Abstract
Background
Primary thymic adenocarcinoma (PTAC) and primary thymic squamous cell carcinoma (PTSCC) are rare malignancies with unclear prognostic differences due to limited comparative studies. This study aimed to systematically analyze their clinicopathological features and survival outcomes in a Chinese cohort.
Methods
In this retrospective cohort study, 70 patients (56 PTSCC, 14 PTAC) treated at Cancer Hospital Chinese Academy of Medical Sciences between [1999–2018] were analyzed. Clinicopathological data were collected, including Masaoka stage, treatment modalities, and resection status. Survival analysis used Kaplan-Meier curves and Cox regression. Propensity score matching (PSM) was applied for subgroup comparisons.
Results
PTAC exhibited significantly worse overall survival (OS) than PTSCC [median survival time (MST): 1.29 vs. 5.51 years, P=0.002]. Multivariate analysis identified pathological subtype [PTAC vs. PTSCC, hazard ratio (HR) =0.078; 95% confidence interval (CI): 0.033–0.184; P<0.001] and advanced Masaoka stage as independent prognostic factors. Subgroup analysis revealed PTAC conferred higher mortality in advanced-stage (III/IV), large tumors (>5 cm), and symptomatic patients. R0 resection improved OS compared to R1/R2 (13.62 vs. 4.82 years, P=0.003). Exploratory analysis of neoadjuvant therapy (n=3) suggested potential survival benefits (4.82–5.88 vs. 1.77–3.32 years in matched controls).
Conclusions
PTAC is more aggressive than PTSCC, particularly in advanced stages. Pathological subtype stratification is critical for prognostication and treatment optimization. These findings underscore the need for subtype-specific management strategies in thymic carcinomas.
Keywords: Thymic carcinoma, primary thymic adenocarcinoma (PTAC), primary thymic squamous cell carcinoma (PTSCC), prognostic factors, treatment strategy
Highlight box.
Key findings
• Primary thymic adenocarcinoma (PTAC) is an independent predictor of poor prognosis, especially in advanced-stage disease.
What is known and what is new?
• Thymic carcinoma is a type of malignant tumor with high malignancy and rarity.
• This is the first study to systematically compare these two rare cancers, establishing that histological subtype is a critical prognostic factor.
What is the implication, and what should change now?
• Thymic carcinoma should not be treated as a single disease. Treatment strategies and prognostic assessments must now be tailored to the specific pathological subtype [PTAC vs. primary thymic squamous cell carcinoma (PTSCC)]. Future research and clinical trials need to stratify patients based on this distinction.
Introduction
Thymic carcinoma (also referred to as “type C thymoma”) is a rare malignant neoplasm originating from thymic epithelial cells, with an incidence rate of 0.07–0.38 per 100,000 per year. It constitutes 14–22% of all thymic epithelial tumors (TETs) (1). They demonstrate high aggressiveness and are most frequently diagnosed at advanced stages (III or IV) (2). Current management of thymic carcinoma primarily relies on surgical resection, with neoadjuvant therapy emerging as an active research focus. Chemotherapy has been demonstrated to enhance surgical resectability in locally advanced thymic carcinoma (3,4). In recent years, immunotherapy as a neoadjuvant strategy has demonstrated potential, although its associated toxicities have restricted broad clinical application, necessitating validation through large-scale clinical trials (5-7).
According to the World Health Organization (WHO) histological classification system, thymic carcinoma can be classified into multiple pathological subtypes (8), with squamous cell carcinoma and adenocarcinoma representing two predominant categories. However, due to the scarcity of cases, clinical investigations of these subtypes have been limited to case reports. Current research predominantly treats thymic carcinoma as a single disease entity, with prognostic models mainly incorporating staging and surgical resection completeness without subtyping differentiation (9,10). The prognostic independence of histological subtypes remains undetermined, though some studies have reported no significant survival disparities across histological subtypes (11). Some studies have also pointed out the differences in the survival prognosis among mucoepidermoid carcinoma, undifferentiated carcinoma, and squamous cell carcinoma (12). However, there is no literature systematically studying whether there are differences in the prognosis between primary thymic adenocarcinoma (PTAC) and primary thymic squamous cell carcinoma (PTSCC). In terms of the selection of treatment regimens, studies have shown that thymic squamous cell carcinoma may be more sensitive to chemotherapy than other subtypes (12). Nevertheless, limited by the sample size, further exploration is still needed.
Although squamous cell carcinoma and adenocarcinoma both originate from the thymus, their potential disparities in prognostic profiles and therapeutic strategies remain incompletely elucidated due to the absence of systematic comparative investigations. To address this knowledge gap, we conducted a systematic retrospective analysis using clinical data from patients diagnosed with thymic squamous cell carcinoma and thymic adenocarcinoma at our institution from 1999 to 2018. Our study is the first to systematically investigate the survival and prognostic factors of PTAC. It is also the first study to compare whether there is a relationship between thymic adenocarcinoma and thymic squamous cell carcinoma and prognosis. This study aims to enhance the understanding of the pathological characteristics of squamous cell carcinoma and adenocarcinoma of the thymus, and to improve the clinical management strategies for thymic carcinoma. We present this article in accordance with the TRIPOD reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2371/rc).
Methods
Patients and clinical data
This retrospective cohort study evaluated 70 consecutive thymic carcinoma patients treated at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (Beijing, China) from January 1999 to December 2018. Inclusion criteria comprised: (I) histopathologically confirmed thymic squamous cell carcinoma or adenocarcinoma per 2021 WHO criteria; (II) isolated thymic malignancy without synchronous tumors; (III) complete records including imaging, treatment logs, and ≥5-year follow-up. Exclusion criteria were: (I) non-target histologies (e.g., neuroendocrine carcinoma); (II) the patient refused the follow-up; (III) the patient’s medical records are missing; (IV) extra-thymic malignancies. The case selection workflow is detailed in Figure 1.
Figure 1.
Study flow diagram. PTAC, primary thymic adenocarcinoma; PTSCC, primary thymic squamous cell carcinoma.
Clinical data from the seventy enrolled patients—including demographic characteristics (age, gender), histopathological subtypes, and therapeutic interventions—were systematically retrieved through structured querying of the institution’s clinical database using a natural language processing (NLP)-enhanced search protocol. Tumor staging was performed according to the revised Masaoka-Koga staging system (7), and histopathological diagnosis underwent independent blinded review by two board-certified thoracic pathologists. To ensure data integrity, three dedicated auditors conducted daily data audits supplemented by twice-weekly randomized validations. Subsequently, independent replication and blinded scrutiny of research outcomes were performed to confirm methodological consistency.
Follow-up data were obtained through structured telephone interviews and outpatient clinical evaluations. Therefore, the primary endpoint of this study was overall survival (OS), defined as the duration from treatment initiation to all-cause mortality. All patients underwent standardized follow-up protocols: every 3 months during the first post-treatment year, every 6 months for years 2–3, and annually thereafter. Surveillance evaluations included contrast-enhanced computed tomography (CT) scans of the neck, thorax, and abdomen, complemented by routine serological profiling.
This study was reviewed and approved by the Institutional Review Board (IRB) of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No. 24/306-4586). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This retrospective, non-interventional study anonymized the patients, so the requirement for obtaining informed consent from the patients was waived.
Treatment methods
Diagnosis was confirmed via percutaneous or surgical biopsy, followed by histopathological review by two independent thoracic pathologists. For cases with mixed features, the predominant histological component was recorded. All 70 patients received relevant treatments after diagnosis. The main treatments received by the patients included surgical treatment and non-surgical treatment. Among them, the non-surgical treatments received by the patients included radiotherapy, chemotherapy and targeted therapy. We divided the treatment patterns of the patients into three major categories: surgical treatment (Group A), non-surgical treatment (Group B), and non-surgical treatment followed by surgery (Group C). Among the patients who received the treatment pattern of Group C, they were divided into those who received adjuvant treatment after surgery and those who underwent surgery after neoadjuvant treatment.
Statistical analyses
All statistical analyses were performed using SPSS, version 24.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics and frequency analysis were used to characterize the clinical data. Survival analyses were performed using Kaplan-Meier curves, and differences between groups were evaluated using the log-rank test. To determine the influence of clinicopathological features on survival, both univariate and multivariate Cox regression analyses were employed. A P value of less than 0.05 was considered statistically significant. The calibration curve was used to compare the predicted and observed probabilities of survival in the cohort study. Nomograms and calibration curves were developed along with bootstraps of 200 resamples to reduce the overfit bias. Exploratory analyses were performed to test survival heterogeneity of PTAC and PTSCC in different subgroups, and forest plots were used to present the results. For patients receiving neoadjuvant therapy, we used propensity score matching (PSM) to match the corresponding patients.
Results
Demographic information and tumor characteristics
As summarized in Table 1, our retrospective cohort comprised 70 patients diagnosed with thymic carcinoma (exclusively squamous cell carcinoma or adenocarcinoma) at the National Cancer Center/National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences between January 1999 and December 2018. The cohort comprised 43 male (61.4%) and 27 female patients (38.6%), yielding a male-to-female ratio of 1.6:1. The mean age at diagnosis was 49.80±12.58 years (range, 14–78 years). Notably, a subset of patients exhibited smoking history (52.9%, n=37) and alcohol consumption history (32.9%, n=23). Among all patients, 70.0% presented with clinical symptoms, with pain being the predominant manifestation (57.1% of symptomatic cases). Other reported symptoms included hoarseness and digital paresthesia.
Table 1. Characteristics of 70 patients.
| Characteristic | Value, n (%) |
|---|---|
| Sex | |
| Male | 43 (61.4) |
| Female | 27 (38.6) |
| Age, years | |
| <50 | 35 (50.0) |
| ≥50 | 35 (50.0) |
| Smoking | |
| Yes | 37 (52.9) |
| No | 33 (47.1) |
| Drinking | |
| Yes | 23 (32.9) |
| No | 47 (67.1) |
| Symptom | |
| Yes | 49 (70.0) |
| No | 21 (30.0) |
| Tumor size (cm) | |
| >5 | 44 (62.9) |
| ≤5 | 26 (37.1) |
| TNM | |
| I | 6 (8.6) |
| II | 5 (7.1) |
| III | 17 (24.3) |
| IV | 42 (60.0) |
| Histology | |
| Squamous | 56 (80.0) |
| Adenocarcinoma | 14 (20.0) |
| Modalities of treatment | |
| Group A | 14 (20.0) |
| Group B | 32 (45.7) |
| Group C | 24 (34.3) |
| Postoperative adjuvant therapy | 3 (12.5) |
| Neoadjuvant therapy | 21 (87.5) |
Group A, surgery only; Group B, non-surgical therapy; Group C, multimodal therapy (surgery combined with systemic treatment). TNM, tumor, node, metastasis.
The cohort demonstrated the following histopathological distribution: 56 patients (80.0%) with pathologically confirmed squamous cell carcinoma and 14 patients (20.0%) with adenocarcinoma. Tumor size exhibited considerable variation, with the majority (62.9%) exceeding 5 cm in maximum diameter. The majority of patients (85.7%, n=60/70) presented with advanced-stage disease at initial diagnosis: stage III (24.3%, n=17) and stage IV (60.0%, n=42) according to the Masaoka-Koga staging system. Therapeutic approaches were distributed as follows: Group B (non-operative therapy) constituted the largest proportion (45.7%, n=32), followed by Group C (multimodal therapy: combination of surgery and systemic treatment, 34.3%, n=24), and Group A (surgery only, 20.0%, n= 14). Within Group C, the majority (87.5%, n=21) underwent surgical resection followed by adjuvant therapy, while 12.5% (n=3) received neoadjuvant therapy prior to surgery.
Survival
Complete follow-up data were available for all patients through June 30, 2024. At the final analysis, 14.3% (n=10) of patients survived, whereas 85.7% (n=60) succumbed to disease progression. The median OS was 5.08 years [95% confidence interval (CI): 4.12–6.04], with 3-, 5-, and 10-year survival rates of 80.0%, 54.3%, and 18.7%, respectively (Figure 2).As demonstrated in Figure 3, statistically significant associations were observed between OS and histopathological subtype, tumor size, and clinical stage. Notably, among patients undergoing surgical resection (Group A, n=14) or multimodal therapy (Group C, n=24), the presence of postoperative residual disease exhibited a significant correlation with diminished OS.
Figure 2.
OS for all patients with thymic carcinoma, the median OS is 5.08 years, and the survival rates at 3, 5, and 10 years are 80.0%, 54.3%, and 18.7%, respectively. OS, overall survival.
Figure 3.
Univariate analysis of pathological features and prognosis in thymic carcinoma patients. (A) The MST of squamous cell carcinoma patients is significantly longer than that of adenocarcinoma patients, P=0.002. (B) Univariate analysis of MST for patients with maximal tumor diameter ≤5 vs. >5 cm, P=0.003. (C) TNM stage is associated with MST in thymic carcinoma patients, P=0.001. (D) The impact of postoperative residual status on MST, P=0.003. MST, median survival time; PTAC, primary thymic adenocarcinoma; PTSCC, primary thymic squamous cell carcinoma; TNM, tumor, node, metastasis.
Prognostic factor analysis
We evaluated the association between patient prognosis and clinicopathological characteristics, including gender, age, histopathological subtype, symptomatic presentation, tumor diameter, smoking/alcohol history, staging, and treatment modalities (Table 2). Univariate analysis demonstrated that patients with squamous cell carcinoma had a significantly prolonged median survival time (MST) compared to those with adenocarcinoma (5.51 vs. 1.29 years; P=0.002; Figure 3A); patients with tumors ≤5 cm demonstrated significantly superior MST compared to those with tumors >5 cm (7.44 vs. 4.32 years; P=0.003; Figure 3B); the tumor grade is also an important prognostic factor [MST, stage I, II, III, and IV: not available (NA) vs. 13.26 vs. 6.54 vs. 4.23 years, P=0.001] (Figure 3C); among the patients who had received surgical treatment, postoperative residue was an important prognostic factor. The less the postoperative residue, the better the MST (MST, R0 vs. R1 vs. R2: 13.62 vs. 7.23 vs. 4.82 years, P=0.003) (Figure 3D). However, as shown in Figure 4, other clinical factors, including gender, age (<50 or ≥50 years), the presence or absence of a history of smoking and drinking, and the presence or absence of clinical symptoms, were not significantly correlated with the prognosis (P>0.05).
Table 2. Univariate analysis of predictors for MST.
| Characteristic | No. of patients | Survival rate (%) | MST (95% CI), years | P | ||
|---|---|---|---|---|---|---|
| 3-year | 5-year | 10-year | ||||
| Sex | 0.71 | |||||
| Male | 43 | 88.4 | 60.5 | 15.3 | 5.21 (4.966–5.454) | |
| Female | 27 | 66.7 | 44.4 | 25.3 | 4.53 (3.919–5.414) | |
| Age, years | 0.91 | |||||
| ≥50 | 35 | 82.9 | 57.1 | 15.9 | 5.230 (4.164–6.296) | |
| <50 | 35 | 77.1 | 51.4 | 22.7 | 5.020 (3.884–6.156) | |
| Smoking | 0.14 | |||||
| Yes | 37 | 89.2 | 54.1 | 9.3 | 5.070 (4.367–5.773) | |
| No | 33 | 69.7 | 54.5 | 29.8 | 5.510 (2.464–8.556) | |
| Drinking | 0.11 | |||||
| Yes | 23 | 91.3 | 47.8 | 4.3 | 4.820 (3.646–5.994) | |
| No | 47 | 74.5 | 57.4 | 24.6 | 5.260 (3.241–7.279) | |
| Symptom | 0.67 | |||||
| Yes | 49 | 77.6 | 55.1 | 19.2 | 5.120 (4.516–5.724) | |
| No | 21 | 85.7 | 52.4 | 17.1 | 5.070 (3.724–6.416) | |
| Tumor size (cm) | 0.003 | |||||
| >5 | 44 | 72.7 | 38.6 | 11.4 | 4.320 (3.335–5.305) | |
| ≤5 | 26 | 92.3 | 80.8 | 30.7 | 7.440 (6.890–7.990) | |
| TNM | ||||||
| I | 6 | 100 | 83.3 | 83.3 | – | 0.001 |
| II | 5 | 100 | 75.0 | 75.0 | 13.260 (8.380–18.140) | |
| III | 17 | 82.4 | 76.5 | 13.2 | 6.540 (4.779–8.301) | |
| IV | 42 | 73.8 | 35.7 | 7.1 | 4.230 (3.224–5.236) | |
| Histology | 0.002 | |||||
| Squamous | 56 | 91.1 | 62.5 | 20.6 | 5.510 (4.691–6.329) | |
| Adenocarcinoma | 14 | 35.7 | 21.4 | 1.8 | 1.290 (0.000–2.885) | |
| Modalities of treatment | 0.28 | |||||
| Group A | 14 | 92.9 | 78.6 | 28.6 | 6.540 (4.315–8.765) | |
| Group B | 32 | 75 | 43.8 | 14.3 | 4.270 (2.468–6.072) | |
| Group C | 24 | 83.3 | 54.2 | 18.8 | 5.020 (3.964–6.076) | |
| Resection status | 0.003 | |||||
| R0 | 11 | 90.9 | 81.8 | 60.6 | 13.620 (1.482–25.758) | |
| R1 | 11 | 90.9 | 72.7 | 21.2 | 7.230 (4.346–10.114) | |
| R2 | 21 | 71.4 | 47.6 | 9.5 | 4.820 (3.773–5.867) | |
Group A, surgery only; Group B, non-surgical therapy; Group C, multimodal therapy (surgery combined with systemic treatment). CI, confidence interval; MST, median survival time; TNM, tumor, node, metastasis.
Figure 4.
Survival probability of thymic carcinoma patients over time with sex (A), smoking status (B), drinking status (C), symptom status (D) and modality of treatment (E).
Based on the multivariate Cox regression analysis, the pathological type [hazard ratio (HR), 0.078; 95% CI: 0.033–0.184; P<0.001] and pathological stage (2 vs. 1; 3 vs. 1; 4 vs. 1) were independent prognostic factors (Table 3).
Table 3. Multivariate Cox regression analysis of the clinical factors with survival of the patients.
| Variable | HR (95% CI) | P |
|---|---|---|
| Group (squamous vs. adenocarcinoma) | 0.078 (0.033–0.184) | <0.001 |
| Stage | ||
| 1 vs. 2 | 0.420 (0.218–0.808) | 0.009 |
| 1 vs. 3 | 0.173 (0.051–0.593) | 0.005 |
| 1 vs. 4 | 0.014 (0.002–0.134) | <0.001 |
| Smoking (no vs. yes) | 0.870 (0.419–1.804) | 0.87 |
| Drinking (no vs. yes) | 1.360 (0.642–2.882) | 0.42 |
| Diameter (≤5 vs. >5 cm) | 1.248 (0.676–2.304) | 0.48 |
CI, confidence interval; HR, hazard ratio.
Prognostic nomogram for OS
Figure 5A presents the prognostic nomogram integrating statistically independent predictors identified through multivariable Cox regression analysis and clinically significant prognostic factors. In the cohort, the c-index of the prognostic nomogram for predicting OS was 0.782 (95% CI: 0.719–0.844). The calibration plot of the 3-year OS probability (Figure 5B) showed a roughly positive correlation between the nomogram prediction and the actual observation.
Figure 5.
Nomogram and calibration curves for predicting survival probabilities. (A) Nomogram for predicting 3-, 6-, and 12-year survival probabilities. (B) Calibration curves for 3-year survival probabilities. OS, overall survival; PTAC, primary thymic adenocarcinoma; PTSCC, primary thymic squamous cell carcinoma.
Risk groups
As shown in Figure 6, we divided patients with different pathologies into different subgroups for stratified analysis. Through stratification analysis of patients based on staging (stage I+II vs. III+IV), residual status (R0+R1 vs. R2), tumor diameter (≤5 vs. >5 cm), and the presence or absence of symptoms, we found that pathology had a statistically significant impact on the OS of patients in the groups of stage III+IV, R1 vs. R2, tumor diameter >5 cm, and those with symptoms. We found that regardless of whether there was a history of smoking and drinking, pathology had a statistically significant impact on the OS of patients (P<0.05). Whether the pathology was squamous cell carcinoma or adenocarcinoma had a statistically significant impact on the OS of patients in the two subgroups of male patients and those aged less than 50 years.
Figure 6.
Subgroup analysis of survival outcomes. CI, confidence interval; HR, hazard ratio; PTAC, primary thymic adenocarcinoma; PTSCC, primary thymic squamous cell carcinoma.
Patients receiving neoadjuvant therapy
There were 3 patients who received neoadjuvant therapy plus surgical treatment. Meanwhile, through PSM, we selected 3 patients from those who received non-surgical treatment to correspond to them one by one. Table 4 shows their basic information. As shown in Table 4, the pathologies of all 6 patients were squamous cell carcinoma. The survival times (4.82, 4.33, 5.88 years) of the 3 patients who received neoadjuvant therapy were all higher than those of their matched patients (3.32, 1.77, 2.12 years).
Table 4. Baseline characteristics and survival of matched patients.
| Pair | Group | ID | Survival time (years) | Censoring status | Sex | Stage | Tumor diameter (cm) | Treatment | Symptom | Smoking | Drinking | Age (years) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Neoadjuvant therapy group | 55 | 4.82 | Censored | Male | 4 | >5 | Su + neoAdj | Yes | Yes | Yes | 43 |
| 1 | Matched group | 40 | 3.32 | Censored | Male | 4 | ≤5 | Adjuvant | Yes | Yes | Yes | 62 |
| 2 | Neoadjuvant therapy group | 32 | 4.33 | Censored | Female | 4 | >5 | Su + neoAdj | No | No | No | 60 |
| 2 | Matched group | 53 | 1.77 | Censored | Female | 4 | >5 | Adjuvant | Yes | No | No | 55 |
| 3 | Neoadjuvant therapy group | 56 | 5.88 | Uncensored | Female | 3 | ≤5 | Su + neoAdj | Yes | No | No | 34 |
| 3 | Matched group | 68 | 2.12 | Censored | Female | 3 | >5 | Adjuvant | No | No | No | 37 |
Su + neoAdj, surgery + Neoadjuvant therapy.
Discussion
Thymic carcinoma is a malignant tumor originating from thymic epithelial cells. It has various pathological subtypes, among which adenocarcinoma and squamous cell carcinoma are both important pathological classifications (9). It has been reported that the age at diagnosis, tumor size, histological grade, surgical intervention, and resection method are correlated with the prognosis of thymic carcinoma patients (13,14). Complete resection (R0) can prolong progression-free survival (PFS) and OS, and R0 resection is an important prognostic factor for improved survival (15,16). At present, most current studies are case reports, primarily focusing on pathological features, and lack systematic research and analysis. Moreover, the currently reported treatment strategies for PTAC are mostly based on those for thymic carcinoma (9). There remains a lack of systematic research on the prognosis of PTAC, including potential independent prognostic factors and standardized treatment regimen.
This study collected 20-year data comprising 14 PTAC and 56 PTSCC patients with complete clinical and follow-up records. PTAC remains exceedingly rare worldwide; despite two decades of collection, only 14 confirmed cases were included. Nevertheless, this represents the largest and most rigorously documented cohort of its kind to date. Large-scale clinical studies on the prognostic impact of thymic carcinoma pathological subtype are currently lacking, with prior evidence limited to case reports (17,18). These constraints hinder the development of prospective studies or clinical trials in thymic carcinoma, contributing to the absence of standardized diagnostic and treatment approaches in clinical practice (19). Here, we conducted a systematic comparison between PTAC and the more common PTSCC and, through integrated clinical profiling, identified key prognostic factors, thereby providing a basis for subtype-specific prognosis and treatment strategy. Due to the rarity of PTAC, research on it is very limited, and we are also the first study to systematically analyze its survival and prognostic factors. We compared it with the relatively prevalent PTSCC and found a significantly worse OS than PTSCC. The Masaoka stage was applied in this study, and its impact on prognosis has been described in previous studies (9,10,17). To our knowledge, the Masaoka staging system remains the most consistent prognostic factor to date. Through the stratified analysis of the two patient groups, we found that adenocarcinoma was a significant risk factor for patient survival compared with squamous carcinoma in the stage III–IV group, R2 resection group, tumor diameter >5 cm group, and the group with clinical symptoms. In contrast, in another group (stage I and II group, R0+R1 resection group, tumor diameter ≤5 cm group, and the group without clinical symptoms), the comparison between the two did not show statistical significance. This indicates that the malignancy of PTAC is higher than that of PTSCC, and the difference in malignancy between the two becomes more pronounced as the disease progresses to advanced stages. PTSCC demonstrates well-defined squamous differentiation, exhibits relatively slow growth, and shows strong local invasion with low distant metastasis. Its favorable prognosis is largely attributed to the ease of achieving R0 resection through surgery. This may be one of the key factors for a better prognosis (18); PTAC, a rare non-squamous and non-neuroendocrine subtype of thymic carcinoma, may originates from ectopic glands or mucous-secreting structures within the thymus. Characterized by aggressive biological behavior, it typically presents with early metastasis, high postoperative recurrence rates, and poor response to radiotherapy and chemotherapy (19). Additionally, our study also found that among male patients and those aged <50 years, PTAC exhibits a higher degree of malignancy compared to PTSCC. This is a novel finding, and the underlying mechanisms warrant further investigation.
The standard treatment strategy for PTSCC and PTAC remains to be refined, and surgery has been the preferred treatment in all previous studies, with 5-year survival rates ranging between 58% and 80% (9,17,20-23). Ahmad et al.’s multicenter study (10) demonstrated that R0 resection significantly prolonged patients’ OS, and our study yielded similar results. In our study, among the patients who underwent surgical treatment (approximately 54.3%), the OS of those with R0 resection was significantly higher than that of R1 resection patients, while the OS of R1 resection patients was markedly higher than that of R2 resection patients. The differences among the three groups had obvious statistical significance, further demonstrating that R0 resection significantly improves patient prognosis. In our study, the three different therapy modalities showed a trend of differences in OS, but this trend was not sufficient (no statistical difference). The lack of difference may be attributed to the need for further refinement of specific treatment protocols, such as detailed non-surgical regimens or the extent of surgical resection. Therefore, expanding the sample size and conducting more stratified analyses are required, which will also be the focus of our future research.
Thymic carcinoma is highly invasive and is often diagnosed at an advanced stage, making R0 resection difficult. For patients who cannot undergo direct surgery, neoadjuvant therapy can shrink the tumor and create the possibility of resection. According to the guidelines of the National Comprehensive Cancer Network (NCCN) of the United States, surgery after neoadjuvant chemotherapy or chemoradiotherapy is the standard treatment for stage III/IVA (Masaoka stage) thymic tumors (23). Studies have shown that neoadjuvant chemotherapy can achieve complete remission in some patients, partial remission in 25% to 92% (24-27), and radical resection rate in 22% to 80%. Compared with preoperative radiotherapy alone, concurrent chemoradiotherapy has more advantages in terms of short-term efficacy and resection rate (27-29). In addition, immunotherapy also shows potential (5,30), and research on its combination with chemotherapy for advanced thymic carcinoma is ongoing (31). In our study, since only three patients received neoadjuvant therapy, we could only observe a trend toward benefit compared with adjuvant therapy alone. As our research is based on a real-world cohort study, our sample was derived from routine clinical practice. The findings regarding neoadjuvant therapy in this study should be considered exploratory. To definitively evaluate the impact of neoadjuvant therapy on thymic carcinoma prognosis, multicenter prospective studies are required, incorporating stratified analyses of the effects of different neoadjuvant schemes on different pathologies. These findings will help guide future research directions.
There are several shortcomings in this study. Firstly, due to the rarity of this pathology, our limited sample size may introduce bias to the results. Additionally, since the cases span a period of 20 years, this could also lead to potential bias. Therefore, we need to carry out a multi-center study to include more cases. Furthermore, owing to the limited number of cases, we were unable to perform PSM between PTSCC and PTAC patients before conducting the study, which may lead to other factors interfering with the results. Nevertheless, our research already represents the largest case series and the longest study duration in this field. Besides, we have only compared PTSCC and PTAC, with plans to expand the analysis to include more pathological subtypes in the future. Finally, our study is a retrospective study, and more reliable results may require a follow-up prospective, randomized controlled study.
Conclusions
Our study is the first to explore the impact of PTAC and PTSCC on patient prognosis. Due to the rarity and limited number of cases, future multicenter studies are warranted. Preliminary findings suggest that PTAC is a highly aggressive malignancy, and patients with advanced-stage PTAC exhibit poorer prognosis compared to those with advanced-stage PTSCC. Early intervention can significantly improve patient outcomes.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was reviewed and approved by the Institutional Review Board (IRB) of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No. 24/306-4586). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This retrospective, non-interventional study anonymized the patients, so the requirement for obtaining informed consent from the patients was waived.
Footnotes
Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2371/rc
Funding: This study was supported by the Fundamental Research Funds for the Central Universities (No. 2017PT32001), the National Key Research and Development Program (No. 2017YFC1308700), and the Chinese Academy of Medical Sciences Central Public Interest Scientific Institution Basal Research Fund (No. 2022-RW320-13).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2371/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2371/dss
References
- 1.Koizumi T, Otsuki K, Tanaka Y, et al. National incidence and initial therapy for thymic carcinoma in Japan: based on analysis of hospital-based cancer registry data, 2009-2015. Jpn J Clin Oncol 2020;50:434-9. 10.1093/jjco/hyz203 [DOI] [PubMed] [Google Scholar]
- 2.Roden AC, Fang W, Shen Y, et al. Distribution of Mediastinal Lesions Across Multi-Institutional, International, Radiology Databases. J Thorac Oncol 2020;15:568-79. 10.1016/j.jtho.2019.12.108 [DOI] [PubMed] [Google Scholar]
- 3.Kaira K, Imai H, Yamaguchi O, et al. Salvage Chemotherapy in Patients with Previously Treated Thymic Carcinoma. Cancers (Basel) 2021;13:5441. 10.3390/cancers13215441 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Roden AC, Yi ES, Cassivi SD, et al. Clinicopathological features of thymic carcinomas and the impact of histopathological agreement on prognostical studies. Eur J Cardiothorac Surg 2013;43:1131-9. 10.1093/ejcts/ezs529 [DOI] [PubMed] [Google Scholar]
- 5.Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018;19:347-55. 10.1016/S1470-2045(18)30062-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Conforti F, Zucali PA, Pala L, et al. Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022;23:1287-96. 10.1016/S1470-2045(22)00542-3 [DOI] [PubMed] [Google Scholar]
- 7.Girard N, Ponce Aix S, Cedres S, et al. Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial. ESMO Open 2023;8:101576. 10.1016/j.esmoop.2023.101576 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Marx A, Chan JK, Coindre JM, et al. The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes. J Thorac Oncol 2015;10:1383-95. 10.1097/JTO.0000000000000654 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hosaka Y, Tsuchida M, Toyabe S, et al. Masaoka stage and histologic grade predict prognosis in patients with thymic carcinoma. Ann Thorac Surg 2010;89:912-7. 10.1016/j.athoracsur.2009.11.057 [DOI] [PubMed] [Google Scholar]
- 10.Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 2015;149:95-100, 101.e1-2. [DOI] [PubMed]
- 11.Ruffini E, Detterbeck F, Van Raemdonck D, et al. Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database. J Thorac Oncol 2014;9:541-8. 10.1097/JTO.0000000000000128 [DOI] [PubMed] [Google Scholar]
- 12.Yang X, Zhao K, Li C, et al. Thymic Squamous Cell Carcinoma: A Population-Based Surveillance, Epidemiology, and End Result Analysis. Front Oncol 2020;10:592023. 10.3389/fonc.2020.592023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Wu J, Wang Z, Jing C, et al. The incidence and prognosis of thymic squamous cell carcinoma: A Surveillance, Epidemiology, and End Results Program population-based study. Medicine (Baltimore) 2021;100:e25331. 10.1097/MD.0000000000025331 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Fu H, Gu ZT, Fang WT, et al. Long-Term Survival After Surgical Treatment of Thymic Carcinoma: A Retrospective Analysis from the Chinese Alliance for Research of Thymoma Database. Ann Surg Oncol 2016;23:619-25. 10.1245/s10434-015-4825-4 [DOI] [PubMed] [Google Scholar]
- 15.Zhou MX, Chen YY, Huang C, et al. Identification of predictors of long-term survival and prognostic outcomes in thymic squamous cell carcinoma: A real-world study. Cancer Med 2023;12:14025-36. 10.1002/cam4.6049 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Hishida T, Nomura S, Yano M, et al. Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study. Eur J Cardiothorac Surg 2016;49:835-41. 10.1093/ejcts/ezv239 [DOI] [PubMed] [Google Scholar]
- 17.Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878-84; discussion 884-5. 10.1016/s0003-4975(03)00555-1 [DOI] [PubMed] [Google Scholar]
- 18.Fang W, Detterbeck F, Ackman JB, et al. International Thymic Malignancy Interest Group Standard Definitions, Policies, and Reporting Measures for Thymic Epithelial Tumors. J Thorac Oncol 2026;21:102-11. 10.1016/j.jtho.2025.09.1757 [DOI] [PubMed] [Google Scholar]
- 19.Hong Q, Han R, Chen C, et al. Clinical characteristics and prognosis of primary thymic adenocarcinoma: A single-center retrospective analysis. Thorac Cancer 2024;15:1815-21. 10.1111/1759-7714.15407 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Hamaji M, Allen MS, Cassivi SD, et al. The role of surgical management in recurrent thymic tumors. Ann Thorac Surg 2012;94:247-54; discussion 254. 10.1016/j.athoracsur.2012.02.092 [DOI] [PubMed] [Google Scholar]
- 21.Weksler B, Dhupar R, Parikh V, et al. Thymic carcinoma: a multivariate analysis of factors predictive of survival in 290 patients. Ann Thorac Surg 2013;95:299-303. 10.1016/j.athoracsur.2012.09.006 [DOI] [PubMed] [Google Scholar]
- 22.Weissferdt A, Moran CA. Thymic carcinoma, part 1: a clinicopathologic and immunohistochemical study of 65 cases. Am J Clin Pathol 2012;138:103-14. 10.1309/AJCP88FZTWANLRCB [DOI] [PubMed] [Google Scholar]
- 23.Filosso PL, Guerrera F, Rendina AE, et al. Outcome of surgically resected thymic carcinoma: a multicenter experience. Lung Cancer 2014;83:205-10. 10.1016/j.lungcan.2013.11.015 [DOI] [PubMed] [Google Scholar]
- 24.Grassin F, Paleiron N, André M, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma. A French experience. J Thorac Oncol 2010;5:893-7. [DOI] [PubMed] [Google Scholar]
- 25.Park S, Ahn MJ, Ahn JS, et al. A prospective phase II trial of induction chemotherapy with docetaxel/cisplatin for Masaoka stage III/IV thymic epithelial tumors. J Thorac Oncol 2013;8:959-66. 10.1097/JTO.0b013e318292c41e [DOI] [PubMed] [Google Scholar]
- 26.Rena O, Mineo TC, Casadio C. Multimodal treatment for stage IVA thymoma: a proposable strategy. Lung Cancer 2012;76:89-92. 10.1016/j.lungcan.2011.10.004 [DOI] [PubMed] [Google Scholar]
- 27.Wright CD, Choi NC, Wain JC, et al. Induction chemoradiotherapy followed by resection for locally advanced Masaoka stage III and IVA thymic tumors. Ann Thorac Surg 2008;85:385-9. 10.1016/j.athoracsur.2007.08.051 [DOI] [PubMed] [Google Scholar]
- 28.Bretti S, Berruti A, Loddo C, et al. Multimodal management of stages III-IVa malignant thymoma. Lung Cancer 2004;44:69-77. 10.1016/j.lungcan.2003.09.022 [DOI] [PubMed] [Google Scholar]
- 29.Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg 2014;147:36-44, 46.e1. [DOI] [PubMed]
- 30.Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol 2019;37:2162-70. 10.1200/JCO.2017.77.3184 [DOI] [PubMed] [Google Scholar]
- 31.Asao T, Shukuya T, Mimori T, et al. Study Design and Rationale for Marble Study: A Phase II Trial of Atezolizumab (MPDL3280A) Plus Carboplatin and Paclitaxel in Patients With Advanced or Recurrent Thymic Carcinoma (JTD2101). Clin Lung Cancer 2023;24:e247-53. 10.1016/j.cllc.2023.05.004 [DOI] [PubMed] [Google Scholar]