Pattern of invasion of oral squamous cell carcinoma and its relation to the presence of nodal metastases - a review.

Squamous cell carcinomas of the oral cavity represent the largest group of malignancies in this area. Currently, there are many prognostic histopathological factors, according to which the maxillofacial surgeon in collaboration with the oncologist is able to determine the prognosis and subsequently also set an appropriate therapy. Nowadays, the squamous cell carcinoma invasion pattern in the area of the "invasive tumor front" seems to be a very important prognostic factor. The invasion pattern is connected to metastatic potential (and to the presence of subclinical microscopic metastases) and may well be the answer to why even early-stage tumors do not respond to standard therapy. That is to say, based on varying invasion pattern, oral cavity squamous cell carcinomas with identical TNM manifest varying clinical behavior and growth tendencies and a varying metastatic potential.

SPARC promotes the proliferation and metastasis of oral squamous cell carcinoma by PI3K/AKT/PDGFB/PDGFRß axis.

Oral squamous cell carcinoma (OSCC) is a highly lethal cancer in the world, and the prognosis of OSCC is poor with a 60% 5-year survival rate in recent decades. Here, we introduced a novel secretory and acid glycoprotein with cysteine rich (secreted protein acidic and rich in cysteine, SPARC), which is correlated with the worst pattern of invasion (WPOI) and prognosis of OSCC. SPARC expression levels were measured in OSCC tissues and normal tissues using quantitative polymerase chain reaction and immunohistochemistry. The influence of SPARC on cell proliferation was examined by cell counting kit-8, colony formation, and Edu tests. Then, the effect of SPARC on the metastasis of OSCC cells was detected by wound healing and transwell migration assays. Next, the biologic characteristics of SPARC shared by STRING were analyzed. Furthermore, the underlying mechanisms were confirmed by western blot analysis. SPARC revealed higher expression in OSCC tissues than nontumor tissues. Higher SPARC expression was correlated with poorer tumor differentiation, poorer WPOI pattern, and significantly and shorter overall survival. Knockdown SPARC significantly restrained OSCC cell growth, migration, and invasion. In addition, bioinformatics analysis found SPARC had a coexpression network with the platelet-derived growth factor-B (PDGFB) and PI3K/AKT signaling pathways with minimal false discovery rate. Furthermore, SPARC promotes OSCC cells metastasis by regulating the expressions of PDGFB, PDGFRß, p-PDGFRß , and the PI3K/AKT pathway. Higher SPARC expression was positively correlated with poor WPOI and differentiation in OSCC. SPARC activates the PI3K/AKT/PDGFB/PDGFRß axis to promote proliferation and metastasis by OSCC cell lines. Therefore, SPARC may be a potential therapeutic target for patients with OSCC.

Adjuvant therapy for intermediate risk factors in oral cancer: Can we reach a consensus?

Oral carcinoma is a common disease that poses challenges in treatment management, especially for advanced cases. Adjuvant therapies, such as radiation and chemoradiation therapy, are typically used for advanced oral cancer patients. However, there is uncertainty regarding the use of adjuvant therapy for early-stage patients with certain soft histological parameters. The UICC manual of clinical oncology suggests that adjuvant therapy for such parameters is desirable but not essential. These parameters include perineural invasion, lymphovascular invasion, single nodal positivity, and patterns of invasion, which complicate the decision-making process for including adjuvant therapy. This review aims to provide evidence-based literature for effectively managing this patient group and developing treatment protocols based on current evidence.

Assessment of Bone Invasion and Its Correlation With Brandwein-Gensler Criteria in Oral Squamous Cell Carcinoma.

Background The most prevalent form of head-neck cancer is squamous cell carcinoma (SCC). Apart from all sites like the tongue, labial mucosa, and buccal mucosa, the prevalence of oral squamous cell carcinoma (OSCC) is more common in gingivobuccal sulcus due to the habit of keeping tobacco quid. With regards to anatomical relationships in the mouth and proximity to bone, OSCC invades the maxilla and mandible. However, bone invasion significantly influences the pathological staging of OSCC. Histological parameters such as Brandwein-Gensler worst pattern of invasion (WPOI), lymphocytic host response (LHR), and perineural invasion (PNI) hold significance for determining the need for adjuvant therapy. This study aims to correlate Brandwein-Gensler Criteria (BGC) with bone invasion and also to include the bone invasion criteria as a prognostic parameter in OSCC. This study aimed to assess bone invasion and correlate it with Brandwein-Gensler criteria in OSCC. Methods The research was conducted retrospectively, analyzing 65 cases of OSCC that underwent surgical intervention. Data was gathered from the Oral Pathology department's archives at Sharad Pawar Dental College (SPDC), Wardha. Pathologists assessed bone invasion without the knowledge of other factors to minimize bias. Subsequently, the cases were classified into well-differentiated (WDSCC), moderately differentiated (MDSCC), and poorly differentiated squamous cell carcinomas (PDSCC) based on histological grading, followed by the evaluation of WPOI, LHR, and PNI using the Brandwein-Gensler risk scoring system. Results This study found a notable association between bone invasion and BGC, with a calculated significance level of p = 0.047. LHR shows patterns as 1, 2, and 3. There were five (7.6%) cases with pattern III, 45 (69.23%) cases with pattern II, and 15 (23.08%) cases with pattern I. Similarly, PNI is scored as 0, 1, and 3. There were seven (10.77%) cases with score 3, 17 (26.15%) with score 1, and 41 (63.03%) with score 0. In the case of the WOPI, which is classified as patterns I to V, there were seven (10.77%) cases with pattern V, 27 (41.54%) cases with pattern IV, 23 (35.38%) cases with pattern III, and eight (12.231%) cases with pattern II, whereas no cases were noted with pattern I. Conclusion Although bone invasion and BGC are independent parameters, the BGC score should be considered in treatment planning. Patients with bone invasion and those with a higher BGC score should be strongly considered for adjuvant treatment.

WPOI-4/5 Correlates With Lymph Node Recurrence and Poor Prognosis in Early-stage Tongue Squamous Cell Carcinoma.

BACKGROUND/AIM: Neck management in patients with early-stage tongue cancer remains controversial. The worst pattern of invasion (WPOI) of the primary tumor has been associated with the incidence of regional metastasis. We investigated the prognostic role of WPOI, especially in relation to regional lymph node recurrence and disease-specific survival (DSS). PATIENTS AND METHODS: We retrospectively reviewed medical records and evaluated tumor specimens of 38 patients with early-stage tongue cancer who underwent primary tumor resection without elective neck dissection. RESULTS: Regional lymph node recurrence rates were significantly higher in patients with WPOI-4/5 compared with WPOI-1 to -3. The 5-year DSS rates were significantly higher for WPOI-1 to -3 than for WPOI-4/5. Notably, patients with WPOI-1 to -3 achieved a 100% 5-year DSS rate with salvage neck dissection and postoperative treatment, even those with cervical lymph node recurrence, whereas patients with WPOI-4/5 had a poorer prognosis. CONCLUSION: Patients with WPOI-1 to -3 tumors can be followed up without neck dissection until regional lymph node recurrence is detected, with a good course after salvage treatment. In contrast, patients with WPOI-4/5 tumors who are followed up until the appearance of regional lymph node recurrence have a poor prognosis, even with adequate treatment for recurrent disease.

Impact of Histologic Risk Factors on Recurrence Rates for Oral Cavity Squamous Cell Carcinoma.

OBJECTIVES: This study assesses the impact of adverse histologic risk factors including worst pattern of invasion (WPOI), predominant pattern of invasion (PPOI), tumor budding, and tumor infiltrating lymphocytes (TILS), on risk of recurrence in patients with early-stage Oral Cavity Squamous Cell Carcinoma (OCSCC). METHODS: Retrospective chart review was performed at a single institution to identify patients with OCSCC who underwent surgical excision. Inclusion criteria included T1-T2 stage disease based on AJCC seventh edition guidelines, no cervical lymph node involvement, no perineural invasion (PNI), no lymphovascular invasion (LVI), no post-operative adjuvant radiation therapy, and cancer involving only the oral tongue or floor of mouth. Patients were excluded if they had positive final margins. A subset of 35 patients were selected for additional histologic review to determine WPOI, PPOI, TB, and TILS. Bivariable and multivariable cox analysis were performed to determine variables associated with recurrence. RESULTS: One hundred and sixty-one patients met criteria and were included in the analysis. Variables that were significantly associated with recurrence on bivariable analysis included tumors with high risk PPOI (groups 4 and 5; P = .021), TB with 10 or more buds (P = .021), T-stage (P = .001), neck dissection (P = .03), and depth of invasion (DOI) >4 mm (P = .044). Multivariable cox proportional hazards found T-stage (HR: 6.40; 95% CI 1.67, 24.50; P = .007), neck dissection (HR: 0.23; 95% CI 0.07, 0.82; P = .023), and TBs (HR: 1.17; 95% CI 1.05, 1.30; P = .006) to be most predictive of recurrence. CONCLUSIONS: TB is a strong predictor of recurrence. WPOI, PPOI, and TILS were not statistically significant risk factors for recurrence.

Early-Stage Oral Tongue Squamous Cell Carcinoma and a Positive Sentinel Lymph Node Biopsy: Description of a Prognostic Correlation between Pre-Treatment Inflammatory Biomarkers, the Depth of Invasion and the Worst Pattern of Invasion.

The aim of this study was to investigate the correlation between pre-treatment inflammatory biomarkers and the post-operative depth of invasion (DOI) and worst pattern of invasion (WPOI) in early-stage oral tongue squamous cell carcinoma (OTSCC) by means of positive sentinel lymph node biopsy (SLNB). A retrospective analysis of patients affected by cN0 T1-T2 OTSCC who had undergone an SLNB at the National Cancer Institute of Naples was performed. The patients were studied using an evaluation of the pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), and a histopathological analysis of the DOI and WPOI. The statistical analysis showed that among the prognostic biomarkers, the NLR was a significant predictor of high WPOI values (p = 0.002). The cut-off NLR value was 2.52 with a probability of developing a positive sentinel lymph node biopsy (SLNB) of 30.3%. In contrast, the DOI value was 5.20 with a probability of developing a positive SLNB of 31.82%. Regarding the WPOI, increasing the WPOI class increased the likelihood of a positive SLNB occurrence, and a positive significant correlation was found between the WPOI and SLNB (Csp = 0.342; p < 0.001). Pre-treatment NLR, together with post-surgical DOI and WPOI, can be a reliable predictor of occult neck metastasis in patients affected by early-stage OTSCC with a clinically negative neck. Further prospective studies with a larger series will be needed to confirm the results obtained and to better define the NLR, WPOI and DOI cut-off values in order for elective neck dissection to be recommended in relation to a clinically negative neck.

Worst pattern of invasion in oral squamous cell carcinoma is an independent prognostic factor.

Introduction: Biologic aggressiveness of OSCC (Oral Cavity Squamous Cell Carcinoma), has intrigued research in various prognosticating histopathological markers over past few decades. DOI (Depth of Invasion) is one such histopathological factor which affects outcomes and was included in the AJCC 8th edition TNM staging. Pattern of Invasion (POI) has been widely reported as an adverse prognostic factor associated with higher locoregional failure and poor prognosis. However, these factors are not utilized for treatment decision making and for outcome assessment. Materials and methods: This is a retrospective analysis of 320 patients with OSCC who underwent treatment, from October 2018-February 2020. Clinic demographic details were extracted from electronic medical records. Univariate and multivariate analysis was done for the parameters. WPOI (Worst Pattern of Invasion) was correlated with all histopathological prognostic factors. Survival analysis was done using Kaplan Meier for WPOI type's I-V. DFS (Disease free Survival) was evaluated for different grades of WPOI. Results: We analyzed the results comparing, early and advanced T (Tumor) stages, cohesive WPOI I-III, non-cohesive WPOI IV-V. Univariate analysis showed a significant association of T-stage (p = 0.001), N (Nodal) -stage (p = 0.002), DOI (p = 0.008), PNI (Peri-neural invasion) (0.001) and Tumor differentiation Grade (p = 0.001). On multivariate analysis, non-cohesive WPOI (IV & V) showed significant association with grade, PNI, DOI (0.002, 0.033 & 0.033 respectively). Non-cohesive WPOI had significantly higher locoregional failures and short DFS. Conclusion: Presence of invasive WPOI is associated with advanced T stage, poor differentiation, PNI, greater depth of invasion, and higher chances of nodal metastasis. WPOI is associated with poor DFS, treatment intensification in early stage disease with WPOI type IV & V may improve survival.

Macrophage CCL22 expression promotes lymphangiogenesis in patients with tongue squamous cell carcinoma via IL-4/STAT6 in the tumor microenvironment.

The C-C motif chemokine ligand 22 (CCL22) chemokine is produced by M2-like tumor-associated macrophages (TAMs) in the tumor microenvironment. Chemokine C-C motif receptor 4 (CCR4), the CCL22 receptor, on T helper2 (Th2) cells leads to a Th2 cytokine-dominant environment. In our previous study, lymph node metastasis was the main predictor of tongue squamous cell carcinoma (SCC) via CCL22. Therefore, the present study aimed to investigate the effects of CCL22 and a Th2 cytokine-predominant tumor microenvironment on vascular endothelial growth factor (VEGF)-C expression and lymphangiogenesis. The post-operative courses of 110 patients with early-stage tongue SCC with a histopathological diagnosis based on the 8th TNM classification were followed up (mean/median follow-up time, 47.1/42.0 months) from surgery until death or the last follow-up visit, and subsequent lymph node relapse was assessed. Lymphangiogenesis and the immunohistochemical expression of several markers (CCL22, CCR4 and VEGF-C) were evaluated. The Kaplan-Meier method was used to plot lymph node relapse-free survival and overall survival curves, which were compared using the log-rank test. In vitro, the association between CCL22 and VEGF-C by interleukin (IL)-4/signal transducer and activator of transcription 6 (STAT6) stimulation was examined. Lymphangiogenesis was significantly associated with lymph node relapse (P<0.001) and a CCL22+ macrophage ratio (P<0.001). CCL22+ TAMs were positive for VEGF-C and surrounded by CCR4+ cells. Additionally, VEGF-C expression was increased in IL-4/STAT6-stimulated macrophages. In addition, the STAT6 signaling pathway was activated in the SCC cells in the deeply invaded part of the tumor along with the aggregated macrophages. In conclusion, TAM CCL22 expression led to lymph node relapse via VEGF-C expression within the tumor microenvironment and the IL-4/STAT6 signaling pathway in early stage tongue SCC. Additionally, the worst pattern of invasion and depth of invasion were revealed to be useful parameters for lymph node relapse in patients with tongue SCC. The present study suggested that CCL22 contributed to the role of M2-like differentiated TAMs in prognosis and lymph node relapse via IL-4/STAT6 and VEGF. The IL-4/STAT6 signaling pathway may be a new molecular target for tongue SCC.