Brain metastasis of pleuropulmonary blastoma: case reports

Introduction

Pleuropulmonary blastoma (PPB) is the most common primary malignant lung tumor in children under 6 years old (1). Approximately more than 90% of PPB cases are associated with DICER1 gene mutations (2). PPB is primarily categorized into types I, II, and III (3). Patients with types II/III PPB are prone to distant metastasis, with brain metastasis being the most common, and have a poor prognosis. We report three cases of PPB brain metastasis. All three cases were in remission following our treatment. We present these cases in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-341/rc).

Case presentation

Case 1

A 2-year-old girl was hospitalized with a fever. Chest X-ray revealed a space-occupying lesion in the right thorax, so a needle biopsy was performed. Postoperative pathology showed primitive neuroectodermal tumor. She then underwent regular chemotherapy at the Chinese People’s Liberation Army General Hospital, which included alternating treatment with VTC (vincristine, cyclophosphamide, topotecan) and VCP + VP16 (vincristine, cyclophosphamide, cisplatin and etoposide) for 5 courses (Table 1). Enhanced computed tomography (CT) suggested an irregular space-occupying lesion in the right chest cavity that was smaller compared to before, considered mediastinal tumor. Histopathologic findings after mediastinal mass resection suggested type II PPB with focal atelectasis of surrounding lung tissue. The patient received 1 year of chemotherapy, consisting of alternating treatment with regimens of VTCP (vincristine, cyclophosphamide, topotecan, and cisplatin), and AVTC (vincristine, cyclophosphamide, topotecan, and actinomycin D) given in 15 courses (Table 1). After regular follow-up examinations, there was no recurrence or metastasis. Unfortunately, after stopping chemotherapy for 7 years, the child experienced severe headaches due to a head injury. Brain magnetic resonance imaging (MRI) revealed a large patchy lesion with high density in the right frontal and temporal lobes, approximately 6.4 cm × 5.9 cm × 6.2 cm in size, causing compression of surrounding brain tissue. The patient underwent craniotomy to remove the tumor at another hospital. The pathology report indicated malignancy, which, combined with immunohistochemical results, was considered infantile myofibroblast sarcoma. The patient came to Beijing Children’s Hospital for treatment and received one month of temporary chemotherapy according to the chemotherapy regimen for pediatric medulloblastoma, which included three cycles of chemotherapy using drugs such as CVD (vincristine, cyclophosphamide and cisplatin). The postoperative pathological sections were re-examined and sent to several hospitals for interpretation. All of them were diagnosed as PPB with intracranial metastasis. Subsequently, we utilized paraffin-embedded tissue sections obtained from surgical specimens to perform whole-exome sequencing of genes associated with solid tumors and sarcomas. The genetic testing revealed: there was PIK3CA gene amplification, HGF gene amplification, and PDGFRA gene exon 18 showed a somatic mutations c.2525A>T (p.D842V). The 7th exon of the TP53 gene showed a somatic mutations c.743G>A (p.R248Q), and the 25th exon of the DICER1 gene showed a somatic mutations c.5439G>T (p.E1813D). Based on an individual’s previous or current history of pulmonary PPB, intracranial metastasis of PPB was reconsidered, and the treatment regimen was changed to a 3-cycle IVADO (vincristine, actinomycin D, doxorubicin, ifosfamide) and 4-cycle IVA (vincristine, actinomycin D, ifosfamide) chemotherapy regimen with concurrent radiotherapy. The right frontotemporal lobe tumor area received a radiation dose of 44.86 Gray, while the local tumor area received 56 Gray. At present, the child has stopped treatment for 23 months, and the primary tumor is in complete remission, with no new tumors seen.

Case 2

A 3-year-old girl was hospitalized with a cough and underwent chest CT which revealed patchy and extensive density increase in the left lung with unclear borders, suspicious of a tumor. Tumor resection was performed, and histopathological examination confirmed the diagnosis of PPB type II. Brain MRI showed no significant abnormalities. The child then underwent a six-course chemotherapy treatment using an alternative regimen of AVCP (doxorubicin, vincristine, cyclophosphamide, and cisplatin), alternating with IVE (ifosfamide, etoposide, and vincristine). Regular re-examinations showed no recurrence after radiation therapy (total of 18 times with 20 Gray). Unfortunately, a year after the end of treatment, a brain MRI reexamination revealed a new mass in the right frontal lobe (5.0 cm × 5.1 cm × 4.3 cm) considered an intracranial metastatic tumor. An intracranial tumor resection was performed at the Tsinghua University Yuquan Hospital, and histopathology supported the intracranial metastasis of PPB. The patient came to Beijing Children’s Hospital for postoperative positron emission tomography/computed tomography (PET/CT) showed no clear tumor residue. Subsequently, 2 courses of IVADO chemotherapy regimen, 4-cycle ICE (ifosfamide, carboplatin and etoposide regimen), and 4-cycle VTC were performed, during which synchronous radiation therapy was performed, and the right frontal lobe tumor bed area was radiotherapy for 5 times with a total dose of 30 Gray. At present, the treatment has been stopped for 17 months, and the lung tumor is stable and in complete remission. In case 2, sequencing of the whole exon of the solid tumor gene in tumor samples revealed a germline mutation in exon 21 of the DICER1 gene, c.3091C>T (p.Q1031X), and a somatic mutations in exon 26 of the DICER1 gene, c.5127T>A (p.D1709E). Additionally, a somatic mutations was detected in exon 2 of the NRAS gene, c.37G>C (p.G13R) mutation. Moreover, the father of the child tested positive for a mutation in exon 21 of the DICER1 gene.

Case 3

A 2-year-old boy was diagnosed with a cough. Chest CT showed a space-occupying lesion in the left chest, which led to consideration of a tumor. There were no abnormalities in cranial MRI. A tumor resection was performed, and pathological diagnosis was PPB type III. After 4 months of regular chemotherapy (alternating treatment with doxorubicin, vincristine, cyclophosphamide, and cisplatin regimens, as well as ifosfamide, etoposide, and actinomycin regimens for 6 courses) at the Children’s Hospital Affiliated Shandong University, the boy was doing well without recurrence. However, half a year after the end of chemotherapy, enhanced MRI showed occupation of the right temporal lobe, with a size of 3.2 cm × 3.4 cm × 3.2 cm, and slightly thickened and enhanced right temporal meninges. The patient was admitted to Beijing Children’s Hospital for medical care and underwent surgical resection of the metastatic tumor in the right temporal region, with simultaneous removal of part of the affected meninges. Histopathology showed metastatic PPB and tumor infiltration into the pia meninges, and metastatic PPB was diagnosed. Postoperative brain CT showed that the original lesion had been eliminated. Unfortunately, in the first month after the operation, brain enhanced MRI showed a significant mass in the left frontal lobe, with a diameter of about 6.6 cm, and edema around the tumor. It was suspected that intracranial metastasis would occur again. The left frontal mass was resected again (Figure 1), and the diagnosis was supported by pathology. Afterwards, regular chemotherapy was performed for 8 months (IVADO regimen with 4 courses, cisplatin and IVA regimen with 5 courses, carboplatin and IVA regimen with 3 courses). During chemotherapy, the whole brain radiotherapy was performed 15 times, with a total dose of 27 Gray, and the two intracranial metastatic lesions radiotherapy was performed 9 times, with a total dose of 18 Gray. Currently, 50 months after chemotherapy, the tumor is stable and in complete remission. Of note, reviewing family history shows the child’s grandmother has thyroid nodules, which have been surgically removed. After 18 months of stopping chemotherapy, the child found a nodule under the right lobe of the thyroid, 0.6 cm × 0.4 cm × 0.8 cm in size. It is recommended to have regular re-examination.

Figure 1 Case 3: head computed tomography before (A) and after (B) surgery for intracranial metastases (the arrow indicates an intracranial metastatic tumor of pleuropulmonary blastoma).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patients’ parents 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

PPB is a rare intrathoracic tumor in children. It is classified into three types (I, II, and III), with a fourth type (Ir) added in 2006 (4,5). Type II and III PPB are more aggressive than type I, accounting for 80–85% of all PPB cases (1). In types II and III PPB patients, local recurrence and hematogenous metastasis account for mortality, with the central nervous system (CNS) being the most common site of extra-thoracic metastasis (6). In an international study of 235 PPB cases, including 124 type II, 21 type II–III, and 90 type III, 26 cases of CNS metastasis with or without local chest recurrence were identified. Among 16 prognostic factors, only PPB type (III worse than II) and distant metastatic disease were significantly associated with adverse outcomes (7). In a study of international PPB registries and documented cases, brain metastases occurred in 5/53 type II, 15/44 type III, and 19/143 type II/III, for a total of 39 cases. Metastases occurred 1–60 months (median 11.5 months) after diagnosis, mainly supratentorial. Cumulative probability of brain metastases within 5 years was 11% type II and 54% type III, again concluding type III more likely to develop brain metastases (8).

Presently, it is impossible to predict which patients with PPB will have brain metastases, but type III is a strong risk factor. Other solid tumors in children are not as prone to brain metastasis as PPB. For most sarcomas, the incidence of brain metastasis is 5% or less (9). A possible factor may be massive extension to large thoracic vessels and heart, allowing entry into arterial circulation. PPB brain metastases can be fulminant, with imaging changes occurring rapidly (10). The 2 cases reported in this article are type II, and 1 is type III. In case 1, intracranial metastasis occurred 7.5 years after treatment. The International PPB Registry recommends 3-month surveillance MRIs until 36 months post-diagnosis (8).

When a patient with PPB develops intracranial lesions, it is necessary to distinguish whether it is primary brain tumor or PPB intracranial metastasis (11). Differential diagnosis can be achieved by evaluating the individual’s history of pulmonary PPB, combined with genetic testing of chest and CNS lesions (8). In case 1, postoperative pathological diagnosis of intracranial tumors was infantile myofibroblastic sarcoma. Combining the individual’s history of pulmonary PPB with the results of genetic testing, we are re-considered it as PPB intracranial metastasis.

The optimal treatment for patients with PPB CNS metastases remains undetermined. Nakano et al. (12) described two PPB cases with brain metastasis treated with gross total resection of the metastatic tumors. Both underwent chemotherapy and radiation therapy. One patient received whole brain irradiation and intrathecal chemotherapy after radiotherapy. Intrathecal chemotherapy may be useful due to its suggested efficacy in treating atypical teratoid/rhabdoid tumor and prophylaxis of cerebrospinal dissemination of tumor cells (13). Another patient underwent metronomic chemotherapy with an antiangiogenic multiagent regimen for 22 months. The efficacy of oral metronomic chemotherapy in pediatric brain tumors has been reported (14). Both patients are alive and in full remission. Ferguson et al. (15) reported two PPB cases with recurrent brain metastases. One patient received a combination of chemotherapy, surgery, and autologous stem cell transplantation, and later developed brain metastases 2 years later. The patient underwent tumor genomics testing and received irinotecan and pazopanib based on FGFR1 gene amplification and TOPO1 protein overexpression, and participated in four cycles of the larotrectinib trial before disease progression and death. Another patient underwent a combined treatment of chemotherapy and surgery. Two months later, brain metastasis occurred, and the patient received gamma knife radiotherapy followed by two cycles of ifosfamide, carboplatin, and etoposide treatment. Subsequently, metronomic chemotherapy was administered. This patient, as reported by Ferguson et al. (15), is identical to case 2 reported by Nakano et al. (12). Shim et al. (16) reported a type II PPB patient with intracranial and bone metastases treated with multiple modalities of chemotherapy, radiotherapy, and intraventricular topotecan for isolated CNS recurrence and remained in remission 3 years after recurrence. The three cases reported in this study received multidisciplinary combined treatment of surgery, chemotherapy, and radiotherapy after the occurrence of PPB brain metastases, and the tumors did not progress at present. Although the optimal chemotherapy and radiotherapy strategies have not yet been clearly defined, the combined treatment regimen proposed in this study opens up new possibilities for the treatment of CNS metastases in PPB.

Conclusions

In conclusion, clinicians should pay particular attention to the high incidence of brain metastasis in types II and III PPB, and actively conduct brain CT contrast or MRI examinations every 3 months after the diagnosis of chest tumors. The combination of surgery, chemotherapy, and radiotherapy is one potential treatment option for children with intracranial metastasis of PPB.

Acknowledgments

All authors would like to thank the participating patients and their families.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-341/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-341/prf

Funding: This study was supported by the Beijing Natural Science Foundation (No. 7222054) and the National Natural Science Foundation of China (grant Nos. 82293660/82293665).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-341/coif). All authors report that this study was supported by the Beijing Natural Science Foundation (No. 7222054) and the National Natural Science Foundation of China (grant Nos. 82293660/82293665). 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patients’ parents 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.

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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