staging system is used to determine the
prognosis of LSCC by considering factors such as surgical margin status,
tumor differentiation, lymphovascular invasion, perineural invasion, and
recipient of adjuvant therapy (18, 19). However, studies have shown that
even among patients with the same tumor stage, there is significant
discordance in the predictability of routinely reported prognostic
factors (12). Furthermore, upstaging or downstaging occurs in a third of
LSCC patients, impacting margin status, therapeutic approaches, and
recurrence rate (20). It is essential to identify an independent
prognostic factor to determine which patients are suitable for
organ-preserving treatment, as the impact of total laryngectomy on
psychological and functional aspects can be significant (21). Our
research indicates that a significant percentage of cases, over 62%,
were classified as stage IV, despite exhibiting well-differentiated
features in more than 62% of cases. Additionally, although the
mortality rate was high at 63%, vascular and perineural invasion were
present in less than 30% of cases. These findings highlight the
potential discrepancies between clinical and histopathological
prognostic factors.
Recent studies suggest that a combined TB/CNS-based grading system holds
promise in predicting outcomes for SCC patients across various sites
(22). TB is recognized as an independent prognostic factor in many solid
tumors (18) and even preoperative biopsies can provide valuable
information about invasion depth, lymph vascular invasion, and invasion
patterns (23). In oral SCC, TB has been shown to negatively impact
survival outcomes, regardless of tumor location or pathological stage
(24, 25). Therefore, validating the prognostic significance of TB and
CNS is beneficial, as routine H&E-stained slides can assess them with
high interobserver, and intraobserver agreement (26). However, studies
on SCCs of the larynx and hypopharynx are limited, and results vary due
to differences in pathological and clinical variables.
Various methods for detecting TB have been suggested, but the scoring
system proposed by Boxberg et al. is sufficient for the risk
stratification of LSCCs. Boxberg et al. developed their approach based
on a validated grading system for esophageal SCC, which incorporates the
budding activity score and intratumoral CNS score. TB quantifies the
dissociative growth of cancer cells, while CNS represents the highest
level of cellular discohesion qualitatively. Combining these two factors
provides insight into tumor invasion and can identify early signs of
metastasis (27). This grading system is an independent prognostic factor
for patient survival in SCCs of the larynx, hypopharynx, esophagus, oral
cavity, and lung (12, 28).
Our analysis indicates that the presence of TB is significantly
correlated with nodal involvement, vascular invasion, and mortality
rate. Ekmekci et al. also found a statistical correlation between lymph
node metastasis, perineural invasion, and lymphovascular invasion with
TB, although their scoring system differed from ours (29). We found that
categorizing TB into low-budding and high-budding activity is more
practical and reproducible than the three-tier semiquantitative grading
used in Ekmekci’s study. However, some studies suggest that the 3-tier
system has better prognostic power (30). The correlation between TB and
lymph node metastases was confirmed in the study of Abd Raboh et al.,
who evaluated the predictive value of TB in LSCC using pan-cytokeratin
immunostaining (31). Similar results were observed in oral,
nasopharyngeal, hypopharyngeal, lung, and cervical SCCs (27, 32-34).
Synchronous increased TB activity and perineural invasion were also
reported in oral SCCs (35).
Additionally, TB was considered an independent predictor of regional
metastases in patients with clinically node-negative T1 and T2 oral SCCs
(36, 37). The study by Karpathiou et al. further confirmed the
association between TB and advanced T classification (14). The
predictive ability of TB for lymph node metastasis is valuable as
routinely reported lymph node status can be underestimated due to
inadequate dissection and sampling (38).
Furthermore, there is no agreement on the most effective predictive
methods for detecting regional metastases in patients with node-negative
head and neck SCCs in the early stages (36, 39). As a result, including
TB analysis in pathology reports can alert clinicians to patients with a
poor prognosis. Elseragay et al. have even proposed that TB analysis can
enhance the predictive accuracy of the WHO histopathologic grading
system in early oral SCCs.
Our study observed that high TB scores were significantly linked to a
greater likelihood of extra-laryngeal extension and a higher clinical
stage. Patients with high TB scores also had a considerably higher death
rate compared to those with low TB scores. Similarly, Pasaoglu et al.
reported a substantial decline in disease-free and overall survival in
patients with high TB scores (15). Additionally, Imai et al. conducted a
retrospective analysis of the risk factors for cervical lymph node
metastasis in endoscopically resected superficial hypopharyngeal
cancers. This study suggested that high tumor budding is a robust
predictor of cervical nodal involvement; however, the multivariate
analysis did not support a significant correlation between these two
factors, potentially due to limitations caused by focusing solely on a
specific site and procedure (40).
It is worth noting that the TB score is associated with lymph node
metastasis, local recurrence, lymphoid infiltration, and infiltrative
pattern of invasion, which has been validated in oral SCCs (41). Caruntu
et al. also discovered a link between high TB scores and larger tumor
dimensions as well as advanced clinical stages (35). As a result, it is
recommended to report the TB score for each case to emphasize the
significance of implementing a more rigorous follow-up plan.
Although research on CNS is significantly more limited than TB studies,
the literature reports a correlation between single-cell invasion and a
worse prognosis (13, 42, 43). ). Our study discovered a significant
connection between a smaller CNS, a higher clinical stage, and a more
significant extra-laryngeal extension. We also found that smaller CNS
were linked to a higher mortality rate, particularly in cases of
single-cell invasion. These results align with the existing, limited
data in the literature. Karpathiou et al. explored the prognostic
significance of TB and CNS in laryngeal and hypopharyngeal SCCs,
tumor-stroma ratio, and stroma type. Their data confirms the adverse
prognostic effect of smaller CNS accompanied by poorer lymphocytic
reaction, which indicates the relation of tumor microenvironment with
cancer progression (14, 44). Tan et al. found the association of
perineural invasion and stage with CNS, in addition to the significance
of TB in predicting overall survival. They suggested adding TB and CNS
to pathologic reports as histopathologic biomarkers that indicate a
higher probability of recurrence, metastases, and poor survival (45).
Our multivariate analysis indicates that TB, CNS, and clinical stage are
independent prognostic factors for mortality. This aligns with prior
research that indicates high TB and smaller CNS are linked to adverse
outcomes in oral SCC (46). Sarioglu et al. have also suggested that TB
is a valuable prognostic factor for distant-metastases-free survival
(47). Likewise, Jesinghaus et al. have confirmed the prognostic impact
of TB and CNS on overall, disease-free, and disease-specific survival
independent of clinical stage in esophageal SCCs. They have also
demonstrated the efficacy of TB and CNS in predicting the depth of
infiltration and nodal involvement in biopsy samples (48). Yadav et al.
have identified TB as an independent poor prognostic marker in oral SCCs
exhibiting de-differentiation, loss of adhesion, and
epithelial-to-mesenchymal transformation (49).
Our study has further revealed that TB is associated with a significant
decrease in disease-free survival. Additionally, single-cell invasion,
small CNS, and intermediate CNS have a statistically significant
negative effect on DFS. These results, together with the findings
reported in the literature, support the recognition of TB and CNS as
independent risk factors for poor DFS in LSCC(50). High TB has also been
correlated with shorter DFS and reduced overall survival in head and
neck and oral SCC (31). Clinical stage is another associated factor with
DFS.
However, our study found no correlation between DFS and the
histopathologic grade of differentiation. The impact of histologic grade
on the survival of LSCC patients remains a topic of debate, with some
studies confirming its association with tumor aggressiveness and
metastases, while others find the relationship to be unclear (51, 52).
To clarify this ambiguity, a larger population matched-pair analysis
could aid in more accurately comparing survival rates across different
histologic grades.
Despite its limitations, our study supports the potential role of TB and
CNS in determining the prognosis of LSCC. The two-parameter scoring
system used in our study is easily evaluated during basic
histopathologic examination and does not require additional ancillary or
biomolecular studies. While differences in parameters, follow-up
duration, and study designs may confound the results of our study and
previous ones, the overall conclusion underscores the importance of the
TBNS grading system in LSCC. Given its accessibility and low
interobserver variability, including TBNS scores in pathology reports
could facilitate individualized risk assessment and treatment planning.
Several studies have validated the association of TB with lymph node
metastasis and overall survival, highlighting the detrimental impact of
higher TB. Integrating TBNS scores into pathology reports can aid
personalized patient care regardless of the scoring method.