Tumour budding in oral squamous cell carcinoma:a meta-analysis

Abstract Background: Tumour budding has been reported as a promising prognostic marker in many cancers. This meta-analysis assessed the prognostic value of tumour budding in oral squamous cell carcinoma (OSCC). Results: A total of 16 studies evaluated the prognostic value of tumour budding in OSCC. The meta-analysis showed that tumour budding was significantly associated with lymph node metastasis (odds ratio=7.08, 95% CI=1.75–28.73), disease-free survival (hazard ratio=1.83, 95% CI=1.34–2.50) and overall survival (hazard ratio=1.88, 95% CI=1.25–2.82). Conclusions: Tumour budding is a simple and reliable prognostic marker for OSCC. Evaluation of tumour budding could facilitate personalised management of OSCC

Biopsy quality is essential for preoperative prognostication in oral tongue cancer

Abstract A role for incisional biopsy in preoperative prognostication is increasingly being advocated in oral tongue squamous cell carcinomas (OTSCC). Biopsies at two locations were compared, and prognostic factors in biopsies and their corresponding resections were evaluated. A total of 138 OTSCC biopsy slides from Finland and Saudi Arabia were compared for size (horizontal and vertical) and invasive front. The Finnish cases were assessed for tumor stroma ratio (TSR) and tumor‐infiltrating lymphocytes (TILs) using light microscopy and digital image analysis assessment and compared. Furthermore, TSR, TILs, and previously analyzed budding and depth of invasion (BD) score in biopsies were compared with their evaluation in the corresponding resections. Fifty‐nine percent of Finnish and 42% of Saudi Arabian biopsies were ≥ 5 mm deep, while 98% of Saudi Arabian and 76% of Finnish biopsies were ≥ 5 mm wide. Assessment of invasion front was possible in 72% of Finnish in comparison with 40% of Saudi Arabian biopsies. There was 86.8% agreement between TSR and 75% agreement between TIL evaluation using light microscopy and digital assessment. Significant agreement was obtained on comparing the TSR (p = 0.04) and BD (p < 0.001) values in biopsies and resections. Biopsies of ≥ 5 mm depth from representative OTSCC areas are essential for prognostic information. Clinical pathologists are advised to assess BD score and TSR for prognostic features in such biopsies

Emerging histopathologic markers in early-stage oral tongue cancer:a systematic review and meta-analysis

Abstract Although there are many histopathologic prognosticators, grading of early oral tongue squamous cell carcinoma (OTSCC) is still based on morphological cell differentiation which has low prognostic value. Here we summarize the emerging histopathological markers showing powerful prognostic value, but are not included in pathology reports. Using PubMed, Scopus, Ovid Medline, and Web of Science databases, a systematic literature search was preformed to identify early OTSCC studies that investigated the prognostic significance of hematoxylin–eosin-based histopathologic markers. Our meta-analysis showed that tumor budding was associated with overall survival (hazard ratio [HR] 2.32; 95% CI 1.40–3.84; p < 0.01) and disease-specific survival (DSS) (1.89; 95% CI 1.13–3.15; p = 0.02). Worst pattern of invasion was associated with disease-free survival (DFS) (1.95; 95% CI 1.04–3.64; p = 0.04). Tumor–stroma ratio was also associated with DFS (1.75, 95% CI 1.24–2.48; p < 0.01) and DSS (1.69; 95% CI 1.19–2.42; p < 0.01). Tumor budding, worst pattern of invasion, and tumor–stroma ratio have a promising prognostic value in early OTSCC. The evaluation and reporting of these markers is cost-effective and can be incorporated in daily practice

Tumor-infiltrating lymphocytes associate with outcome in nonendemic nasopharyngeal carcinoma:a multicenter study

Abstract The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been studied recently in many cancers. For the first time in a nonendemic region, we have evaluated the prognostic value of TILs in a whole population–based nationwide cohort of nasopharyngeal carcinoma (NPC) in Finland. A total of 115 cases from Finnish hospitals were included. TILs were analyzed using hematoxylin and eosin–stained slides according to the criteria of the International Immuno-Oncology Biomarker Working Group. TILs were evaluated separately in stromal and tumor compartments. The log-rank test and univariable and multivariable analyses were used to compare survival in patients with tumors with low and high TILs. A significant positive correlation was observed between the occurrence of intratumoral and stromal TILs (P < .001). In multivariable analysis, NPC cases with low intratumoral TILs had poor overall survival with a hazard ratio (HR) of 2.55 and 95% confidence interval (95% CI) of 1.60 to 4.05 (P < .001). Cases with low intratumoral TILs also had poor disease-specific survival (HR, 2.02; 95% CI, 1.16–3.52; P = .015). Keratinized tumors with low intratumoral TILs were associated with an even poorer overall survival (HR, 3.94; 95% CI, 2.17–7.15; P < .001) and a poor disease-specific survival (HR, 2.97; 95% CI, 1.46–6.05; P = .009). Our study demonstrates that the evaluation of TILs is simple and can be assessed routinely in NPC

Clinical significance of tumor-stroma ratio in head and neck cancer:a systematic review and meta-analysis

Abstract Background: The clinical significance of tumor-stroma ratio (TSR) has been examined in many tumors. Here we systematically reviewed all studies that evaluated TSR in head and neck cancer. Methods: Four databases (Scopus, Medline, PubMed and Web of Science) were searched using the term tumo(u)r-stroma ratio. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were followed. Results: TSR was studied in nine studies of different subsites (including cohorts of nasopharyngeal, oral, laryngeal and pharyngeal carcinomas). In all studies, TSR was evaluated using hematoxylin and eosin staining. Classifying tumors based on TSR seems to allow for identification of high-risk cases. In oral cancer, specifically, our meta-analysis showed that TSR is significantly associated with both cancer-related mortality (HR 2.10, 95%CI 1.56–2.84) and disease-free survival (HR 1.84, 95%CI 1.38–2.46). Conclusions: The assessment of TSR has a promising prognostic value and can be implemented with minimum efforts in routine head and neck pathology

Histological characteristics of early‐stage oral tongue cancer in young versus older patients:a multicenter matched‐pair analysis

Abstract Little is known about the histopathological characteristics that may differentiate early oral tongue cancer (OTSCC) between young and older patients. From a total of 311 cases diagnosed with clinically early‐stage OTSCC at 6 institutions, only 42 patients were young patients were aged ≤45 years. For comparison, 42 patients >60 years old were matched for center of management, clinical stage and gender. We compared epithelial and stromal histopathologic parameters between the two groups. Most of the parameters were similar between the two groups, although the young patients appeared to have marginally higher intensity of tumor budding, histologic risk score, infiltrative pattern of invasion and tumor‐stroma ratio. However, none of the factors showed significant difference when comparing the two groups. The histological parameters reflect mechanisms of invasive growth and tissue response to invasive growth, but not the etiological difference in OTSCC between young and older patients. Further investigations are necessary to compare the genetic background of early OTSCC in the two groups

Assessment of tumor-infiltrating lymphocytes predicts the behavior of early-stage oral tongue cancer

Abstract Tumor-infiltrating lymphocytes (TILs) have shown a promising prognostic value in many epithelial cancers. We sought to assess the prognostic value of TILs in a multicenter cohort of early oral tongue squamous cell carcinoma (OTSCC). The percentage of TILs was assessed on the surgical resection slides stained with hematoxylin and eosin. The assessment of TILs was performed in the stromal compartment and in the intraepithelial compartment (at the invasive front and at the center of the tumor). We followed the method that was described recently by the International Immuno-Oncology Biomarker Working Group for the assessment of TILs. A total of 308 cases from the 5 Finnish university hospitals and from A.C. Camargo Cancer Center, São Paulo, Brazil, were included. We found a promising prognostic value for stromal TILs at the invasive front in the multivariable analysis with a hazard ratio of 2.61 (95% confidence interval [CI], 1.77‐3.83; P<0.001) for overall survival, 1.99 (95% CI, 1.07‐3.69; P=0.040) for disease-specific survival, and 1.94 (95% CI, 1.14‐3.29; P=0.020) for disease-free survival. In conclusion, evaluation of TILs is simple and can aid in identifying the high-risk cases of early OTSCC. The method introduced by the International Immuno-Oncology Biomarker Working Group can be used for standardized determination of TILs in early OTSCC

Improving risk stratification of early oral tongue cancer with TNM-Immune (TNM-I) staging system

Abstract Although patients with early-stage oral tongue squamous cell carcinoma (OTSCC) show better survival than those with advanced disease, there is still a number of early-stage cases who will suffer from recurrence, cancer-related mortality and worse overall survival. Incorporation of an immune descriptive factor in the staging system can aid in improving risk assessment of early OTSCC. A total of 290 cases of early-stage OTSCC re-classified according to the American Joint Committee on Cancer (AJCC 8) staging were included in this study. Scores of tumor-infiltrating lymphocytes (TILs) were divided as low or high and incorporated in TNM AJCC 8 to form our proposed TNM-Immune system. Using AJCC 8, there were no significant differences in survival between T1 and T2 tumors (p > 0.05). Our proposed TNM-Immune staging system allowed for significant discrimination in risk between tumors of T1N0M0-Immune vs. T2N0M0-Immune. The latter associated with a worse overall survival with hazard ratio (HR) of 2.87 (95% CI 1.92–4.28; p < 0.001); HR of 2.41 (95% CI 1.26–4.60; p = 0.008) for disease-specific survival; and HR of 1.97 (95% CI 1.13–3.43; p = 0.017) for disease-free survival. The TNM-Immune staging system showed a powerful ability to identify cases with worse survival. The immune response is an important player which can be assessed by evaluating TILs, and it can be implemented in the staging criteria of early OTSCC. TNM-Immune staging forms a step towards a more personalized classification of early OTSCC

Stromal categorization in early oral tongue cancer

Abstract Stromal categorization has been used to classify many epithelial cancer types. We assessed the desmoplastic reaction and compared its significance with other stromal characteristics in early (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC). In this multi-institutional study, we included 308 cases treated for early OTSCC at five Finnish university hospitals or at the A.C. Camargo Cancer Center in São Paulo, Brazil. The desmoplastic reaction was classified as immature, intermediate, or mature based on the amount of hyalinized keloid-like collagen and myxoid stroma. We compared the prognostic value of the desmoplastic reaction with a stromal grading system based on tumor-stroma ratio and stromal tumor-infiltrating lymphocytes. We found that a high amount of stroma with a weak infiltration of lymphocytes was associated statistically significantly with a worse disease-free survival with a hazard ratio (HR) of 2.68 (95% CI 1.26–5.69), worse overall survival (HR 2.95, 95% CI 1.69–5.15), and poor disease-specific survival (HR 2.66, 95% CI 1.11–6.33). Tumors having a high amount of stroma with a weak infiltration of lymphocytes were also significantly associated with a high rate of local recurrence (HR 4.13, 95% CI 1.67–10.24), but no significant association was found with lymph node metastasis (HR 1.27, 95% CI 0.37–4.35). Categorization of the stroma based on desmoplastic reaction (immature, intermediate, mature) showed a low prognostic value for early OTSCC in all survival analyses (P > 0.05). In conclusion, categorization of the stroma based on the amount of stroma and its infiltrating lymphocytes shows clinical relevance in early OTSCC superior to categorization based on the maturity of stroma