Prognostic Effect of a Tumor Invasion Pattern Mimicking Crawling Between Muscle Fibers in Oral Tongue Carcinoma
DaisukeBaba
M.D.
1,2,3NaoyaSakamoto
M.D., Ph.D.
4MotohiroKojima
M.D., Ph.D.
5MasashiWakabayashi
M.Sc.
6TetsuyaNakatsura
M.D., Ph.D.
1RyuichiHayashi
M.D., Ph.D.
7GenichiroIshii
M.D., Ph.D.
3,8ShingoSakashita
M.D., Ph.D.
4,9✉Phone+81-4-7133-1111Emailssakashi@east.ncc.go.jp1Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
2Department of Head and Neck Oncology and OtolaryngologyTochigi Cancer CenterUtsunomiyaJapan
3Course of Advanced Clinical Research of CancerJuntendo University Graduate School of MedicineTokyoJapan
4Division of Pathology, Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
5Department of Surgical Pathology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
6Biostatistics Division, Center for Research Administration and SupportNational Cancer Center Hospital EastKashiwaJapan
7Department of Head and Neck SurgeryNational Cancer Center Hospital EastKashiwaJapan
8Department of Pathology and Clinical LaboratoriesNational Cancer Center Hospital EastKashiwaJapan
96-5-1 Kashiwanoha277-8577Kashiwa-shiChibaJapan
Daisuke Baba, M.D.1,2,3, Naoya Sakamoto, M.D., Ph.D.4, Motohiro Kojima, M.D., Ph.D.5, Masashi Wakabayashi, M.Sc.6, Tetsuya Nakatsura, M.D., Ph.D.1, Ryuichi Hayashi, M.D., Ph.D.7, Genichiro Ishii, M.D., Ph.D.3,8, Shingo Sakashita, M.D., Ph.D.4*
1. Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
2. Department of Head and Neck Oncology and Otolaryngology, Tochigi Cancer Center, Utsunomiya, Japan.
3. Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan.
4. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
5. Department of Surgical Pathology & Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
6. Biostatistics Division, Center for Research Administration and Support, National Cancer Center Hospital East, Kashiwa, Japan
7. Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
8. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan.
*Corresponding Author:
Shingo Sakashita
Address: 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba, 277–8577 Japan
Telephone: +81-4-7133-1111
Email: ssakashi@east.ncc.go.jp
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Acknowledgement
We thank Editage (www.editage.com) for revising the language of the manuscript. We also thank Kazuto Matsuura for being partly involved in the conceptualization of this study.
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Abstract
Purpose
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The Union for International Cancer Control classification can predict the outcome of patients with oral tongue squamous cell carcinoma, which has a poor prognosis. However, in some cases, cancer relapse occurs earlier than in others, despite an identical stage. Pathological findings are the first step in detecting features associated with a high risk of recurrence. Herein, we identified a novel pathological feature, termed Broadening Amoeboid Behavior of Advancing tumor cells (BABA), characterized by an invasive tumor front where cancer cells progress between muscle fibers in an amoeboid manner. A
Furthermore, we investigated its prognostic significance in oral tongue carcinoma.Methods
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This retrospective cohort study enrolled patients with oral tongue carcinoma who were referred to the National Cancer Center Hospital East Japan between January 2011 and December 2017. Herein, the main pathological features were reevaluated by two investigators who were blinded to the clinical data. Additionally, recurrence-free survival rates according to pathological features, including BABA, were calculated and compared.Results
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Herein, 211 patients were included, with a median follow-up duration of 4.8 years. Patients with BABA exhibited 2-year overall and recurrence-free survival rates of 78% (p = 0.02) and 39% (p < 0.001), respectively. In multivariable analysis, lymphatic invasion, venous invasion, BABA, and nodal metastasis were strong prognostic factors for recurrence, with hazard ratios (95% confidence intervals) of 2.1 (1.2–3.6), 2.0 (1.1–3.4), 2.2 (1.3–3.7), and 2.0 (1.2–3.6), respectively.Conclusion
The new pathological feature, BABA, is a potent prognostic factor for oral tongue squamous cell carcinoma recurrence.
Keywords:
amoeboid behavior
invasive front
progress
prognosis
muscular fiber
pathological feature
oral tongue squamous cell carcinoma
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Introduction
Oral cavity carcinoma is the 13th most common cancer globally, with 373,000 new cases diagnosed annually. The primary subtype is oral tongue carcinoma (OTC), which has shown a rising incidence, unlike other head and neck cancers (Deneuve et al. 2022; Global Burden of Disease 2019 Cancer Collaboration et al. 2022; Stepan et al. 2023). OTC is generally treated using surgery, followed by postoperative therapies if required, based on pathological findings indicative of high recurrence risk. Currently, high risk is considered as extranodal extension (ENE) into the neck lymph nodes. Conversely, local features, such as vascular invasion and perineural spread, which are not tumor features per se, are optional factors for adjuvant therapy (National Comprehensive Cancer Network 2025).
Some pathological features of primary tumor cells in the context of OTC recurrence have been investigated; the worst pattern of invasion (WPOI) has been reported as a prognostic factor in OTC (Bryne et al. 1989, 1992; Brandwein-Gensler et al. 2005; Calabrese et al. 2020; Köhler et al. 2022; Yasuda et al. 2023). In the WPOI classification, first reported by Bryne et al. (1989), the tumor margin appearance is categorized as types 1 to 4. Briefly, type 1 shows a broad pushing tumor invasion pattern, type 2 exhibits a finger-like broad pushing pattern, type 3 exhibits invasive tumor islands with more than 15 cells per island, and type 4 exhibits islands with 15 or fewer cells; type 4 is considered to have a high risk of recurrence (Supplemental Fig. 1). Brandwein-Gensler et al. (2005) completed the current version of WPOI by adding type 5 WPOI, which presents with satellite tumor islands > 1 mm away from the main island. Several studies have reported WPOI types 4 and 5 as unfavorable prognostic factors (Bryne et al. 1992; Calabrese et al. 2020; Köhler et al. 2022; Yasuda et al. 2023).
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In the 8th edition of the American Joint Committee on Cancer (AJCC) guidelines, WPOI type 5 is an independent factor associated with a high risk of recurrence (American Joint Committee on Cancer et al. 2017). However, a potential issue exists in etiological differences between WPOI types 1–4 and type 5: WPOI types 1–4 describe the tumor margin status, whereas type 5 WPOI reflects satellite lesions, including perineural spread. This leads to the evaluation of different pathological processes within the same classification.Regarding disease progression, OTC tends to spread along muscle fibers (Calabrese et al. 2020). The three-dimensional anatomy of the tongue, comprising muscle fiber bundles arranged in various directions, allows tumors to infiltrate radially. While most cases show expanded growth patterns with inflammation, we observed that in some cases, tumor cells advanced between muscular fibers three-dimensionally without expanded growth patterns, which frequently contained tumor islands characteristic of WPOI types 4 and 5 (Fig. 1). The appearance of tumor cells advancing between muscular fibers resembled the crawling movement of amoebas; thus, we termed the phenomenon “Broadening Amoeboid Behavior of Advancing tumor cells (BABA).” Although most cases with BABA were classified as WPOI type 4 or 5, their features differed from those of typical WPOI type 4. Therefore, we hypothesized that BABA has a unitary etiology in WPOI types 4 and 5 and is an independent prognostic factor.
Fig. 1
A positive case for BABA.
Patients and Methods
Patients
Patients with OTC who were referred to the National Cancer Center Hospital East Japan between January 2011 and December 2017 were included herein. Those with squamous cell carcinoma were eligible if they were aged ≥ 18 years and had not received prior treatment. Patients were excluded if they had previously received radiotherapy to the head and neck region, had concurrent carcinoma of a different type, did not undergo curative surgery, or had undergone post-surgical treatment. Additionally, patients with insufficient hematoxylin and eosin-stained specimens for reevaluating pathological findings were excluded from this study. Patient characteristics and pathological findings were collected from electronic clinical records. Hematoxylin and eosin-stained specimens were reviewed by two authors who were blinded to the clinical data. Age, sex, pT and pN classification, ENE status, lymphatic invasion, venous invasion, perineural extension, margin status, WPOI, and BABA levels were evaluated. Informed consent was obtained from all patients, and the study was approved by the Ethical Committee of the International Cancer Center (No. 2020072).
Treatment strategy
The cancer board, which included head and neck surgeons, head and neck general practitioners, plastic surgeons, and radiologists, determined the treatment plan. In general, local resection was performed for cT1 and cT2 tumors without clinical nodal metastasis, whereas cN-positive patients underwent additional neck dissection. For cT3 and cT4 cases, local resection, neck dissection, and reconstruction surgery were performed regardless of nodal metastasis. Postoperative radiotherapy, with or without chemotherapy, was administered to patients with four or more lymph node metastases, contralateral lymph node metastases, or positive surgical margins based on pathological findings. However, the attending physician had the flexibility to adjust the treatment method, provided that the individual patient’s condition precluded them from receiving additional therapy.
Procedure
All variables, except the histological grade, were divided into two groups for analysis. pT3 and pN1 were used to divide the cases into two groups to distinguish early-stage cases from advanced cases within the staging system. Regarding WPOI, types 1–3 were categorized into one group, while type 4 was classified as a separate group, based on previous research. Meanwhile, type 5 was evaluated independently of types 1–4, as it may have a different etiological basis.
Concept of BABA
Conceptually, the features of BABA resemble those of cactus spines. Assuming that the tumor mass was a cactus body, a collection of cancer cells, referred to as those exhibiting BABA, represented the spines extending from the cactus body. Some OTC cases demonstrate this characteristic, where cancer cells advance between muscular fibers without causing necrosis, fibrosis, or inflammatory changes, as if amoebas are silently crawling between these fibers (Supplemental Fig. 1). We considered cancer cells advancing in this manner to be BABA-positive when their distance from the edge of the tumor mass was ≥ 1 mm. This threshold was determined based on the criterion that a distance ≥ 1 mm between the main tumor island and satellite regions was adopted for diagnosing type 5 WPOI. Defining the length and angle of BABA as x cm and θ, respectively, if a specimen is dissected as shown in Supplemental Fig. 2A, the distance calculated for type 5 WPOI is x sinθ cm. Then, to calculate the minimum length of BABA (x cm) required to satisfy 1 cm of x sinθ cm for type 5 WPOI, the angle θ must approach 90°. Hence, the minimum length is calculated as: 1 cm ≤ x lim (θ → 90°) x sinθ = x
The reason BABA is compared with type 5 WPOI is as follows. During sample preparation, if a BABA-positive specimen is cut as shown in Supplemental Fig. 2B and the distance between the tumor margin and the satellite region is ≥ 1 mm, the tumor is classified as type 5 of WPOI. Conversely, if the specimen is cut as shown in Supplemental Fig. 2C and the calculated distance is < 1 mm, the tumor is classified as type 3 or 4 WPOI. However, the cases presented in Supplemental Figs. 2B and 2C were considered to have the same oncological behavior. Other cases, such as tumors presented in Supplemental Figs. 2D and 2E, were classified as type 5 WPOI; however, the oncological behavior of tumor cells at the invasive front may differ.
Definition of BABA
BABA is diagnosed in the following steps (Figs. 1 and 2). First, observe the specimen at low magnification, such as 20x or 40x. In this image, a tumor mass line resembling a cactus body is imagined. In most cases, this imaginary tumor mass line can be easily identified by the presence of dense immune cells or fibrosis at the invasive front of the tumor. Second, depict a tumor margin line resembling a cactus body and spines. Third, measure the distance from the imaginary mass line to the margin line where tumor cells have advanced between muscular fibers and compressive expansion is absent. Finally, define the sample as BABA positive if the distance is ≥ 1.0 mm.
Fig. 2
A negative case for BABA.
The following cautionary points should be considered when diagnosing BABA. First, tumor cells sometimes begin to advance between muscular fibers after the expanded growth pattern ends beyond the imaginary tumor mass line. In these cases, we only calculated the distance from the end of the expanded growth pattern to the tumor margin line. Second, because samples contain not only the BABA pattern but also a slightly expanded pattern, it is difficult to determine whether a sample is BABA-positive or -negative. These were defined as BABA-negative because if the specimen was truly BABA-positive, other BABA-positive areas should be observed in the same specimen.
Outcome
Overall survival (OS) was defined as the duration from the date of initial treatment to the date of the last follow-up or death. Recurrence-free survival (RFS) was defined as the duration from the date of initial treatment to the date of recurrence or the last follow-up if the patient did not experience recurrence.
RFS and OS were estimated using the Kaplan–Meier method. A univariable Cox proportional hazard model was constructed for each variable to assess its impact on RFS and OS. Multivariable Cox proportional hazard models were used to identify significant prognostic factors using stepwise selection methods with Akaike’s information criterion. An additional evaluation combining BABA with another factor was conducted using the Kaplan–Meier method for OS and RFS, and the Fine–Gray model was adopted to estimate the recurrence pattern tendency with death and other recurrence patterns as competing risks. Two-tailed statistical tests were conducted, with a significance level of p < 0.05 in univariable analyses. Patients with missing data were excluded from the study. All statistical analyses were performed using the EZR software (version 2.8-0; Saitama Medical Center, Jichi Medical University, Saitama, Japan).
Results
Herein, 316 patients were initially recruited. After excluding cases of recurrence, previous radiotherapy to the head and neck region, concurrent carcinoma of a different type, non-radial therapy, insufficient pathological data, and post-surgical treatment, 211 patients were included in the analyses (Supplemental Fig. 3). Patient characteristics according to the presence of BABA are presented in Table 1. In brief, lymphovascular and perineural invasion, WPOI type 4 or 5, advanced stage, and ENE were significantly more common among BABA-positive cases. OS and RFS according to the presence of BABA (Fig. 3) differed significantly between BABA-positive and -negative cases (p = 0.002 and < 0.001, respectively). Multivariable analysis for OS showed that BABA and WPOI types 4 or 5 were excluded during the statistical variable selection process. Moreover, pN ≥ 1 and venous invasion remained unfavorable factors, with hazard ratios (HRs) of 2.4 (95% confidence interval [CI] 1.2–4.5, p = 0.01) and 3.0 (95% CI 1.5–6.3, p = 0.003), respectively (Table 2). Conversely, in the multivariable analysis for RFS, pN ≥ 1, lymphatic invasion, venous invasion, and BABA exhibited higher HRs at 2.0 (95% CI 1.2–3.6, p = 0.01), 2.1 (95% CI 1.2–3.6, p = 0.01), 2.0 (95% CI 1.1–3.4, p = 0.01) and 2.2 (95% CI 1.3–3.7, p = 0.01), respectively. Meanwhile, WPOI types 4 or 5 had a lower HR of 1.7 (95% CI 0.9–3.4). Furthermore, the Fine–Gray model for evaluating the recurrence pattern revealed that BABA was only related to local recurrence, with an HR of 2.0 (95% CI 1.0–4.0, p = 0.04).
Fig. 3
Kaplan–Meier curves for OS and DFS according to BABA classification.
BABA | p-value | |||||
|---|---|---|---|---|---|---|
(-) | (+) | Fisher | χ2 | M-W | ||
Age | median(range) | 64(53–74) | 60(45–71) | 0.04 | ||
Sex | Males | 106 | 24 | 0.7 | ||
Females | 67 | 14 | ||||
Margin status | negative | 153 | 32 | 0.3 | ||
close/positive | 24 | 9 | ||||
lymphatic invasion | (-) | 152 | 28 | 0.04 | ||
(+) | 21 | 10 | ||||
venous invasion | (-) | 106 | 5 | < 0.0001 | ||
(+) | 67 | 33 | ||||
perineural invasion | (-) | 144 | 15 | < 0.0001 | ||
(+) | 29 | 23 | ||||
WPOI (type 1–4) | type1(-)3 | 75 | 1 | < 0.001 | ||
type4 | 98 | 37 | ||||
WPOI (type5) | (-) | 143 | 21 | < 0.0005 | ||
(+) | 30 | 17 | ||||
pT | ≤ 3 | 122 | 12 | < 0.0001 | ||
4≤ | 51 | 26 | ||||
pN | 0 | 146 | 22 | < 0.0005 | ||
1≤ | 27 | 16 | ||||
extranodal extension | (-) | 162 | 28 | < 0.0005 | ||
(+) | 11 | 10 | ||||
| BABA, Broadening Amoeboid Behavior of Advancing tumor cells; WPOI, worst pattern of invasion; M-W, Mann–Whitney U test. | ||||||
OS | Univariable | Multivariable | ||||
|---|---|---|---|---|---|---|
variables | HR | 95%CI | p-value | HR | 95%CI | p-value |
Females | 0.7 | 0.4–1.4 | 0.3 | |||
pT ≥ 3 | 2.4 | 1.3–4.4 | 0.004 | |||
pN ≥ 1 | 3.6 | 2.0–6.7 | < 0.001 | 2.4 | 1.2–4.5 | 0.01 |
ENE (+) | 3.0 | 1.4–6.5 | 0.005 | |||
lymphatic invasion (+) | 2.8 | 1.4–5.6 | 0.004 | |||
venous invasion (+) | 4.0 | 2.0–7.9 | < 0.001 | 3 | 1.5–6.3 | 0.003 |
perineural invasion (+) | 2.3 | 1.2–4.2 | 0.01 | |||
margin status incomplete/close | 1.2 | 0.5–3.0 | 0.6 | |||
BABA (+) | 2.6 | 1.4–5.0 | 0.004 | |||
WPOI 4,5 | 3.6 | 1.5–8.6 | 0.004 | |||
RFS | Univariable | Multivariable | ||||
variables | HR | 95%CI | p value | HR | 95%CI | p value |
Females | 1.2 | 0.7–1.8 | 0.50 | |||
pT ≥ 3 | 1.4 | 0.9–2.2 | 0.10 | 0.7 | 0.4–1.1 | 0.10 |
pN ≥ 1 | 2.9 | 1.8–4.7 | < 0.001 | 2.0 | 1.2–3.6 | 0.01 |
ENE (+) | 4.1 | 2.4–7.1 | < 0.001 | |||
lymphatic invasion (+) | 3.3 | 2.0–5.5 | < 0.001 | 2.1 | 1.2–3.6 | 0.01 |
venous invasion (+) | 3.4 | 2.1–5.5 | < 0.001 | 2.0 | 1.1–3.4 | 0.01 |
perineural invasion (+) | 1.9 | 1.2–3.1 | < 0.01 | |||
margin status incomplete/close | 1.3 | 0.7–2.4 | 0.50 | |||
BABA (+) | 3.0 | 1.9–4.8 | < 0.001 | 2.2 | 1.3–3.7 | 0.01 |
WPOI 4,5 | 3.3 | 1.8–6.2 | < 0.001 | 1.7 | 0.9–3.4 | 0.10 |
| BABA, Broadening Amoeboid Behavior of Advancing tumor cells; WPOI, worst pattern of invasion; HR, hazard ratio; CI, confidence interval; OS, overall survival; RFS, recurrence-free survival; ENE, extranodal extension. | ||||||
| Figure | ||||||
| ① tumor mass line; ② protrusion line; ③ distance ≥ 1.0mm | ||||||
| BABA, Broadening Amoeboid Behavior of Advancing tumor cells. | ||||||
| ① tumor mass line; ② protrusion line; ③ compressive expansion→distance = 0 mm | ||||||
| BABA, Broadening Amoeboid Behavior of Advancing tumor cells. | ||||||
Next, OS and RFS stratified by the presence of pN and BABA indicated that the prognoses were worse in BABA-positive and pN-positive cases (p = 0.049 and p < 0.001, respectively; Fig. 4). The median OS and RFS were 27.5 and 3.5 months, respectively. In the univariable analysis, the Fine–Gray model for assessing the recurrence pattern showed that BABA-positive and pN-positive cases underwent significant local and regional recurrences, with HRs of 9.2 (95% CI 2.5–33, p < 0.001) and 4.5 (95% CI 1.9–11, p < 0.001), respectively.
Fig. 4
Kaplan–Meier curves for OS and DFS according to BABA classification and local lymph node metastasis.
Discussion
In this study, we evaluated BABA at the invasive tumor front as a risk factor for recurrence and compared it with preexisting pathological risk factors, notably WPOI, which revealed BABA to be an independent prognostic factor for RFS. Interestingly, almost all patients exhibiting both BABA and nodal metastases experienced recurrence within a short period after treatment.
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Pathological features at primary tumor sites have been examined; however, only WPOI—other than tumor size and lymph node involvement—is mentioned in the AJCC guidelines, without a strong consensus for its integration as a staging factor (Chang et al. 2024; Elseragy et al. 2022; Michcik et al. 2023). While a concise appearance affecting prognosis is required, we discovered BABA with cancer cells advancing in a stranded manner between muscular fibers without expanding growth in positive cases (Fig. 1). To our knowledge, similar findings have not been reported in a clinical setting, except in the context of epithelial-to-mesenchymal transition or collective-to-amoeboid transition in biological research (van Zijl et al. 2011). Herein, BABA was the sole factor related to local recurrence, probably because this subtle invasion pattern makes it difficult for surgeons to decide on appropriate margins, resulting in insufficient resection. Additionally, BABA may exhibit a strong ability in cancer cells to advance locally, as observed in epithelial-to-mesenchymal transition and collective-to-amoeboid transition.Nodal metastasis can be regarded as the consequence of tumor cells being transferred to lymph nodes through lymphovascular ducts; in cases with lymph node metastasis, tumor cells can disperse to distant areas (Ji et al. 2023). Hence, lymph node metastasis is considered one of the strongest prognostic factors in almost all cancers, including OTC. As BABA can represent local aggressiveness, we hypothesized that when present concurrently with lymph node metastasis—indicating the tumor’s ability to spread to distant areas—the tumor would exhibit the most aggressive behavior. As expected, patients with both BABA and lymph node metastases experienced more local and regional recurrences, with an extremely short RFS duration in the univariable analysis. These mixed findings can serve as a strong indicator for identifying aggressive cases that may experience recurrence soon after treatment. Moreover, because the margin is not radically resected when resecting lymph node metastases, as it is when resecting the primary area, BABA-positive and pN-negative cases did not show a noticeable difference from BABA-negative and pN-positive cases.
However, this study has limitations due to its single-center, retrospective design and racially homogeneous population, which may result in limited generalizability. Additionally, we primarily adopted slightly older cases where ENE status was not utilized to select patients for post-radiation treatment, thereby eliminating its effect. Therefore, the genuine clinical relevance of BABA should be verified in more recent cases. Furthermore, conclusions regarding concurrent BABA and lymph node metastasis require careful consideration, as we were unable to perform multivariable analyses for this combined factor due to the limited number of patients. In the future, multicenter prospective studies are required to enhance the evidence level of this discovery.
Nevertheless, this study can still have a significant impact on clinical practice. Provided that BABA is diagnosed before treatment and urgent systemic treatment is tailored accordingly, patients with BABA can experience more favorable outcomes. Unfortunately, as BABA cannot be diagnosed using currently available modalities, future advancements in imaging examinations for its detection are warranted.
Conclusions
The current study revealed that BABA, a progression pattern in the marginal tumor area, was associated with the recurrence of OTC. BABA with concurrent lymph node metastasis may indicate a more dismal prognosis in OTC.
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Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Competing Interests
The authors have no relevant financial or non-financial interests to disclose.
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Author Contribution
DB, NS, MK, TN, RH, GI, and SS conceived and designed the study. DB and MW developed the statistical analysis plan and conducted statistical analyses. All authors contributed to the interpretation of the results. DB drafted the original manuscript. GI and SS supervised the study. All authors reviewed the manuscript draft and revised it critically on intellectual content. All authors approved the final version of the manuscript to be published.
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Data Availability
Raw data were generated at National Cancer Center Hospital East. Derived data supporting the findings of this study are available from the corresponding author S.S. on request.
Ethics Approval
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This study was performed in line with the principles of the Declaration of Helsinki. A
Approval was granted by the Ethics Committee of the International Cancer Center (Date:20.06.2020/No. 2020072).Consent to Participate
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Informed consent was obtained from all individual participants included in the study.Electronic Supplementary Material
Below is the link to the electronic supplementary material
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