Mediastinal tumors: why, when, and how to biopsy?

Introduction

The mediastinum is like a box of Pandora. You never know what to find on the inside until you open the box (1). According to the Greek mythology Pandora received a box as a gift from the gods. Driven by curiosity Pandora opened the box thus releasing curses upon mankind (2). Likewise, opening the mediastinum to take a surgical biopsy of a well encapsulated, non-invasive tumor may initiate undesired complications like postoperative chest pain, hemorrhage, wound infection, pleural effusion, or tumor spread not becoming apparent until at a later stage during patient’s follow-up.

The decision to biopsy a mediastinal mass should be well thought through in advance following discussion during a multidisciplinary tumor board conference and balanced against any possible risk.

In this short review we will discuss three questions: why, when, and how to biopsy mediastinal tumors?

Why to biopsy mediastinal tumors?

The finding of a mediastinal mass of unknown origin often poses a diagnostic challenge for clinicians. A correct diagnosis prior to initiating any treatment is important. Therefore, a good understanding of the anatomical boundaries of the three different mediastinal compartments (prevascular, visceral, paravertebral) as proposed by the International Thymic Malignancy Interest Group is of utmost importance (3). Also, profound knowledge is needed on the different structures running in each mediastinal compartment (Table 1) that may become the primary origin for a wide variety of benign and malignant mediastinal lesions (Table 2) (4).

Patients with a mediastinal mass can be completely asymptomatic when discovered at the time of an incidental finding on imaging or present with clinical symptoms that may help to guide towards correct diagnosis. These symptoms can either be systemic (so called B symptoms such as anorexia, fever, night sweating), local (dyspnea, cough, stridor, hemoptysis, dysphagia, chest pain, hoarseness, Horner’s syndrome, superior vena cava syndrome), or paraneoplastic related to a wide range of auto-immune disorders (ptosis, diplopia, dysarthria, muscle weakness, neurologic syndromes, anemia, skin disorders, endocrine disorders, opportunistic infections) such as often is the case with thymic epithelial tumors (TETs). Mostly known and described syndromes are myasthenia gravis (MG), red blood cell aplasia, and hypogammaglobulinemia (Good syndrome) (5-7). With attention to patient’s age and gender together with clinical characteristics, a narrowed differential diagnosis on the exact nature of the mediastinal mass becomes possible (8). Together with thoracic imaging [chest X-ray; chest computed tomography (CT), magnetic resonance imaging, positron emission tomography (PET), other nuclear scans] describing the exact localization and internal characteristics of the mass (9-12) and laboratory tests including tumor markers, antibodies, and hormones (Table 3) (13-16), a clinical diagnosis can be made in most patients. Increased beta human chorionic gonadotropin (beta-HCG) or alpha fetoprotein (AFP) serum levels in a patient with a mediastinal mass are highly indicative for the presence of an extragonadal germ cell tumor. In patients with a suspicion of a TET anti-acetylcholine receptor (AChR) antibodies should be routinely analyzed prior to thymectomy, even in those without clinical symptoms or neurologic signs of MG. One in four of these patients will have anti-AChR antibodies and more than 90% will develop clinical MG within 6 years after thymectomy (17).

When to biopsy mediastinal tumors?

Pretreatment tissue biopsy of mediastinal lesions is not always required when clinical diagnosis is confirmed or highly probable based on the above-mentioned findings.

Also, an incisional biopsy in a patient with a solitary, well circumscribed, solid, non-invasive (encapsulated) and resectable mediastinal tumor on preoperative imaging and with negative tumor markers is contraindicated in order to avoid tumor spilling that may increase the risk for pleural tumor spread during late follow-up. This is especially the case for TET. Primary resection without preoperative tissue diagnosis is then advocated (Figure 1A). In a survey of members of the European Society of Thoracic Surgeons reported in 2011, the uselessness of a routine histologic confirmation before surgery was queried. Ninety one percent of the responding centers do not routinely look for histological confirmation when thymoma is suspected. The most frequent comment was that in case CT scan strongly suggests the presence of a thymoma (small, resectable, encapsulated lesion with no radiological sign of invasion) or when MG is associated, no preoperative histological diagnosis is required (18). Similarly, a well circumscribed lesion in the posterior mediastinum suspicious of a benign neurogenic tumor can be resected primarily without previous biopsy when resection is indicated.

Figure 1 Two patients presenting with an epithelial thymic tumor in the prevascular mediastinum. (A) The tumor in the image was a well encapsulated stage I thymoma resected upfront with no need for preoperative biopsy (no); (B) the tumor in the image was an invasive stage III thymoma on surgical biopsy taken via right anterior mediastinotomy (yes). Patient was treated with 3 courses of induction chemotherapy prior to resection via median sternotomy. CT, computed tomography; AFP, alpha fetoprotein; HCG, human chorionic gonadotropin.

On the other hand, a surgical biopsy for histopathological, immunohistochemical and molecular analysis is indicated in patients presenting with an irregular, lobular, large tumor invading mediastinal structures (Figure 1B). Also in patients with a mediastinal mass and elevated AFP or β-HCG serum levels indicative for the presence of an extragonadal germ cell tumor, a biopsy of the mass for further analysis may occasionally be needed to exclude morphologic mimics presenting in the mediastinum. It has been reported that solitary fibrous tumor, Ewing sarcoma, or rhabdomyosarcoma may also produce elevated AFP or β-HCG serum levels (19). However, a surgical biopsy may delay needed preoperative chemotherapy and make subsequent surgery more difficult.

Establishing the correct nature of the tumor on biopsy is needed as pathology will guide neoadjuvant therapy with the hope to enhance local resectability prior to surgical exploration at a later stage (20). Also, definitive tissue diagnosis is mandatory to exclude the need for any surgical treatment and to plan definitive systemic therapy or other methods for local tumor control (e.g., in case of lymphoproliferative disease).

How to biopsy mediastinal tumors?

An ultrasound or CT-guided core needle biopsy with multiple passages may result in sufficient tissue for definitive diagnosis of tumors in the prevascular (21,22) or paravertebral (23) mediastinum. For tumors in the visceral mediastinum, endo-bronchial (EBUS) (24) or esophageal endoscopic (EUS) (25) ultrasound-guided needle aspiration may be helpful in the diagnosis of mediastinal masses of unknown etiology. However, a false negative biopsy due to inadequate tissue sampling is always possible, but less likely with a core-needle biopsy thereby avoiding a surgical biopsy.

Making a correct diagnosis on a fragmented tissue specimen is not always an easy job for a pathologist. The sensitivity and diagnostic yield of fine needle aspiration in anterior mediastinal masses is reported to be lower compared to core needle biopsy, especially for non-carcinomatous tumors such as thymomas and lymphomas (26,27). Cases with non-definitive fine needle aspiration biopsy diagnoses are largely due to sampling error and/or insufficient cellularity (28). Making a wrong histologic diagnosis on preoperative needle sampling has been reported when compared to the postoperative pathologic analysis of the resected specimen (29).

In case more adequate tissue is desired for histology, immunohistochemistry, and molecular testing to fully characterize the tumor, a surgical biopsy either minimally-invasive or occasionally via open way may be needed to obtain more tissue for histopathology and immunological staining. Depending on the exact location of the mass in any mediastinal compartment (Figure 2), different surgical approaches can be chosen varying between median or lateral cervical incision for highly located prevascular tumors, anterior mediastinotomy for parasternal lesions in the prevascular mediastinum; video-assisted mediastinoscopy as an alternative to EBUS or EUS for a mass in the visceral mediastinum; or video-assisted (VATS) or robot-assisted (RATS) thoracoscopy to biopsy a lesion in the prevascular or paravertebral mediastinum. Minimally invasive procedures such as VATS and RATS offer the possibility to also sample hilar or pleural abnormalities concomitantly identified. Occasionally a partial sternotomy or limited thoracotomy may be needed to reach the tumor for adequate tissue biopsy. In one study in patients with a suspicion of a lymphoproliferative disease extending in the prevascular and visceral compartment, the authors reported that diagnostic accuracy was lower for cervical mediastinoscopy (80.4%) compared to anterior mediastinotomy (95.9%) (30).

Figure 2 A different surgical approach to biopsy a mediastinal tumor is chosen according to its location in one of the mediastinal compartments. (A) A large pretracheal lymphadenopathy from a small cell lung carcinoma in the visceral mediastinum biopsied in this patient through cervical mediastinoscopy; nowadays endobronchial ultrasound core needle biopsy would be the first choice to obtain tissue; (B) a mediastinal large B cell lymphoma in the prevascular mediastinum biopsied via left anterior mediastinotomy; (C) two large para-aortic lymphadenopathies from a non-small cell lung carcinoma in the prevascular mediastinum biopsied via left video-assisted thoracoscopy. The red circles indicate tumor margins.

Taking a biopsy of a residual lesion suspicious for lymphoma recurrence on PET imaging following definitive chemo-radiotherapy can be hazardous because of dense mediastinal fibrosis. A core biopsy by opening the fibrotic capsula is needed to sample adequate tissue. Occasionally, the residual mass can be entirely resected by thymectomy to ensure that the residual fluorodeoxyglucose (FDG)-avid zone shown on PET scan is included in the specimen (Figure 3).

Figure 3 The case of a 56-year-old female treated with 5 cycles of chemotherapy for Hodgkin lymphoma. (A) PET-CT scan suggested a necrotic mass with residual tumor activity in the outer layer; (B) instead of taking a blind biopsy, the residual mass was completely resected with thymectomy via left thoracoscopy. A necrotic lesion with thick sterile pus was found in the resected specimen. Pathologic examination confirmed persistent Hodgkin lymphoma. PET-CT, positron emission tomography/computed tomography.

A frozen section is helpful to check the quality of the biopsy, but is less effective for a precise tissue diagnosis of some primary mediastinal lesions, which may have a similar histologic appearance such as thymoma and lymphoma. Flow cytometry analysis on a fresh biopsy though can be done fast and add to the diagnosis of a lymphoma, particularly lymphoblastic lymphoma.

The definitive pathological report based on histology, immunohistochemistry, and molecular testing needs to be awaited prior to initiating any treatment except in case of a life-threatening condition such as critical airway compression or superior vena cava syndrome.

Conclusions

The finding of a mediastinal mass often poses a diagnostic challenge for clinicians. Pretreatment tissue biopsy of mediastinal lesions is not always required in case the diagnosis is confirmed or highly probable based on clinical symptoms and signs, thoracic imaging and laboratory tests. Upfront surgical resection without pathologic confirmation may be indicated for well encapsulated and non-invasive suspicious mediastinal lesions. Tissue diagnosis prior to surgical resection is recommended for locally advanced or unresectable mediastinal tumors in order to confirm the suspected diagnosis and to guide induction therapy or definitive systemic treatment. An ultrasound or CT-guided core needle biopsy may result in sufficient tissue for definitive diagnosis while the diagnostic yield of fine needle biopsy is lower. A surgical biopsy may be needed to obtain more tissue for histology, immunohistochemistry and molecular testing. A frozen section is helpful to check the quality of the biopsy but is less effective for a precise tissue diagnosis.

Acknowledgments

This paper was presented as an invited lecture at the 14^th Annual Meeting of the International Thymic Malignancy Interest Group, October 30–November 1, 2024, Yokohama, Japan.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Malgorzata Szolkowska) for “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-29/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-29/coif). “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” was commissioned by the editorial office without any funding or sponsorship. P.M.C. reports consulting fees paid to his institution from MSD, Merck, and Servier; participation in an advisory board for MSD; and service as a member of the CTG/CRM Belgium. The authors have no other conflicts of interest to declare.

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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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