Research ArticleClinical Studies

Extranodal Extension and Epithelial Cell Adhesion Molecule Over-expression in Oral Squamous Cell Carcinoma

HIROMASA FUKUSHIMA, TOMOFUMI NARUSE, KOHEI FURUKAWA, KEISUKE OMORI, TARO MIYOSHI, KEI-ICHIRO MIURA, MITSUNOBU OTSURU and MASAHIRO UMEDA
Anticancer Research November 2023, 43 (11) 5155-5166; DOI: https://doi.org/10.21873/anticanres.16716

Abstract

Background/Aim: Concomitant chemoradiotherapy (CCRT) with cisplatin is commonly administered after neck dissection in patients with oral squamous cell carcinoma (OSCC) showing extranodal extension (ENE). This study investigated whether the efficacy of CCRT differed depending on the degree of ENE and whether the expression of epithelial cell adhesion molecule (EpCAM) was associated with prognosis. Patients and Methods: Patients with OSCC who underwent neck dissection and had histologically proven neck metastasis (pN+) were investigated retrospectively. ENE was divided into ENE minor (ENEmi; <2 mm) and ENE major (ENEma; ≥2 mm). The expression of EpCAM was also immunohistochemically examined using tissues obtained during neck dissection. Results: One hundred and seventy pN+ cases [ENE(−), n=89; ENEmi, n=23; ENEma, n=58] were included. Multivariate analysis revealed that advanced T stage and ENEma were significantly correlated with poor prognosis. The 5-year disease-specific survival rates in ENE(−), ENEmi, and ENEma groups were 73.7%, 75.5%, and 28.0% respectively. An add-on effect of postoperative CCRT was not seen in the ENEmi group; however, postoperative CCRT improved the survival of patients in the ENEma group. In the ENEma group, the prognosis was significantly worse in EpCAM-positive patients than in EpCAM-negative patients. Conclusion: Postoperative CCRT may improve prognosis in ENEma cases. EpCAM expression may be a poor prognostic factor in ENEma cases. On the other hand, postoperative CCRT did not have a significant effect on prognosis in ENEmi cases. Among them, although there was no significant difference in the survival rate, postoperative CCRT could be omitted in ENEmi/EpCAM(−) cases.

Key Words:

For oral squamous cell carcinoma (OSCC), the National Comprehensive Cancer Network (NCCN) guidelines recommend surgical treatment as the initial approach, followed by postoperative concomitant chemoradiotherapy (CCRT) when extranodal extension (ENE) of the disease involving cervical lymph nodes or a positive margin of the primary tumor is observed on histopathological examination (1). ENE is a risk factor for local recurrence, cervical recurrence, and distant metastasis. Overall survival (OS) has been reported to be reduced in ENE-positive cases (2-4). Yamada et al. classified ENEs of OSCC into three types. Among them, type C, defined as macroscopic tumor invasion into perinodal fat of muscle tissue, was found to be associated with a significantly poor prognosis (5). Furthermore, a detailed histopathological examination revealed that patients having ENE with features of tumor budding had decreased recurrence-free survival rates in addition to decreased OS rates (6). However, recent reports suggest that the prognostic significance of ENE depends on its extent. Wreesman et al. reported that in OSCC, ENE major (defined as extending more than 1.7 mm beyond the lymph node capsule) was associated with decreased disease-specific survival (DSS), whereas ENE minor (defined as extending less than 1.7 mm beyond the lymph node capsule) was associated with DSS similar to that in patients without ENE (7). A previous multicenter collaborative study also reported that in ENE-positive and resection margin-positive cases, compared with postoperative radiotherapy (RT), postoperative CCRT with cisplatin was associated with a predominantly improved local control rate but not with improved survival (8). This might be because each institution had different criteria for the extent of ENE and made no distinction between clinical and histological ENEs. We believe that a uniform assessment of ENE is necessary. The American Joint Committee on Cancer (AJCC) staging manual, which is the basis for the 8th edition of the TNM classification revised in 2017, classifies ENE into ENE minor (ENEmi) and ENE major (ENEma) (3). Histopathologically, ENEmi is defined as the extension of tumor cells less than 2 mm from the capsule, and ENEma is defined as the extension of tumor cells beyond 2 mm from the capsule. However, although the current pN classification does not incorporate this definition of ENE, the AJCC recommends that more detailed data should be collected and analyzed in the future.

Several biomarkers have been reported to predict prognosis in patients with oral cancer (9-11). Among them, the expression of epithelial cell adhesion molecule (EpCAM) was significantly associated with tumor size, lymph node metastasis, histological differentiation, and invasive pattern in tongue cancer, and cancer cell lines with EpCAM over-expression had a higher invasive potential than those without EpCAM over-expression (12). EpCAM is a transmembrane glycoprotein involved in intercellular adhesion and is detected in the basement membrane of most epithelial tissues (13, 14). From a clinical point of view, EpCAM antigen has garnered great interest as a marker for cancer immunotherapy, and EpCAM over-expression has been reported in cancers, such as colon and breast cancers (13, 15, 16). Although the correlation between EpCAM over-expression and the invasive and metastatic potential of cancer cells, as well as its underlying mechanism, remain to be fully elucidated, in general, the intercellular adhesion activity of EpCAM is relatively weak, and over-expression of EpCAM reduces the intercellular adhesiveness of cancer cells, thereby facilitating the acquisition of invasive and metastatic potential (14, 17). In the present study, in accordance with the AJCC recommendations, we classified patients with cervical metastatic extranodal lymph node invasion of OSCC into the ENEmi and ENEma groups and compared their treatment outcomes, prognoses, and postoperative adjuvant therapies. Furthermore, we analyzed the cellular biology of ENEmi and ENEma using supplementary EpCAM immunochemical staining and evaluated the utility of EpCAM over-expression as a clinically relevant molecular marker.

Patients and Methods

Patients. Retrospective data of patients with OSCC who underwent surgical treatment at the Department of Oral and Maxillofacial Surgery, Nagasaki University Hospital, between 2004 and 2021 were collected from medical records. Of these patients, those who underwent neck dissection and had histologically proven lymph node metastases were enrolled in the study. Patients with ENE or positive resection margins received postoperative adjuvant therapy according to the NCCN guidelines if they consented.

Histopathological examination. Lymph node specimens obtained during neck dissection were examined histopathologically. Slides of all collected lymph nodes were embedded in paraffin, stained with hematoxylin and eosin, and subsequently evaluated under a microscope for the presence of tumor tissue and ENE. ENE was defined as a complete rupture of the lymph node capsule, and the extent of ENE was determined as the maximum distance between the outer surface of the lymph node capsule and the invasive front of the extranodal tumor. Tumor involvement close to the lymph node capsule or of the surrounding fatty tissue was not considered ENE if the capsule was not ruptured. Microscopic measurements in millimeters were performed visually using a measuring tape. In instances where multiple lymph nodes exhibited ENE, the greatest extent of invasion was chosen as the representative distance of extracapsular invasion for that patient. According to the AJCC recommendations, we classified ENEs into ENEmi (Figure 1A) and ENEma (Figure 1B). The correlations between ENE and various clinicopathological factors, including sex, age, pT factor, pN factor, histological differentiation, lymphatic invasion, venous invasion, perineural invasion, resection margins, and postoperative adjuvant therapy, were investigated. pT and pN factors were assessed according to TNM classification (8th edition). OS, DSS, and locoregional control were compared as survival rates.

Figure 1.
Figure 1.

Major and minor extranodal extensions. A) Minor extranodal extension (ENE) of the tumor. ENEmi: ENE minor; Hematoxylin–eosin; ×40. B) Major ENE of the tumor into surrounding fibrous and adipose tissues. ENEma: ENE major; Hematoxylin–eosin; ×40.

Immunohistochemical staining and evaluation. Serial sections with 4-μm thickness each were obtained from paraffin-embedded tissue blocks. The sections were deparaffinized using xylene, dehydrated using ethanol, immersed in Target Retrieval Solution 10× (DAKO, Glostrup, Denmark), autoclaved at 121°C for 5 min, and subsequently treated for antigen activation. Endogenous peroxidases were inactivated by incubation in methanol (containing 0.3% H2O2) for 30 min. Immunohistochemical staining was performed using the EnVision system (EnVision+, Dako, Carpinteria, CA, USA). The primary antibody used was against EpCAM (dilution 1:50, mouse, ab224826, Cambridge, UK). The sections were incubated overnight with monoclonal antibodies at 4°C. The sections were then immersed in diaminobenzidine (DAB) solution for visualization, counterstained with Meyer’s hematoxylin, dehydrated using ethanol, and cleared using xylene before being sealed with Marinol. Positive controls were obtained by substituting the primary antibody with phosphate-buffered saline, whereas negative controls were obtained by immunostaining normal lymph nodes with an antibody against EpCAM. EpCAM expression was defined as the presence of specific staining of the tumor cell membrane, and EpCAM over-expression was evaluated by calculating the immunostaining score, comprising the percentage score and the intensity score. The percentage score represents the estimated percentage of tumor cells that stained positive (0, none; 1, <10%; 2, 10-50%; 3, 50-80%; 4, >80%). The intensity score indicates the estimated staining intensity (0, no staining; 1, weak; 2, moderate; 3, strong). The total score ranges from 0 to 12. In accordance with a previous study by Gastal et al. (15), over-expression of EpCAM was defined as a total score of 4 or higher.

Statistical analysis. The relationship between ENE and each variable was analyzed using Fisher’s exact test for categorical data and one-way ANOVA for continuous data. Factors related to OS and DSS were analyzed using univariate and multivariate Cox regression analyses. The cumulative survival rates based on postoperative treatments were calculated using the Kaplan–Meier method and analyzed using the log-rank test. All statistical analyses were performed using SPSS software (version 26.0; Japan IBM Co., Ltd., Tokyo, Japan). Two-tailed p-values less than 0.05 were considered statistically significant.

Ethics. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Health, Labor, and Welfare, Japan. Ethical approval was obtained from the institutional review Board (IRB) of Nagasaki University Hospital (approval no. 22112104). Since this was a retrospective study, identifiable patient information was removed, and the research plan was published on the homepages of the participating hospitals’ websites, along with an opt-out option in accordance with IRB instructions.

Results

Patient characteristics. Table I summarizes the characteristics of 170 patients who underwent cervical dissection and had histologically proven neck metastasis (pN+). The mean age of the patients was 66.2 years. The tongue was the most common primary site (69 cases), followed by the mandibular gingiva, maxillary gingiva, and floor of the mouth. Among these cases, there were 108 cases of initial dissection and 62 cases of secondary cervical dissection for lymph node metastasis detected during follow-up after the initial N0 diagnosis. Eighty-nine cases were ENE(−), and 81 cases were ENE(+), of which 23 were ENEmi and 58 were ENEma.

View this table:
Table I.

Patient characteristics.

Differences among ENE(−), ENEmi, and ENEma groups. The 170 pN+ patients were divided into ENE(−) (n=89), ENEmi (n=23), and ENEma (n=58) groups, and their features were compared (Table II). In univariate analysis, ENE(+) was more common in later dissection cases than in first dissection cases. Histological findings revealed that ENE(+) was significantly higher in patients with lymphatic or perineural invasion. However, on comparing ENEmi and ENEma groups, ENEma was found to be more common in men than in women, but other factors were not significantly different.

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Table II.

Relationship between extranodal extension (ENE) and each variable (univariate analysis).

Treatment and outcomes. The 5-year OS rates were 66.9%, 63.4 %, and 24.3% for ENE(−), ENEmi, and ENEma groups, respectively. The 5-year DSS rates were 73.7%, 75.5%, and 28.0% for ENE(−), ENEmi, and ENEma groups, respectively, indicating that the prognoses of ENE(−) and ENEmi groups were similar, but the prognosis of the ENEma group was significantly worse (Figure 2). The 5-year distant metastasis-free rates were 86.2%, 86.5%, and 55.3% for ENE(−), ENEmi, and ENEma groups, respectively, indicating that distant metastasis occurred in the ENEma group, leading to a poor prognosis (Figure 3). Factors significantly influencing OS were identified through univariate [the level of ENE (p=0.003)] and multivariate [age (p=0.028) and the level of ENE (p=0.002)] analyses (Table III). In the univariate analysis, the level of metastasis (p=0.038) and degree of ENE (p=0.003) were significant factors, whereas, in the multivariate analysis, T stage (p=0.041) and degree of ENE (p=0.003) were significant factors (Table IV). The association between postoperative treatment and prognosis in ENE(+) patients was investigated. Postoperative CCRT was performed in 24 (29.6%) patients and RT alone in six (7.4%) patients, while the remaining 51 (63.0%) patients did not receive postoperative treatment. The 5-year OS rates in the ENEmi group were 57.4% without postoperative treatment and 66.4% with postoperative RT. The 5-year DSS rates were 74.1% with no postoperative treatment, 66.7% with postoperative RT, and 100% with postoperative CCRT; however, the association between postoperative treatment and prognosis was unclear owing to the small number of patients in each group (Figure 4). In contrast, in the ENEma group, the 5-year OS rates were 23.3% with no treatment, 66.7% with postoperative RT, and 22.8% with postoperative CCRT. Similarly, the 5-year DSS rates were 30.9%, 66.7%, and 24% with no treatment, postoperative RT, and postoperative CCRT, respectively. While there seemed to be a trend towards prolonged survival with CCRT compared with no postoperative treatment, the difference was not statistically significant (Figure 5). Nevertheless, in the subgroup of 32 patients whose first metastasis was ENEma, the 5-year OS rates were 0% with no postoperative treatment, 50% with postoperative RT, and 24.3% with postoperative CCRT, whereas the respective 5-year DSS rates were 0%, 50%, and 25.7%, indicating that postoperative treatment was beneficial in improving prognosis. However, the difference in prognosis between RT and CCRT remains unclear (Figure 6).

Figure 2.
Figure 2.

Kaplan–Meier curves for the 5-year overall survival (OS) and 5-year disease-specific survival (DSS) according to the level of progression of extranodal extension (ENE). ENE(−) and ENEmi groups had similar OS and DSS rates; however, the ENEma group had a significantly poor prognosis. ENEmi: ENE minor; ENEma: ENE major.

Figure 3.
Figure 3.

Kaplan–Meier curves for the 5-year distant metastasis-free rates according to the level of progression of extranodal extension (ENE). Compared with ENE(−) and ENEmi groups, distant metastasis occurred in the ENEma group, indicating a poor prognosis. ENEmi: ENE minor; ENEma: ENE major.

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Table III.

Factors related to the overall survival in 81 patients with extranodal extension.

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Table IV.

Factors related to the disease specific survival in 81 patients with extranodal extension.

Figure 4.
Figure 4.

Kaplan–Meier curves for postoperative treatment and 5-year overall survival (OS) and 5-year disease-specific survival (DSS) rates in 23 patients with minor extranodal extension (ENE). Forty-nine (37.0%) patients received adjuvant therapy; no association between postoperative therapy and prognosis was evident based on the 5-year OS and 5-year DSS rates. CCRT: Concomitant chemoradiotherapy; ENEmi: ENE minor; RT: radiotherapy.

Figure 5.
Figure 5.

Kaplan–Meier curves for postoperative treatment and 5-year overall survival (OS) and 5-year disease-specific survival (DSS) rates in 58 patients with major extranodal extension (ENE). For both OS and DSS, there was a trend towards prolonged survival in the group that received adjuvant therapy compared with the group that received no adjuvant therapy, but the difference was not statistically significant. CCRT: Concomitant chemoradiotherapy; ENEma: ENE major; RT: radiotherapy.

Figure 6.
Figure 6.

Kaplan–Meier curves for postoperative treatment and 5-year overall survival (OS) and 5-year disease-specific survival (DSS) rates in 32 patients with first metastatic major extranodal extension (ENE). For both OS and DSS, the no postoperative treatment group showed poorer prognosis compared with the group that received adjuvant therapy, indicating that postoperative therapy was effective in improving prognosis. However, the difference in prognosis between radiotherapy (RT) and concomitant chemoradiotherapy (CCRT) was not clear.

Correlation between EpCAM over-expression and clinicopathological features. Among the 81 ENE(+) patients, 36 (44.4%) exhibited EpCAM over-expression. Extranodally infiltrated SCC cells exhibited a propensity towards robust EpCAM staining intensity (Figure 7). Univariate analysis revealed that EpCAM-positivity was more prevalent in patients with a poor performance status (PS) (p=0.020) and ENEma (p=0.013). Nonetheless, no significant factors were identified in multivariate analysis (Table V).

Figure 7.
Figure 7.

Representative immunohistochemically stained sections for assessing epithelial cell adhesion molecule (EpCAM) expression in cases of minor and major extranodal extensions. High-intensity over-expression of EpCAM was observed at the invasive front of SCC cells. In addition, strong staining was observed on the plasma membrane of the cells. Immunopositivity for EpCAM (A) and hematoxylin–eosin staining (B) in a case of ENEmi. Original magnification: ×100, for each. Immunopositivity for EpCAM (C, D) and HE staining (E) in a case of ENEma. Original magnification: ×100 (C, E); ×400 (D). ENEmi: ENE minor; ENEma: ENE major.

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Table V.

Relationship between EpCAM over-expression and each variable (univariate analysis).

Correlation between EpCAM over-expression and prognosis. The association between EpCAM over-expression and prognosis was assessed in 81 ENE(+) patients. In the ENEmi group, the 5-year OS and DSS rates of patients with EpCAM over-expression were 60% and 60%, respectively, which tended to be lower than those of EpCAM-negative patients (OS and DSS rates of 64.2% and 80.2%, respectively). However, no significant differences were observed between the groups. In contrast, in the ENEma group, the 5-year OS and DSS rates of patients with EpCAM over-expression were 0% each, whereas those of EpCAM-negative patients were 48.7% and 56.2%, respectively, indicating a significant correlation between EpCAM over-expression and poor prognosis (Figure 8).

Figure 8.
Figure 8.

Kaplan–Meier curves for epithelial cell adhesion molecule (EpCAM) expression and 5-year overall survival (OS) and 5-year disease-specific survival (DSS) rates in 81 patients with extranodal extension (ENE). In patients with ENEmi, 5-year OS and DSS rates tended to be lower in EpCAM-over-expressing cases than in EpCAM-negative cases. On the other hand, in the ENEma group, the 5-year OS and DSS rates in EpCAM-over-expressing cases were 0% each, and in EpCAM-negative cases, these were 48.7% and 56.2%, respectively, showing a significant correlation between EpCAM over-expression and poor prognosis. ENEmi: ENE minor; ENEma: ENE major.

Discussion

Patients with OSCC with ENEma had a worse prognosis than those with ENEmi and ENE. Moreover, postoperative adjuvant therapy was more effective in patients with ENEma than in the remaining patients. This study further suggests that EpCAM positivity in patients with ENEma is associated with a particularly poor prognosis, indicating that EpCAM could be a novel prognostic factor for OSCC.

ENE is a negative prognostic factor in patients with OSCC, and in these patients, the more invasive the tumor is in the periadventitial tissue, the higher the recurrence rate and the poorer the prognosis (5, 6). In the present study, 81 ENE-positive patients were classified into ENEmi and ENEma groups according to the AJCC system and compared. Although there was no association between ENE and histological factors, ENEma was associated with a significantly poor prognosis. The 5-year distant metastasis-free rates indicated that compared with ENE(−) and ENEmi groups, distant metastasis occurred in patients with ENEma, leading to a poor prognosis. de Carvalho et al. conducted a prospective analysis of 170 patients with SCC of the larynx or hypopharynx and found a 3.5-fold higher incidence of local recurrence and distant metastasis in cases of pathological penetration of the lymph node capsule than in those without ENE (18). This finding supports the notion that ENE is a negative prognostic indicator in these patients. Previous studies have reported that the number of lymph node metastases with ENE, as well as level IV or V metastases, are associated with a poor prognosis (19). The present study highlights the correlation between the level of ENE progression and prognosis, as well as other risk factors.

The current standard of care for patients with OSCC with a high risk of recurrence involves surgical resection followed by postoperative radiotherapy with or without chemotherapy (1). According to two randomized trials [European Organization for Research and Treatment of Cancer (EORTC) 22931 and Radiation Therapy Oncology Group (RTOG) 9501], ENE with positive lymph nodes and positive or close margins is a high-risk factor for head and neck squamous cell carcinoma (HNSCC) recurrence (20-22). Data from these trials showed that postoperative CCRT significantly improved locoregional control (LRC), DFS, and OS rates (20-22). Based on these studies, several international guidelines recommend postoperative CCRT as the standard of care for patients having resectable advanced HNSCC with a high risk of recurrence. However, in a study of 18 patients with OSCC with positive margins or ENE who underwent surgery and either postoperative RT or cisplatin-based CCRT, compared with postoperative RT, postoperative CCRT with cisplatin was associated with a significant improvement in LRC rate but not with improved DFS or OS rates, indicating that cisplatin-based CCRT did not significantly improve survival (8). However, this study did not classify ENEs. Therefore, in the present study, we classified ENEs into ENEmi and ENEma to evaluate the benefit of postoperative treatment. In patients with first metastasis and ENEma, the 5-year OS and DSS rates suggested an additional survival benefit from adjuvant therapy, whereas in the ENEmi group, adjuvant therapy had no significant effect on survival. Therefore, depending on the patient’s PS and background, postoperative adjuvant therapy is essential for ENEma but not for ENEmi. The criteria for extranodal invasion distance to determine whether adjuvant therapy should be administered are controversial (23, 24), and further case series studies are necessary to determine the need for adjuvant therapy according to extranodal invasion distance.

In patients with breast cancer, EpCAM over-expression is associated with pathological parameters, such as tumor differentiation, tumor size, and axillary lymph node metastases, and some studies have reported that EpCAM over-expression is an independent marker of poor survival (15). Moreover, in patients with oral cancer, overexpression of EpCAM is significantly associated with tumor size, histological grade, local recurrence of tumor, and patient survival and may be an important biomarker for predicting prognosis in the future (25). In the present study, tissue samples from metastatic lymph nodes of patients with OSCC and ENE were examined for EpCAM over-expression. EpCAM over-expression was observed in 36 of 81 cases (44.4%) of OSCC with ENE, whereas normal lymph nodes revealed no EpCAM expression. This indicates that EpCAM over-expression is associated with OSCC carcinogenesis. EpCAM over-expression in OSCC did not correlate with pathological or histological factors. Although there was no significant difference in the over-expression of EpCAM in ENEmi cases, the over-expression of EpCAM in ENEma cases was significantly associated with a poor prognosis, indicating that EpCAM affected the progression of OSCC and EpCAM expression might be a prognostic factor in patients with OSCC. Our research team has also shown that EpCAM over-expression in human tongue cancer cell lines increases the invasiveness of tongue cancer cells (12). In the present study, immunohistological analysis of extracapsular invasive cancer cells showed a significant association between EpCAM over-expression and ENEma, indicating that ENEma cancer cells may have a prognostic impact on oral cancer by regulating capsular cell-cell adhesion, thereby acquiring strong invasive potential beyond the capsule.

This was a single-center, retrospective study, and not all patients eligible for adjuvant CCRT received the treatment owing to physician discretion and adverse events. Therefore, there may be significant biases in treatment outcomes, and it remains uncertain whether the results can be generalized. However, to the best of our knowledge, this is the first study to evaluate both ENE and EpCAM in oral cancer. Further studies involving multiple centers are required to establish a more comprehensive understanding.

Conclusion

The prognosis of ENEmi was almost similar to that of ENE(−), and postoperative CCRT did not have a significant effect on prognosis in ENEmi cases. Among them, although there was no significant difference in survival rate, postoperative CCRT could be omitted in ENEmi/EpCAM(−) cases. Additionally, postoperative CCRT may improve prognosis in ENEma cases. EpCAM expression may be a poor prognostic factor in ENEma cases.

Acknowledgements

The Authors would like to thank Editage (www.editage.jp) for English language editing.

Footnotes

  • Authors’ Contributions

    HF and TN conceived the idea of the study. HF, TN, and KF conducted the experiments. HF and MU analyzed the data. HF, TN, and MU drafted the manuscript. KO, TM, KM, and MO revised the manuscript. All Authors revised the manuscript, provided final approval for publication, and agreed to be responsible for the work performed.

  • Conflicts of Interest

    The Authors have no conflicts of interest relevant to this article.

  • Received September 12, 2023.
  • Revision received October 5, 2023.
  • Accepted October 6, 2023.

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Extranodal Extension and Epithelial Cell Adhesion Molecule Over-expression in Oral Squamous Cell Carcinoma
HIROMASA FUKUSHIMA, TOMOFUMI NARUSE, KOHEI FURUKAWA, KEISUKE OMORI, TARO MIYOSHI, KEI-ICHIRO MIURA, MITSUNOBU OTSURU, MASAHIRO UMEDA
Anticancer Research Nov 2023, 43 (11) 5155-5166; DOI: 10.21873/anticanres.16716
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