Safe diagnostic management of malignant mediastinal tumors in the presence of respiratory distress: a 10-year experience

Malignant mediastinal tumors in children include neuroblastoma, lymphoma, acute lymphoblastic leukemia, Langerhans histiocytosis, and germ cell tumor, among others. The primary treatment for these pediatric malignant mediastinal tumors is chemotherapy. Therefore, an accurate diagnosis is indispensable for selecting the appropriate chemotherapeutic regimen. Although not an intrinsically common complication, these mediastinal tumors can occasionally cause respiratory distress. In patients with respiratory distress whose bronchus is compressed by a mediastinal tumor, respiratory failure is likely to occur, especially when muscle-relaxant drugs are used for general anesthesia or mechanical ventilation [1]. Therefore, avoiding tumor biopsies for mediastinal tumors under general anesthesia has been recommended; the use of alternative diagnostic methods has also been advocated [2].

In our hospital, we have historically avoided diagnostic biopsy under general anesthesia for pediatric patients with malignant mediastinal tumors with respiratory distress. To assess the safety and efficacy of our diagnostic strategy and establish a safe diagnostic protocol for future pediatric patients with malignant mediastinal tumor causing some degree of respiratory distress, we conducted a thorough review of our previous 10-year diagnostic and treatment experience.

This study protocol was approved by Nagoya University Hospital Institutional review board (2019–0089). Because this was a retrospective observational study and the data analyzed were anonymized, informed consent from participants or their parents/guardians was obtained through an opt-out method on our hospital website in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. The medical records of all children diagnosed with malignant mediastinal tumor with respiratory distress at Nagoya University Hospital, Japan from January 2007 to December 2018 were retrospectively reviewed. Dyspnea, massive pleural effusion, wheezing, and hypoxemia owing to mediastinal tumors were considered to indicate respiratory distress. Data on sex, age at onset, primary symptoms, location of tumor, management strategy (especially the method of diagnosis and definitive diagnosis), clinical course, prognosis during the acute phase (within 3 months from the onset of respiratory symptoms), and long-term outcome were also reviewed.

During the study period, 44 pediatric patients with mediastinal tumor required surgical intervention at the department of pediatric surgery at our institution; in 24 patients, the tumor was malignant. Of these 24 patients with malignant mediastinal tumors, 12 patients (6 boys and 6 girls) had respiratory distress. The median age at onset was 59 months (interquartile range 5.8–112.3 months). There were four stage 3 non-Hodgkin lymphoma, three stage 3 neuroblastomas, two acute lymphocytic leukemias, and three other tumors (malignant rhabdoid tumor, Langerhans histiocytosis, and stage 4 SMARCA4-deficient thoracic sarcoma). Of these 12 tumors, 7 were located in the anterior mediastinum and 5 in the posterior mediastinum.

A favorable prognosis in pediatric patients with malignant mediastinal tumors is obtained by appropriate chemotherapy rather than by surgical intervention. Therefore, an efficient and accurate diagnosis of the tumor is imperative to achieve the desired outcome. However, performing biopsies under general anesthesia to arrive at an accurate diagnosis is dangerous in patients with respiratory distress caused by mediastinal tumors, as invasive mechanical ventilation can aggravate airway obstruction by increasing mass effect, and may threaten the life of the patient. Therefore, in order to evaluate safe diagnostic strategies for pediatric patients with malignant mediastinal tumors with respiratory distress, we retrospectively analyzed the records of 12 such patients treated at our hospital.

In 11 of the 12 cases, accurate tumor diagnosis was achieved at our hospital without using measures requiring general anesthesia. Among these 11 cases, two neuroblastoma cases did not involve tumor biopsy and were instead diagnosed by tumor markers. In the one patient who was diagnosed under general anesthesia, the tumor was sub-totally resected with ECMO stand-by, as there was no alternative due to severe tracheal compression caused by the tumor.

Based on this study, the diagnostic strategy for pediatric malignant mediastinal tumors with respiratory distress was summarized depending on the location of the tumor as shown in Fig. 5. For anterior mediastinal tumors, which mostly include lymphoma, we utilized cytology and flow cytometry of the pleural effusion, if present. If there was no pleural effusion, we performed core needle biopsy under local anesthesia to maintain spontaneous breathing [3]. Acute lymphoblastic leukemia is also noted among anterior mediastinal tumors [2] and is usually suspected based on peripheral blood smear test results. At our hospital, peripheral blood and bone marrow smears are routinely prepared for patients with suspected hematologic malignancy and those with solid tumor requiring evaluation for bone marrow metastases such as neuroblastoma.

In contrast, the majority of posterior mediastinal tumors were neuroblastomas. We can used tumor markers such as homovanillic acid (HVA) and vanillylmandelic acid (VMA) for the diagnosis. As the chemotherapeutic protocol for neuroblastomas varies by risk group, accurate information on the MYCN status, pathological status of differentiation, and genetic aberration is necessary to ensure adequate treatment. As neuroblastomas are heterogenetic tumors, a needle biopsy is usually not recommended [4]. Therefore, a thoracoscopic biopsy under careful general anesthesia is desirable if the respiratory condition allows. However, as neuroblastomas arising from the mediastinum are generally known to have a better prognosis than those arising from the adrenal glands [5], chemotherapy may be performed when the respiratory condition is too severe for general anesthesia (Fig. 5). In such cases, a liquid biopsy may provide useful information on factors such as the MYCN status and genetic aberration [6, 7]. In the future, multi-gene panel testing, which searches for mutations in several genes simultaneously using next-generation sequencing technology, will be added for pediatric oncology/hematology patients including those with similar cases at our hospital. When neuroblastoma, which can enlarge during chemotherapy due to necrosis or tumor bleeding, causes severe respiratory distress [8], partial resection is of little value for saving the patient’s life. We must adopt a “Wait and See” approach under ECMO until chemotherapy and interventional radiology show an effect on tumor regression and hemostasis [9]. When the neuroblastoma does not originate from the mediastinum but rather develops into the mediastinum from the retroperitoneum, the prognosis is usually poorer than when it originates from the mediastinum [5], and careful observation is required.

If HVA and VMA are negative in posterior mediastinal tumors, rarer tumors, such as germ cell tumor, liposarcoma, and SMARCA4-deficient thoracic sarcoma should be considered in the differential diagnosis [10]. In such cases, a biopsy must be performed by any means necessary. If a needle biopsy is possible, it should be a priority. However, when imaging examinations suggest that a needle biopsy is too difficult to safely pursue, a thoracoscopic or open biopsy under general anesthesia should be considered. Blank et al. proposed risk stratification strategies for anesthetic management [11]. No serious complications are expected in patients at low risk; asymptomatic or mildly symptomatic, without postural symptoms or radiographic evidence of significant compression of structures. However, in intermediate-; mild to moderate postural symptoms, tracheal compression < 50% and for those at high-risk with severe postural symptoms, stridor, cyanosis, tracheal compression > 50% or tracheal compression with associated bronchial compression, pericardial effusion or in those with SVC syndrome, individualized management approaches are necessary. During anesthesia, the maintenance of spontaneous respiratory effort is strongly recommended by several studies in order to avoid the risk of airway collapse [11, 12]. In high-risk patients in particular, preparation for the use of cardiopulmonary bypass or ECMO is also recommended [11]. With these diagnostic strategies, we were able to obtain satisfactory outcomes.

There are a few limitations associated with our study. First, the patients displaying tumor-related respiratory distress were evaluated retrospectively from the available medical records. A prospective study would therefore be desirable. Second, as the number of cases was limited, a thorough evaluation with a larger sample size should be performed in the future.

We reviewed our 10-year experience with patients who had developed respiratory symptoms due to malignant mediastinal tumors, with a focus on the diagnostic approach. In 11 of 12 cases, safe and accurate diagnosis was achieved using methods that did not require general anesthesia, thus eliminating the additional risk of increased respiratory distress or respiratory collapse. Our review confirmed that our diagnostic strategy, that considered the tumor location, was both safe and effective in achieving a good prognosis for the patients involved.