Locally advanced thymoma treated with lattice radiotherapy: a case report

Introduction

Thymomas are a rare neoplasm originating from thymic epithelial cells that has an overall incidence of 0.13 per 100,000 person-years in the United States, with a peak in the seventh decade of life (1). Surgical excision is the mainstay of treatment. For borderline resectable tumors, neoadjuvant chemotherapy with or without radiotherapy can increase potential of surgical excision, while definitive concurrent chemoradiotherapy is reserved for unresectable disease (2,3). However, it can be difficult to treat bulky lesions with doses high enough to provide durable control or significant downstaging without unacceptable toxicity.

Lattice radiotherapy (LRT) is a novel approach in the field of radiation oncology. It is a type of spatially fractionated radiotherapy (SFRT). LRT employs a ‘lattice’ pattern, delivering higher doses of radiation to specific vertices, just like small islands, within the tumor while maintaining lower doses in the surrounding healthy tissues. This method creates a spatial dose distribution that maximizes tumor cell kill and minimizes collateral damage to adjacent normal structures. The technique not only focuses on the direct cytotoxic effect on tumor cells but also potentially stimulates a more robust immunological response against the tumor (4-6).

Promising results of LRT have been demonstrated in non-small cell lung cancer (NSCLC), sarcoma, and gynecological malignancy (4,7-10), among whom only one patient with cT4cN1cM0 squamous cell carcinoma of the lung underwent surgical resection (pneumonectomy) after LRT, demonstrating pathological complete response (9). The use of LRT for bulky thymomas in a neoadjuvant setting has never been investigated. Here, we report the first case of advanced thymoma treated with neoadjuvant chemotherapy, LRT with concurrent chemotherapy, and surgical resection. We present this case in accordance with the CARE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-4/rc).

Case presentation

A 50-year-old Taiwanese woman without underlying diseases or clinically relevant family and psycho-social history initially presented with cough and mild dyspnea in March 2022. She sought help from a tertiary medical center in Taiwan, where chest and abdomen computed tomography (CT) scan found a 13.6 cm heterogenous mass at the left upper lung with mediastinal invasion, left pleural effusion, and left lower lung atelectasis. Biopsy for tissue proof was recommended, but she refused.

Due to progression of dyspnea and emergence of left chest wall pain, left arm soreness, and weight loss of 3 kg in 3 weeks in August 2022, she came to our institution to seek treatment. Thoracocentesis with biopsy to the left upper lung tumor confirmed a diagnosis of thymoma, negative for nuclear protein in testis (NUT) and Epstein-Barr encoding region (EBER), likely type B1 or B2 thymoma.

Laboratory workup did not find elevated carcinoembryonic antigen (CEA, 0.93 ng/mL), alpha fetoprotein (AFP, 5.53 ng/mL), or thyroglobulin (62.42 ng/mL). However, high lactate dehydrogenase (LDH) was noticed (824 U/L), possibly due to necrosis of tumor cells. Brain, chest, and abdomen contrast-enhanced CT (Figure 1) found a 17 cm mass occupying the left mediastinum and left hemithorax, with pleural, pericardial, and chest wall invasion (Figure 1A,1B), and a 9 mm left upper lung nodule, suspicious for metastasis (Figure 1C). No other definite distant metastases were noted. She did not have signs or symptoms of myasthenia graves.

Figure 1 Contrast CT scan performed at diagnosis (A-C) and 3 weeks after the completion of radiotherapy (D-F). Pre-treatment CT shows a 17 cm heterogeneously-enhancing mediastinal mass with left pleura invasion, pericardial invasion, chest wall invasion, left pleural effusion, and left lower lung atelectasis (A,B), as well as a 9 mm left upper lung nodule, suspicious for metastasis (C, red arrow). Post-radiotherapy CT showed necrotic change of the thymic tumor with largest diameter 12.5 cm (A-E), suspicious for left pleural invasion, while the left upper lung nodule decreased in size to 5 mm (F, red arrow). CT, computed tomography.

Overall, the impression was thymoma, type B1 with pleural, pericardial, and chest wall invasion, cT3N0M1b, Modified Masaoka stage IVB. Considering the patient’s relatively young age, good performance status, and limited metastasis, we suggested treatment with radically palliative intent, aiming for surgical resection, and the patient agreed. Due to rapid progression and huge size of tumor, initial treatment was etoposide (70 mg/m²) and cisplatin (70 mg/m²) administered monthly for three cycles. However, while follow-up CT showed smaller left upper lung nodule, the size of her left mediastinal mass remained stable and her clinical stage was unchanged.

As surgical resection was still not feasible, radiotherapy was suggested for this patient to improve tumor response. Due to the bulky tumor size, LRT was considered. After explanation of the investigational nature of LRT and its possible benefits and side effects, the patient agreed to the treatment and received a high dose, conformal boost to vertices within the tumor followed by conventional radiotherapy to the whole tumor. She underwent CT simulation with vacuum bag immobilization and abdomen compression for respiratory motion control. Breath hold was not feasible due to her dyspnea. Planning CT scan slice thickness was 1 mm, with 4D-CT acquired at a slice thickness of 5 mm.

For the LRT boost, 10 spherical vertices with diameters of 1.5 cm were delineated within the thymic tumor by her radiation oncologist (W.C.Y.). The vertice placement and LRT boost was adapted from the method proposed by Duriseti et al. (4). The center-to-center distance between vertices was at least 2 cm, and each vertice was at least 2 cm away from critical organs at risk (Figure 2). The total volume of vertices was 17.1 cm³. For conventional radiotherapy, the entire tumor was delineated as the gross tumor volume (GTV). The clinical target volume (CTV) was the GTV with no expansion, with a 5 mm margin to form the PTV. The total PTV volume was 1,729.8 cm³. The left upper lung nodule was not treated with radiotherapy.

Figure 2 Representative target delineation of LRT plan. 20 Gy in a single fraction was prescribed to ten spherical vertices, each 1.5 cm in diameter (green line), while the clinical target volume (blue line) and planning target volume (yellow line) received 45 Gy in 25 fractions. The center-to-center distance between vertices was no less than 2 cm. LRT, lattice radiotherapy.

We prescribed 20 Gy in a single fraction to the vertices for the LRT boost, followed by 45 Gy in 25 fractions to the PTV. For the LRT boost, minimization of the inter-vertice dose was prioritized over target coverage, with a maximum dose of 130% to 140% of the prescribed dose. Normal tissue constraints adhered to TG101 guidelines (11). For the conventional radiotherapy plan, we adhered to thoracic radiotherapy guidelines and constraints. In the plan summation, performed by direct addition of doses and fractions, we aimed to achieve minimal doses between neighboring vertices less than the sum of the conventional radiotherapy dose (45 Gy) and 50% of the LRT boost dose (10 Gy).

For the LRT boost, volumetric-modulated arc therapy (VMAT) technique with 10 MV flattening-filter-free photon beams was used. The 100% dose coverage of the vertices volume was 38.8%, with a maximum dose reaching 131% and a minimal dose of 64.4%. For conventional radiotherapy, VMAT technique with 10 MV photon beams was used. 98.6% of the PTV received 100% of the prescribed dose, and 100% of the CTV received 100% of the prescribed dose.

Representative isodose curves and dose profiles, as well as dose volume histogram, are shown in Figure 3. After plan summation, the minimal dose between vertices were all less than 55 Gy, with the lowest dose being 50.5 Gy as shown in Figure 3D,3E. The LRT boost plan is shown in Figure S1, demonstrating a valley-to-peak ratio of 28% axially and 15% craniocaudally, respectively. Organs at risk such as spinal cord, lung, heart, esophagus, and stomach received doses within safe ranges for conventional radiotherapy, with the spinal cord receiving a maximum of 30.1 Gy and 11.5% and 30.1% of the lung receiving 20 and 5 Gy, respectively.

Figure 3 Representative isodose curves of LRT plan after summation of LRT boost and conventional radiotherapy plans on axial (A) and coronal (B) planes, with respective dose profiles presented in (D) (corresponding to A) and (E) (corresponding to B), as well as DVH for targets and normal tissues (C). CTV, clinical target volume; PTV, planning target volume; LRT, lattice radiotherapy; DVH, dose volume histogram.

She received the LRT boost concomitantly with the fourth cycle of etoposide and cisplatin, then conventional radiotherapy began the following day. Radiotherapy was completed over a treatment duration of 50 days. During this time, her chemotherapy was shifted to paclitaxel (135 mg/m²) and carboplatin (area under curve 5) in hopes of achieving better response. She received one cycle of paclitaxel and carboplatin during radiotherapy, followed by one more cycle after completion of radiotherapy. Overall, she tolerated chemoradiotherapy with only grade 2 fatigue and grade 2 paresthesia. She still complained of cough and dyspnea on exertion, but did not need oxygen supplement.

Follow-up contrast-enhanced CT was performed at 3 weeks after completion of radiotherapy. Though left pleural invasion was still suspected, no more pericardial or chest wall invasion was seen, and there was marked necrotic change of the left mediastinal mass with maximum diameter decreased from 17 to 12.5 cm (Figure 1D,1E) and smaller size of the left upper lung nodule (Figure 1F).

At our tumor board discussion, it was suggested that the patient undergo radical resection followed by two cycles of adjuvant paclitaxel and carboplatin, then oral UFUR. After explanation, the patient agreed to undergo operation, and received left hemiclamshell thoracotomy for mediastinal tumor excision, pericardiectomy with pericardial membrane repair, and left lung wedge resection 6 weeks after completion of radiotherapy. The operative findings were a cystic 16 cm encapsulated tumor with serous content (Figure 4A,4B). Pathology study found thymoma extending to the mediastinal fat and focally adhesive to lung tissue, with treatment effect present and clear margins, immunoreactive to cytokeratin, CD3, and PAX8 and focally positive for p63, negative for CD5 or CD117. There was small amount of lymphocyte infiltration, and some CD8+ cells were noted within the tumor (Figure 4C-4F). Our pathologist could not identify areas that had received LRT boost based on either macroscopic or microscopic differences in appearances. Only fibrous adhesion was found within the left lung specimen. The post-treatment stage was ypT1aNx, modified Masaoka stage I.

Figure 4 Resected thymoma (A,B) with representative photomicrographs (C-F). Formalin-fixed, paraffin-embedded tissue tumor specimens were sectioned for microscopic examination and stained with hematoxylin and eosin. The post-irradiation thymoma shows focal degenerative change (C) and area of coagulative necrosis with residual tumor cells at periphery (D,E). For immunohistochemical (IHC) staining of CD8, 4-µm-thick sections from the formalin-fixed, paraffin-embedded tissue block were de-waxed with xylene and rehydrated through a graded series of ethanol. Antigen retrieval was performed by autoclaving the sections in citrate buffer (pH 6.0) for 10 min at 121 ℃ and then incubated with anti-CD8 antibody (clone SP16, Spring Bioscience, Inc., Pleasanton, CA, USA; 1:100 dilution) for 1 hour. The UltraVision Quanto Detection System HRP DAB (Thermo Fisher Scientific, Fremont, CA, USA) was used according to the manufacturer’s instructions. The sections were counterstained with hematoxylin and then mounted. The infiltrative T-lymphocytes among thymoma are highlighted by CD8 immunostain in membranous staining pattern (F).

Adjuvant chemotherapy was suggested, but the patient opted to postpone further systemic treatment. Follow-up contrast-enhanced CT performed 10 months post-operation did not find local recurrence.

All procedures performed in this report were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

In this case of locally advanced, unresectable, type B1 thymoma with poor response to neoadjuvant chemotherapy, LRT led to tumor shrinkage, operation feasibility, and complete resection. Adverse effects were limited, with only grade 2 fatigue attributed to radiotherapy. At ten months post-operation, no recurrence was found.

Thymoma is a rare malignancy with an incidence between 0.13 and 0.32 per 100,000 persons per year (1). The cornerstone of treatment is complete surgical resection with total thymectomy. Neoadjuvant chemotherapy can be administered to downstage tumor and increase resectability, and the addition of radiotherapy could potentially improve tumor response and possibility of surgical resection (12). However, due to the mediastinal location, high-dose radiotherapy carries risk of significant toxicity (13). This worry increases with tumor size, which is correlated with invasion and resectability (14). Thus, for large, invasive thymoma unresponsive to neoadjuvant chemotherapy, it may be difficult for conventional radiotherapy to provide further benefit without intolerable toxicity.

SFRT was initially delivered with the GRID technique, where the use of blocks perforated with holes allowed small areas within bulky tumors to be treated to ablative doses while the majority of the tumor received a safe peripheral dose (15). Reports showed a symptom control rate of 70–90% and tumor response rate of up to 80% in bulky and locally advanced tumors (15,16). LRT is a 3D extension of the GRID technique (6,17), and promising results have been reported as following.

Amendola et al. demonstrated a median volume reduction of 42% without significant toxicities in of 10 advanced NSCLC patients undergoing LRT with 18 Gy in single fraction to vertices with a 3 Gy peripheral dose, followed by conventional radiotherapy of 45 to 59.4 Gy (7). In another case series of 10 patients with bulky cervical cancers who received 24 Gy in 3 fractions to vertices with a 9 Gy peripheral dose, followed by conventional radiotherapy of 39.6 to 45 Gy concurrent with cisplatin chemotherapy, they showed a complete metabolic response rate of 89% (8). In the prospective, non-randomized trial LATTICE_01, 31 bulky tumors of different histological types received a median of 15 Gy in a single fraction to vertices followed by hypofractionated radiotherapy, and had a response rate of 96.7% (18). Efficacy has also been reported in LRT administered with simultaneous integrated boost (SIB). In the single-arm phase I trial LITE SABR M1, 22 bulky tumors were treated with 20 Gy in 5 fractions every other day to the entire tumor with SIB to 66.7 Gy to vertices. There was a median volume regression of 24.4%, with nearly 40% of tumors exhibiting greater than 80% volume reduction (19). In a systemic review, it was noted that acute toxicities of LRT are generally mild and well-tolerated (20). These clinical series are summarized in Table 1.

The therapeutic benefit of GRID therapy appears to stem from immune system activation by high-dose radiotherapy, through bystander and abscopal effects induced by cytokine-mediated signal transduction and the activation of T-cells against tumor cells, as demonstrated by Peters et al. in a human lung adenocarcinoma model tumor system in mice and in 71 patients with advanced bulky tumors (21). Similar activation of the host immune system and induction of abscopal effects has been shown in LRT through mice models (5,22). Aside from the induction of tumor antigen release due to high dose to vertices, the low peripheral dose could stimulate T-cell recruitment. In the SBRT-PATHY study, where only hypermetabolic segments of bulky tumors were treated with 1–3 fractions of 10–12 Gy, pathological examination of a surgical specimen acquired after radiotherapy found dense immune reaction at the tumor border with CD8+ T-lymphocyte infiltration (23).

As an abundance of CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) has been observed in thymomas (24), it is possible that LRT can be further efficacious in thymoma compared to other tumors. However, only one case of advanced thymoma treated with LRT has been previously reported, and the patient did not undergo surgical resection after radiotherapy (19). Indeed, there are few reports of the pathological results of LRT, as most cases are treated with palliative intent.

To the best of our knowledge, this is the first report of an advanced thymoma treated with LRT and surgical resection. We selected 20 Gy for the LRT boost dose based on previous doses used in the literature (7,20) as well as planning feasibility and patient safety. As currently there is a lack of widely accepted guidelines for neoadjuvant radiotherapy for thymoma (3), we followed the LRT boost with 45 Gy in 25 fractions based on institutional experience. Despite not demonstrating response to chemotherapy, the primary tumor responded to LRT, allowing for complete resection. Pathological review showed lymphocyte infiltration and the presence of CD8+ cells, with the tumor downstaged from cT3 (chest wall invasion) to ypT1a (extension to mediastinal fat without invasion of mediastinal pleura). The treatment was tolerated smoothly with little adverse effects, and imaging follow-up at ten months did not show recurrence. Previous reports have shown a 5-year recurrence free survival in Masaoka stage IV disease to be 52.4% (25) and an average disease-free time of 5 years, with a time to relapse of 3 years in patients with stage II to stage IV disease (26). Thus, longer follow-up is warranted. However, the effect of LRT in downstaging this patient’s thymoma and allowing for curative resection is still notable.

Additionally, the left upper lung metastatic nodule regressed to yield only fibrous adhesion in the surgical specimen. This response could be partially attributed the abscopal effects of LRT, but it is difficult to evaluate the benefit of LRT as opposed to chemotherapy, since the nodule had partial response to initial chemotherapy.

The limitations of this study include its retrospective nature and single case number with relatively short follow-up time considering potential for late recurrence in thymoma, as well as difficulty in identifying areas receiving LRT boost within the tumor on pathology review and thus drawing correlations between radiotherapy delivery and histopathological changes. Fiducial markers could perhaps serve a dual purpose of guiding LRT boost and pathology review. Further prospective clinical trials and radio-biological studies are warranted to investigate the therapeutic benefit and radio-biological mechanisms of LRT.

Conclusions

LRT could be delivered safely to a bulky thymic tumor and resulted in successful downstaging, allowing complete surgical resection. LRT can be considered in large tumors as neoadjuvant treatment strategies and might be particularly suited for thymomas due to their lymphocyte-rich characteristic.

Acknowledgments

The authors thank Yih-Leong Chang (MD, PhD) for providing relevant pathological reports and photomicrographs.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-4/rc

Peer Review File: Available at https://tro.amegroups.com/article/view/10.21037/tro-24-4/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-24-4/coif). The authors have no 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. All procedures performed in this report were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was obtained. A copy of the written consent is available for review by the editorial office of this journal.

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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