Tracheomediastinal fistula induced by concurrent chemoradiotherapy in small cell lung cancer: A case report and literature review

Abstract Tracheomediastinal fistula is a rare but life‐threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features.


INTRODUCTION
Small cell lung cancer is a highly aggressive tumor with a poor prognosis, although it initially responds to chemotherapy or chemoradiotherapy. 1 Concurrent chemoradiotherapy stands as the cornerstone for managing unresectable localized limited-stage small-cell lung cancer (LD-SCLC).Here, we experienced a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in LD-SCLC.Tracheomediastinal fistula is a life-threatening and very rare complication of cancer.Consequently, previous reports have been limited primarily to case studies and the characteristics remain largely unknown.

CASE REPORT
A 72-year-old male patient presented at our hospital with complaints of dysphagia and blurred vision.A chest x-ray and computed tomography (CT) revealed no evident tumorous lesions in the lung fields, although a 40 mm enlarged paratracheal lymph node was detected (Figure 1a,b).18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) showed abnormal accumulation in the corresponding lymph node, with no evidence in other lymph nodes or distant metastases (Figure 1c).Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed, and histopathological examination revealed necrotic lesions with infiltration of atypical cells positive for CD56, synaptophysin, and chromogranin A (Figure 2), leading to a diagnosis of small cell lung carcinoma (cT0N2M0 stage IIIA).As the acetylcholine receptor antibody titer was positive at 31.5 nmol/L, the patient was concomitantly diagnosed with moderate generalized myasthenia gravis (defined as Myasthenia Gravis Foundation of America classification of IIIb).In order to treat dysphagia, prednisolone and pyridostigmine were administered, leading to an amelioration of his symptoms.
Concurrent chemoradiotherapy with cisplatin and etoposide along with accelerated hyperfractionated radiotherapy (45 Gy) was administered.On day 7 of the first course, the patient exhibited a fever of 37.9 C, neutropenia (519/μL), and elevated inflammatory markers (C reactive protein [CRP] 16.91 mg/dL), leading to a diagnosis of febrile neutropenia (Figure 3a).A chest CT revealed an enlargement of the paratracheal lymph node to 55 mm (Figure 3b).A 14-day course of antibiotic treatment ameliorated his symptoms and reduced inflammatory markers, despite a continued increase in the lymph node size to 73 mm (Figure 3c).The enlarged lymph node exhibited homogenous low attenuation with no definite contrast enhancement in the adjacent mediastinal fat or fluid collections.Serum neuron-specific enolase (NSE) decreased (Figure 3a).We decided to continue the chemotherapy treatment at a reduced dosage, and introduced pegfilgrastim to prevent febrile neutropenia.On day 9 of the second course, the patient exhibited a fever of 38.9 C and increased sputum production.Blood tests showed neutropenia (60/μL) and elevated inflammatory markers (CRP 26.23 mg/dL), leading to a diagnosis of recurrent febrile neutropenia (Figure 3a).A chest CT revealed a reduction in the size of the paratracheal lymph node to 54 mm with intraluminal cavitation, which perforated into the trachea (Figure 3d).In addition, heterogenous contrast enhancement was observed in the mediastinal fat on chest CT.Taken together, we diagnosed the patient with mediastinitis subsequent to the formation of a tracheomediastinal fistula.Although additional intervention such as surgery or stent placement was considered, the control of infection was prioritized.Despite conducting multiple assessments of blood and sputum cultures, blood cultures were all negative and sputum culture revealed only oral microbiota.Due to the development of febrile neutropenia, the possibility of Pseudomonas Aeruginosa infection could not be excluded.Consequently, in managing febrile neutropenia and mediastinitis, the patient received antibiotic treatment with meropenem for 31 days, resulting in successful recovery despite the persistent fistula.Given the high risk of severe infection, continuation of chemotherapy was not performed.Four months after the initiation of treatment, there was no evident recurrence of cancer; thus, stent placement was considered to repair the fistula.

DISCUSSION
Concurrent chemoradiotherapy dramatically reduces tumor volume of SCLC over a short period of time, and in one study 77% of LD-SCLC patients with stage III disease  showed radiological tumor response (defined as complete or partial response). 2In the present case, the metastatic paratracheal lymph node exhibited progressive enlargement during concurrent chemoradiotherapy, which made it difficult to distinguish treatment response from tumor progression or abscess formation.Serum NSE decreased throughout the treatment period, indicating a favorable response to chemoradiotherapy, as NSE correlates with response to treatment. 3urthermore, the initially heterogeneous enhancement of the enlarged lymph node transformed into homogeneous low attenuation without adjacent fat enhancement.This change was accompanied by concomitant improvements in inflammatory markers, indicating a reduced likelihood of abscess or mediastinitis. 4We determined that the effects of chemoradiotherapy induced necrosis in tumor cells, contributing to the enlargement of the paratracheal lymph node.Pathological examination could differentiate between them, although a re-evaluation through EBUS-TBNA was not performed as the procedure was considered to be high-risk for perforation and infection.PET, magnetic resonance imaging or serum IL-8 might contribute to identify these differential diagnosis. 5,6A more definitive diagnostic tool is warranted, while a comprehensive diagnosis based on physical examination, imaging findings, as well as serum inflammatory and tumor markers has to be made.Adverse events associated with concurrent chemoradiotherapy include myelosuppression, esophagitis, and pneumonitis, while tracheomediastinal fistula is a very rare complication.To the best of our knowledge, there have been no reported cases of tracheomediastinal fistula formation during chemoradiotherapy for small cell lung cancer.In order to identify common features, risk factors, and treatment strategies for tracheomediastinal fistula, we searched and reviewed relevant case reports from 2013 to 2023 using keywords such as "mediastinal," "fistula," and "cancer" on PubMed.][9][10][11][12][13][14] The median age was 60 (range: 22-75), and seven out of nine were men.The underlying diseases included six cases of lung cancer, and two cases of lymphoma.Among nine cases, three cases were treated with chemoradiotherapy and two cases were treated with vascular endothelial growth factor inhibitor (bevacizumab).6][17] The duration from the initial treatment of tumors to fistula formation varied from 2 weeks to 3 months.Intriguingly, seven out of nine cases developed fistula on the anterior or lateral wall of the trachea with better prognosis, while fistulas located on the posterior walls of mainstem bronchus were associated with a poor prognosis.This might be because the posterior walls of the lower trachea and mainstem bronchus are contiguous with the sparse connective tissue known as the "danger space," easily facilitating the spread of infection. 18ost reports lacked detailed descriptions of necrotic features and tumor size, while the present case exhibited necrosis in a huge mediastinal lymph node.Necrotic features and tumor size could be the risk factors of fistula formation.In the case reports reviewed, the use of steroids was not documented; however, numerous reports highlight the potential risks associated with steroid use in perforation of intestine, diverticula, and esophagus; [19][20][21] thus, prednisolone for treatment of myasthenia gravis might contribute to delayed healing in damaged areas, resulting in tracheomediastinal fistula.
The treatment strategy for tracheomediastinal fistula is very limited.Surgery, stent placement, 7,9 and argon plasma coagulation 8 can be performed to treat the fistula, although most patients might opt for palliative care because of their general condition (Table 1).Patients who underwent interventions such as stent placement or surgical debridement exhibited better outcomes in the reviewed case reports.As tracheomediastinal fistula and subsequent mediastinitis are critical complications, early detection and immediate antibiotic treatment are essential for a favorable outcome.To administer appropriate antibiotic treatment as soon as possible when mediastinitis occurs, careful and close observation is necessary during chemoradiotherapy in small cell lung cancer with metastatic paratracheal lymph nodes.Additionally, patients with small cell lung cancer have a poor prognosis and chemoradiotherapy is the only curative treatment option available for inoperable LD-SCLC.Therefore, despite the risk of tracheomediastinal fistula development in an enlarged lymph node, chemoradiotherapy may be advisable to achieve a cure for LD-SCLC.
In summary, we describe a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in small cell lung cancer.As tracheomediastinal fistula is a lifethreatening complication, we should be aware of the risks and perform careful and close observation during concurrent chemoradiotherapy.

F I G U R E 1
Radiological imaging at initial diagnosis.(a) A chest x-ray showed an enlarged hilar shadow on the right side.(b) A computed tomography showed an enlarged right anterior paratracheal lymph node.(c) 18Ffluorodeoxyglucose-positron emission tomography showed a highly enhanced signal in an enlarged paratracheal lymph node.White arrow: metastatic paratracheal lymph node.F I G U R E 2 Pathological and immunohistochemical examination.(a) Tumor cells displayed a proliferation of atypical cells with hyperchromatic nuclei and scant cytoplasm, accompanied by massive necrotic tissue (hematoxylin and eosin).(b-d) Tumor cells showed positive staining for CD56 (b), synaptophysin (c), and chromogranin A (d).
F I G U R E 3 Time course of treatment, serum markers, and computed tomography.(a) Time course of treatment and the change of serum markers.(b) An enlarged paratracheal lymph node (55 mm) at day 8 after initiation of chemoradiotherapy when febrile neutropenia occurred.(c) A further enlarged paratracheal lymph node (73 mm) at day 33 after initiation of chemoradiotherapy.(d) Fistula between the paratracheal lymph node and trachea at day 44.White arrow: metastatic paratracheal lymph node.CDDP, cisplatin; CRP, C reactive protein; CT, computed tomography; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; ETP, etoposide; MEPM: meropenem; MG, myasthenia gravis; NSE, neuron-specific enolase; PSL, prednisolone.T A B L E 1 Summary of previously reported cases of tracheomediastinal and bronchomediastinal fistulas.