Preoperative biopsy is not associated with overall survival in patients with surgically resected localized thymoma

Abstract

Objectives:

Society guidelines discourage biopsy of thymic epithelial tumors (TETs) due to the perceived risk of local seeding or pleural dissemination. However few studies have evaluated this concern, and the true risk of preoperative biopsy remains unknown.

Methods:

We queried the United States’ National Cancer Database for adults with localized TETs who underwent upfront R0 thymectomy 2004–2015. Use of preoperative biopsy over time was assessed with the Cochran-Armitage test. Postoperative outcomes were compared with chi-square and Wilcoxon rank sum tests. Overall survival (OS) was analyzed with Kaplan-Meier and Cox proportional hazard methods.

Results:

We identified 1,056 patients. The median age was 61 years; 47% (492) were male. Use of preoperative percutaneous biopsy increased 2006–2015 from 18% to 33% (p<0.001). Patients who underwent biopsy had larger tumors [median 6.6 vs 5.0 cm], more open operations [72% (150) vs 62% (331)] and regional lymphadenectomies [44% (118) vs 33% (250)], and a longer length of hospitalization (median 4 vs 3 days). Thirty-day mortality was similar between the groups. There was no difference in 10-year OS between the biopsy and no-biopsy groups [75% (95% CI 69%−82%) vs 76% (95% CI 73%−80%), p=0.8]. After adjusting for age, sex, primary payor, histology, and tumor size, OS was similar between the biopsy and no-biopsy groups [AHR 0.97 (95% CI 0.72–1.29), p=0.9].

Conclusions:

In this analysis of patients with localized TETs undergoing upfront R0 thymectomy, preoperative biopsy is not associated with worse overall survival. More study is needed to further explore whether biopsy increases risk of recurrence.

Graphical Abstract

AHR adjusted hazard ratio, CI confidence interval

Introduction

Thymoma and thymic carcinoma are rare epithelial neoplasms that arise in the anterior mediastinum. The standard of care for tumors deemed resectable on preoperative imaging is upfront thymectomy. Current society guidelines, including those from the National Comprehensive Cancer Network, the Society of Thoracic Surgeons, and the European Society for Medical Oncology, discourage biopsy of resectable thymic tumors because of concern for biopsy tract seeding or pleural dissemination and subsequent disease recurrence. [1–3] Thymic epithelial neoplasms are thus typically biopsied in only two settings: diagnostic uncertainty, and prior to neoadjuvant therapy for invasive disease not amenable to upfront surgical resection.

Biopsy tract recurrence has been described only in isolated case reports. [4, 5] Several other reports have documented chest wall metastases in the absence of preoperative tissue diagnosis, challenging the assumption that the biopsy was responsible for these recurrences. [6, 7] Evidence for an association between preoperative biopsy and pleural dissemination is similarly sparse. The most compelling data is from a review of 19 patients with pleural metastasis, which found preoperative biopsy to be independently associated with pleural metastasis. [8] This analysis did not distinguish between synchronous and metachronous pleural metastasis, and information regarding the biopsy route and surgical approach was not available. While the series highlights the need for further investigation, whether preoperative biopsy represents a true risk for either biopsy tract or pleural recurrence remains an open question.

Given the rare and indolent nature of thymomas, answering this question requires a large multi-institutional dataset with extended longitudinal follow-up. Since recurrence data is not available in a national cancer registry in the United States, we used the American College of Surgeons National Cancer Database to assess whether preoperative biopsy of thymic epithelial neoplasms is associated with decreased overall survival.

Patients and Methods

The National Cancer Database (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. It contains demographic and clinical data contributed by more than 1,500 CoC-accredited institutions capturing approximately 72% of all cancer diagnoses in the United States. NCDB data are freely available to investigators from CoC-accredited institutions. Since the data are derived from a deidentified NCDB file, this study was deemed exempt from review by the Mayo Clinic Institutional Review Board.

Patients were identified with International Classification of Diseases for Oncology 3^rd edition topography codes for primary site of thymus (C37.9) and histology codes for thymic epithelial tumor (8580–8586). The primary sites of anterior mediastinum (C38.1) and mediastinum NOS (C38.3) were also queried for thymic epithelial histology, but no patients were identified in these sites. Since the predominant staging system in clinical use is Masaoka staging, the American Joint Committee on Cancer (AJCC) stage is not routinely recorded in the NCDB for thymic tumors. We thus used a collaborative stage variable, in use from 2004 through 2015, to identify patients with localized thymoma (collaborative stage extension codes 100 and 300), and limited our analysis to the years in which this variable was recorded. We included patients who underwent upfront surgical resection with a negative margin. Patients who had positive lymph nodes diagnosed before surgery, and those who had a preoperative diagnostic or staging procedure other than primary site biopsy were excluded from the study. Patients were placed into biopsy and no-biopsy groups for comparison based on the surgical and diagnostic staging procedure variable (codes 00 and 02). A flow diagram is demonstrated in Figure 1 and specific codes used for cohort selection are available in Supplemental Table 1.

Figure 1.

Flow diagram of cohort selection

Categorical data are expressed as counts and percentages, and are compared with chi-square tests. Continuous data are expressed as median and interquartile range, and are compared with Wilcoxon rank sum tests. Trends in biopsy use by year over the study period were assessed with the Cochran-Armitage test for trend. Overall survival was analyzed with the Kaplan-Meier method and the groups were compared with log-rank tests. The proportional hazards assumption was checked with Schoenfeld residuals. Factors associated with overall survival were assessed with univariable and multivariable Cox proportional hazard models.

In addition to preoperative biopsy, the intervention of interest, covariates that were both considered confounders based on clinical expertise and available in the data were included in the multivariable model. We did not include the Charlson Deyo Index (CDI) variable in the primary analysis as publicly available NCDB documentation suggests this variable represents both comorbidities and treatment complications rather than a comorbidity index as originally described by Deyo et al. [9, 10] However, we then repeated the analysis with the CDI variable to assess if its inclusion altered the results. In addition, we performed a subgroup analysis using the same Cox proportional hazards model to separately evaluate patients who underwent open and minimally invasive resections.

A second analysis was performed using inverse probability of treatment weighting (IPTW) based on the propensity score. The propensity score was estimated with a logistic regression model using the same covariates included in the multivariable model above. Weights were calculated for the Average Treatment Effect estimand using the WeightIt package. A weighted Cox proportional hazards regression model was then fitted using the estimated weights with the biopsy indicator as the sole covariate in the model. Robust standard errors were used to account for the use of weights. As with the unweighted multivariable Cox proportional hazards model above, the analysis was performed first without, then with, the CDI variable. Analysis was performed on R statistical software (The R Foundation, Vienna, Austria).

Results

We identified 1,056 patients who met inclusion criteria. The median age was 61 years (IQR 51, 69) and 47% (492 patients) were male. Preoperative biopsy was performed in 26% of the total cohort (273 patients). Use of preoperative biopsy increased over study period, from 18% in 2006 to 33% in 2015 (p = 0.005).

Cohort characteristics and surgical outcomes are described in Table 1. Patients who underwent preoperative biopsy were more likely to have larger tumors (median 6.6 cm vs 5.0 cm), an open operation (72% vs. 62%), and regional lymphadenectomy (44% vs. 33%).

Table 1.

Cohort characteristics

	N	Overall N = 1,056a	No biopsy N = 783a	Preoperative biopsy N = 273a	p-value c
Age	1,056	61 (51, 69)	61 (51, 69)	61 (53, 69)	0.5
Sex	1,056				0.7
Male		492 (47%)	368 (47%)	124 (45%)
Female		564 (53%)	415 (53%)	149 (55%)
Facility type	971				0.7
Community cancer program		42 (4.3%)	29 (4.0%)	13 (5.2%)
Comprehensive community cancer program		298 (31%)	219 (30%)	79 (32%)
Academic/research program		440 (45%)	334 (46%)	106 (42%)
Integrated network cancer program		191 (20%)	139 (19%)	52 (21%)
Primary payor	1,044				0.4
Private insurance		549 (53%)	414 (53%)	135 (50%)
Other		495 (47%)	361 (47%)	134 (50%)
WHOb histologic classification	1,056				0.5
Thymoma, NOS		187 (18%)	145 (19%)	42 (15%)
Type A		122 (12%)	94 (12%)	28 (10%)
Type AB		294 (28%)	208 (27%)	86 (32%)
Type B1		138 (13%)	106 (14%)	32 (12%)
Type B2		143 (14%)	101 (13%)	42 (15%)
Type B3		86 (8.1%)	64 (8.2%)	22 (8.1%)
Thymic carcinoma		86 (8.1%)	65 (8.3%)	21 (7.7%)
Tumor size	1,056	5.5 (3.7, 8.0)	5.0 (3.5, 7.1)	6.6 (5.0, 9.0)	<0.001
Surgical approach	740				<0.001
Minimally invasive		223 (30%)	180 (34%)	43 (21%)
Open		481 (65%)	331 (62%)	150 (72%)
No surgical procedure at this facility		36 (4.9%)	20 (3.8%)	16 (7.7%)
Lymphadenectomy	1,038				<0.001
No lymphadenectomy		670 (65%)	519 (67%)	151 (56%)
Regional lymphadenectomy		368 (35%)	250 (33%)	118 (44%)

^an (%); Median (IQR)

^bWHO = World Health Organization

^cPearson’s chi-square test; Wilcoxon rank sum test.

On univariable analysis length of hospitalization was longer among those with preoperative biopsy (4 vs 3 days, p = 0.008), but 30-day mortality (0.4% vs 0.5%, p > 0.9) and 30-day readmission (4.8% vs 3.6%, p = 0.4) was similar between the groups.

Ten-year overall survival was 76% for the entire cohort, and did not differ between the biopsy and no-biopsy groups [75% (95% CI 69%, 82%) vs 76% (95% CI 73%, 80%)]. Factors associated with overall survival on univariate analysis were age, sex, histologic classification, tumor size, and primary payor (Table 2). In this unadjusted analysis, preoperative biopsy was not associated with overall survival (HR 1.05, p = 0.8), as seen in Figure 2. After adjusting for age, sex, primary payor, histologic classification, and tumor size, there remained no association between preoperative biopsy and overall survival [HR 0.97 (95% CI 0.72–1.29), p = 0.9]. (Multivariable model not shown in a table to avoid Table 2 fallacy. [11]) This finding remained unchanged when the analysis was repeated with the addition of the CDI variable [HR 0.98 (95% CI 0.73, 1.31), p = 0.9].

Table 2.

Univariable Cox proportional hazards model for overall survival

	HRa	95% CIb	p-value
Age (per year)	1.06	1.05, 1.07	<0.001
Sex
Male	1.00	1.00	Reference
Female	0.75	0.58, 0.96	0.022
WHOc histologic classification
Thymoma, NOS	1.00	1.00	Reference
Type A	0.96	0.59, 1.56	0.9
Type AB	0.91	0.62, 1.34	0.6
Type B1	0.80	0.50, 1.29	0.4
Type B2	0.85	0.53, 1.38	0.5
Type B3	1.30	0.80, 2.10	0.3
Thymic carcinoma	2.13	1.37, 3.30	<0.001
Tumor size (per mm)d	1.01	1.00, 1.01	0.001
Biopsy procedure
No biopsy	1.00	1.00	Reference
Preoperative biopsy	1.05	0.78, 1.39	0.8
Facility type
Community cancer program	1.00	1.00	Reference
Comprehensive community cancer program	0.93	0.49, 1.74	0.8
Academic/research program	0.78	0.42, 1.45	0.4
Integrated network cancer program	0.90	0.47, 1.73	0.7
Unknown	0.19	0.07, 0.54	0.002
Primary payor
Private insurance	1.00	1.00	Reference
Other	2.90	2.21, 3.81	<0.001

^aHR = Hazard Ratio

^bCI = Confidence Interval

^cWHO = World Health Organization

³mm = millimeter

Figure 2.

Unadjusted Kaplan-Meier curve for overall survival

In a subgroup analysis separately evaluating patients who underwent open and minimally invasive resections, no association between preoperative biopsy and overall survival was detected in either cohort [Open: HR 0.87 (95% CI 0.56, 1.36), p = 0.5; Minimally invasive: HR 0.96 (95% CI 0.38, 2.41), p >0.9].

In the second analysis, after adjustment for confounding using IPTW, covariate balance was found to be adequate with standardized mean differences <0.1 for all included covariates (Supplemental Figure 1). In the weighted Cox model, there was no association between preoperative biopsy and overall survival [HR 1.01 (95% CI 0.76, 1.35), p = 0.9]. This finding also remained unchanged when the analysis was repeated with the addition of the CDI variable [HR 0.99 (95% CI 0.74, 1.33), p = 0.9].

Discussion

The safety of preoperative biopsy of thymic epithelial neoplasms remains controversial. Traditional dogma holds that biopsy increases the risk of recurrence through biopsy tract seeding or pleural dissemination. Although there is a paucity of data to support this claim, it remains standard clinical practice to avoid preoperative biopsy when possible. In our National Cancer Database analysis of patients who underwent surgical resection of localized thymoma, we found no difference in overall survival between those who received preoperative biopsy and those who did not. While more studies are needed to evaluate safety, our findings suggest that reluctance to pursue preoperative tissue diagnosis in early-stage thymoma may not be warranted.

These results are consistent with the only identified study analyzing the association between preoperative biopsy and survival: A single-center retrospective review of 136 patients with thymoma found no association between biopsy and overall survival (OS) or disease-specific survival (DSS). [12] Unlike our study, which excluded patients with unresectable disease, this analysis included patients of all stages. Patients with advanced disease are more likely to undergo biopsy prior to systemic therapy, and would be expected to have poorer OS and DSS; that there was no association between biopsy and survival even on unadjusted analysis in this heterogenous cohort is further evidence for its safety.

Much of the current literature focuses on the association between preoperative biopsy and recurrence, rather than survival. Local recurrence attributed to biopsy tract seeding has been reported in two patients. The first patient underwent biopsy for tissue diagnosis prior to chemotherapy; four months after the completion of chemotherapy the patient developed recurrence at the biopsy puncture site, which was treated with surgical resection. [4] The second patient developed a 6-cm chest wall mass 12 years after resection of a Masaoka stage I thymoma. [5] Although the preoperative biopsy site could not be definitively identified at the time of recurrence, the biopsy was presumed responsible as the mass was not contiguous with the site of the resected tumor. However, several reports of non-contiguous chest wall metastasis in patients who did not undergo preoperative biopsy demonstrate that, although rare, isolated metachronous chest wall metastasis is possible [6, 7], and authors of the second case acknowledge that the patient’s recurrence may be unrelated to preoperative biopsy. In the only large study of recurrence after percutaneous needle biopsy for tissue diagnosis of thymoma, none of the 225 patients who underwent biopsy were found to have biopsy tract recurrence after a median follow-up of 38.8 months. [13] Although a longer duration of observation may be warranted given the indolent nature of thymic epithelial neoplasms, these results do not support the hypothetical concern for needle tract seeding.

Evidence for an association between preoperative biopsy and pleural recurrence is similarly lacking. One review of 162 patients who underwent surgical resection of thymoma included 19 patients with pleural metastasis and found core needle or surgical biopsy (but not fine needle aspiration) to be independently associated with pleural implants. [8] However, synchronous and metachronous pleural metastasis were analyzed in aggregate; the cohort included patients with advanced disease at presentation, and the multivariable model did not account for tumor stage or resection margin status. It is thus difficult to draw conclusions regarding the association between preoperative biopsy and pleural dissemination in patients with early-stage disease, as in our cohort. In contrast, the study of 225 patients who underwent percutaneous needle biopsy of thymoma found no association between transpleural vs parasternal biopsy route and pleural metastasis. [13] Since a transpleural approach is thought to be a potential mechanism of pleural seeding, this provides evidence that an observed association may be attributable to a factor other than biopsy.

Overall, the current literature on this topic is limited in volume and heterogenous in both patient population and outcome. Studies suggesting a causal effect of preoperative biopsy on recurrence consist of case reports and small series, while larger analyses have not detected an association. While our results corroborate the safety of preoperative biopsy, resolving this longstanding controversy will require further studies.

Current advances in technology and therapeutic options may make these studies increasingly urgent. Thymic epithelial tumors have long been considered difficult to treat with systemic therapy; while immunotherapy and targeted therapy have become preferred systemic agents in many cancer types, chemotherapy remains the standard systemic treatment for thymoma as other therapies have proven unsafe or ineffective in these patients. Recent technologic advances may change this paradigm. With the development of next-generation sequencing and precision oncology, an increasing number of actionable mutations in thymic epithelial tumors have been discovered. [14] These new therapeutic targets have led to the development of molecular therapies that have shown promising results in early clinical trials, and may increase the population of patients that would qualify for systemic treatment. Preoperative biopsy for tissue diagnosis may thus become increasingly relevant for treatment planning; if unfounded, concern regarding the danger of biopsies may adversely impact patient management.

One intriguing finding of our study is the trend towards increasing use of biopsy in this cohort with early-stage disease, from 17% at the beginning of the study period to 33% at the end. Possible explanations for this finding include parallel trends in incidence, stage at presentation, or imaging modality, none of which were assessed in this study. Alternatively, increasing use of biopsy could represent diminishing clinical concern for associated recurrence.

This study has several limitations. First, the NCDB does not include information on recurrence. A 2025 analysis assessing the quality of recurrence reports demonstrated that current practices are not yet sufficiently reliable for use of recurrence data in research. [15] While we could not directly analyze recurrence rates after preoperative biopsy in this study, patients with thymoma who experience recurrence have been demonstrated to have poorer overall survival than those without [16, 17] regardless of recurrence location [18]. It is thus reasonable to infer that recurrence rates would be similar between the two groups given similar overall survival. It is less likely, but still consistent with our data, that recurrence could differ but, after treatment of the recurrence, not affect survival. It is also possible that despite the observed length of follow-up, this time was insufficient for a potential difference in recurrence rates to impact overall survival.

Second, the NCDB does not include staging information for thymic epithelial tumors since the most widely used staging system, the Masaoka system, differs from the standard AJCC system used for cancer registries. The only reliable method to identify stage is with a collaborative stage variable, which is available in NCDB for 2004 through 2015. The year limitation is compatible with the indolent natural history of thymomas; and a long follow-up would be required to detect differences in survival, and more recently diagnosed patients would not substantially contribute to that analysis. However, the collaborative stage variable does not correspond with any staging system in use. While we are confident that our cohort represents patients with early-stage disease who underwent upfront surgery, we are unable to determine the precise clinical stages of our cohort.

Third, the variable for biopsy identification does not include information on approach; we are unable to determine whether biopsies followed a transpleural or transsternal route. Given the theorized mechanism for pleural dissemination during biopsy is violation of the pleural space, future studies should include this factor in their analysis when possible. However, a recent review found no difference in pleural recurrence between approaches, suggesting biopsy route may not be as important as previously thought. [13]

Finally, there is likely residual unmeasured confounding as tumor size in the biopsy group was larger than in the non-biopsy group. Yet tumor size has previously been associated with poor outcomes, and we would thus expect patients who underwent biopsy to demonstrate decreased overall survival. [19] That we found no difference in overall survival on both unadjusted and adjusted analysis supports the conclusion that preoperative biopsy is not associated with survival.

Conclusions

In our NCDB analysis, preoperative biopsy is not associated with worse overall survival in patients with completely resected early-stage thymic epithelial tumors. The longstanding concern that preoperative biopsy could increase the risk of recurrence is not supported by our data. Recent advances in the discovery of actionable mutations and targeted therapy may soon increase the clinical relevance of this question, and further study is needed to confirm safety.

Data availability statement:

The data are owned by the American College of Surgeons (ACS) and are freely available upon request from ACS by investigators from Commission on Cancer-accredited institutions.